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{
"abstract": "OBJECTIVE\nWe conducted a phase I trial of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, combined with amrubicin, a topoisomerase II inhibitor. The aim was to determine the maximum tolerated dose, the dose-limiting toxicities (DLTs), and the pharmacokinetics of this combination in patients with non-small cell lung cancer who had received previous chemotherapy.\n\n\nMETHODS\nA total of 9 patients with stage IV disease were treated at 3-week intervals with erlotinib once daily on days 1 through 21 plus a 5-minute intravenous injection of amrubicin on days 1 through 3.\n\n\nRESULTS\nThe dose levels evaluated were erlotinib (mg/body)/amrubicin (mg/m): 100/30 (n=3), 100/35 (n=3), and 150/30 (n=3). The maximum tolerated dose of erlotinib and amrubicin was 100 mg/body and 35 mg/m because 2 of the 3 patients experienced DLTs during the first cycle of treatment at the third dose level of 150 mg/body and 30 mg/m. Cessation of erlotinib administration for 8 days because of grade 3 leukopenia and grade 3 skin infection (erysipelas) were the DLTs. No drug-drug interactions between erlotinib and amrubicin were observed in this study. The overall response rate was 33%, including 3 partial responses, in the 9 patients. The median progression-free survival for all patients was quite long, 11.3 months, and the median overall survival has not yet been reached.\n\n\nCONCLUSIONS\nCombined erlotinib plus amrubicin therapy seems to be highly effective, with acceptable toxicity, against non-small cell lung cancer. The recommended dose for phase II studies was erlotinib 100 mg once daily on days 1 through 21, and amrubicin 35 mg/m on days 1 through 3 administered every 21 days.",
"affiliations": "*Department of Respiratory Medicine, Kitasato University School of Medicine ‡Department of Clinical Physiology, Kitasato University School of Allied Health Sciences, Sagamihara, Kanagawa †Division of Integrative Omics and Bioinformatics, National Cancer Center Research Institute, Tokyo §Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan.",
"authors": "Otani|Sakiko|S|;Hamada|Akinobu|A|;Sasaki|Jiichiro|J|;Wada|Mayuko|M|;Yamamoto|Michiko|M|;Ryuge|Shinichiro|S|;Takakura|Akira|A|;Fukui|Tomoya|T|;Yokoba|Masanori|M|;Mitsufuji|Hisashi|H|;Toyooka|Issei|I|;Maki|Sachiyo|S|;Kimura|Michiko|M|;Hayashi|Nobuatsu|N|;Ishihara|Mikiko|M|;Kasajima|Masashi|M|;Hiyoshi|Yasuhiro|Y|;Katono|Ken|K|;Asakuma|Maiko|M|;Igawa|Satoshi|S|;Kubota|Masaru|M|;Katagiri|Masato|M|;Saito|Hideyuki|H|;Masuda|Noriyuki|N|",
"chemical_list": "D018943:Anthracyclines; D011799:Quinazolines; C055866:amrubicin; D000069347:Erlotinib Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0b013e3182a2d98d",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "38(4)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride; D004886:Erysipelas; D005260:Female; D006801:Humans; D007970:Leukopenia; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011799:Quinazolines; D016896:Treatment Outcome",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "405-10",
"pmc": null,
"pmid": "26214085",
"pubdate": "2015-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Phase I and pharmacokinetic study of erlotinib administered in combination with amrubicin in patients with previously treated, advanced non-small cell lung cancer.",
"title_normalized": "phase i and pharmacokinetic study of erlotinib administered in combination with amrubicin in patients with previously treated advanced non small cell lung cancer"
}
|
[
{
"companynumb": "JP-ASTELLAS-2015US030286",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "021743",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"drugstructuredosagenumb": "150",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ERLOTINIB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMRUBICIN"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INFUSION",
"drugdosagetext": "30 MG/M2, OTHER ON DAY 1-3",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER",
"drugintervaldosagedefinition": null,
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"drugstructuredosagenumb": "30",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "AMRUBICIN"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "OTANI S, HAMADA A, SASAKI J, WADA M, YAMAMOTO M, RYUGE S ET AL.. PHASE I AND PHARMACOKINETIC STUDY OF ERLOTINIB ADMINISTERED IN COMBINATION WITH AMRUBICIN IN PATIENTS WITH PREVIOUSLY TREATED, ADVANCED NON-SMALL CELL LUNG CANCER.. AMERICAN JOURNAL OF CLINICAL ONCOLOGY. 2015;38(4):405-410",
"literaturereference_normalized": "phase i and pharmacokinetic study of erlotinib administered in combination with amrubicin in patients with previously treated advanced non small cell lung cancer",
"qualification": "5",
"reportercountry": "GB"
},
"primarysourcecountry": "JP",
"receiptdate": "20150825",
"receivedate": "20150825",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 11415202,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20151125"
}
] |
{
"abstract": "Heavy menstrual bleeding is a common condition among women of childbearing age. Although hysterectomy was the usual approach in acute cases in the past, other minimally invasive therapies or pharmacological alternatives, such as the levonorgestrel intrauterine device have shown to be highly effective. This case report presents the case of a pluripathological patient with acute heavy menstrual bleeding and severe anemia, who was successfully managed with ulipristal acetate, a selective progesterone receptor modulator. Bleeding control was achieved in 6 d without side effects, avoiding the need for surgery. This report suggests that ulipristal acetate could be useful in the treatment of acute uterine bleeding even in a structurally normal uterus without fibroids.",
"affiliations": "a Department of Obstetrics and Gynaecology , Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona , Barcelona , Spain.;a Department of Obstetrics and Gynaecology , Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona , Barcelona , Spain.;a Department of Obstetrics and Gynaecology , Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona , Barcelona , Spain.;a Department of Obstetrics and Gynaecology , Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona , Barcelona , Spain.;a Department of Obstetrics and Gynaecology , Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona , Barcelona , Spain.",
"authors": "Estadella|Josep|J|http://orcid.org/0000-0001-7140-3091;Español|Pia|P|;Ascencio|Fiorella|F|;Perelló|Josep|J|;Calaf|Joaquim|J|",
"chemical_list": "D009649:Norpregnadienes; C555622:ulipristal acetate",
"country": "England",
"delete": false,
"doi": "10.1080/09513590.2017.1417376",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0951-3590",
"issue": "34(7)",
"journal": "Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology",
"keywords": "Abnormal uterine bleeding; heavy menstrual bleeding; hysterectomy; selective progesterone receptor modulator; ulipristal acetate",
"medline_ta": "Gynecol Endocrinol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D005260:Female; D006801:Humans; D008595:Menorrhagia; D009649:Norpregnadienes; D016896:Treatment Outcome; D014592:Uterine Hemorrhage",
"nlm_unique_id": "8807913",
"other_id": null,
"pages": "554-557",
"pmc": null,
"pmid": "29260904",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ulipristal acetate for the management of acute heavy menstrual bleeding without fibroids.",
"title_normalized": "ulipristal acetate for the management of acute heavy menstrual bleeding without fibroids"
}
|
[
{
"companynumb": "ES-MYLANLABS-2018M1027383",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
"drugadministrationroute": "015",
"drugauthorizationnumb": "202739",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "52 MG, UNK, SINGLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MENORRHAGIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosagenumb": "52",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVONORGESTREL."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
"drugadministrationroute": "015",
"drugauthorizationnumb": "202739",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "52 MG, UNK,SINGLE",
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"medicinalproduct": "LEVONORGESTREL."
},
{
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"activesubstancename": "LEVONORGESTREL"
},
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"medicinalproduct": "LEVONORGESTREL."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PRAVASTATIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "DYSLIPIDAEMIA",
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"medicinalproduct": "PRAVASTATIN."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
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"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "UNK",
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"drugindication": "PRIMARY HYPOTHYROIDISM",
"drugintervaldosagedefinition": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVOTHYROXINE."
}
],
"patientagegroup": null,
"patientonsetage": "34",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Device expulsion",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Menorrhagia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ESTADELLA, J? ESPANOL, P? ASCENCIO, F? PERELLO, J? CALAF, J. ULIPRISTAL ACETATE FOR THE MANAGEMENT OF ACUTE HEAVY MENSTRUAL BLEEDING WITHOUT FIBROIDS.. GYNECOL. ENDOCRINOL.. 2017?1-4",
"literaturereference_normalized": "ulipristal acetate for the management of acute heavy menstrual bleeding without fibroids",
"qualification": "1",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20180502",
"receivedate": "20180502",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14838110,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180711"
},
{
"companynumb": "ES-ALLERGAN-1774380US",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PRAVASTATIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "DYSLIPIDAEMIA",
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"medicinalproduct": "PRAVASTATIN."
},
{
"actiondrug": "4",
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"activesubstancename": "LEVONORGESTREL"
},
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"drugdosageform": null,
"drugdosagetext": "52 MG, SINGLE",
"drugenddate": null,
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"drugindication": "MENORRHAGIA",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "LEVONORGESTREL UNK"
},
{
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"activesubstancename": "LEVONORGESTREL"
},
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"medicinalproduct": "LEVONORGESTREL UNK"
},
{
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"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
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"drugadministrationroute": "015",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVONORGESTREL UNK"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
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"drugindication": "PRIMARY HYPOTHYROIDISM",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVOTHYROXINE."
}
],
"patientagegroup": null,
"patientonsetage": "34",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Device expulsion",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Menorrhagia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ESTADELLA, J? ESPANOL, P? ASCENCIO, F? PERELLO, J? CALAF, J.. ULIPRISTAL ACETATE FOR THE MANAGEMENT OF ACUTE HEAVY MENSTRUAL BLEEDING WITHOUT FIBROIDS. GYNECOLOGICAL ENDOCRINOLOGY. 2017?1-4",
"literaturereference_normalized": "ulipristal acetate for the management of acute heavy menstrual bleeding without fibroids",
"qualification": "1",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20180102",
"receivedate": "20180102",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14344161,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180509"
}
] |
{
"abstract": "Amiodarone-induced pulmonary toxicity (APT) is a severe side effect that can lead to lung fibrosis or fatal respiratory failure. Usually APT occurs during long term therapy after administration of prolonged loading doses or high cumulative doses. We present the case of a 58 year old woman who underwent thoracic surgery with lobe resection. She developed atrial fibrillation with hemodynamic-instability on the first post-operative day. We initiated amiodarone therapy and four days later she developed respiratory failure. The pulmonary function further deteriorated showing signs of an acute respiratory distress syndrome (ARDS). We therefore started mechanical ventilation, but still the gas exchange did not improve. A computer tomography-(CT)-scan presented bilateral interstitial and alveolar infiltrations. The patient also presented with leukocytosis, elevated C-reactive protein (CRP) levels however without elevated procalcitonin (PCT) concentrations. In the tracheal secretion we only harvested foam cells, but got no evidence for pathogens causing pneumonia. We immediately started glucocorticoid therapy with prednisolone 50 mg/d for five days. Almost instantaneously the gas exchange ameliorated. We were able to wean the patient from the respirator within five days. Pulmonary infiltrations were nearly vanished in a CT-scan few days later and completely disappeared in follow up examinations. This case demonstrates a per-acute onset of APT caused by a low loading dose in association with thoracic surgery. The initiation of glucocorticoid therapy in parallel to amiodarone withdrawal led to full recovery of the patient. One should consider APT when signs of pulmonary failure occur during brief periods of amiodarone therapy especially after thoracic surgery.",
"affiliations": "Department for Anesthesiology and Intensive Care Medicine, St. Vincentius-Clinic, Karlsruhe, Germany.;Department for Anesthesiology and Intensive Care Medicine, St. Vincentius-Clinic, Karlsruhe, Germany.;Department for Thoracic Surgery, St. Vincentius-Clinic, Karlsruhe, Germany.;Department for Anesthesiology and Intensive Care Medicine, St. Vincentius-Clinic, Karlsruhe, Germany.;Department for Anesthesiology and Intensive Care Medicine, St. Vincentius-Clinic, Karlsruhe, Germany.",
"authors": "Baumann|Heiko|H|;Fichtenkamm|Phillip|P|;Schneider|Thomas|T|;Biscoping|Jürgen|J|;Henrich|Michael|M|",
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"country": "England",
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"doi": "10.1016/j.amsu.2017.07.034",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)Ann Med Surg (Lond)Annals of Medicine and Surgery2049-0801Elsevier S2049-0801(17)30275-310.1016/j.amsu.2017.07.034Case ReportRapid onset of amiodarone induced pulmonary toxicity after lung lobe resection – A case report and review of recent literature Baumann Heiko aFichtenkamm Phillip aSchneider Thomas bBiscoping Jürgen aHenrich Michael [email protected]∗a Department for Anesthesiology and Intensive Care Medicine, St. Vincentius-Clinic, Karlsruhe, Germanyb Department for Thoracic Surgery, St. Vincentius-Clinic, Karlsruhe, Germany∗ Corresponding author. Steinhaeuserstr. 18, D-76135 Karlsruhe, Germany. Tel.: +49 0 721 8108 2119; fax: +49 0 721 8108 2103.Steinhaeuserstr. 18KarlsruheD-76135Germany [email protected] 7 2017 9 2017 19 7 2017 21 53 57 14 2 2017 14 7 2017 15 7 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Amiodarone-induced pulmonary toxicity (APT) is a severe side effect that can lead to lung fibrosis or fatal respiratory failure. Usually APT occurs during long term therapy after administration of prolonged loading doses or high cumulative doses. We present the case of a 58 year old woman who underwent thoracic surgery with lobe resection. She developed atrial fibrillation with hemodynamic-instability on the first post-operative day. We initiated amiodarone therapy and four days later she developed respiratory failure. The pulmonary function further deteriorated showing signs of an acute respiratory distress syndrome (ARDS). We therefore started mechanical ventilation, but still the gas exchange did not improve. A computer tomography-(CT)-scan presented bilateral interstitial and alveolar infiltrations. The patient also presented with leukocytosis, elevated C-reactive protein (CRP) levels however without elevated procalcitonin (PCT) concentrations. In the tracheal secretion we only harvested foam cells, but got no evidence for pathogens causing pneumonia. We immediately started glucocorticoid therapy with prednisolone 50 mg/d for five days. Almost instantaneously the gas exchange ameliorated. We were able to wean the patient from the respirator within five days. Pulmonary infiltrations were nearly vanished in a CT-scan few days later and completely disappeared in follow up examinations. This case demonstrates a per-acute onset of APT caused by a low loading dose in association with thoracic surgery. The initiation of glucocorticoid therapy in parallel to amiodarone withdrawal led to full recovery of the patient. One should consider APT when signs of pulmonary failure occur during brief periods of amiodarone therapy especially after thoracic surgery.\n\nHighlights\n• Amiodarone-induced pulmonary toxicity (APT) can develop after low dose and short term amiodarone therapy.\n\n• The early generation of APT is supported by thoracic surgery.\n\n• APT can cause severe adult respiratory distress syndrome, leading to respiratory failure.\n\n• Glucocorticoid therapy ameliorates APT symptoms and can restore respiratory failure in early state.\n\n\n\nKeywords\nAmiodaronePulmonary toxicityThoracic surgeryGlucocorticoid therapyInflammationLung fibrosis\n==== Body\n1 Introduction\nAmiodarone is frequently used to treat effectively a broad variety of arrhythmias including atrial fibrillation. However it has a wide range of side effects among these APT occurs in approximately 2–10% of treated patients and it is the most severe side effect due to its association to amiodarone induced death [1]. Usually APT correlates with high cumulative doses that have been administered over months to years and with high daily doses above 400 mg [2]. The earliest appearance of APT has been reported to occur within few weeks after initiation of amiodarone treatment. The mechanisms underlying APT are rather complex and are not fully understood. It is assumed that amiodarone has either a direct toxic effect onto lung cells or via an indirect immunological pathway [3], [4]. Both processes are supported by the fact that amiodarone and its metabolite desathylamiodarone accumulate in the lung where they reach concentrations that exceed serum levels by 100–500 times [5]. The cell injury induces a persistent inflammation causing a chronic pneumonitis eventually leading to lung fibrosis [6]. Main clinical diagnostic features are newly occurring dyspnea and decreased carbon monoxide diffusion capacity [7]. In conventional X-ray images APT displays mainly the pattern of regional to diffuse alveolar or interstitial opacities and can also present as a mixture of both [8], [9]. However radiologic patterns can exist without clinical symptoms. So far we do not know any report about acute pulmonary toxicity that develops within few days after initiation of a low-dose amiodarone therapy. The following case report follows the SCARE criteria for surgical case reports [10].\n\n2 Presentation of case\nA 58 year old female patient underwent a right upper lobe resection because of an adenocarcinoma. Her medical history reported of preexisting chronic obstructive pulmonary disease, smoking, arterial hypertension, paroxysmal atrial fibrillation and diabetes mellitus type II. The lobe resection was performed via a thoracotomy under general anesthesia. The blood loss during this surgery was estimated at 800 ml, the patient received no transfusion. Two chest drains were inserted in “Bülau position” with negative pressure adjusted at 15 mmHg. Following the surgical procedure she was extubated and carried to the intensive care unit (ICU) breathing spontaneously. On the first postoperative day she developed atrial fibrillation with hemodynamic instability. According to the guidelines a biphasic cardioversion was applied three times (120 J each) without success. Heart frequency control was achieved with digitonin and metoprolol. In parallel we started oral amiodarone therapy with a loading dose of 3 times 200 mg/d. The maintenance dose of 200 mg/d was planned for further three months. Five days after starting the amiodarone therapy the patient developed dyspnea under light physical stress. A subsequent diuretic treatment did not improve the clinical aspect. Soon she developed an acute respiratory failure accompanied with leukocytosis of 32/nl but without fever. In several bronchoscopic lavages (BAL) we harvested specimen for microbiologic diagnostic. But we gained no evidence for an infectious pneumonia, however we started an empirical antibiotic therapy using piperacillin/tazobactam. In a subsequent CT-scan we detected diffuse bilateral opal consolidations (Fig. 1), pleural effusion with atelectasis of the middle lobe and enlarged pulmonary lymph nodes. A pulmonary arterial embolism was excluded. The respiratory situation further deteriorated showing the signs of a severe ARDS so we started invasive pressure controlled ventilation (FiO2: 0.9, PEEP: 14 cm H2O, PaO2/FiO2: 89). In repeated bronchoscopies we found clear mucus and physiological mucosa; in a further BAL we only harvested foam cells. A transthoracic echocardiography diagnosed normal global ventricular function. Using the pulse contour cardiac output technology we estimated slightly enhanced extravascular lung water index of 11.9 ml/kg. Histo-pathologic investigation of the excised right upper lobe obtained evidence of a adenocarcinoma with low grade differentiation. This pathological investigation provided no signs of any infection or other inflammatory or rheumatic process. Since we had no evidence for an infection we suspected an APT, only CRP levels were increased while PCT serum levels were unaltered (Table 1). We immediately stopped the amiodarone therapy and started prednisolone therapy with 50 mg/d. Several hours after the first prednisolone dose was administered the respiratory situation improved and we weaned the patient from the respirator. She was extubated three days later, still requiring non-invasive ventilation. She was discharged from the ICU to a low care ward two days later. Additionally the radiological aspect improved as demonstrated in a further CT-scan performed at the day she left the ICU (Fig. 1). The prednisolone therapy was maintained and slowly tapered. The patient fully recovered without any sign of recurrent symptoms after complete withdrawal of the glucocorticoid therapy. The Patient was routinely re-evaluated during the follow-up care period of two years. She still presents in a good condition with no further restrictions in her daily life. Consecutive CT-scans demonstrated no lung infiltrations or fibrotic remodelling one year after the APT incidence (Fig. 1c). Also in conventional thoracic radiograph taken two years later we found no structural residues of the APT (Fig. 1d).Fig. 1 CT-image of patient with amiodarone-induced pulmonary toxicity. a) Five days after starting amiodarone therapy bilateral alveolar and interstitial infiltrations became obvious. Apparently only little pleural effusion was found in the right cavity, following surgery on this side. b) Almost complete recovery from pneumonitic infiltrations after withdrawal of amiodarone therapy and treatment with glucocorticoids for five days. c) CT-scan recorded one year after the APT incidence displays complete remission of pulmonary infiltrates. d) A conventional anterior-posterior radiograph taken twenty-two months after APT demonstrates almost normal pulmonary structures without pulmonary residues.\n\nFig. 1Table 1 Serological findings after initiating amiodarone therapy.\n\nTable 1\tDay 1\tDay 2\tReference\t\nleukocytes\t25,8\t26,2\t4,0–10,0/nl\t\nhemoglobin\t9,1\t8,6\t12–16 g/dl\t\nplatelets\t575\t571\t150–450/nl\t\ncreatinine\t0,57\t0,6\t<1,1 mg/dl\t\nCRP\t39,2\t41,4\t<1,0 mg/dl\t\nPCT\t<0,1\t0,17\t<0,1 μg/l\t\nTSH\t1,0\t\t0,46–4,6 mU/l\t\nTroponin I\t0,03\t\t<0,034 μg/l\t\n\n\n3 Discussion\nAPT has initially been reported with varying incidences reaching 61% of treated patients [11]. Albeit in recent studies the incidence of APT ranges between 1.6% and 2.9%. These reduced APT incidences are nowadays achieved by using lower loading doses over brief periods followed by low maintenance doses [7], [12].\n\nHowever, APT may still occur after several months of amiodarone treatment and can also remain undetected or underestimated especially in intensive care patients [3], [12], [13]. The present case shows an unusual early development of APT. So far it has been reported, that APT follows after high dose amiodarone application for more than a week [14]. Thus we observed severe respiratory failure following five days after initiation of a low dose amiodarone therapy. So far this seems to be uncommon, in the current literature the period until respiration is being impaired is more prolonged ranging up to several months [15], [16], [17]. In few case reports APT became apparent only after the application of high cumulative amiodarone doses above 12.5 g which often lead to fatal outcome yet that is in contrast to this case [18], [19], [20]. Fatal outcomes may also occur long after the initiation of amiodarone therapy and too independently from the cumulative dose after the therapy had been finished. Overall mortality rates of APT range between 1 and 33% depending on the respiratory situation [2], [19]. Further, thoracic surgery promotes the onset of APT, this observation is supported by the assumption that inflammatory processes are responsible for the generation of APT. The latter predominantly causes fatal outcome [14], [21], [22]. But there exists a high inter-individual diversity of amiodarone susceptibility ranging from early toxicity already induced after short term treatment <14 d to cumulative doses <10 g accompanied with low serum levels [19], [23]. It has also been reported that low maintenance doses <305 mg/d do not prevent APT. According to the current data it is recommended to apply 200 mg/d as a maintenance dose to keep the probability for APT as low as possible [19].\n\nPivotal for APT generation is the amiodarone accumulation and its major metabolite desethylamiodarone in the lung where both reach concentrations of 100–500 fold compared to serum levels [5]. These high pulmonary concentrations also exceed concentrations in the heart, the classical amiodarone target. Further, amiodarone is compartimentalized mainly in pneumocytes type II. This accumulation accompanied with low tissue clearance rates further the theory of a direct toxicity [2], [14]. However immunologic processes may also be relevant for the induction of long term lung damage or fibrosis [24]. The findings of the present case support an immunologic process in the generation of APT. We observed high serum concentrations of CRP and leukocytes but unaltered PCT levels and several sterile BAL probes. In the lung lobe that was excised before initiating the amiodarone therapy we found no evidence of inflammation or fibrosis, indicating that amiodarone was the sole inducer of the inflammation. Typical for APT seems to be the infiltration of CD8 T lymphocytes that can be found via BAL or in tissue biopsies [25]. Here we mainly observed neutrophil infiltration, small numbers of lymphocytes and foam cells.\n\nAPT can occur in treated patients with different manifestation forms. A chronic interstitial pneumonitis can be found most often that goes along with ARDS, organizing pneumonia and/or a solitary mass [1], [26]. In our patient we found a bilateral interstitial pneumonitis with clinical symptoms of an ARDS becoming already visible after brief therapy and with a low cumulative dose. We found no sign of lung fibrosis, which usually develops after long term exposure. The diagnosis criteria of APT are still not defined and too there exist no consistent monitoring mechanisms of this disease. Clinical findings are dyspnoea and unproductive cough thus these symptoms are rather unspecific. During APT these symptoms may exist over month with progressive character until a diagnosis has been found.\n\nIn patients that are believed to suffer from APT several different diagnostic methods should be performed to exclude other pathologic pulmonary functions. Before starting an amiodarone therapy it is recommended to X-ray the lung [27]. In our patient we already had several X-ray images before and after der thoracic surgery. Additionally when the first symptoms occurred we immediately performed a CT-scan. This allowed us to evaluate morphological changes in detail. The distribution pattern of the pulmonary alterations was typically bilateral, with interstitial and alveolar infiltrations displaying the characteristics for alveolar proteinosis [28], [29]. The asymmetrical or patchy infiltrations found in the CT-scan seem to be common in APT. Conventional chest X-ray images may underestimate the extent of the APT thus the CT-images are superior to detect early infiltrations or changes in lung structure especially in prone position [30]. The impaired diffusion capacity of carbon monoxide (>20%) can be used to strengthen the diagnosis, however it is recommended to measure carbon monoxide diffusion capacity already before initiating amiodarone therapy [31], [32]. So far serological findings are non-specific for APT they only can indicate an inflammatory process [3], [33].\n\nTo minimize the likelihood of APT it is recommended to induce the therapy for supraventricular arrhythmias with low amiodarone loading doses of 600 mg/d for four weeks or 1000 mg/g for seven days. The maintenance dose should range between 100 and 400 mg/d [33].\n\nWhen there exists strong suspicion for APT it is of paramount importance to permanently interrupt the amiodarone administration, thus this may only be sufficient in some situations. However, often the withdrawal of amiodarone does not improve the respiratory function and in long term observations it has been noticed that symptoms of APT may return more than eight months after amiodarone therapy has been finished [1], [34]. The latter we did not observe in the follow up period, whether in radiologic scans nor in clinical investigations. The administration of glucocorticoids can reduce the inflammatory reaction and improve clinical symptoms. It may be necessary to extend the corticoid therapy for several months to attain complete recovery [19]. A continuation of the amiodarone therapy has to be avoided while the patient still receives glucocorticoids, since recurrent symptoms with progressive impaired lung function have been observed under these conditions. It is difficult to recommend a certain corticoid dosage because no controlled clinical trials exist investigating this issue. So far doses of prednisolone between 40 mg and 60 mg per day are recommended over periods of days to weeks [19], [23]. Glucocorticoid therapy of more than six months is required to avoid any return of the symptoms then it should be reduced slowly. In our patient we observed a full recovery within few days, clinical symptoms improved immediately accompanied by normalised CT-scan. The procedure of short term glucocorticoid therapy may be insufficient in patients receiving high doses amiodarone over longer periods. Thus the approach in glucocorticoid therapy of APT in our patient can't be transferred in general to all other cases. In follow up investigations of two years we observed a full recovery of the radiologic scans and of clinical signs. Many patients who received high doses of amiodarone present in long term investigations structural changes in terms of lung fibrosis and too they permanently suffer from impaired gas exchange. In the case of returning symptoms or impairment of pulmonary function the corticoid therapy has to be continued. A recurring APT may be more severe and can lead to fatal outcome. The lung-fibrosis induced by amiodarone is an irreversible process and glucocorticoids may only briefly improve clinical aspects. Patients developing ARDS often require mechanical ventilation, because respiratory failure is rapidly progressing and it responds rarely to glucocorticoid treatment.\n\n4 Conclusion\nIn contrast to our existing knowledge APT can be triggered by low cumulative doses during short therapeutic periods. This issue has to be considered especially in cases with pre-existing lung disease and/or in combination with thoracic surgery. One should be aware of sudden appearing symptoms that indicate respiratory insufficiency without any evidence for infection. However, infections have to be excluded by microbiological monitoring in combination with control of serum parameters that indicate inflammation or infection. Glucocorticoid therapy should be started after confirmation of APT. When clinical symptoms improve very soon the patient will almost completely recover.\n\nEthical approval\nThe patient was informed that the data concerning her case would be submitted for publication. The patient gave written consent to publish her case.\n\nSources of funding\nHeiko Baumann: none.\n\nPhillip Fichtenkamm: none.\n\nThomas Schneider: none.\n\nJürgen Biscoping: none.\n\nMichael Henrich: none.\n\nAuthor contribution\nHeiko Baumann: data collection, data analysis, writing.\n\nPhillip Fichtenkamm: data collection, data analysis.\n\nThomas Schneider: data collection, data analysis.\n\nJürgen Biscoping: data analysis, writing.\n\nMichael Henrich: data collection, data analysis, writing.\n\nConflicts of interest\nHeiko Baumann: none.\n\nPhillip Fichtenkamm: none.\n\nThomas Schneider: none.\n\nJürgen Biscoping: none.\n\nMichael Henrich: none.\n\nGuarantor\nHeiko Baumann.\n\nMichael Henrich.\n==== Refs\nReferences\n1 Schwaiblmair M. Berghaus T. Haeckel T. Amiodarone-induced pulmonary toxicity: an under-recognized and severe adverse effect? Clin. Res. Cardiol. 99 2010 693 700 20623129 \n2 Hughes M. Binning A. Intravenous amiodarone in intensive care. Time for a reappraisal? 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"title": "Rapid onset of amiodarone induced pulmonary toxicity after lung lobe resection - A case report and review of recent literature.",
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"abstract": "Primary resistant Hodgkin lymphoma is an aggressive disease with few treatment options and short survival. Neoplastic cells of classical Hodgkin lymphoma are heavily dependent on microenvironmental stimuli, regularly express PD-L1, and a relevant proportion of relapsed patients is sensitive to blocking of the PD1/PD-L1 axis. However, response duration is limited and further treatment options are unknown but urgently needed. We report a case of a patient without relevant response to five subsequent chemotherapy regimens who immediately and dramatically responded to an anti-PD1 mab. During the following two years she responded to the anti-CTLA-4 mab ipilimumab, the Jak2 inhibitor ruxolitinib, and a combination of lenalidomide plus cyclophosphamide given in subsequent relapses. A thorough genomic analysis demonstrated seven genomic alterations with six of them not previously described in this disease (i.e. BRIP1 G212fs*62, KRAS L19F, KDM5A R1239W, MYC A59T, ARIDA1A E1683fs*15 and TP53 277Y). Three alterations were considered actionable and one of them drugable. The number of mutations increased over time and the BRIP1 mutation was found to be a germline mutation.",
"affiliations": "IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria.;IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria.;IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria.;IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria.;Department of Nuclear Medicine, Paracelsus Medical University, A-5020 Salzburg, Austria.;Ordensklinikum Linz, A-4010 Linz, Austria.;IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria.;IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria.;Cancer Cluster Salzburg, A-5020 Salzburg, Austria.;IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria.",
"authors": "Greil|Richard|R|;Pleyer|Lisa|L|;Jansko|Bettina|B|;Feierabend|Carmen|C|;Rettenbacher|Lukas|L|;Stiefel|Olga|O|;Rass|Christoph|C|;Morre|Patrick|P|;Neureiter|Daniel|D|;Greil-Ressler|Sigrun|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.25037",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 297556992503710.18632/oncotarget.25037Case ReportSequential immunotherapy in a patient with primary refractory Hodgkin lymphoma and novel mutations Greil Richard 123Pleyer Lisa 123Jansko Bettina 1Feierabend Carmen 1Rettenbacher Lukas 4Stiefel Olga 5Rass Christoph 1Morre Patrick 1Neureiter Daniel 36Greil-Ressler Sigrun 11 IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria2 Salzburg Cancer Research Institute, A-5020 Salzburg, Austria3 Cancer Cluster Salzburg, A-5020 Salzburg, Austria4 Department of Nuclear Medicine, Paracelsus Medical University, A-5020 Salzburg, Austria5 Ordensklinikum Linz, A-4010 Linz, Austria6 Institute of Pathology, Paracelsus Medical University, A-5020 Salzburg, AustriaCorrespondence to:Richard Greil,[email protected] 4 2018 17 4 2018 9 29 20928 20940 12 4 2017 15 3 2018 Copyright: © 2018 Greil et al.2018This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Primary resistant Hodgkin lymphoma is an aggressive disease with few treatment options and short survival. Neoplastic cells of classical Hodgkin lymphoma are heavily dependent on microenvironmental stimuli, regularly express PD-L1, and a relevant proportion of relapsed patients is sensitive to blocking of the PD1/PD-L1 axis. However, response duration is limited and further treatment options are unknown but urgently needed.\n\nWe report a case of a patient without relevant response to five subsequent chemotherapy regimens who immediately and dramatically responded to an anti-PD1 mab. During the following two years she responded to the anti-CTLA-4 mab ipilimumab, the Jak2 inhibitor ruxolitinib, and a combination of lenalidomide plus cyclophosphamide given in subsequent relapses. A thorough genomic analysis demonstrated seven genomic alterations with six of them not previously described in this disease (i.e. BRIP1 G212fs*62, KRAS L19F, KDM5A R1239W, MYC A59T, ARIDA1A E1683fs*15 and TP53 277Y). Three alterations were considered actionable and one of them drugable. The number of mutations increased over time and the BRIP1 mutation was found to be a germline mutation.\n\nimmunotherapymolecular targetsgene mutationslymphoma\n==== Body\nINTRODUCTION\nRisk-adapated designs of conventional chemotherapy and radiotherapy have led to remarkable high cure rates in Hodgkin lymphoma with 94.8% 5 year failure-free survival in early stages with as few as two cycles of ABVD and involved field irradiation [1] and 91.4% 3year PFS rates with 6 cycles of BEACOPP escalated in advanced stages [2]. However, 10 year failure rates may be still as high as 28% for BEACOPP escalated and 36% for ABVD [3]. Prognosis is dismal in patients with relapse and even worse in those with primary resistant disease who require high-dose chemotherapy with autologous stem cell transplant or allogeneic transplant in order to achieve long-term remission or cure, although the proportion of patients rescued by these approaches is disappointingly low [4, 5]. These patients definitely require new drugs and treatment approaches. Concerning the fact that 20–44% of all patients are older than 60 years [6–8] and cannot stand intensive chemotherapy or even 4 cycles of ABVD and fare poorly under such treatment [9] further emphasizes the need for new strategies.\n\nTargeted therapies with high tolerability and modes of action different from chemotherapy are therefore needed in a substantial proportion of patients as rescue therapy and may substitute for chemo- or radiotherapy with their untoward long-term side effects in the future. However, adequate molecular targets for such strategies are few in classical Hodgkin lymphoma with anti-CD20 mabs failing in this setting [2]. The armed anti-CD30 mab Brentuximab vedotin has proven efficacy in patients in relapse [10] but with only few patients gaining long-term benefit [11]. Nevertheless, the drug is moving forward into first line strategies.\n\nHodgkin lymphoma is characterized by a rich spectrum of immunological and inflammatory cells surrounding and feeding the neoplastic cells and production of a concert of cytokines which suppress lymphoma-directed immunity [12]. PD-L1 is genomically altered and overexpressed in a relevant proportion [13, 14] and involved in exhaustion and suppression of antitumoral immunity. Anti-PD1 mabs have shown to be successful in relapsed and some refractory patients [15–17] and attract high interest for further development of immunological strategies [18]. However, efficient treatment after failure to anti-PD1 mabs is highly required and new treatment options and novel targets of personalized therapy are needed. We report a case of a primary chemorefractory patient with classical Hodgkin lymphoma sensitive to anti-PD1 mab and to three further immunological treatments in subsequent relapses. In addition, analysis by comprehensive next generation sequencing (NGS) revealed 6 novel mutations previously not described in Hodgkin lymphoma with one of them occurring in germline. The results obtained may be useful for further development of personalized medicine in this disease.\n\nRESULTS\nIn September 2014, a then 29 year old woman presented to us with a 76 months history of primarily resistant Hodgkin lymphoma, first diagnosed in May 2008 as classical Hodgkin lymphoma, nodular sclerosis subtype 1, stage IIB with risk factors. The patient received 8 cycles of BEACOPP escalated with some clinical response, but the first post-treatment 18FDG PET/CT showed new lesions (November 2008). The responsible physicians were not sure as to whether consider primary resistance or infection and in agreement with the patient suggested a watch and wait policy. During the next 59 months the disease continuously progressed with the occurrence of Pel-Epstein fever and novel nodes confirmed by 18FDG PET/CT. In July 2013, mediastinal bulky disease together with signs of heavy pruritus had developed and the patient received two cycles of DHAP (Dexamethason, Cisplatin, high-dose cytosine-arabinoside) without clinical or radiological response. She was switched to brentuximab-vedotin but within the first cycle rapid and life-threatening progression of the mediastinal bulk with obstruction of the bronchus and pulmonary infiltration developed and the responsible physicians decided for emergency pneumonectomy. Further two cycles of brentuximab-vedotin were without success but the patient responded with a CR to the subsequent R-GemOx (Rituximab, Gemcitabine, Oxaliplatin) regimen, unfortunately with a simultaneous failure in stem cell mobilization. Within three further months (i.e. July 2014) she again was clinically and radiologically progressive. She received DexaBEAM (Dexamethasone, BCNU, etoposide, cytarabin, melphalan) without remission and refused the allogeneic stem cell transplant offered to her.\n\nWhen she presented to us, the patient suffered from severe B symptoms, showed massive nodes, had a highly inflammatory lab and underwent a combination of pixantrone, paclitaxel and G-CSF. She developed sepsis with opportunistic infection from which she slowly and only partially recovered. In February 2015, then 83 months after the primary diagnosis, the patient was severely ill with tachycardia, dyspnea, multiple small nodular pulmonary infiltrations, a 5 cm pericardial infiltration, large mediastinal, hilar and subdiaphragmatic nodes as well as new liver lesions (stage IVEB) (Figure 1A). Her LDH was 492 U/l (normal range 135-225 U/L), CRP 23.7 mg/dl (normal range < 0.6 mg/dl), the temperature was 37° C without definite signs of infections, her blood pressure had dropped to 87/58 mmHg, and her heart beat rate was 126/min.\n\nFigure 1 Course of disease under immunologic treatment\n(A) CT scan showing massively enlarged axillary and subdiaphragmal lymph nodes prior to the start of nivolumab, (B) CT control two months after start of nivolumab showing massive regression of nodes in both regions, (C) 18FDG PET/CT in progression during nivolumab and prior to start of ipilimumab (D) treatment response during ipilimumab (E) 18FDG PET/CT cervical, axillary , and subdiaphragmal lymph node progression after ipilimumab and prior to start of ruxolitinib (F) 18FDG PET showing ruxolitinib-induced remission.\n\nNivolumab at a dose of 3 mg/kg was started and the patient improved immediately even during infusion (vanishing of pruritus, cardiovascular improvement). She achieved a PR as documented by CT scan as of May 2015 (Figure 1B) and was kept on the drug with excellent tolerability and without relevant side effects. In October 2015 she developed pruritus and the control 18FDG PET/CT scan in November 2015 showed relapse in cervical, retrolaryngeal, subpectoral and axillary nodes (Figure 1C). Due to the previous pneumonectomy radiotherapy was withheld, nivolumab was stopped and the patient was switched to ipilimumab at a dose of 3 mg/kg beginning in November 2015. The patient again achieved a clinical response and a PR in 18FDG PET/CT scan (Figure 1D). However, in March 2016 elevations of liver enzymes, i.e. glutamat-oxalacetat-transaminase (NCCT grade 4), alanin-aminotransferase (NCCT grade 4), gamma glutamyltransferase (NCCT grade 3), alkaline phosphatase (NCCT grade 3), and bilirubin (NCCT grade 2) were observed although the liver synthesis capacity remained unchanged. The 18FDG PET/CT in April 2016 showed a mixed response with a significant remission in axillary lymph nodes on the left side, but with some new neoplastic lesions in the right axilla. Ipilimumab was stopped due to hepatotoxicity and steroids implemented. Her liver values recovered slowly and completely, but unfortunately she further progressed from Hodgkin lymphoma with rapidly growing and symptomatic nodes in June 2016 (Figure 1E), which was histologically confirmed. She was switched to ruxolitinib at a starting dose of 20mg daily (10 mg bid) and then 50 mg daily (25 mg bid)) and again within days showed decrease in node size, pruritus and B symptoms and she entered remission in 18FDG PET/CT scan in September 2016 (Figure 1F). She relapsed in November 2016 underwent radiotherapy of skeletal disease and due to enlarged lymph nodes in February 2017 was switched to lenalidomide 20 mg q21d and cyclophosphamide 50 mg/po q28d and again showed immediate shrinkage of lymph nodes. As of October 2017 the patient is very well without any B symptoms and without restrictions in her daily life. Treatment is associated with a complete vanishing of palpable nodes, which recur when treatment has to be stopped for reasons of drug-induced cytopenia, but nodes rapidly disappear within days when treatment is started again.\n\nFor confirmation of histology as well as for the potential identification of immunological and molecular targets valuable for future treatment options, lymph nodes were excised when the patient was in progression after the 8th application of nivolumab (7th line of therapy; August 2015), and again in progression after ipilimumab (8th line of therapy; June 2016). These specimens as well as material from the initial lymph node biopsy taken from the chemonaive patient in May 2008 were investigated by an experienced hematopathologist and stained for markers specific for Hodgkin lymphoma as well for checkpoint molecules potentially involved in the regulation of anti-lymphoma immunity (Figure 2). Reed Sternberg and Hodgkin cells coexpressed CD15 and CD30 (Figure 2, lane a), CD20 and nuclear MUM1; the number of Ki67 positive cells was low (results not shown). Aberrant weak expression of PAX5 was seen (Figure 2 lane b). EBV-association was excluded by negative staining for LMP1 and in situ hybridization for EBER (Figure 2, lane b). PD-L1 expression on Hodgkin cells was high in the initial biopsy, but was significantly decreased in the nodes taken in relapse after treatment with nivolumab and ipilimumab, respectively (lane d). The surrounding Hodgkin-associated lymphocytic bystander population showed a predominant CD4-positive phenotype (lane c) with really low expression level of PD1. Furthermore, comprehensive analysis of the immunological checkpoint proteins CTLA4, LAG3, IL7R (CD127) and BTLA (CD272) showed an increase of CTLA4 and a decrease of IL7R and BTLA at the different time points, whereas the expression of LAG3 was continuously low (lanes e,f,g,h).\n\nFigure 2 Immunohistochemistry\nThree lymph node biopsies were taken in May 2008 (initial diagnosis, column 1), in progression after 8 cycles of nivolumab (August 2015, column 2), and after 12 cycles of nivolumab and treatment with 7 cycles of ipilimumab (June 2016, column 3). The obtained specimens were comprehensively analysed for diagnostic (CD15, CD30, PAX5, LMP, In-situ-Hybridization for EBER, CD4 and CD8) and possible therapeutic (PD-L1, PD1, CTLA4, LAG3, IL7R (CD127) and BTLA (CD272)) purposes with immunohistochemistry. First, the histomorphological Reed Sternberg and Hodgkin cells could be detected with CD15 and CD30 (lane a) and PAX5 (weak, lane b). An EBV-association was excluded by negative staining for LMP1 and in-situ-hybridization for EBER (lane b). Second, PD-L1 expression on Hodgkin cells decreased from the initial biopsy with the highest protein expression pattern in comparison to biopsies taken in relapse after treatment with nivolumab and ipilimumab (lane d). Interestingly, the PD1 expression (lane d) in the surrounding Hodgkin-associated lymphocytic bystander population with predominant CD4-positive phenotype (lane c) was low. Third, intensive analysis of the immunological checkpoint proteins CTLA4, LAG3, IL7R (CD127) and BTLA (CD272) revealed an increase of CTLA4 and a decrease of IL7R and BTLA by continuously low expression pattern for LAG3 throughout the different time periods (lanes e to h). (Note that the first antigen designated at the left side of each lane always depicts the left part of the microphotograph, whereas the antigen given after the slash describes the relevant right part of the photo, respectively. Magnification of 1 × 400 for all immunohistochemical pictures).\n\nIn addition, material from all the three lymph node samples as well as DNA from peripheral blood obtained in progression after ruxolitinib in May 2017 were sent out for analysis by NGS to Foundation One (Tables 1 and 2). Over the course of the disease, seven genes were found to be altered (Table 2), with mutations in BRIP1 G212fs*62, KRAS L19F, MYC A59T, ARIDA1A E1683fs*15, KDM5A R1239W and TP53 277Y to the best of our knowledge never reported before in Hodgkin lymphoma. Over time, the mutational architecture became more complex. Two mutations were present at the time of initial diagnosis. 97 months later and after 6 lines of chemotherapy and two lines of immunotherapy five mutations were observed with only two of them recognized initially (Table 2). Analysis of DNA of peripheral blood carried out in progression after ruxolitinib suggested germline mutation for BRIP1 and this was confirmed by DNA collected from peripheral blood and buccal swabs (Tables 1, 2 and Figure 3A, 3B). In addition, the liquid biopsy demonstrated the presence of a TP53 C227Y mutation in the circulating free DNA which was not caused by a germline mutation (Figure 3C).\n\nTable 1 Results from NGS testing\nGenomic finding detected\tPreviously described in Hodgkin lymphoma1\tFDA-approved therapies in patients’ tumor type\tFDA-approved therapies in another tumor type\tPotential clinical trials\t\nBRIP1 G212fs*622\tNot found in any of 9 Hodgkin lymphoma cases in the Cosmic database (Dec 2016);\nNot studied according to Pubmed in Hodgkin lymphoma (August 2017)\tNone\tOlaparib3\tNCT00576654\t\nKDM5A R1239W\tNo reports in Hodgkin lymphoma\n(Pubmed, August 2017)\tNone\tNone\tNone\t\nKRAS L19F\tNot identified in 48 Hodgkin lymphoma samples analyzed in COSMIC database (Dec 2016), no significant reports in Pubmed /August 2017)\tNone\tTrametinib, Cobimetinib\tNCT01742988\nNCT01991938\t\nMYC A59T\tNo MYC mutation found in 9 cases of Hodgkin lymphoma analyzed in COSMIC database (August 2017)\tNone\tNone\tNCT02431260\nNCT01943851\nNCT01949883\t\nARIDA1A E1683fs*15 4\tNo reports\tNone\tNone\tNone\t\nB2M M1R\tInactivating mutations described in classical Hodgkin lymphoma\tNone\tNone\tNone\t\nTP53 C277Y\tNo descriptions in Hodgkin lymphoma\nPubmed, August 2017\tNone\tNone\tNone\t\n1Data is given according to reports from FoundationOne. Descriptions are given according to COSMIC database.\n\n2BRIP1 G212fs*62 equivalent to FANCJ (Fanconi Anemia complementation group J). The gene is considered important for DNA repair and maintenance of chromosomal stability. The observed alteration disrupts the BRCA1 binding site and is predicted to be inactivating.\n\n3A patient with serous ovarian cancer harboring a BRIP1 mutation exhibited a long-lasting response to olaparib [47].\n\n4ARIDA1A is supposed to be a tumor suppressor and part of the chromatin remodeling complex. Mutations are reported to occur in 2% of hematopoietic and lymphoid malignancies (COSMIC 2016). ARIDA 1 expression has been associated with dexamethasone resistance [59].\n\nVariants of unknown significance: CAD P1465L, DDX3XA541V, FLT1 R1257C, GNA13 E138QK121fs*4, HDAC4 Q154H, KDM4C S436G, MAFB H166R, PCLo R3605Q, PDGFRA T200S, RELN P672L, SDHA G3V, SETB1 K1341E, TSC1 N762S, Tumor mutation burden unknown, XPO1 R231I, ZNF703 A401–H402insPTH LGGSSCSTCSA.\n\nTable 2 Genomic alterations in lymph node biopsies, liquid biopsy and germline\nTime point after x lines of therapy\tMost recent therapy\tSubsequent therapy\tTissue\tGenomic Findings\t\nChemo-naive, May 2008\tNone\tBEACOPP escalated\tpretracheal lymph node1\t(1)BRIP1 G212fs*62\n(2)MYC A59T\t\nAugust 2015,\nduring 7th line\t8 cycles of nivolumab\t4 cycles of nivolumab\n7 cycles of iplimumab\tlymph node cervical/supraclavicular1\t(1)BRIP1 G212fs*62\n(2)KDM5A R1239W\t\nJune, 2016\nafter 8th line\t8 lines of therapy including nivolumab and ipilimumab\truxolitinib\tlymph node accessorius region left2\t(1)BRIP1 G212fs*62\n(2) MYC A59T\n(3)KRAS L19F\n(4)ARID1A E1683fs*15\n(5)B2M M1R\t\nJuly 2017\nafter 9th line\truxolitinib\tcyclophos-phamide/lenalidomide\tperipheral blood2\t(1)BRIP1 G212fs*62\n(2)TP53 C277Y\t\nJuly and October 2017\tcyclophos-phamide/\nlenalidomide\ttreatment ongoing\tbuccal swap3\t1)BRIP1 G212fs*62\t\n1Results according to Foundation One which interrogates 315 genes as well as introns of 28 genes involved in rearrangements.\n\n2 Results according to Foundation One Hem test which analyzes 406 genes as well as selected introns of 31 genes involved in gene rearrangements, and performs RNA sequencing of 265 genes.\n\n3 performed in house (for details see Material and Methods section and Figure 3). With the only exception of B2MG, all genes are tested in both test systems.\n\nWith the exception of the B2MG gene, all genes analyzed were included in both panels of Foundation One.\n\nFigure 3 PCR sequencing of germline DNA\n(A) IGV Alignment BRIP1 G212fs*62: BRIP1 G212fs*62 mutation was detected in buccal swab DNA and in peripheral blood DNA of the patient. The forward and reverse sequence alignment stops at G212 due to the frameshift in the mutated sample. Negative control sample aligns perfectly to the reference sequence. BRIP1: reference sequence of BRIP NM_032043; BuccalSwabRev: DNA from buccal swab of the patient (reverse strand); BuccalSwabFor: DNA from buccal swab of the patient (forward strand); PBRev: DNA from peripheral blood (PB) of the patient (reverse strand); PBFor: DNA from PB of patient (forward strand), negRev: negative control DNA from PB (reverse strand); negFor: negative control DNA from PB (forward strand). (B) BRIP1 nucleotide insertion leads to a frameshift mutation. (C) IGV Alignment TP53 Exon 8: TP53 C277Y mutation could not be detected in buccal swab DNA. Alignments are identical to the reference sequence. TP53: reference sequence (NM_001126114), TP53 buccal For: DNA from buccal swab of patient. TP53buccal Rev: DNA from buccal swab of patient.\n\nDISCUSSION\nThe course of disease for this patient is remarkable for several reasons\nFirst, relapsed/refractory Hodgkin lymphoma provides a therapeutic dilemma. High dose chemotherapy with autologous stem cell transplant is considered standard of care for relapsed patients with improved PFS but questionable OS benefit over conventional rescue chemotherapy regimens [5, 19, 20]. Shortened time between first diagnosis and relapse (<12 months), anemia, B symptoms, bulk at initial presentation, involvement of extranodal sites [5] as well as positive 18FDG PET [21], >3 salvage regimens and chemoresistance predict high risk and unfavorable course. Even with autotransplant, only 41% of patients with a high risk score were progression free after 4 years in a recent study [22]. In groups of purely primary refractory patients, prognosis was even worse with 5 year OS rates of 36% [23] to 48% [24] and in case of simultaneously present poor risk factors 28% [21]. Due to the extremely poor prognosis of patients put on conventional chemotherapy (e.g. OS of 3 to 16 months [25, 26]), immediate proceeding to high dose chemotherapy and autotransplant probably with double transplantation in high risk patients is recommended in these patients [4, 27].\n\nIn this case, the initially responsible physicians and the patient herself could not reach consensus on the early implementation of autotransplant, and at the time they consented, stem cells could not be collected any more, supporting the necessity for early transplant. Out of six lines of therapy including brentuximab vedotin, the patient responded to only one and for a period of only 3 months. Given the simultaneous presence of a very high risk score the survival time of the patient without any efficient therapy is remarkable.\n\nSecond, the patient was immediately life-threatened by her disease in February 2015 and she received nivolumab 3 months after the first presentation of efficacy data of the drug at the American Society of Hematology, December 2014 [15], although the drug was not commercially available at that time in Europe. The effect was extremely fast, despite the fact that the patient presented with nearly all risk factors currently defined for this disease. Checkpoint inhibitors cause significant benefit in patients in relapse after autologous stem cell transplant ± brentuximab treatment or after brentuximab-treatment in case of ineligibility for transplant, with RR/CR rates between 87%/17% [15], 67%/9% [16] for nivolumab and 64%/16% for pembrolizumab [17] and median durations of all responses of 7.8 months for nivolumab [16] and 70% longer than 6 months for pembrolizumab [17]. However, treatment recommendations for patients relapsing after anti-PD1 and brentuximab vedotin as in this case do not exist to our knowledge and options are few.\n\nSequential administration of different checkpoint inhibitors have been shown efficient in melanoma, with the sequence of nivolumab followed by ipilimumab proving more efficient than the inverse sequence [28]. However, only few cases of heavily pretreated patients with Hodgkin lymphoma (all after allo-transplant) have been reported in the literature, with 2/14 achieving a CR after ipilimumab [29]. We are not aware of a report on the sequential use of nivolumab and ipilimumab in this disease and find it notable that the patient developed a remission after ipilimumab again. This may be important for the design of future trials. Combined inhibition of PD1 or PD-L1- and CTLA4-mediated suppression of anti-lymphoma immunity seems supported by the finding that CTLA4 significantly increased during treatment with nivolumab and ipilmumab and remained so after the stop of treatment with this drug (Figure 2, lane e). LAG 3 [30] and BTLA4 [31] have been involved in the immunosuppression in Hodgkin lymphoma and synergistic effects in the restitution of the exhausted immune response between anti-PD1 and anti-LAG3 have been shown in several tumor systems [32, 33]. However, LAG 3 expression in Hodgkin lymphoma has predominantly been observed in EBV+ cases [30]. This case was EBV- and in fact the initial expression of LAG3 and BTLA was very weak and weak respectively (Figure 2, lanes f and h). The former remained low and the latter even decreased further during immunotherapy. These results would not favor targeting these molecules together with PD1 in combination strategies at least in a case similar to ours.\n\nThird PD-1L was strongly expressed on Sternberg Reed cells in the present case (Figure 2, lane d), but PD-L1 was neither amplified, translocated nor mutated although copy number alterations, amplifications [13, 14] and translocations of MHC class II transactivator CII TA with subsequent activation of PD-L1 and PD-L2 [34] are frequent in this lymphoma and associated with advanced stage and inferior outcome of first line therapy [14, 35]. EBV-induced expression of LMP1 has also been shown to activate PD-L1 expression but this case was EBV and LMP1 negative [36]. However, proinflammatory cytokines released from the micromilieu like TNFa [37] and IFNg [38] may be responsible for upregulation of PD-L1 in this case.\n\nFourth, JAK2 gene amplification cooccurrs with PD-L1 amplification in Hodgkin lymphoma [13] and the amplified JAK2 gene dosage further increases PD-L1 expression. However, no genomic alterations of the JAK1, JAK2, and JAK3 genes were detected in our case. This is important since very recently JAK2 gene mutations have been involved in resistance against PD1 blockade [39].\n\nJAK 2 inhibition has proven efficient in vitro and in xenotransplant experiments [40] and JAK2inhibition therefore is a reasonable approach in Hodgkin lymphoma. Inhibition of JAK2 may counteract prosurvival pathways in this disease [40], downregulate PD-L1 expression and enhance immunogenicity [13, 38]. In fact, three of seven patients who had relapsed after conventional chemotherapy (not including checkpoint inhibitors) responded to the drug in a small trial [41]. The fact that the patient achieved an 18FDG PET/CT-confirmed remission with a very rapid improvement in clinical symptoms is encouraging.\n\nFifth, even in relapse after ruxolitinib, the patient again responded to an immunomodulatory regimen consisting of lenalidomide and cyclophosphamide previously shown effective in resistant or relapsed Hodgkin lymphoma [42]. The fact that four immunomodulatory regimens applied in sequence to a life-threatened patient without relevant response or response duration to six previous chemotherapy regimens underlines the therapeutic potential of this approach.\n\nIn addition, the occurrence of a mutation within the B2MG gene as in this case is usually considered to interrupt the structure and function of the MHC I complex and antigen presentation thus contributing to immune escape. It has been described as the most frequent mutation of Sternberg Reed cells [43]. Decrease or absence of B2Mg/MHC I has a negative prognostic impact independent of PD-L1/PD-L2 amplification [35]. This contrasts with the high efficacy of anti-PD1 and anti-CTLA4 strategies and may point to effector mechanisms of targeting PD1 and CTLA4 apart from restitution of CD8+ effector cells from exhaustion, like e.g. elimination of Treg cells [44] and evolution and diversification of the TCR repertoire [21] by anti-CTLA4 abs and inhibition of generation, maintenance and function of T reg cells [45] and expansion of NK cells by anti-PD1 targeting [46].\n\nSixth, the extensive molecular analysis revealed six mutations which to the best of our knowledge have not previously been described in Hodgkin lymphoma. Three of these mutations were considered actionable (Table 1) and at least the BRIP1 G212fs*62 mutation might be directly targeted by PARP inhibitors like olaparib [47]. The BRIP1 mutation was clearly a germline mutation as demonstrated by its presence in all tumor samples analyzed and its presence in DNA extracted from peripheral blood and buccal swabs (Figure 3). BRIP1 germline mutations have recently been shown to be associated with an increased risk in epithelial ovarian cancer and some high grade ovarian serous disease. A truncating BRIP1 mutation has been identified in a small proportion of women suffering from epithelial ovarian cancer in Iceland [48]. In a recent investigation of 3,236 patients with epithelial ovarian cancer and 2,000 control persons deleterious and missense mutations were associated with an 11.22 times increased risk for epithelial ovarian cancer [49] leading to an estimate of a weak to moderate risk of 3.41 times in mutation carriers as compared to the general population. Similar findings were obtained in an analysis from patients with ovarian cancer recruited to clinical trials [50]. In addition, BRIP1 germline mutations have been identified in breast cancer patients [51, 52], and in prostate cancer patients with at least one additional cancer [53]. The family history of the patient showed only one case of breast cancer in her grandmother occurring at the age of 83, and a benign neuroendocrine tumor of the intestine in her father, but no evidence of an increased familial cancer risk in general and for cancer types associated with BRIP1 mutations until now. To the best of our knowledge, this is the first report of a BRIP1 germline mutation in Hodgkin lymphoma. The frequency of this mutation should be analyzed in a larger number of patients. If confirmed, it might have impact on potential novel treatment strategies as well as follow-up investigations in cancer survivorship programs for this disease.\n\nFinally, analysis of cf DNA in blood drawn after ruxolitinib and prior to the most recent treatment regimen also showed the presence of a TP53 C277Y mutation which was not caused by a genomic germline alteration (Figure 3C). Despite the very low number of Reed Sternberg and Hodgkin cells present in Hodgkin lymphoma genomic alterations have been demonstrated in cf DNA even in early stages of disease and these aberrations correlated well with results from lymph node biopsies [54]. Clonal evolution during immunotherapy thus is the most likely interpretation of this finding. Such an evolution is certainly intriguing. There may be a correlation between the mere number of mutations per megabase defined as mutational burden and response to checkpoint inhibitors though this correlation may significantly differ in distinct cancer entities [55]. However, mutational burden is difficult to define in tumors with such a low tumor cell content as is the case in Hodgkin lymphoma and in fact could not be evaluated in our case. The interrelation between defined genomic alterations and their development over time and specific immune reactions against potentially resulting neoantigens and even more the influence of certain immunomodulatory strategies on this interaction in individual cases is extremely complex. The understanding of these processes is in its infancies and requires extensive workup with sophisticated techniques. [56]. Such investigation was outside of the scope of this study which however supports the necessity for systematic work in this regard.\n\nTaken together, this case shows the remarkable effects of sequentially applied immunomodulatory drugs in Hodgkin lymphoma and offers possible solutions for desperately ill patients with this disease but may also be useful for considering novel treatment designs in clinical trials even in earlier stages of disease.\n\nCONCLUSIONS\nImmunotherapy has a high potential in chemoresistant Hodgkin lymphoma with no cross-resistance to different immunomodulators. Response with the drugs chosen after failure of anti-PD1 mab has not been described and the results may be important for the design of novel even chemo-free regimens. Novel actionable and drugable targets are reported.\n\nMETHODS\nImmunohistochemistry (IHC)\nIHC was done on the lymph nodes excised at the inital diagnosis of the Hodgkin lymphoma (05/2008) as well as in relapses after immunotherapy (early 08/2015 and late 06/2016). IHC was routinely done on FFPE tissue. In brief, 4 µm sections were mounted on glass slides, deparaffinized with graded alcohols, and stained using the following primary abs: anti-CD-4 (rabbit monoclonal (rm), clone SP35, Ventana, ready-to-use (rtu)), anti-CD-8 (rm, SP57, Ventana, rtu), anti-CD-15 (mouse monoclonal (mm), MMA, Ventana, rtu), anti-CD-20 (mm, L26, Ventana, rtu), anti-CD-30 (mm, Ber-H2, Ventana, rtu), anti-PAX5 (rm, SP34, Ventana, rtu), anti-Ki67 (rm, 30-9, Ventana, rtu), anti-Mum1 (rm, MRQ-43, Cell Marque, rtu), anti-PD-1 (mm, Nat105, Ventana, rtu) and anti-PD-L1 (rm, 28-8, Abcam, dilution 1:300) as well as anti-LMP (mm, CS.1-4, DAKO, rtu). In addition, the following anti-checkpoints-antibodies were immunohistochemically established: anti-CTLA4 (mm, clone BNI3, Abcam, 1:50), anti-LAG3 (rm, EPR20261, Abcam, 1:500), anti-IL7R alpha (CD127) (rabbit polyclonal (rp), clone not stated, Abcam, 1:200) and anti-BTLA (CD272) (rp, clone not stated, Abcam, 1:800). All immunohistochemical stainings were performed on a Benchmark Ultra (Ventana) platform with the OptiView DAB IHC detection kit for PD-1, PD-L1 and CTLA4 antibodies or UltraView Universal DAB detection kit (both kits Ventana) for all other antibodies. Finally, the chromogenic in situ hybridization for EBER (Ventana) was applied according the manufactory instructions using the same platform.\n\nGenomic analysis\nTissue sample from the three lymph nodes excised at different time points and DNA extracted from peripheral blood were sent to FoundationOne in Boston, MA, USA.\n\nSequencing of germline DNA\nDNA from peripheral blood and buccal swab was isolated according to the technical manual Maxwell 16 Buccal Swab LEV DNA Purification Kit.\n\nBRIP1 G212fs*62 mutation\nPrimers for Exon 7 and PCR conditions were chosen according to Lewis et al., 2005 [57]. The following primer sequences were used: BRIP Exon7 For 5′ -> 3′: TTCCATGTGAGGTTTGATAACG; BRIP Exon7 Rev 5′ -> 3′: GCAGTTAATTTGATTTTCCGAAG; The PCR Mastermix (20 μl/reaction) consisted of 10 μl GoTaq® G2 Hot Start Master Mix (Promega),6 μl nuclease free water; 1 μl forward primer (10 μM); 1 μl reverse primer (10 μM) and 2 μl DNA (15 ng).\n\nAnalysis of TP53 C277Y mutation\nPrimers for exon 8 were selected according to Abaigar et al. 2016 [58]. In brief, the following primer sequences were used: P53 Exon8 For 5′->3′: GGACAGGTAGGACCTGATTTC; TP53 Exon8 Rev 5′->3′: TCTCCATCCAGTGGTTTCTTC; The PCR mastermix (20 µl/reaction) consisted of 10 µl GoTaq® G2 Hot Start Master Mix (Promega); 6 µl nuclease free water; 1 µl forward primer (10 µM); 1 µl reverse primer (10 µM) and 2 µl DNA (15 ng). PCR conditions were again chosen according to Abaigar et al. 2016 [58]. The PCR product was purified with ExoSAP-IT™ PCR product cleanup reagent. 4 µl ExoSAP-IT® reagent and 10 µl PCR product were mixed and incubated at 37° C for 15 min and then deactivated by incubation at 80° C for 15 min. Sequencing reaction was done with the ABI Prism® BigDye® Terminator v3.1 cycle sequencing chemistry. The sequencing reaction mix (10 µl) consisted of 1 µl BigDye® Terminator, 2 µl BigDye® Terminator v3.1 reaction mix, 4, 5 µl nuclease free water, 0,5µl forward primer (10 µM), 0, 5 µl reverse primer (10 µM) and 2 µl clean PCR product.\n\nPatient informed consent\nInformed consent of the patient for reporting the results was obtained. There are no conflicts of interest for this report for any of the authors.\n\nAuthor contributions\n\nRG analyzed the data and wrote the final draft of the manuscript. DN performed and analyzed the immunohistochemistry, LR interpreted 18FDG PET scans, OS provided external data of the patient, SGR, PM, CF, CR and PM were involved in the care of the patient and in presentation and editing of material. LP and BJ were responsible for the establishment and performance of the BRIP1 and p53 mutation analyses carried out in Salzburg. All authors carefully and critically read the manuscript.\n\nCONFLICTS OF INTEREST\n\nThere are no conflicts of interests for the authors.\n==== Refs\nREFERENCES\n1 Engert A Plutschow A Eich HT Lohri A Dorken B Borchmann P Berger B Greil R Willborn KC Wilhelm M Debus J Eble MJ Sokler M Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma N Engl J Med 2010 363 640 652 https://doi.org/10.1056/NEJMoa1000067 20818855 \n2 Borchmann P Haverkamp H Lohri A Mey U Kreissl S Greil R Markova J Feuring-Buske M Meissner J Duhrsen U Ostermann H Keller U Maschmeyer G Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group Lancet Oncol 2017 18 454 63 https://doi.org/10.1016/S1470-2045(17)30103-1 28236583 \n3 Engert A Diehl V Franklin J Lohri A Dörken B Ludwig WD Koch P 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MJ Brennan T Yekensky R Sun J Barrett JC Analysis of candidate homologous repair deficiency genes in a clinical trial of olaparib in patients (ots) with platinum-sensitive, relapsed serous ovarian cancer (PSR SOC) J Clin Oncol 2014 32 S5536 \n48 Rafnar T Gudbjartsson DF Sulem P Jonasdottir A Sigurdsson A Jonasdottir A Besenbacher S Lundin P Stacey SN Gudmundsson J Magnusson OT le Roux L Orlygsdottir G Mutations in BRIP1 confer high risk of ovarian cancer Nat Genet 2011 43 1104 1107 https://doi.org/10.1038/ng.955 21964575 \n49 Ramus SJ Song H Dicks E Tyrer JP Rosenthal AN Intermaggio MP Fraser L Gentry-Maharaj A Hayward J Philpott S Anderson C Edlund CK Con ti D AOCS Study Group, and Ovarian Cancer Association Consortium Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer J Natl Cancer Inst 2015 107 djv214 https://doi.org/10.1093/jnci/djv214 26315354 \n50 Norquist BM Harrell MI Brady MF Walsh T Lee MK Gulsuner S Bernards SS Casadei S Yi Q Burger RA Chan JK Davidson SA Mannel RS Inherited Mutations in Women With Ovarian Carcinoma JAMA Oncol 2016 2 482 490 https://doi.org/10.1001/jamaoncol.2015.5495 26720728 \n51 Walsh T Mandell JB Norquist BM Casadei S Gulsuner S Lee MK King MC Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women JAMA Oncol 2017 3 1647 53 https://doi.org/10.1001/jamaoncol.2017.1996 28727877 \n52 Tedaldi G Tebaldi M Zampiga V Danesi R Arcangeli V Ravegnani M Cangini I Pirini F Petracci E Rocca A Falcini F Amadori D Calistri D Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer Oncotarget 2017 8 47064 47075 https://doi.org/10.18632/oncotarget.16791 28423363 \n53 Pilie PG Johnson AM Hanson KL Dayno ME Kapron AL Stoffel EM Cooney KA Germline genetic variants in men with prostate cancer and one or more additional cancers Cancer 2017 123 3925 3932 https://doi.org/10.1002/cncr.30817 28657667 \n54 Vandenberghe P Wlodarska I Tousseyn T Dehaspe L Dierickx D Verheecke M Uyttebroeck A Bechter O Delforge M Vandecaveye V Brison N Verhoef GE Legius E Non-invasive detection of genomic imbalances in Hodgkin/Reed-Sternberg cells in early and advanced stage Hodgkin's lymphoma by sequencing of circulating cell-free DNA: a technical proof-of-principle study Lancet Haematol 2015 2 e55 65 https://doi.org/10.1016/S2352-3026(14)00039-8 26687610 \n55 Rooney MS Shukla SA Wu CJ Getz G Hacohen N Molecular and genetic properties of tumors associated with local immune cytolytic activity Cell 2015 160 48 61 https://doi.org/10.1016/j.cell.2014.12.033 25594174 \n56 Spranger S Gajewski TF Impact of oncogenic pathways on evasion of antitumour immune responses Nat Rev Cancer 2018 18 139 147 https://doi.org/10.1038/nrc.2017.117 29326431 \n57 Lewis AG Flanagan J Marsh A Pupo GM Mann G Spurdle AB Lindeman GJ Visvader JE Brown MA Chenevix-Trench G Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer Breast Cancer Res 2005 7 R1005 16 https://doi.org/10.1186/bcr1336 16280053 \n58 Abaigar M Robledo C Benito R Ramos F Diez-Campelo M Hermosin L Sanchez-Del-Real J Alonso JM Cuello R Megido M Rodriguez JN Martin-Nunez G Aguilar C Chromothripsis Is a Recurrent Genomic Abnormality in High-Risk Myelodysplastic Syndromes PLoS One 2016 11 e0164370 https://doi.org/10.1371/journal.pone.0164370 27741277 \n59 Pottier N Yang W Assem M Panetta JC Pei D Paugh SW Cheng C Den Boer ML Relling MV Pieters R Evans WE Cheok MH The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia J Natl Cancer Inst 2008 100 1792 1803 https://doi.org/10.1093/jnci/djn416 19066270\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "9(29)",
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"keywords": "gene mutations; immunotherapy; lymphoma; molecular targets",
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"title": "Sequential immunotherapy in a patient with primary refractory Hodgkin lymphoma and novel mutations.",
"title_normalized": "sequential immunotherapy in a patient with primary refractory hodgkin lymphoma and novel mutations"
}
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"abstract": "BACKGROUND\nIn chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF), non-invasive ventilation (NIV) is generally recommended and has proven its benefits by reducing endotracheal intubation (ETI) rates, intensive care unit (ICU) admissions, complications, and mortality. Choosing between immediate ETI or NIV trial is often difficult when such patients present with an altered mental status. Some guidelines recommend avoiding NIV when consciousness is impaired given the risk of aspiration, and some authors suggest that a pH < 7.25 is highly predictive of NIV failure. Though clinical response to a well-adjusted NIV treatment can be both swift and spectacular, these contraindications probably encourage physicians to proceed to immediate ETI. Some studies indeed report that NIV was not even considered in as many as 60% of patients who might have benefited from this therapy, though ETI related complications might have been avoided had NIV been successfully applied.\n\n\nMETHODS\nWe report two cases of ARF in COPD patients who were successfully treated by NIV in prehospital setting and avoided ETI despite contraindications (altered mental status with a Glasgow Coma Scale < 8) and failure risk factors (severe respiratory acidosis with pH < 7.25).\n\n\nCONCLUSIONS\nIn COPD patients presenting ARF, NIV trial could be considered even when relative contraindications such as an altered level of consciousness or a severe respiratory acidosis are present.",
"affiliations": "Division of Emergency Medicine, Department of Anaesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals and Faculty of Medicine University of Geneva, CH-1211, Geneva, Switzerland. [email protected].;Division of Emergency Medicine, Department of Anaesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals and Faculty of Medicine University of Geneva, CH-1211, Geneva, Switzerland.",
"authors": "Fubini|P E|PE|http://orcid.org/0000-0003-1371-6465;Suppan|L|L|",
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"fulltext": "\n==== Front\nInt J Emerg Med\nInt J Emerg Med\nInternational Journal of Emergency Medicine\n1865-1372 1865-1380 Springer Berlin Heidelberg Berlin/Heidelberg \n\n284\n10.1186/s12245-020-00284-y\nCase Report\nPrehospital reversal of profound respiratory acidosis and hypercapnic coma by non-invasive ventilation: a report of two cases\nhttp://orcid.org/0000-0003-1371-6465Fubini PE [email protected] Suppan L grid.150338.c0000 0001 0721 9812Division of Emergency Medicine, Department of Anaesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals and Faculty of Medicine University of Geneva, CH-1211, Geneva, Switzerland \n7 5 2020 \n7 5 2020 \n2020 \n13 2219 2 2020 26 4 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nIn chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF), non-invasive ventilation (NIV) is generally recommended and has proven its benefits by reducing endotracheal intubation (ETI) rates, intensive care unit (ICU) admissions, complications, and mortality. Choosing between immediate ETI or NIV trial is often difficult when such patients present with an altered mental status. Some guidelines recommend avoiding NIV when consciousness is impaired given the risk of aspiration, and some authors suggest that a pH < 7.25 is highly predictive of NIV failure. Though clinical response to a well-adjusted NIV treatment can be both swift and spectacular, these contraindications probably encourage physicians to proceed to immediate ETI. Some studies indeed report that NIV was not even considered in as many as 60% of patients who might have benefited from this therapy, though ETI related complications might have been avoided had NIV been successfully applied.\n\nCase presentation\nWe report two cases of ARF in COPD patients who were successfully treated by NIV in prehospital setting and avoided ETI despite contraindications (altered mental status with a Glasgow Coma Scale < 8) and failure risk factors (severe respiratory acidosis with pH < 7.25).\n\nConclusion\nIn COPD patients presenting ARF, NIV trial could be considered even when relative contraindications such as an altered level of consciousness or a severe respiratory acidosis are present.\n\nKeywords\nAcute respiratory failureAltered mental statusNon-invasive ventilationRespiratory acidosisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAcute respiratory failure (ARF) in chronic obstructive pulmonary disease (COPD) patients is a well-known indication for non-invasive ventilation (NIV) trial [1]. The benefits provided by this therapy are numerous and well-studied, the most prominent being reductions in mortality as well as in endotracheal intubation (ETI) and intensive care unit (ICU) admission rates [2, 3]. The main contraindication to NIV is the need for emergent ETI, considered to be mandatory when consciousness is severely impaired, when the patient is unable to cooperate, or when the airways need to be protected because of a high aspiration risk [4]. Unfortunately, COPD patients with ARF often meet these criteria because of hypercapnic coma, and the role of NIV in this setting is therefore still debated [5, 6]. Furthermore, some authors suggest that a pH < 7.25 is linked to a high risk of NIV failure event if a trial might still be considered [7, 8]. The underutilization of NIV in hypercapnic COPD exacerbations suggested by some reports might be at least partially due to these contraindications, which could encourage physicians to immediately proceed with ETI [9].\n\nIn Geneva, an emergency mobile unit called “Service Mobile d’Urgence et de Réanimation” (SMUR), staffed by an advanced paramedic and a physician, can be dispatched to assist a regular ambulance in case of life-threatening emergencies [10]. All SMUR vehicles have been equipped by a Hamilton T1 ventilator (Hamilton Medical, Bonaduz, Switzerland) since 2013, and the decision to initiate NIV is made by the physician according to his clinical evaluation. A portable blood gas analyzer (iStat, Abbott Point of Care Inc., Princeton, USA) is available to guide treatment decision and assess the patients’ evolution.\n\nWe report here two cases of ARF in COPD patients with severe respiratory acidosis and hypercapnic coma successfully treated by NIV in the prehospital setting.\n\nCase presentation\nCase 1: A 71-year-old woman known for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3 COPD under long-term supplemental oxygen therapy was found in respiratory distress the morning after having received Oxazepam 30 mg for anxiety and insomnia during the previous evening. Upon arrival, prehospital providers noted a Glasgow Coma Scale (GCS) of 6 with no focal deficit, shallow breathing with a respiratory rate over 40 breaths per minute, and a pulsed oxygen saturation of 80% under supplementary oxygen (6 L/min) through nasal cannula. There was no hemodynamic compromise, and the patient was apyretic. Reservoir oxygen face mask was applied and arterial blood gas obtained, showing severe respiratory acidosis (pH 7.17, pCO2 15.6 kPa, pO2 24.1 kPa, bicarbonates 43 mmol/L).\n\nA NIV trial was started using bi-level positive airway pressure ventilation mode, targeting a tidal volume of 6 ml/kg ideal body weight. Patient was under continuous medical surveillance during transport to the emergency room (ER) and showed progressive neurological improvement with a GCS rising to 10. After 60 min of ventilation, a new arterial blood gas sample was drawn showing improvement of her respiratory acidosis (FiO2 21%: pH 7.31, pCO2 10.0 kPa, pO2 7.1 kPa, bicarbonates 37 mmol/L). She was then admitted to ICU to continue NIV, which was successfully continued. ETI was never required, and the patient was transferred to the internal medicine ward after 2 days before being discharged from the hospital after 14 days.\n\nCase 2: A 70-year-old man known for GOLD stage 4 COPD under long-term supplemental oxygen therapy who had been treated by bronchodilators, antibiotics, and steroids for a week, called the ambulance dispatch central because of increasing dyspnea and chest pain. When prehospital providers arrived on site, the patient was unconscious (GCS 3) and in severe respiratory distress with central cyanosis, rapid/shallow breathing. The pulsed oxygen saturation was of 70% under supplementary oxygen (6 L/min) through nasal cannula. He was hemodynamically stable. Ventilation using a bag-valve mask was quickly initiated, and arterial blood gas obtained, showing severe respiratory acidosis (pH 7.07, pCO2 > 17.0 kPa, pO2 40.1 kPa, bicarbonates not recorded due to equipment error). The patient had signed a legal document asking not to be resuscitated nor intubated. A bi-level positive airway pressure ventilation NIV trial was started, and both intravenous aspirin and unfractionated heparin were administered. Constant medical surveillance was provided during transport. Upon arrival in the ER after 30 min of NIV, the patient had a GCS of 14. After 70 min of ventilation, a new arterial blood gas sample was drawn showing improvement of his respiratory acidosis (FiO2 32%: pH 7.24, pCO2 12.2 kPa, pO2 7.6 kPa, bicarbonates 38 mmol/L). Pulmonary embolism was ruled out by CT scan and, because of chest pain and elevated cardiac biomarkers, coronary catheterization was performed showing chronic proximal anterior-interventricular artery occlusion that was treated by stenting. The patient was then admitted to the ICU to continue NIV before being transferred to the internal medicine ward after 2 days and finally discharged from the hospital after 20 days.\n\nDiscussion\nThough ETI should have been performed in both these patients according to some guidelines [4, 7], use of prehospital NIV allowed us to avoid this high-risk procedure and its potential complications.\n\nThe decision to perform ETI in advanced COPD patients must be carefully weighed as such patients frequently present a prolonged and difficult ventilation weaning and as ETI has been linked with an increased mortality rate [11]. Some authors therefore suggest that it might be worth trying NIV even in patients showing altered level of consciousness [5, 6].\n\nIn-hospital underutilization of NIV is nevertheless often reported, with ETI being chosen in as many as 60% of patients meeting criteria for NIV trial. The contraindications found in some guidelines are probably among the most important factors leading the physicians to favor immediate ETI [9]. In the prehospital setting, the proportion of NIV underutilization might be even greater, as logistic-related issues might cause delays in both time before first medical contact and NIV instauration. Such delays might lead to further respiratory and neurological compromise, finally making emergent ETI unavoidable.\n\nThe cases we reported are examples of situations in which the choice between NIV trial and ETI is particularly challenging. The first patient presented with ARF induced by benzodiazepine intoxication, while the second patient had a COPD exacerbation probably precipitated by NSTEMI, assuming that cardiac ischemia was not a consequence of severe hypoxia. In both cases, we believe that clinical improvement was entirely due to NIV as it was the only effective treatment administered by the prehospital team. Indeed, no flumazenil was given to the first patient despite probable benzodiazepine intoxication, and the second patient was given aspirin and heparin, but no nitrates, diuretics, or inotropic medication.\n\nEven if these two patients presented with ARF of different etiologies, their clinical picture at first medical contact was similar. They both had baseline advanced COPD, a pH < 7.25, and a GCS < 8. Within the first hour, respiratory acidosis regressed (with a pH increase of 0.14 and 0.17 respectively) and neurological status improved (with GCS improving from 6 to 10 and from 3 to 14 respectively) in both cases, making it possible to avoid ETI. For the first patient, NIV was tried because of the potential harmful effects of ETI and mechanical ventilation in the context of advanced COPD. Conversely, while the second patient undoubtedly met criteria for immediate ETI, the procedure was not performed to respect his will. Nevertheless, clinical improvement was even more spectacular in this case, with the patient recovering an almost normal level of consciousness in only 30 min.\n\nThe main limitation of this report is that it only describes two cases. Nevertheless, both cases show that NIV could reasonably be attempted in patients in whom ETI should have been performed according to some guidelines. Indeed, though some authors argue that all patients at high aspiration risk should be intubated, it is our opinion that the risks linked to NIV should be weighed against the risks linked to ETI, and that the kind of clinical surveillance that can be provided should be taken into account.\n\nAs a physician-staffed emergency mobile unit assists regular ambulances in case of life-threatening emergencies such as ARF in our prehospital system, critical patients are constantly monitored by an emergency physician throughout transport [10]. In a system allowing well trained healthcare providers to immediately react by withdrawing the NIV mask, tilting the patient on the side, suctioning the airways, or even performing immediate rapid-sequence intubation, we believe that NIV can be considered even in situations where ETI is still often considered as a first choice.\n\nIn conclusion, for COPD patients presenting ARF, NIV trial could be considered even when relative contraindications such as an altered level of consciousness or a severe respiratory acidosis are present. In such cases, continuous medical surveillance is mandatory, and physicians should be ready to perform ETI should complications arise or the trial fail.\n\nAbbreviations\nARFAcute respiratory failure\n\nCOPDChronic obstructive pulmonary disease\n\nNIVNon-invasive ventilation\n\nETIendotracheal intubation\n\nICUIntensive care unit\n\nGCSGlasgow Coma Scale\n\nGOLDGlobal Initiative for Chronic Obstructive Lung Disease\n\nEREmergency room\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable\n\nAuthors’ contributions\nPEF and LS contributed equally to this work. Both authors read and approved the final manuscript.\n\nFunding\nThe authors report no sources of funding.\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\nNot applicable\n\nConsent for publication\nNot applicable\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Rochwerg B, Brochard L, Elliott MW, et al. Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure. Eur Respir J. 2017. 10.1183/13993003.02426-2016.\n2. Ram FS, Picot J, Lightowler J, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2004. 10.1002/14651858.cd004104.pub3.\n3. Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet. 2000. 10.1016/S0140-6736(00)02323-0.\n4. Evans TW, Albert RK, Angus DC, et al. International consensus conferences in intensive care medicine: noninvasive positive pressure ventilation in acute respiratory failure. American Journal of Respiratory and Critical Care Medicine. 2001. 10.1164/ajrccm.163.1.ats1000.\n5. Gónzalez Díaz G, Carrillo Alcaraz A, Pardo Talavera JC, et al. Noninvasive positive-pressure ventilation to treat hypercapnic coma secondary to respiratory failure. Chest. 2005. 10.1378/chest.127.3.952.\n6. Scala R, Naldi M, Archinucci I, Coniglio G, Nava S. Noninvasive positive pressure ventilation in patients with acute exarcerbations of COPD and varying levels of consciousness. Chest. 2005. 10.1378/chest.128.3.1657.\n7. Confalonieri M, Garuti G, Cattaruzza MS, et al. A chart of failure risk for noninvasive ventilation in patients with COPD exacerbation. Eur Respir J. 2005. 10.1183/09031936.05.00085304.\n8. Squadrone E, Frigerio P, Fogliati C, et al. Noninvasive vs invasive ventilation in COPD patients with severe acute respiratory failure deemed to require ventilatory assistance. Intensive Care Med. 2004. 10.1007/s00134-004-2320-7.\n9. Sweet DD, Naismith A, Keenan SP, Sinuff T, Dodek PM. Missed opportunities for noninvasive positive pressure ventilation: a utilization review. J Crit Care. 2008. 10.1016/j.jcrc.2007.04.002.\n10. Gartner BA, Fehlmann C, Suppan L, Niquille M, Rutschmann OT, Sarasin F. Effect of noninvasive ventilation on intubation risk in prehospital patients with acute cardiogenic pulmonary edema: a retrospective study. Eur J Emerg Med. July 2019;1. 10.1097/MEJ.0000000000000616.\n11. Peñuelas O, Frutos-Vivar F, Fernández C, et al. Characteristics and outcomes of ventilated patients according to time to liberation from mechanical ventilation. Am J Respir Crit Care Med. 2011. 10.1164/rccm.201011-1887oc.\n\n",
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"affiliations": "Department of Nephrology, Toho University Faculty of Medicine, Tokyo, Japan.;Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;Department of Virology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;Department of Microbiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;Department of Pathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.;Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.",
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] |
{
"abstract": "Murine typhus is a flea-borne rickettsiosis caused by Rickettsia typhi. When severe, endothelial dysfunction can lead to acute kidney injury secondary to prerenal azotemia or acute tubular necrosis. Here, we describe an unusual cause of kidney injury during the course of murine typhus-focal segmental glomerulosclerosis.",
"affiliations": "Division of Infectious Diseases, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.;Division of General Medicine, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.;Division of General Medicine, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas.",
"authors": "Blanton|Lucas S|LS|;Berman|Megan A|MA|;Afrouzian|Marjan|M|",
"chemical_list": "C108666:APOL1 protein, human; D000075944:Apolipoprotein L1",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.20-0116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "103(3)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000328:Adult; D001741:African Americans; D000818:Animals; D000075944:Apolipoprotein L1; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007303:Insect Vectors; D007677:Kidney Function Tests; D008297:Male; D009154:Mutation; D051437:Renal Insufficiency; D012286:Rickettsia typhi; D005423:Siphonaptera; D014437:Typhus, Endemic Flea-Borne",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "1017-1019",
"pmc": null,
"pmid": "32588799",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "18260783;20647424;27294131;20090849;25043277;8153286;20203164;25168831;23438974;8438048;11005205;25100047;31198534;5695625;20635188;682354;434998;29912688;17379175;15200874;25561578;11231808;881266",
"title": "Case Report: Renal Failure due to Focal Segmental Glomerulosclerosis in a Patient with Murine Typhus.",
"title_normalized": "case report renal failure due to focal segmental glomerulosclerosis in a patient with murine typhus"
}
|
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"reactionoutcome": "6"
}
],
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},
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"literaturereference": "BLANTON LS, BERMAN MA, AFROUZIAN M.. CASE REPORT: RENAL FAILURE DUE TO FOCAL SEGMENTAL GLOMERULOSCLEROSIS IN A PATIENT WITH MURINE TYPHUS. AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE. 2020?103(3):1017?1019",
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},
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}
] |
{
"abstract": "This report presents the transplantation of two kidneys and the liver from a deceased donor with suspected autoimmune encephalomeningitis (ADEM). Due to an atypical post-transplantation clinical course, the transplanted kidneys were biopsied and this disclosed diffuse large B-cell (DLBC) lymphoma of the intravascular type in each kidney. The same malignancy was found in the postmortem donor brain examination. The renal allografts from the two recipients were removed: despite every effort, one patient died, while chemotherapy was successful in the second. No malignancy was observed in the liver transplant recipient, who received prophylactic chemotherapy. These cases highlight the occasional failure of organ donor disease screening and the consequent unforeseen complications.",
"affiliations": "Nephrology-Transplant Center, Department of the Regional Public Hospital in Szczecin, Szczecin, Poland.",
"authors": "Dziewanowski|Krzysztof|K|;Drozd|Radosław|R|;Parczewski|Miłosz|M|;Klinke|Małgorzata|M|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ctr.12417",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-0063",
"issue": "28(10)",
"journal": "Clinical transplantation",
"keywords": "diffuse large B-cell lymphoma; kidney transplantation; liver transplantation; transplant complications",
"medline_ta": "Clin Transplant",
"mesh_terms": "D000970:Antineoplastic Agents; D002102:Cadaver; D005260:Female; D006085:Graft Survival; D006801:Humans; D007674:Kidney Diseases; D016030:Kidney Transplantation; D008107:Liver Diseases; D016031:Liver Transplantation; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D012307:Risk Factors; D014019:Tissue Donors; D014184:Transplantation, Homologous",
"nlm_unique_id": "8710240",
"other_id": null,
"pages": "1080-3",
"pmc": null,
"pmid": "25040461",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiorgan transplantation from a deceased donor with intravascular diffuse large B-cell lymphoma: transmission of the disease and results of treatment.",
"title_normalized": "multiorgan transplantation from a deceased donor with intravascular diffuse large b cell lymphoma transmission of the disease and results of treatment"
}
|
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{
"abstract": "Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at ×10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical \"safe space\" for post-approval risk management to identify high-risk clinical scenarios.",
"affiliations": "Simcyp Limited, a Certara Company, Blades Enterprise Centre, John Street, S2, 4SU, Sheffield, UK. [email protected].;Simcyp Limited, a Certara Company, Blades Enterprise Centre, John Street, S2, 4SU, Sheffield, UK.;Critical Path Institute, Tucson, Arizona, USA.;Critical Path Institute, Tucson, Arizona, USA.;Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.;Critical Path Institute, Tucson, Arizona, USA.;Certara USA, Inc, Princeton, New Jersey, USA.;Simcyp Limited, a Certara Company, Blades Enterprise Centre, John Street, S2, 4SU, Sheffield, UK.",
"authors": "Patel|Nikunjkumar|N|;Hatley|Oliver|O|;Berg|Alexander|A|;Romero|Klaus|K|;Wisniowska|Barbara|B|;Hanna|Debra|D|;Hermann|David|D|;Polak|Sebastian|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D000077266:Moxifloxacin",
"country": "United States",
"delete": false,
"doi": "10.1208/s12248-018-0199-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-7416",
"issue": "20(3)",
"journal": "The AAPS journal",
"keywords": "QT prolongation; hERG; moxifloxacin; quantitative systems toxicology; torsade de pointes",
"medline_ta": "AAPS J",
"mesh_terms": "D000465:Algorithms; D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D006321:Heart; D006801:Humans; D008133:Long QT Syndrome; D008954:Models, Biological; D000077266:Moxifloxacin; D018570:Risk Assessment; D016171:Torsades de Pointes; D057170:Translational Research, Biomedical",
"nlm_unique_id": "101223209",
"other_id": null,
"pages": "47",
"pmc": null,
"pmid": "29541956",
"pubdate": "2018-03-14",
"publication_types": "D016428:Journal Article",
"references": "25087753;22318027;24060671;22947121;15076220;17876386;14594906;21224008;11306689;27233533;28986934;25006781;26784016;21306581;29520534;22289150;23651875;11040340;24140591;14512100;11782904;18651388;26159617;24576511;25940083;26170255;19699852;24078832;15124219;26601174;28878692;22303293;28607619;19287043;29175411;9687407;15172012;16474415;17088870;16565318;19381840;27813448;16158069;19680025;28051093;19238652;28202629;21146653;11125032;11181910;27060526;29181593;19673885;23812503;21637795;27282641;21228407;25505415;19778217;11999291;23713767;17054943;22882246;23417505;18587422;26011050",
"title": "Towards Bridging Translational Gap in Cardiotoxicity Prediction: an Application of Progressive Cardiac Risk Assessment Strategy in TdP Risk Assessment of Moxifloxacin.",
"title_normalized": "towards bridging translational gap in cardiotoxicity prediction an application of progressive cardiac risk assessment strategy in tdp risk assessment of moxifloxacin"
}
|
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},
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{
"reactionmeddrapt": "PO2 increased",
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},
{
"reactionmeddrapt": "Ventricular fibrillation",
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},
{
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{
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},
{
"reactionmeddrapt": "Aneurysm",
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],
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},
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"abstract": "BACKGROUND\nPheochromocytoma is a rare endocrine tumor arising from chromaffin cells and having extensive and profound effects on the cardiovascular system by continuously or intermittently releasing catecholamines. The clinical manifestations of pheochromocytoma are diverse, and the typical triad, including episodic headache, palpitations, and sweating, only occurs in 24% of pheochromocytoma patients, which often misleads clinicians into making an incorrect diagnosis. We herein report the case of a patient with intermittent chest pain and elevated myocardial enzymes for 2 years who was diagnosed with pheochromocytoma.\n\n\nMETHODS\nA 49-year-old woman presented with intermittent chest pain for 2 years. Two years ago, the patient experienced chest pain and was diagnosed with acute myocardial infarction, with 25% stenosis in the left circumflex. The patient still had intermittent chest pain after discharge. Two hours before admission to our hospital, the patient experienced chest pain with nausea and vomiting, lasting for 20 min. Troponin I and urinary norepinephrine and catecholamine levels were elevated. An electrocardiogram indicated QT prolongation and ST-segment depression in leads II, III, aVF, and V3-V6. A coronary computed tomography angiogram revealed no evidence of coronary artery disease. Echocardiography showed left ventricular enlargement and a decreased posterior inferior wall motion amplitude. Contrast-enhanced computed tomography demonstrated an inhomogeneous right adrenal mass. The patient successfully underwent laparoscopic right adrenalectomy, and histopathology confirmed adrenal pheochromocytoma. During the first-year follow-up visits, the patient was asymptomatic. The abnormal changes on echocardiography and electrocardiogram disappeared.\n\n\nCONCLUSIONS\nClinicians should be aware of pheochromocytoma. A timely and accurate diagnosis of pheochromocytoma is essential for alleviating serious cardiac complications.",
"affiliations": "Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi Province, China.;Department of Electrocardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi Province, China. [email protected].;Department of Gastroenterology, Xi'an Children's Hospital, Xi'an 710068, Shaanxi Province, China.;Ultrasonic Diagnosis Center, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi Province, China.;Department of Cardiology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi Province, China.",
"authors": "Wu|Hao-Yu|HY|;Cao|Yi-Wei|YW|;Gao|Tian-Jiao|TJ|;Fu|Jian-Li|JL|;Liang|Lei|L|",
"chemical_list": null,
"country": "United States",
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"doi": "10.12998/wjcc.v9.i15.3752",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i15.pg3752\n10.12998/wjcc.v9.i15.3752\nCase Report\nPheochromocytoma in a 49-year-old woman presenting with acute myocardial infarction: A case report\nWu HY et al. Pheochromocytoma presenting with acute myocardial infarction\nWu Hao-Yu Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China\n\nCao Yi-Wei Department of Electrocardiology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China. [email protected]\n\nGao Tian-Jiao Department of Gastroenterology, Xi’an Children’s Hospital, Xi'an 710068, Shaanxi Province, China\n\nFu Jian-Li Ultrasonic Diagnosis Center, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi Province, China\n\nLiang Lei Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi'an 710068, Shaanxi Province, China\n\nAuthor contributions: Wu HY and Cao YW drafted the manuscript; Wu HY, Fu JL, and Liang L participated in the treatment of this patient; Wu HY, Cao YW, and Gao TJ revised the manuscript; all authors have read and approved the final version of the manuscript.\n\nSupported by the Natural Science Basic Research Program of Shaanxi Province, No. 2020JQ-939 ; and the Science and Technology Development Incubation Fund Project of Shaanxi Provincial People’s Hospital, No. 2019YXQ-08 .\n\nCorresponding author: Yi-Wei Cao, MD, PhD, Doctor, Department of Electrocardiology, Shaanxi Provincial People’s Hospital, No. 256 West Youyi Road, Xi'an 710068, Shaanxi Province, China. [email protected]\n\n26 5 2021\n26 5 2021\n9 15 37523757\n10 1 2021\n15 2 2021\n8 3 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nPheochromocytoma is a rare endocrine tumor arising from chromaffin cells and having extensive and profound effects on the cardiovascular system by continuously or intermittently releasing catecholamines. The clinical manifestations of pheochromocytoma are diverse, and the typical triad, including episodic headache, palpitations, and sweating, only occurs in 24% of pheochromocytoma patients, which often misleads clinicians into making an incorrect diagnosis. We herein report the case of a patient with intermittent chest pain and elevated myocardial enzymes for 2 years who was diagnosed with pheochromocytoma.\n\nCASE SUMMARY\n\nA 49-year-old woman presented with intermittent chest pain for 2 years. Two years ago, the patient experienced chest pain and was diagnosed with acute myocardial infarction, with 25% stenosis in the left circumflex. The patient still had intermittent chest pain after discharge. Two hours before admission to our hospital, the patient experienced chest pain with nausea and vomiting, lasting for 20 min. Troponin I and urinary norepinephrine and catecholamine levels were elevated. An electrocardiogram indicated QT prolongation and ST-segment depression in leads II, III, aVF, and V3-V6. A coronary computed tomography angiogram revealed no evidence of coronary artery disease. Echocardiography showed left ventricular enlargement and a decreased posterior inferior wall motion amplitude. Contrast-enhanced computed tomography demonstrated an inhomogeneous right adrenal mass. The patient successfully underwent laparoscopic right adrenalectomy, and histopathology confirmed adrenal pheochromocytoma. During the first-year follow-up visits, the patient was asymptomatic. The abnormal changes on echocardiography and electrocardiogram disappeared.\n\nCONCLUSION\n\nClinicians should be aware of pheochromocytoma. A timely and accurate diagnosis of pheochromocytoma is essential for alleviating serious cardiac complications.\n\nPheochromocytoma\nCatecholamine\nCardiac complications\nAcute myocardial infarction\nChest pain\nCase report\n==== Body\nCore Tip: Pheochromocytoma releases excessive amounts of catecholamines, which can have mild to catastrophic effects on the cardiovascular system, such as hypertension, myocardial infarction, cardiomyopathy, arrhythmias, and heart failure. However, most of the cardiovascular complications are reversible after pheochromocytoma resection. Clinicians should be aware of pheochromocytoma. A timely and accurate diagnosis of pheochromocytoma is essential for alleviating serious cardiac complications.\n\nINTRODUCTION\n\nPheochromocytoma is a rare endocrine tumor arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglion and having extensive and profound effects on the cardiovascular system by continuously or intermittently releasing catecholamines, mainly epinephrine and norepinephrine[1,2]. Pheochromocytoma has two main types, high norepinephrine/epinephrine secretion and high epinephrine/ norepinephrine secretion. The norepinephrine type affects mainly the cardiovascular system, manifesting mainly as hypertension, while the epinephrine type affects mainly the metabolism, manifesting mainly as hyperglycemia. A timely and accurate diagnosis of pheochromocytoma is essential for alleviating serious cardiac complications caused by an overdose of catecholamines. We report the case of a patient with intermittent chest pain and elevated myocardial enzymes for 2 years who was diagnosed with pheochromocytoma, and the abnormal changes in electrocardiogram (ECG) and echocardiography caused by pheochromocytoma disappeared after tumor resection.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 49-year-old woman presented with intermittent chest pain for 2 years.\n\nHistory of present illness\n\nTwo years ago, the patient experienced chest pain lasting for 20 min. The patient was diagnosed with acute myocardial infarction with a significant increase in troponin in a local hospital, and coronary angiography showed 25% stenosis in the left circumflex. The patient was treated with aspirin, clopidogrel, and statins. However, she still had intermittent chest pain, lasting for 5-10 min each time, after discharge. Two hours before admission to our hospital, the patient experienced chest pain with nausea and vomiting lasting for 20 min.\n\nHistory of past illness\n\nA history of hypertension and diabetes was denied.\n\nPersonal and family history\n\nThe patient had a free personal history and denied a family history of premature coronary artery disease.\n\nPhysical examination\n\nVital signs on arrival showed body temperature of 36.8 ℃, blood pressure of 140/80 mmHg, a regular pulse of 84 beats per minute, and a respiratory rate of 18 breaths per minute. Heart and lung examinations showed no abnormalities. Jugular vein engorgement or peripheral edema was not found.\n\nLaboratory examinations\n\nThe troponin I level was 1.14 ng/mL (normal range < 0.04). The urinary norepinephrine level was 296.2 nmol/24 h (normal range 80.3-164.0), and the urinary catecholamine level was 327.8 nmol/24 h (normal range 94.5-238.3). The fasting blood glucose level was 5.6 mmol/L (normal range 3.9-6.1). B-type natriuretic peptide, 24-h urinary epinephrine, hemoglobin, leukocytes, amylase, electrolytes, liver function, renal function, and D-dimer were not significantly abnormal.\n\nImaging examinations\n\nA 12-lead ECG indicated QT prolongation (QTc 533 ms) and ST-segment depression in leads II, III, aVF, and V3-V6 (Figure 1). A coronary computed tomography angiogram revealed no evidence of coronary artery disease (Figure 2). Echocardiography showed left ventricular enlargement (systolic and diastolic diameters of 45 mm and 57 mm, respectively) and a decreased posterior inferior wall motion amplitude (left ventricular ejection fraction of 51%). Chest computed tomography showed no obvious abnormality, but abdominal computed tomography showed an adrenal mass. Contrast-enhanced computed tomography demonstrated an inhomogeneous right adrenal mass (6.1 cm × 3.9 cm, Figure 3).\n\nFigure 1 Twelve-lead electrocardiogram indicated QT prolongation (QTc 533 ms) and ST-segment depression in leads II, III, aVF, and V3-V6 at admission.\n\nFigure 2 Coronary computed tomography angiography revealed no evidence of coronary artery disease. A and B: Left coronary artery; C: Right coronary artery.\n\nFigure 3 Contrast-enhanced computed tomography demonstrated an inhomogeneous right adrenal mass (6.1 cm × 3.9 cm, orange arrows).\n\nFINAL DIAGNOSIS\n\nThe patient was diagnosed with pheochromocytoma.\n\nTREATMENT\n\nThe patient was transferred to the urology department and underwent successful laparoscopic right adrenalectomy. Histopathology confirmed adrenal pheochromocytoma.\n\nOUTCOME AND FOLLOW-UP\n\nThe patient was free of complications during hospitalization. During the first-year follow-up visits, the patient was asymptomatic and had normal blood pressure. Echocardiography showed a normal left ventricular size (systolic and diastolic diameters of 32 mm and 48 mm, respectively), no abnormal wall motion, and normal left ventricular function (left ventricular ejection fraction of 63%). ECG showed that QT prolongation and ST-segment depression in leads II, III, aVF, and V3-V6 disappeared (Figure 4). The patient showed no signs of recurrence and had normal urine norepinephrine and catecholamine levels.\n\nFigure 4 Twelve-lead electrocardiogram indicated QT prolongation and ST-segment depression in leads II, III, aVF and V3-V6 disappeared at the 1-mo follow-up after pheochromocytoma resection.\n\nDISCUSSION\n\nPheochromocytoma, which is derived from chromaffin cells, produces excessive amounts of catecholamines, especially epinephrine and norepinephrine, whose continuous or intermittent release can cause serious cardiovascular complications, such as hypertension, myocardial infarction, cardiomyopathy, arrhythmias, and heart failure[3,4]. It is estimated that the prevalence of pheochromocytoma during a lifetime is approximately 0.015%-0.04%, while its prevalence at autopsy is even higher (approximately 0.05%), which indicates that many pheochromocytomas are not diagnosed during the lifetime and may be the cause of death[5]. According to the laboratory results, the patient in our case belongs to high norepinephrine secreting pheochromocytoma.\n\nHypertension is one of the most common cardiovascular manifestations of pheochromocytoma, which can manifest as persistent or paroxysmal hypertension, mainly depending on the pattern of catecholamine secretion[6]. Approximately 90% of patients with pheochromocytoma have persistent or paroxysmal hypertension. Persistent hypertension is more common in patients with pheochromocytomas that continuously release high levels of norepinephrine. Paroxysmal hypertension is more common in patients with pheochromocytomas that intermittently secrete large amounts of epinephrine[7]. It is worth noting that a small proportion of patients with pheochromocytoma have normal blood pressure[8].\n\nPatients with pheochromocytoma can develop catecholamine cardiomyopathy (including hypertrophic cardiomyopathy, dilated cardiomyopathy, and Takotsubo-like cardiomyopathy), myocardial ischemia, or even myocardial infarction. An increase in catecholamine levels can lead to increased production of reactive oxygen species, increased oxygen consumption, increased cardiac afterload, vasoconstriction, cell hypertrophy, cardiac remodeling, and even myocarditis[1,9]. The patient may present with chest pain, chest tightness, and sweating. ECG may show ST segment elevation or depression and T-wave inversion. Myocardial enzymes can also be elevated.\n\nApproximately 50%-70% of pheochromocytoma patients complain of palpitations. Patients with pheochromocytoma may have a variety of arrhythmias, including atrial flutter, atrial fibrillation, supraventricular tachycardia, torsade de pointe ventricular tachycardia, ventricular fibrillation, and asystolic arrest[10]. Catecholamines can also cause the QT interval to be prolonged, which may induce torsade de pointes ventricular tachycardia and be life-threatening[11,12]. The reasons for arrhythmias caused by pheochromocytoma are considered to be multifactorial. Excessive catecholamine stimulation of beta-adrenergic receptors is one of the main reasons[13-16].\n\nAlthough pheochromocytoma can cause many cardiovascular complications, most of them are reversible after pheochromocytoma resection[17-20]. In our case, the patient did not have the typical triad of pheochromocytoma but presented with acute myocardial infarction that caused abnormal changes in ECG and cardiac structure and function. However, the abnormal changes in ECG and echocardiography caused by pheochromocytoma disappeared after tumor resection.\n\nCONCLUSION\n\nThe clinical manifestations of pheochromocytoma vary, and many patients do not have the typical triad, which easily leads to missing the diagnosis of pheochro-mocytoma. Pheochromocytoma causes an excess of catecholamines, which has a variety of potentially damaging effects on the cardiovascular system. However, most of the cardiovascular complications are reversible after pheochromocytoma resection. Clinicians should be familiar with clinical manifestations of pheochro-mocytoma, which helps raise clinical suspicion and facilitate the early diagnosis and treatment of pheochromocytoma.\n\nInformed consent statement: Informed written consent was obtained from the patient for publication of this report and any accompanying images.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest to disclose.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: January 10, 2021\n\nFirst decision: February 12, 2021\n\nArticle in press: March 8, 2021\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B, B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Roysommuti S S-Editor: Zhang H L-Editor: Wang TQ P-Editor: Wang LL\n==== Refs\n1 Gu YW Poste J Kunal M Schwarcz M Weiss I Cardiovascular Manifestations of Pheochromocytoma Cardiol Rev 2017 25 215 222 28786897\n2 Jia Z Wang BJ Li X Zhang X Pheochromocytoma with delayed tumor thrombus detection in renal vein: A case report World J Clin Cases 2020 8 2849 2854 32742994\n3 Galetta F Franzoni F Bernini G Poupak F Carpi A Cini G Tocchini L Antonelli A Santoro G Cardiovascular complications in patients with pheochromocytoma: a mini-review Biomed Pharmacother 2010 64 505 509 20580187\n4 Zelinka T Petrák O Turková H Holaj R Strauch B Kršek M Vránková AB Musil Z Dušková J Kubinyi J Michalský D Novák K Widimský J High incidence of cardiovascular complications in pheochromocytoma Horm Metab Res 2012 44 379 384 22517556\n5 Eisenhofer G Rivers G Rosas AL Quezado Z Manger WM Pacak K Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management Drug Saf 2007 30 1031 1062 17973541\n6 Shin JY Kim BH Kim YK Kim TH Kim EH Lee MJ Kim JH Jeon YK Kim SS Kim IJ Pheochromocytoma as a rare cause of hypertension in a 46 X, i(X)(q10) turner syndrome: a case report and literature review BMC Endocr Disord 2018 18 27 29747617\n7 Farrugia FA Charalampopoulos A Pheochromocytoma Endocr Regul 2019 53 191 212 31517632\n8 Pappachan JM Tun NN Arunagirinathan G Sodi R Hanna FWF Pheochromocytomas and Hypertension Curr Hypertens Rep 2018 20 3 29356966\n9 Hernández-Montoliu L Simó-Servat A Villabona C Tako-Tsubo cardiomyopathy induced by pheochromocytoma Endocrinol Diabetes Nutr 2018 65 549 551 30082205\n10 Agrawal S Shirani J Garg L Singh A Longo S Longo A Fegley M Stone L Razavi M Radoianu N Nanda S Pheochromocytoma and stress cardiomyopathy: Insight into pathogenesis World J Cardiol 2017 9 255 260 28400922\n11 Y-Hassan S Falhammar H Cardiovascular Manifestations and Complications of Pheochromocytomas and Paragangliomas J Clin Med 2020 9\n12 Oruganti SS Gambeer Rao M Pisapati VL Adrenal and extra-adrenal pheochromocytomas presenting as life-threatening ventricular arrhythmias: Report of three cases Indian Heart J 2016 68 381 385 27316501\n13 Zhang MM Mao W Wu D Liu P Pheochromocytoma with Ventricular Tachycardia as the Presenting Symptom Chin Med J (Engl) 2016 129 1505 1506 27270552\n14 Naranjo J Dodd S Martin YN Perioperative Management of Pheochromocytoma J Cardiothorac Vasc Anesth 2017 31 1427 1439 28392094\n15 Bai S Yao Z Zhu X Li Z Jiang Y Wang R Wen N Risk factors for postoperative cardiovascular morbidity after pheochromocytoma surgery: a large single center retrospective analysis Endocr J 2019 66 165 173 30518721\n16 Lenders JWM Eisenhofer G Update on Modern Management of Pheochromocytoma and Paraganglioma Endocrinol Metab (Seoul) 2017 32 152 161 28685506\n17 Brunt LM Moley JF Doherty GM Lairmore TC DeBenedetti MK Quasebarth MA Outcomes analysis in patients undergoing laparoscopic adrenalectomy for hormonally active adrenal tumors Surgery 2001 130 629 34; discussion 634 11602893\n18 Anai T Oka K Yokota Y Nishimura Y Hagiya H Otsuka F Massive pheochromocytoma Clin Case Rep 2020 8 2308 2309 33235787\n19 Worrest TC Gilbert EW Sheppard BC Pheochromocytoma: 20 years of improving surgical care Am J Surg 2019 217 967 969 30922520\n20 Afana M Panchal RJ Simon RM Hejab A Lahiri SW Khandelwal AK Hudson MP Pheochromocytoma-Induced Takotsubo Cardiomyopathy Tex Heart Inst J 2019 46 124 127 31236077\n\n",
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"keywords": "Acute myocardial infarction; Cardiac complications; Case report; Catecholamine; Chest pain; Pheochromocytoma",
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"title": "Pheochromocytoma in a 49-year-old woman presenting with acute myocardial infarction: A case report.",
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"reactionmeddrapt": "Electrocardiogram QT prolonged",
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}
],
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},
"primarysource": {
"literaturereference": "WU HY, CAO YW, GAO TJ, FU JL, LIANG L. PHEOCHROMOCYTOMA IN A 49?YEAR?OLD WOMAN PRESENTING WITH ACUTE MYOCARDIAL INFARCTION: A CASE REPORT. WORLD JOURNAL OF CLINICAL CASES. 2021?9(15):3752?3757",
"literaturereference_normalized": "pheochromocytoma in a 49 year old woman presenting with acute myocardial infarction a case report",
"qualification": "3",
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},
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}
] |
{
"abstract": "We present a case report of a patient who developed severe reversible cerebral vasoconstriction syndrome, which was worsening despite typical interventional and supportive care. We administered a stellate ganglion block (SGB) and monitored the vasospasm with transcranial Doppler measurements.\n\n\n\nA 25-year-old woman was admitted with recurrent headaches and neurological symptoms, which angiography showed to be caused by diffuse, multifocal, segmental narrowing of the cerebral arteries leading to severe ischemia in multiple regions. Typical treatment was initiated with arterial verapamil followed by supportive critical care, including nimodipine, intravenous fluids, permissive hypertension, and analgesia. Vasospasm was monitored daily via transcranial Doppler ultrasound (TCD). After symptoms and monitoring suggested worsening vasospasm, an SGB was administered under ultrasound guidance. Block success was confirmed via pupillometry, and repeat TCD showed improved flow through the cerebral vasculature. Improvement in vascular flow was accompanied by a gradual reduction in acute neurological symptoms, with the patient reporting no headaches the following morning.\n\n\n\nFor patients with reversible cerebral vasoconstriction syndrome who develop severe signs or symptoms despite typical treatment, sympathetic blockade may be a possible rescue therapy. This may extend to other causes of severe vasospasm as well, and further study is needed to determine if the SGB should be included in routine or rescue therapy.",
"affiliations": "Anesthesiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA [email protected].;Anesthesiology, Yale School of Medicine, New Haven, Connecticut, USA.;Anesthesiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Neurology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.",
"authors": "Davis|Jeffrey|J|0000-0002-2692-0425;Ozcan|Mehmet S|MS|;Kamdar|Jay K|JK|;Shoaib|Maria|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/rapm-2021-102675",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "46(8)",
"journal": "Regional anesthesia and pain medicine",
"keywords": "autonomic nerve block; neurologic manifestations; regional anesthesia; treatment outcome",
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": "D000328:Adult; D001340:Autonomic Nerve Block; D005260:Female; D006439:Hemodynamics; D006801:Humans; D013233:Stellate Ganglion; D014661:Vasoconstriction; D020301:Vasospasm, Intracranial",
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "732-734",
"pmc": null,
"pmid": "33875578",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Stellate ganglion block used to treat reversible cerebral vasoconstriction syndrome.",
"title_normalized": "stellate ganglion block used to treat reversible cerebral vasoconstriction syndrome"
}
|
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{
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{
"abstract": "In a randomized, nonblinded clinical trial, 36 consecutive patients with generalized convulsive status epilepticus were treated with either combination diazepam and phenytoin (DZ/DPH) or phenobarbital (PB). Phenytoin was added to the PB regimen if seizures persisted for 10 minutes after beginning therapy. The cumulative convulsion time (total time spent in active convulsive movements) was shorter for the PB group than for the DZ/DPH group (median, 5 versus 9 minutes, p less than 0.06); the response latency (elapsed time from initiation of therapy to the end of the last convulsion) was also shorter for the PB group (median, 5.5 versus 15 minutes, p less than 0.10). The median cumulative convulsion time is between 0 and 14 minutes shorter for the PB regimen than for the DZ/DPH regimen (95% confidence interval). Similarly, the median response latency for the PB regimen is between 1 minute longer and 20 minutes shorter than that for the DZ/DPH regimen (95% confidence interval). The frequencies of intubation, hypotension, and arrhythmias were similar in the two groups. Eleven of 18 patients in the PB group responded to phenobarbital monotherapy. We conclude that the PB regimen is rapidly effective, comparable in safety, and enjoys certain practical advantages in comparison with the DZ/DPH regimen.",
"affiliations": "Department of Neurology, University of California, Davis Medical Center, Sacramento 95817.",
"authors": "Shaner|D M|DM|;McCurdy|S A|SA|;Herring|M O|MO|;Gabor|A J|AJ|",
"chemical_list": "D010672:Phenytoin; D003975:Diazepam; D010634:Phenobarbital",
"country": "United States",
"delete": false,
"doi": "10.1212/wnl.38.2.202",
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"issn_linking": "0028-3878",
"issue": "38(2)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D000368:Aged; D002986:Clinical Trials as Topic; D003975:Diazepam; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital; D010672:Phenytoin; D011446:Prospective Studies; D011897:Random Allocation; D013226:Status Epilepticus",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "202-7",
"pmc": null,
"pmid": "3277082",
"pubdate": "1988-02",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Treatment of status epilepticus: a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin.",
"title_normalized": "treatment of status epilepticus a prospective comparison of diazepam and phenytoin versus phenobarbital and optional phenytoin"
}
|
[
{
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},
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"abstract": "BACKGROUND\nAcrometastases of the hand are an unusual sign of lung cancer onset and may often be mistaken for other benign disorders, thus delaying diagnosis and treatment.\nA 58-year-old man presented at the Rheumatology Clinic with a lump in the distal phalanx of the right index finger associated with intense pain, swelling, rib pain, and hemoptysis.\nGiven the clinical manifestations, an x-ray of the right hand was performed, and it revealed an osteolytic lesion in the distal phalanx of the right index finger. The subsequent CT of the thorax and abdomen showed a lung tumor, osteolytic lesions in the ribs, sternum, and the thoracic spine.\n\n\nMETHODS\nAmputation of the phalanx was decided on account of intense pain refractory to NSAIDs and opioids. Pathology assessment established the diagnosis of bone metastases secondary to lung adenocarcinoma. The patient underwent 6 cycles of first-line palliative chemotherapy with cisplatin and gemcitabine with partial response according to the RECIST 1.1. criteria. EGFR and ALK testing were not available at the time. A year later, the patient presented with progressive disease, which lead to 6 more cycles of chemotherapy with docetaxel. The disease progressed during chemotherapy and the patient was switched to erlotinib.\n\n\nRESULTS\nAfter 7 months of anti-EGFR treatment, the patient passed away due to disease progression, thus having an overall survival of 25 months.\n\n\nCONCLUSIONS\nOn rare occasions, acrometastases of the hand may be the first manifestation of a lung cancer and, as such, they must be taken into consideration in the differential diagnosis of rheumatologic disorders. They are a poor prognosis marker, but some cases like this one can have a better survival than reported in the literature, most likely due to that particular cancer's biology.",
"affiliations": "\"Gr.T. Popa\" University of Medicine and Pharmacy.;\"Gr.T. Popa\" University of Medicine and Pharmacy.;\"Gr.T. Popa\" University of Medicine and Pharmacy.;Early Phase Clinical Trials Unit, Addenbrooke's Hospital, Cambridge, UK.;\"Gr.T. Popa\" University of Medicine and Pharmacy.;\"Gr.T. Popa\" University of Medicine and Pharmacy.;\"Gr.T. Popa\" University of Medicine and Pharmacy.;\"Gr.T. Popa\" University of Medicine and Pharmacy.;Cardiology Department, Emergency Hospital \"Sf. Spiridon,\" Iaşi, Romania.;\"Gr.T. Popa\" University of Medicine and Pharmacy.;\"Gr.T. Popa\" University of Medicine and Pharmacy.",
"authors": "Afrăsânie|Vlad-Adrian|VA|;Adavidoaiei|Anca Maria|AM|;Zamisnicu|Iuliana Hunea|IH|;Funingănă|Ionut Gabriel|IG|;Marinca|Mihai Vasile|MV|;Gafton|Bogdan|B|;Clement|Dana Elena|DE|;Păduraru|Marius-Ionut|MI|;Demşa|Irina|I|;Miron|Lucian|L|;Alexa-Stratulat|Teodora|T|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1097/MD.0000000000017892",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31804306MD-D-18-0919010.1097/MD.0000000000017892178927300Research ArticleClinical Case ReportA very rare presentation of lung cancer Metastases to the distal phalanx of index–case reportAfrăsânie Vlad-Adrian MDabAdavidoaiei Anca Maria MDa∗Zamisnicu Iuliana Hunea MDaFuningănă Ionut Gabriel MDdMarinca Mihai Vasile MD, PhDabGafton Bogdan MD, PhDabClement Dana Elena MD, PhDaPăduraru Marius-Ionut MDabDemşa Irina MDcMiron Lucian MDabAlexa-Stratulat Teodora MDabNA. a “Gr.T. Popa” University of Medicine and Pharmacyb Medical Oncology Department, Regional Institute of Oncologyc Cardiology Department, Emergency Hospital “Sf. Spiridon,” Iaşi, Romaniad Early Phase Clinical Trials Unit, Addenbrooke's Hospital, Cambridge, UK.∗ Correspondence: Anca Maria Adavidoaiei, “Gr.T. Popa” University of Medicine and Pharmacy, Iaşi 700115, Romania (e-mail: [email protected]).12 2019 10 12 2019 98 49 e1789217 12 2018 24 9 2019 9 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nAcrometastases of the hand are an unusual sign of lung cancer onset and may often be mistaken for other benign disorders, thus delaying diagnosis and treatment.\n\nPatient concerns:\nA 58-year-old man presented at the Rheumatology Clinic with a lump in the distal phalanx of the right index finger associated with intense pain, swelling, rib pain, and hemoptysis.\n\nDiagnoses:\nGiven the clinical manifestations, an x-ray of the right hand was performed, and it revealed an osteolytic lesion in the distal phalanx of the right index finger. The subsequent CT of the thorax and abdomen showed a lung tumor, osteolytic lesions in the ribs, sternum, and the thoracic spine.\n\nInterventions:\nAmputation of the phalanx was decided on account of intense pain refractory to NSAIDs and opioids. Pathology assessment established the diagnosis of bone metastases secondary to lung adenocarcinoma. The patient underwent 6 cycles of first-line palliative chemotherapy with cisplatin and gemcitabine with partial response according to the RECIST 1.1. criteria. EGFR and ALK testing were not available at the time. A year later, the patient presented with progressive disease, which lead to 6 more cycles of chemotherapy with docetaxel. The disease progressed during chemotherapy and the patient was switched to erlotinib.\n\nOutcomes:\nAfter 7 months of anti-EGFR treatment, the patient passed away due to disease progression, thus having an overall survival of 25 months.\n\nLessons:\nOn rare occasions, acrometastases of the hand may be the first manifestation of a lung cancer and, as such, they must be taken into consideration in the differential diagnosis of rheumatologic disorders. They are a poor prognosis marker, but some cases like this one can have a better survival than reported in the literature, most likely due to that particular cancer's biology.\n\nKeywords\nacrometastasescase reportindex fingerlung adenocarcinomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nLung cancer is one of the most aggressive types of tumors in human pathology and accounts for the greatest number of cancer-related deaths worldwide.[1] Most cases are diagnosed in their metastatic stage.[2] The metastatic patterns may be very different, and localizations of secondary lesions in almost every organ are described in the literature. Most often, metastatic sites in lung cancer are the lungs, the liver, and the bone.[2] Secondary bone lesions are most commonly located in the vertebrae, pelvis, ribs, and sternum.[1] Rarely, they may occur in the bones of the hand or foot, in which case they are named acrometastases.[3] Lung cancer is the main neoplasm causing acrometastases in the hand, followed by kidney and breast cancer.[4] The literature describes 24 such cases.[5] The lesions are most frequently situated in the thumb and least so in the carpal area.[4] Acrometastases very rarely represent the first signs and symptoms of stage IV lung neoplasm and this tends to delay diagnosis; the differential diagnosis of a tumor in the fingers is complex and includes arthritis, osteomyelitis, trauma, gout, Paget disease, cysts, benign, or malignant tumors of the bones or skin. The acrometastases of lung cancer are associated with poor prognosis. The average survival is ∼6 to 7 months, compared to that of 9.7 months in the case of stage IV patients.[2,6–8]\n\nWe are hereby reporting the case of a patient with acrometastases in the distal phalanx of the right index finger, secondary to lung adenocarcinoma. Although the treatment of acrometastases is not standardized, the therapeutic results in this case were favorable and led to extended survival and a good quality of life to this patient, also facilitated by early diagnosis. The patient's survival was 4 times the average rate reported in the literature, which leads us to question how acrometastases impact prognosis.\n\n2 Case presentation\nA Caucasian, 58-year-old retired Lieutenant presented at the Rheumatology Clinic in February 2013 complaining of an intensely painful lump in the distal phalanx of the right index finger, not responding to NSAIDs and opioids, associated with swelling rib pain and hemoptysis. Anamnesis did not reveal any personal, hereditary, or collateral history of cancer. Noteworthy from the medical history was a diagnosis of grade 3 essential hypertension kept under control by ongoing treatment with 40 mg/day of telmisartan and 10 mg/day of amlodipine. Also, the patient was a smoker of 30 pack-years. The physical exam revealed decreased pulmonary sounds in the right upper thorax, and 135/85 mm Hg arterial pressure. The patient also had grade 1 anemia – Hb-13 g/dL and a slightly increased LDH value of 244 U/L. Given the symptoms, an x-ray of the right hand was performed, revealing cvasicomplete distal phalanx osteolysis in the index finger (Fig. 1). This led to the suspicion of neoplasm and, taking into consideration the other symptoms, a CT scan of the thorax and abdomen was recommended. The CT showed a 30/28/17 mm tumor in the posterior segment of the right upper lobe (Fig. 2), infiltrated intrathoracic lymph nodes and other adenopathies: 8/15 mm right inferior paratracheal, 16/10 mm in the aortopulmonary window, 11/6 mm paraaortic, 28/14 mm subcarinal, as well as osteolytic bone lesions located in the sternum, T7 and T8 vertebrae (Fig. 2), C1 and C9 right costal arches, and C3, C4, C5, C7, C8, and C12 left costal arches. In order to confirm the diagnosis, the patient was referred to the Plastic Surgery Clinic, where he underwent the amputation of the distal phalanx. The macroscopic histopathologic exam showed complete osteolysis of the distal segment of the phalanx. The microscopic analysis revealed a well-differentiated adenocarcinoma bone metastase in the distal phalanx, with papillary and micropapillary architecture and complete osteolysis (Fig. 3A and B). Immunohistochemical staining tests confirmed a cytokeratin 7 positive tumor and the TTF-1 was diffusely positive (Fig. 3C). The diagnosis of stage IV lung adenocarcinoma cT2aN3M1b was established in accordance with the 7th edition of AJCC staging.\n\nFigure 1 Hand X-ray: PA and lateral view.\n\nFigure 2 Lung tumor located in the right upper lobe and thoracic lumbar metastases.\n\nFigure 3 Histopathological examination of the acrometastases: (A) adenocarcinoma infiltration in the nail bed (H&E), (B) tumor proliferation with acinar, tubular, and micropapilary pattern (H&E, ×100), (C) TTF1 ×100 diffusely positive (nuclear markers).\n\nIn March 2013, the patient was admitted at the Medical Oncology Clinic. His performance status upon admission was 2 on the ECOG scale. He underwent a first-line chemotherapy protocol with cisplatin (75 mg/m2) and gemcitabine (1000 mg/m2) on days 1 and 8 every 3 weeks. The patient did not benefit from EGFR and ALK testing since these were not available in our country at the time. Six cycles were administered and well tolerated clinically, the main side-effect being grade 1 vomiting. The first imagistic assessment in June 2013 showed a partial response to treatment according to RECIST 1.1., and a subsequent evaluation performed in December 2013 showed stable disease. After 6 more months, in June 2014, the CT scan of the thorax and abdomen described progressive disease into the lungs and bones. A second-line palliative chemotherapy protocol was initiated using 75 mg/m2 of Docetaxel every 3 weeks. The imagistic assessment after 6 cycles showed progressive disease, which lead to the decision to switch treatment to Erlotinib in October 2014, despite the fact that the patient had not presented EGFR mutation. At that time in our country erlotinib was reimbursed for patients with stage IV lung adenocarcinoma without EGFR mutations after first-line chemotherapy. There were no side-effects to erlotinib. In February 2015, the patient had progressive disease and developed pleural effusion (Fig. 4) and after 3 months he died.\n\nFigure 4 CT scan of the lungs showing progressive disease.\n\n3 Discussion\nMetastasizing is the biological phenomenon accounting for 90% of deaths in cancer patients. Secondary lesions may be located in different organs depending on the particular specificity of the tumor cells in relation to that organ and on the vascularization distribution.[9] The bone is the third most frequent site for solid tumor metastases, and the spine, ribs, and pelvis are most often affected. Acrometastases are very rare, as they occur in only 0.1% of the patients diagnosed with bone metastases. Handley was the first to report such a rare manifestation in the hand in 1906.[5,10] Metastases in the hand are infrequent, and as a sign of cancer onset they are extremely rare.[10] According to Flynn's review, the most commonly involved finger is the middle one, followed by the thumb. The distal phalanx is the part most frequently affected, due to the reduced blood flow. Metastases are least likely in the carpal area.[7] Although most data on acrometastases is incomplete and based on retrospective studies, it has been possible to conclude that acrometastases are more common in men than in women, and they mostly affect people between 40 and 80 years old. In a study on 57 British patients with acrometastases, the average age at diagnosis was 63.1. The most common primary tumors accounting for the acrometastases were lung tumors, followed by kidney, and breast tumors. The fact that men are more frequently affected may be explained by the strong correlation between smoking and lung cancer.[8,11] The mechanism underpinning this biological phenomenon is yet to be fully understood, although several hypothesis have been put forward.\n\nSeed and soil theory states that the bone is a fertile ground for the growth of metastatic tumor cells. Once they enter the system, the tumor cells travel through the bone marrow and then migrate through sinusoids toward the surface of the bone. Another explanation is that the bones of distal extremities contain less red marrow than other bones and are at greater distance from the primary tumor. To overcome these unfavorable conditions, several factors are needed in order to facilitate the migration, adhesion, and invasion of the tumor cells.[12] Increased blood flow is considered one such factor favoring the occurrence of acrometastases. This hypothesis is supported by the fact that acrometastases are more common in the dominant hand, which has greater blood flow and is more exposed to trauma. Microscopically, it is presumed that trauma decreases the resistance of support tissues and therefore allows tumor emboli to settle in the skeletal tissue. Other authors suggest that chemotactic factors like prostaglandins released following trauma could be responsible for cellular migration and adherence to the bone tissue.[5,8]\n\nThe symptoms caused by acrometastases are nonspecific, which is why acrometastases can be easily mistaken for other disorders such as arthritis, osteomyelitis, trauma, gout, Paget disease, cysts, benign, or malignant tumors of the bones or skin.[7] Omission of the acrometastases diagnosis can also be due to the hands not being included in standard CT scanning areas.[2] The key symptom which may direct the physician to suspect neoplasm is pain that does not improve to movement or to NSAIDs and opioids.[13]\n\nBecause acrometastases are signs of disseminated disease, in the literature they are generally associated with poor prognosis. Thus, the average survival of such patients has been reported as 6 to 7 months only.[2,6,8] Despite therapeutic progress, the overall survival has not been improved significantly in the last 25 years.[7] In previous studies, there were no statistically significant differences between the survival of patients with acrometastases depending on the location and number of the metastases or the histopathological nature of the primary tumor.[4] However, more recent data is unavailable, so at present it is possible that the median overall survival is actually higher.[14] Our patient had a good survival. He lived for 25 months from the time of the diagnosis, significantly longer than other patient data reported in the literature. This may be due to the lack of updated information, but also to the fact that, in some cases, acrometastases might not be a reliable indicator of poor prognosis. Another aspect that could explain the patients’ longer survival is the individual biology of tumors which determine acrometastasis about which there is little known information.\n\nIn the treatment of acrometastases, there is no well established standard.[11] Surgery, radiotherapy and antalgics play an important role. Healey et al attempted an assessment of treatment methods in a study of 29 patients. They concluded that amputation is the best therapeutic approach for patients with chances of survival beyond 5 months.[7] Also, it is considerably beneficial for cases with refractory pain – a common occurrence in cancer patients[15] or intolerable side-effects to opioids.[7,16] However, other authors have reported good results from more conservatory treatments such as radiotherapy and pain therapy due to unfavorable prognosis. Radiotherapy has the advantage of being able to alleviate pain and partially restore function in the fingers and hand, especially in advanced cases in which amputation is not possible or if the patient does not consent to it. Undoubtedly, apart from the local treatment of acrometastases, mention should be made that the primary neoplasm requires systemic treatment and in most cases that includes chemotherapy, targeted molecular therapies, or immunotherapy.[8,17] The treatment of choice in the presented case was initial amputation of the distal phalanx because the patient was in severe pain not responding to the usual medication.\n\n4 Conclusions\nAcrometastases are extremely rare and may be the first sign of lung cancer. Physicians from non-oncological medical specialties who encounter patients with tumors located in the hand may experience difficulties in establishing prompt and complete diagnosis, while early diagnosis is crucial if good results are to be obtained in such cases. Although most patients with acrometastases have a poor survival in some cases the survival can be much longer questioning the role of cancer biology.\n\nAuthor contributions\nFunding acquisition: Mihai Vasile Marinca, Bogdan Gafton, Dana Elena Clement.\n\nInvestigation: Iuliana Hunea Zamisnicu.\n\nResources: Mihai Vasile Marinca, Bogdan Gafton, Dana Elena Clement, Irina Demsa.\n\nSoftware: Anca Maria Adavidoaiei.\n\nSupervision: Mihai Vasile Marinca, Bogdan Gafton, Dana Elena Clement, Lucian Miron.\n\nWriting – original draft: Vlad-Adrian Afrăsânie, Ionut Gabriel Funingănă, Marius-Ionut Păduraru.\n\nWriting – review & editing: Vlad-Adrian Afrăsânie, Teodora Alexa-Stratulat.\n\nAbbreviations: ALK = anaplastic lymphoma kinase, CT = computed tomography, EGFR = epidermal growth factor receptor, NSAIDs = nonsteroidal anti-inflammatory drugs, RECIST = response evaluation criteria in solid tumors, TTF-1 = thyroid transcription factor 1.\n\nHow to cite this article: Afrăsânie VA, Adavidoaiei AM, Zamisnicu IH, Funingănă IG, Marinca MV, Gafton B, Clement DE, Păduraru MI, Demşa I, Miron L, Alexa-Stratulat T. A very rare presentation of lung cancer: metastases to the distal phalanx of index–case report. Medicine. 2019;98:49(e17892).\n\nPatient has provided the informed consent for publication of the case.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Wong MCS Lao XQ Ho KF \nIncidence and mortality of lung cancer: global trends and association with socioeconomic status . Sci Rep \n2017 ;7 :14300 .29085026 \n[2] Morris G Evans S Stevenson J \nBone metastases of the hand . Ann R Coll Surg Engl \n2017 ;99 :563 –7 .28853594 \n[3] Bricout PB \nAcrometastases . J Natl Med Assoc \n1981 ;73 :325 –9 .7218364 \n[4] Spiteri V Bibra A Ashwood N \nManaging acrometastases treatment strategy with a case illustration . Ann R Coll Surg Engl \n2008 ;90 :W8 –11 .\n[5] Stomeo D Tulli A Ziranu A \nAcrometastasis: a literature review . Eur Rev Med Pharmacol Sci \n2015 ;19 :2906 –15 .26241547 \n[6] Abernethy AP Arunachalam A Burke T \nReal-world first-line treatment and overall survival in non-small cell lung cancer without known EGFR mutations or ALK rearrangements in US community oncology setting . PLoS One \n2017 ;12 :e0178420 .28644837 \n[7] Muñoz-Mahamud E Comballa A Carreño A \nFive cases of acrometastasis to the hand from a carcinoma and review of literature . Hand Surg Rehabil \n2017 ;36 :12 –6 .28137435 \n[8] Flynn CJ Danjoux C Wong J \nTwo cases of acrometastasis to the hands and review of the literature . Curr Oncol \n2008 ;15 :51 –8 .19008991 \n[9] Langley RR Fidler IJ \nThe seed and soil hypothesis revisited – the role of tumor-stroma interactions in metastasis to different organs . Int J Cancer \n2011 ;128 :2527 –35 .21365651 \n[10] Long LS Brickner L Helfend L \nLung cancer presenting as acrometastasis to the finger: a case report . Case Rep Med \n2010 ;234289 .20589088 \n[11] Ashfar A Farhadnia P Khalkhali H \nMetastases to the hand and wrist: an analysis of 221 cases . J Hand Surg Am \n2014 ;39 :923 –32 .24612837 \n[12] Gan K Shen Y \nMetastatic pulmonary adenocarcinoma of the talus: a case report . J Foot Ankle Surg \n2017 ;56 :827 –31 .28633786 \n[13] Kerin R \nMetastatic tumors of the hand . J Bone Joint Surg Am \n1983 ;65 :1331 –5 .6654944 \n[14] Van Veenendaal LM de Klerk G van der Velde D \nA painful finger as first sign of a malignancy . Geriatr Orthop Surg Rehabil \n2014 ;5 :18 –20 .24660095 \n[15] Uritu CM Mihai CT Stanciu GD \nMedicinal plants of the family Lamiaceae in pain therapy: a review . Pain Res Manag \n2018 ;2018 :7801543 .29854039 \n[16] Campa T Fagnoni E Ripamonti C \nPalliative surgery of acrometastases from lung cancer: a case report . Support Care Cancer \n2004 ;12 :202 –4 .14767749 \n[17] Lamarca A Hindi N Belda-Iniesta C \nFoot pain: uncommon presentation of lung cancer . BMJ Case Rep \n2012 ;bcr1220115360 .\n\n",
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] |
{
"abstract": "Clonidine has been used to assist opiate detoxification in the past 10 years. This substance is known to have multiple effects on the central nervous system and to cause withdrawal symptoms when stopped abruptly. The combination of these two effects could result in clonidine having a potential for abuse. Two cases of clonidine abuse/dependence in methadone-maintained patients are presented. Nonmedical use of clonidine in opioid-dependent persons has never been evaluated.",
"affiliations": "Department of Family Medicine, University of Montreal, Canada.",
"authors": "Lauzon|P|P|",
"chemical_list": "D003000:Clonidine; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1016/0740-5472(92)90078-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-5472",
"issue": "9(2)",
"journal": "Journal of substance abuse treatment",
"keywords": null,
"medline_ta": "J Subst Abuse Treat",
"mesh_terms": "D003000:Clonidine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006679:HIV Seropositivity; D006556:Heroin Dependence; D006801:Humans; D008691:Methadone; D015819:Substance Abuse, Intravenous; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders",
"nlm_unique_id": "8500909",
"other_id": null,
"pages": "125-7",
"pmc": null,
"pmid": "1512800",
"pubdate": "1992",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of clonidine abuse/dependence in methadone-maintained patients.",
"title_normalized": "two cases of clonidine abuse dependence in methadone maintained patients"
}
|
[
{
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}
],
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},
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},
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}
] |
{
"abstract": "Psychopharmacologic treatments for eating disorders (EDs) remain unclear, particularly for anorexia nervosa. As in attention-deficit hyperactivity disorder, a dopaminergic mechanism has been implicated in EDs, prompting our use of atomoxetine in an 18-year-old woman with anorexia nervosa, binge/purge type. Atomoxetine is a highly selective norepinephrine reuptake inhibitor with nonaddictive properties and limited effects of appetite suppression. Doses followed those used in a previous trial of atomoxetine in the treatment of binge ED, and response was assessed over 4 months, with significant improvement in ED behaviors and mood. Larger-scale, randomized studies that assess the efficacy of atomoxetine in the treatment of anorexia nervosa, binge/purge type are warranted.",
"affiliations": "Department of Family Medicine, Mayo Clinic and Mayo Clinic Alix School of Medicine, Rochester, MN.;Loyola University Chicago, Chicago, IL.",
"authors": "Wilfahrt|Robert P|RP|;Wilfahrt|Lucy G|LG|;Matthews Hamburg|Abigail|A|",
"chemical_list": "D000069445:Atomoxetine Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000438",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "44(2)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000293:Adolescent; D000856:Anorexia Nervosa; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity; D056912:Binge-Eating Disorder; D005260:Female; D006801:Humans",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "68-70",
"pmc": null,
"pmid": "33538518",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atomoxetine Reduced Binge/Purge Symptoms in a Case of Anorexia Nervosa Binge/Purge Type.",
"title_normalized": "atomoxetine reduced binge purge symptoms in a case of anorexia nervosa binge purge type"
}
|
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}
],
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"reaction": [
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},
{
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}
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},
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}
] |
{
"abstract": "Vertebral osteomyelitis due to Streptococcus viridans following a dental procedure is a rarely reported phenomenon. We discuss the case of a 67-year-old immunocompetent woman who presented with low back pain of 3 weeks duration associated with subjective fever and chills. On admission, the MRI of the lumbar spine showed L5-S1 vertebral osteomyelitis with associated paravertebral and epidural abscesses. Subsequently, detailed history was retaken and the patient reported having had a maxillary tooth extraction followed by a dental implant 2 months prior to the onset of her symptoms. Blood and abscess fluid cultures grew S. viridans Transthoracic echocardiogram showed no evidence of endocarditis. The patient was started on intravenous ceftriaxone but her treatment course was complicated by agranulocytosis requiring a switch to vancomycin. She required a total of 9 weeks of intravenous antibiotics for complete clinical cure.",
"affiliations": "Reading Hospital and Medical Center, Reading, Pennsylvania, USA.;Reading Hospital and Medical Center, Reading, Pennsylvania, USA.;Reading Hospital and Medical Center, Reading, Pennsylvania, USA.;Reading Hospital and Medical Center, Reading, Pennsylvania, USA.",
"authors": "Nazir|Salik|S|;Lohani|Saroj|S|;Tachamo|Niranjan|N|;Rajagopalan|Priya|P|",
"chemical_list": "D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D017116:Low Back Pain; D008159:Lumbar Vertebrae; D008279:Magnetic Resonance Imaging; D010019:Osteomyelitis; D013290:Streptococcal Infections; D014081:Tooth Extraction; D014640:Vancomycin; D034363:Viridans Streptococci",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27268493",
"pubdate": "2016-06-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19918551;14749951;26034758;16523124;19136433;25468170;20371789;26229122;23889700;12493523;18550153",
"title": "Low back pain after a dental procedure: a case of Streptococcus viridans vertebral osteomyelitis.",
"title_normalized": "low back pain after a dental procedure a case of streptococcus viridans vertebral osteomyelitis"
}
|
[
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},
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"literaturereference": "NAZIR S, LOHANI S, TACHAMO N, RAJAGOPALAN P. LOW BACK PAIN AFTER A DENTAL PROCEDURE: A CASE OF STREPTOCOCCUS VIRIDANS VERTEBRAL OSTEOMYELITIS. BMJ CASE REPORTS. 2016;1-3.",
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"abstract": "Pyroglutamic acidemia is an uncommon metabolic disorder, which is usually diagnosed at early ages. The mechanism of action is thought to be glutathione depletion, and its clinical manifestations consist of hemolytic anemia, mental retardation, ataxia, and chronic metabolic acidosis. However, an acquired form has been described in adult patients, who usually present with confusion, respiratory distress, and high anion gap metabolic acidosis (HAGMA). It is also associated with many conditions, including chronic acetaminophen consumption. A 68-year-old white male, with chronic acetaminophen use presented to our service on multiple occasions with severe HAGMA. The patient was admitted to the intensive care unit and required mechanical ventilation and aggressive supportive measures. After ruling out the most frequent etiologies for his acid-base disorder and considering the long history of Tylenol ingestion, his 5-oxiproline (pyroglutamic acid) levels were sent to diagnose pyroglutamic acidemia. Clinicians need to be aware of this cause for metabolic acidosis since it might be a more common metabolic disturbance in compromised patients than would be expected. Subjects with HAGMA that cannot be explained by common causes should be tested for the presence of 5-oxoproline. Discontinuation of the offending drug is therapeutic.",
"affiliations": "Department of Internal Medicine, St Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY.",
"authors": "Romero|Jorge E|JE|;Htyte|Nay|N|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D011761:Pyrrolidonecarboxylic Acid",
"country": "United States",
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"issn_linking": "1075-2765",
"issue": "20(5)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000082:Acetaminophen; D000138:Acidosis; D058186:Acute Kidney Injury; D000368:Aged; D018712:Analgesics, Non-Narcotic; D006801:Humans; D008297:Male; D011761:Pyrrolidonecarboxylic Acid",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "581-4",
"pmc": null,
"pmid": "21519223",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual cause of high anion gap metabolic acidosis: pyroglutamic acidemia. A case report.",
"title_normalized": "an unusual cause of high anion gap metabolic acidosis pyroglutamic acidemia a case report"
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|
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"literaturereference": "ROMERO JE, HTYTE N. AN UNUSUAL CAUSE OF HIGH ANION GAP METABOLIC ACIDOSIS: PYROGLUTAMIC ACIDEMIA. A CASE REPORT. AM J THER. 2013?20:581?584",
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{
"abstract": "We describe a case of type B insulin resistance syndrome associated with systemic lupus erythematosus (SLE) that was refractory to rituximab and successfully treated with a combination of oral glucocorticoids and cyclosporine. Prior to treatment, insulin resistance was severe, and application of a hyperinsulinemic euglycemic clamp was not possible despite the continuous intravenous infusion of insulin at a maximum rate of 9.0 mU/kg/min. The addition of cyclosporine to oral glucocorticoid therapy resulted in remission of insulin resistance. The combination of oral prednisolone and cyclosporine might be effective in treating type B insulin resistance syndrome, particularly in rituximab-resistant cases. However, nephrotoxicity is a particular concern for patients receiving long-term cyclosporine therapy.",
"affiliations": "Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine Matsumoto, Nagano, Japan.;Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine Matsumoto, Nagano, Japan.;Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine Matsumoto, Nagano, Japan.;Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine Matsumoto, Nagano, Japan.;Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine Matsumoto, Nagano, Japan.;Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine Matsumoto, Nagano, Japan.;Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine Matsumoto, Nagano, Japan.;Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of Medicine Matsumoto, Nagano, Japan.",
"authors": "Takei|Masahiro|M|;Ishii|Hiroaki|H|;Kawai|Yuko|Y|;Kato|Kosuke|K|;Sekido|Takashi|T|;Sato|Yoshihiko|Y|;Takeda|Teiji|T|;Komatsu|Mitsuhisa|M|",
"chemical_list": null,
"country": "Japan",
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"fulltext": "\n==== Front\nJ Diabetes InvestigJ Diabetes InvestigjdiJournal of Diabetes Investigation2040-11162040-1124John Wiley & Sons, Ltd Chichester, UK 10.1111/jdi.12337ArticlesEfficacy of oral glucocorticoid and cyclosporine in a case of rituximab-refractory type B insulin resistance syndrome Takei Masahiro *Ishii Hiroaki Kawai Yuko Kato Kosuke Sekido Takashi Sato Yoshihiko Takeda Teiji Komatsu Mitsuhisa 1 Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Shinshu University School of MedicineMatsumoto, Nagano, Japan*\nCorrespondence Masahiro Takei, Tel.: +81-263-37-2686, Fax: +81-263-37-2710, E-mail address: [email protected] 2015 13 3 2015 6 6 734 738 09 9 2014 26 1 2015 02 2 2015 © 2015 The Authors. Journal of Diabetes Investigation published by Asian Association of the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.We describe a case of type B insulin resistance syndrome associated with systemic lupus erythematosus (SLE) that was refractory to rituximab and successfully treated with a combination of oral glucocorticoids and cyclosporine. Prior to treatment, insulin resistance was severe, and application of a hyperinsulinemic euglycemic clamp was not possible despite the continuous intravenous infusion of insulin at a maximum rate of 9.0 mU/kg/min. The addition of cyclosporine to oral glucocorticoid therapy resulted in remission of insulin resistance. The combination of oral prednisolone and cyclosporine might be effective in treating type B insulin resistance syndrome, particularly in rituximab-resistant cases. However, nephrotoxicity is a particular concern for patients receiving long-term cyclosporine therapy.\n\nCyclosporineSystemic lupus erythematosusType B insulin resistance syndrome\n==== Body\nIntroduction\nType B insulin resistance syndrome, a rare form of insulin-resistant diabetes due to the presence of anti-insulin receptor antibodies, is associated with collagen vascular diseases in most cases, such as systemic lupus erythematosus (SLE), scleroderma, Sjögren's syndrome, or occasionally manifests as paraneoplastic syndrome of malignancy1–4. Patients with this syndrome usually present with hyperglycemia that is tolerant to oral antidiabetic agents or high doses of insulin3. The pathogenesis of this syndrome involves the interaction of anti-insulin receptor antibodies and cell surface insulin receptors1–4, with the former blocking the binding of insulin to the latter1,2. This frequent association of type B insulin resistance syndrome with collagen vascular diseases aggravates the clinical situation due to the presence of anti-insulin antibodies that prevent treatment of hyperglycemia, even with large doses of insulin.\n\nHere, we describe a male patient with type B insulin resistance syndrome associated with SLE who was treated with rituximab followed by oral glucocorticoids and cyclosporine. We also review and discuss the effectiveness of cyclosporine in the treatment of this rare syndrome.\n\nCase report\nA 60-year-old man presented to his primary care physician with complaints of thirst, polyuria, weight loss, and dizziness. Past medical history was unremarkable, except for previous surgery for appendicitis. He was not taking any medication and had no family history of diabetes. At the clinic, he was tentatively diagnosed with poorly controlled type 2 diabetes mellitus with a blood glucose level of 419 mg/dL and glycated hemoglobin (HbA1c) level of 12.3%. Despite treatment with calorie restriction (1,600 kcal/day), metformin (500 mg/day), and a high dose of intensive insulin therapy (approximately 100 U/day), hyperglycemia did not improve.\n\nThe patient was referred to our hospital for a detailed examination. He appeared thin and weak despite intensive insulin treatment with a body weight of 53.8 kg (body mass index: 20.0 kg/m2) and had a height of 164 cm. His skin turgor was diminished and reflected dehydration, but acanthosis nigricans, a defining characteristic of severe insulin resistance, was not clinically apparent. Further, he exhibited ataxic gait and photosensitivity to sunlight. Findings of X-ray and ECG studies were normal. Radiological studies, including thoracic abdominal CT or MR imaging with contrast enhancement, revealed no malignant tumors. Brain MR imaging findings were also normal.\n\nLaboratory results are shown in Table1. Hematological abnormalities including thrombocytopenia and lymphopenia were detected. The titer of anti-nuclear antibodies (ANA) was high (1:2,560) with a speckled staining pattern. Further, serum samples were negative for anti-double strand DNA antibodies and positive for anti-Smith antibodies. Fasting capillary glucose levels ranged from 200 to 250 mg/dL, and postprandial levels ranged from 300 to 400 mg/dL. Notably, anti-insulin antibodies were negative, but anti-insulin receptor antibodies were positive. Severe insulin resistance was detected based on highly elevated serum and urine C-peptide levels. We attempted to apply a hyperinsulinemic euglycemic clamp to assess and quantify the degree of insulin resistance (Figure1). However, this was not possible due to the patient's persistent, severe insulin resistance, despite the infusion of a high dose of intravenous insulin up to 9.0 mU/kg/min (Figure1). The patient exhibited photosensitivity and hematological abnormalities (thrombocytopenia and lymphopenia). In addition, the presence of anti-nuclear antibodies and anti-Smith antibodies—which is suggestive of systemic lupus erythematosus (SLE)—was observed along with extreme insulin resistance and anti-insulin receptor antibodies. We therefore diagnosed the patient with type B insulin resistance syndrome associated with SLE, based on the American College of Rheumatology criteria5. Although not apparent at that time, discoid rashes that spread to the scalp and truck and oral ulcers that developed later in the clinical course indicated SLE. Lupus disease activity was further indicated by a high Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, including thrombocytopenia, lymphopenia, low complement levels, high erythrocyte sedimentation rate, and oral ulcers. Given that creatinine clearance was normal for the patient's age and that body weight and urinalysis were normal, except for mild microalbuminuria, lupus nephritis did not appear active at that time.\n\nTable 1 Laboratory results\n\nTest\tResults\tReference range\t\nWhite cell count\t4.76 × 103\t2.97–9.13 × 103 (per mm3)\t\nLymphocyte\t0.618 × 103\t0.7–3.5 × 103 (per mm3)\t\nHemoglobin\t10.2\t12.9–17.4 (g/dL)\t\nHematocrit\t30.6\t38.6–50.9 (%)\t\nPlatelets\t6.3 × 104\t14.3–33.5 × 104 (per mm3)\t\nTotal protein\t6.8\t6.8–8.3 (g/dL)\t\nAlbumin\t3.0\t4.2–5.1 (g/dL)\t\nBUN\t12\t9–22 (mg/dL)\t\nCreatinine\t0.65\t0.6–1.0 (mg/dL)\t\nNa\t138\t136–145 (mmol/L)\t\nK\t4.0\t3.4–4.5 (mmol/L)\t\nCl\t108\t100–108 (mmol/L)\t\nCRP\t0.11\t0–0.1 (mg/dL)\t\nESR\t40\t2–10 (mm/h)\t\nUrine protein\t(±)\tNegative\t\nUrine ketones\t(-)\tNegative\t\nGlucose (fasting)\t210\t70–110 (mg/dL)\t\nGlucose (postprandial)\t318\t70–140 (mg/dL)\t\nHbA1c\t13.5\t4.6–6.2 (%)\t\nC peptide (fasting)\t5.7\t0.6–1.8 (ng/mL)\t\nC peptide (*postprandial)\t9.6\t0–4.0 (ng/mL)\t\nUrine C peptide\t394.8\t20–155 (μg/day)\t\nC3\t15\t86–160 (mg/dL)\t\nC4\t2.0\t17–45 (mg/dL)\t\nCH50\t<2.0\t29–48 (U/mL)\t\nIgG\t2572\t870–1700 (mg/dL)\t\nIgM\t138\t35–220 (mg/dL)\t\nIgA\t384\t110–410 (mg/dL)\t\nRheumatoid Factor\t1\t0–10 (IU/mL)\t\nAnti-nuclear antibody\t1: 2,560, speckled pattern\t<1:40\t\nAnti-dsDNA antibody\tNegative\t\t\nAnti-Sm antibody\tPositive\t\t\nAnti-SSA antibody\tPositive\t\t\nAnti-SSB antibody\tNegative\t\t\nAnti-Scl-70 antibody\tPositive\t\t\nAnti-RNP antibody\tPositive\t\t\nAnti-Jo1 antibody\tNegative\t\t\nAnti-centromere antibody\tNegative\t\t\nAnti-TG antibody\tNegative\t\t\nAnti-TPO antibody\tPositive\t\t\nAnti-IA2 antibody\tPositive\t\t\nAnti-GAD antibody\tNegative\t\t\nAnti-insulin antibody\tNegative\t\t\nAnti-insulin receptor antibody\tPositive\t\t\nAll data are obtained during intensive insulin therapy.\n\n* Postprandial C peptide were measured 2 h after meal.\n\nHbA1c, glycated hemoglobin; BUN, blood urea nitrogen; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; Ig, immunoglobulin; dsDNA, double stranded DNA; Sm, Smith antigen; SSA, Ro/SSA antigen; SSB, La/SSB antigen; Scl-70, DNA-topoisomerase 1; RNP, ribonucleoprotein; TG, thyroglobulin; TPO, thyroid peroxidase; IA2, insulinoma associated protein; GAD, glutamic acid decarboxylase.\n\nFigure 1 Pre-treatment hyperinsulinemic euglycemic clamp. Hyperinsulinemic euglycemic clamp was applied to assess and quantify the degree of resistance to exogenous insulin. Euglycemia was not attainable due to the presence of severe insulin resistance despite the continuous infusion of intravenous insulin at a maximum dose of 9.0 mU/kg/min. Blood glucose levels (BG, red line) showed a linear decrease that was not completely related to the insulin infusion rate (IIR, green columns).\n\nWe first treated the patient with the anti CD-20 monoclonal antibody rituximab, based on a previous case report6. As rituximab was not approved for use in treating SLE by social health insurance in Japan, written informed consent was obtained from the patient and his family before treatment. The use of rituximab in this treatment protocol was approved by the Ethics Committee of Shinshu University and conformed to the provisions of the Declaration of Helsinki. Rituximab therapy was initiated at a dose of 375 mg/m2 of body surface area as an intravenous infusion once a week for 4 weeks, as previously described6. In addition to rituximab, oral prednisolone (20 mg) was also administered to suppress the immune response (Figure2). Unfortunately, the patient's hyperglycemia worsened following the initiation of treatment, most likely due to the adverse effects of glucocorticoids. In addition, severe subcutaneous bacterial infection of the scrotum occurred, and heavy proteinuria developed. We therefore performed a renal biopsy to establish a definite diagnosis. Renal pathology revealed mildly expanded mesangium regions and strong positive immunostaining of C1q and C3c, suggesting diffuse mesangial proliferative nephritis (class II according to World Health Organization classification).\n\nFigure 2 Schematic illustration of glucose metabolism. Rituximab therapy was initiated at a dose of 375 mg per square meter of body surface area as an intravenous infusion once a week for 4 weeks. Five months after the last rituximab infusion, severe insulin resistance showed no improvement. Anti-insulin receptor antibodies declined to an undetectable level following the addition of cyclosporine.\n\nFollowing treatment of severe infection with broad-spectrum antibiotics, we added cyclosporine (starting dose of 100 mg/day, adjusted to 150 mg/day depending on trough levels) to the prednisolone therapy to increase immunosuppression and treat severe proteinuria. Trough levels of cyclosporine were monitored and maintained between 100 and 150 ng/mL for the induction of cyclosporine, and between 50 and 100 ng/mL thereafter. Surprisingly, a month after the addition of cyclosporine to the treatment regimen, the patient began to experience fasting hypoglycemia. We therefore gradually tapered the dose of insulin. We again attempted to apply a hyperinsulinemic euglycemic clamp to assess the degree of insulin resistance after treatment and obtained a mean glucose infusion rate (M value) of approximately 2.69 mg/kg/min, which suggested that insulin resistance was ameliorated. Since the addition of cyclosporine to oral prednisolone, relatively good glycemic control has been maintained, and anti-insulin receptor antibodies have declined to an undetectable level over approximately 1.5 years (Figure2). However, although the platelet number and the complement levels gradually returned to near-normal levels after the addition of cyclosporine, suggesting a suppression of lupus disease activity, the patient's renal function progressively declined (Figure3), and heavy proteinuria had an insufficient response to immunosuppressive therapy. Indeed, nephrotic proteinuria (>3.5 g/g creatinine) was ameliorated, with protein levels decreased to approximately 2.2 g/g creatinine (mean value during follow up period after the addition of cyclosporine), and this degree of proteinuria was maintained thereafter.\n\nFigure 3 Schematic illustration of renal function and lupus activity. Platelet number (Plt) and complement (C3) level gradually returned to near normal after the addition of cyclosporine, suggesting suppression of lupus disease activity. The renal function of the patient gradually declined over the course of immunosuppressive therapy. Vertical axis indicates a scale of serum creatinine, C3, and platelet number. Normal range is as follows: serum creatinine: 0.63–1.05 mg/dL; C3: 86–160 mg/dL; and platelet number: 14.3–33.3 × 104, respectively. Note that the time scale is different from that of Figure2.\n\nDiscussion\nOur treatment regimen referenced a case report from King's College Hospital in London that cited the successful treatment of type B insulin resistance syndrome with rituximab6. Given that the extreme insulin resistance observed in patients with this syndrome is caused by the presence of anti-insulin receptor antibodies, reducing the antibody titer with rituximab might be a reasonable approach. Nevertheless, in the present case, rituximab therapy was ineffective.\n\nPreviously reported treatments for type B insulin resistance syndrome include recombinant human insulin-like growth factor-1 (IGF-1), plasmapheresis, immunoglobulin G (IgG), and various combinations of immunosuppressants2–4,6–10. Based on more than 30 years of expert experience, Malek et al.3 of the NIH notably advocated the use of combination therapy with rituximab, pulse steroids, and immunosuppressive drugs, including cyclophosphamide, cyclosporine, and azathioprine. In addition, Zhang et al.10 also reported a case that was successfully treated with a combination of intravenous cyclophosphamide, methylprednisolone, and IgG. Unfortunately, these reports of highly efficient protocols for treating type B insulin resistance syndrome with fewer adverse effects were not available when our treatment began in April 2010. However, given that the rarity of this disease prevents researchers from conducting randomized placebo-controlled trials, as discussed by Malek et al.3, identifying the most effective course of treatment is difficult10. In this context, our case report may provide an alternative therapeutic regimen, particularly for use in rituximab-resistant cases.\n\nThe calcineurin inhibitor cyclosporine reduces the transcriptional activation of various inflammatory cytokines. In the present case, the addition of cyclosporine to maintenance glucocorticoid therapy led to remission of insulin resistance. Although some case reports have described the use of cyclosporine in combination with other immunosuppressants3,7,8, we consider the combination of cyclosporine and oral glucocorticoids to be a novel approach. Whether the success of our treatment was due to reinforced immunosuppression or effects specific to cyclosporine remains to be elucidated. Our rituximab therapy aimed to achieve remission not of lupus nephritis but of type B insulin resistance syndrome. Following the addition of cyclosporine, the platelet number and complement level gradually returned to near normal, and the SLEDAI score also improved, suggesting a suppression of lupus disease activity. However, the patient's renal function declined during the course of treatment with immunosuppressants. The degree of proteinuria also decreased somewhat after the treatment, albeit not sufficiently, we speculated that this renal impairment was the additive result of both the nephrotoxicity of cyclosporine and influence of chronic active lupus nephritis. Given that nephrotoxicity is a particular concern in patients receiving long-term cyclosporine therapy, the short-term use of cyclosporine might negate this problem. However, as Malek et al.3 described, whether or not type B insulin resistance syndrome recurs once immunosuppression is terminated is unknown. In addition, whether or not our patient should be on cyclosporine to maintain remission of insulin resistance is also unknown. Further study is needed to identify which patients should be on long-term maintenance immunosuppressive therapy to prevent recurrence.\n\nIn conclusion, although caution is required due to nephrotoxicity, cyclosporine might contribute to remission of type B insulin resistance syndrome associated with SLE in rituximab-resistant cases.\n\nWe thank Suguru Mishina of Nikkiso Co., Ltd., for providing technical assistance with the hyperinsulinemic euglycemic glucose clamp.\n\nDisclosure\nThe authors declare no conflict of interest.\n==== Refs\nReferences\nFlier JS Kahn CR Roth J Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance Science 1975 190 63 65 170678 \nKahn CR Flier JS Bar RS The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man N Engl J Med 1976 294 739 745 176581 \nMalek R Chong AY Lupsa BC Treatment of type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies J Clin Endocrinolo Metab 2010 95 3641 3647 \nArioglu E Andewelt A Diabo C Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective Medicine (Baltimore) 2002 81 87 100 11889410 \nPetri M Orbai AM Alarcón GS Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus Arthritis Rheum 2012 64 2677 2686 22553077 \nColl AP Thomas S Mufti GJ Rituximab therapy for the type B syndrome of severe insulin resistance N Engl J Med 2004 350 310 311 14724317 \nEriksson JW Bremell T Eliasson B Successful treatment with plasmapharesis, cyclophosphamide, and cyclosporine in type B syndrome of insulin resistance Diabetes Care 1998 21 1217 1220 9702422 \nKawashiri SY Kawakami A Fujikawa K Type B insulin resistance complicated with systemic lupus erythematosus Intern Med 2010 49 487 490 20190490 \nTran HA Reeves GE Treatment of type B insulin resistance with immunoglobulin: novel use of an old therapy Med J Aust 2009 190 168 19203327 \nZhang S Wang G Wang J Type B insulin resistance syndrome induced by systemic lupus erythematosus and successfully treated with intravenous immunoglobulin: case report and systematic review Clin Rheumatol 2013 32 181 188 23053690\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2040-1116",
"issue": "6(6)",
"journal": "Journal of diabetes investigation",
"keywords": "Cyclosporine; Systemic lupus erythematosus; Type B insulin resistance syndrome",
"medline_ta": "J Diabetes Investig",
"mesh_terms": null,
"nlm_unique_id": "101520702",
"other_id": null,
"pages": "734-8",
"pmc": null,
"pmid": "26543549",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article",
"references": "9702422;11889410;14724317;20190490;23053690;176581;22553077;20484479;170678;19203327",
"title": "Efficacy of oral glucocorticoid and cyclosporine in a case of rituximab-refractory type B insulin resistance syndrome.",
"title_normalized": "efficacy of oral glucocorticoid and cyclosporine in a case of rituximab refractory type b insulin resistance syndrome"
}
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"abstract": "BACKGROUND Intussusception in adults (AI) accounts for 1% of all cases of bowel obstruction. While pediatric intussusception is well known and almost always idiopathic, an underlying cause is usually found in adults. Indication for surgical treatment and intussusception reduction before resection remain controversial in AI. Here, we present an uncommon case of an immunocompromised patient who had multiple intussusceptions. CASE REPORT A 59-year-old woman, who had received a kidney-pancreas transplant for type 1 diabetes with end-stage renal failure, was admitted to our Intensive Care Unit for septic shock of suspected pulmonary origin. A thoraco-abdominal CT scan demonstrated signs of bilateral pneumonia and multiple abdominal intussusceptions, for which she underwent surgery. Four intestinal intussusceptions were found. Manual desinvagination was performed without bowel resection. After surgery, the patient presented a new bowel obstruction, requiring a second surgery, showing recurrence of 1 intussusception. Segmental resection was indicated, but not performed because of the septic shock, requiring high-dose noradrenalin. The patient progressed toward multi-organ failure, leading to her death a few days later. An autopsy revealed that multiple adenomas were responsible for the intussusceptions. CONCLUSIONS This case confirms that AI is rarely a spontaneous disease and that the therapeutic strategy should be planned accordingly. There is currently no systematic approach for AI, and guidelines are needed to improve its management.",
"affiliations": "Department of Visceral and Transplant Surgery, University Hospital of Geneva, Geneva, Switzerland.;Department of Visceral and Transplant Surgery, University Hospital of Geneva, Geneva, Switzerland.;Department of Visceral and Transplant Surgery, University Hospital of Geneva, Geneva, Switzerland.;Department of Visceral and Transplant Surgery, University Hospital of Geneva, Geneva, Switzerland.",
"authors": "Wassmer|Charles-Henri|CH|;Abbassi|Ziad|Z|;Ris|Frédéric|F|;Berney|Thierry|T|",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3193774910.12659/AJCR.919974919974ArticlesIntussusception in an Immunocompromised Patient: A Case Report and Review of the Literature Wassmer Charles-Henri ABCDEFAbbassi Ziad AERis Frédéric EBerney Thierry DEDepartment of Visceral and Transplant Surgery, University Hospital of Geneva, Geneva, SwitzerlandAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Charles-Henri Wassmer, e-mail: [email protected] 15 1 2020 21 e919974-1 e919974-7 08 9 2019 31 10 2019 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 55-year-old\n\nFinal Diagnosis: Septic shock with multi-organ failure\n\nSymptoms: Respiratory distress\n\nMedication: None\n\nClinical Procedure: Laparotomy\n\nSpecialty: Visceral Surgery\n\nObjective:\nRare disease\n\nBackground:\nIntussusception in adults (AI) accounts for 1% of all cases of bowel obstruction. While pediatric intussusception is well known and almost always idiopathic, an underlying cause is usually found in adults. Indication for surgical treatment and intussusception reduction before resection remain controversial in AI. Here, we present an uncommon case of an immunocompromised patient who had multiple intussusceptions.\n\nCase Report:\nA 59-year-old woman, who had received a kidney-pancreas transplant for type 1 diabetes with end-stage renal failure, was admitted to our Intensive Care Unit for septic shock of suspected pulmonary origin. A thoracoabdominal CT scan demonstrated signs of bilateral pneumonia and multiple abdominal intussusceptions, for which she underwent surgery. Four intestinal intussusceptions were found. Manual desinvagination was performed without bowel resection. After surgery, the patient presented a new bowel obstruction, requiring a second surgery, showing recurrence of 1 intussusception. Segmental resection was indicated, but not performed because of the septic shock, requiring high-dose noradrenalin. The patient progressed toward multi-organ failure, leading to her death a few days later. An autopsy revealed that multiple adenomas were responsible for the intussusceptions.\n\nConclusions:\nThis case confirms that AI is rarely a spontaneous disease and that the therapeutic strategy should be planned accordingly. There is currently no systematic approach for AI, and guidelines are needed to improve its management.\n\nMeSH Keywords:\nAdultImmunosuppressionIntussusception\n==== Body\nBackground\nAdult intussusception (AI) is a rare condition that accounts for 1% to 5% of all cases of bowel obstruction [1–7]. It is defined by the protrusion of a proximal bowel segment with his mesentery (intussusceptum) through the lumen of a distal bowel segment (intussuscipiens), resulting in occlusion [2,6–9]. Prolonged invagination causes edema, which can compromise the blood flow, resulting in ischemia and, if left untreated, necrosis and perforation [2,10].\n\nWhile pediatric intussusception is well known and mostly idiopathic, an underlying cause is found in 90% of adult cases [1–4,6,7,11,12]. Among the underlying lesions, malignancy accounts for 40% to 60% and predominates in the large bowel [4]. Furthermore, the risk of developing malignancies is increased in patients on immunosuppressive therapy [13].\n\nAlthough clinical presentation in children is sudden, with acute symptoms such as abdominal pain, abdominal mass, and bloody mucoid stools (the classical triad), adult presentation can be insidious, with intermittent or even chronic symptoms, which can delay the diagnosis. Symptoms of intestinal obstruction are the most common. Others symptoms such as palpable mass or melena are less common [1,3,4,9,12,14].\n\nThe management of AI is controversial regarding indications for surgery and the necessity or feasibility to reduce the intussusception before a resection. Here, by reporting an uncommon case of an immunocompromised patient who had 4 intussusceptions, and by performing a literature review, we attempt to clarify the management of this disease [15].\n\nCase Report\nA 59-year-old woman was transferred from a peripheral hospital to our Intensive Care Unit for suspected pulmonary septic shock. She had a history of type-1 diabetes with end-stage renal failure, for which she had received a combined kidney-pancreas transplant 20 years ago and a second kidney transplant 7 years ago. She was on a mycophenolate mofetil and tacrolimus immunosuppressive regimen.\n\nAt the time of admission, she had received a 10-day course of intravenous antibiotics, with no clinical improvement. Both kidney and pancreas graft function were optimal, with normal creatinine level and glycemia within normal range. A thoracoabdominal CT scan demonstrated bilateral pleural effusion with signs of bilateral pneumonia and multiple abdominal intussusceptions (Figure 1). Immunosuppressive treatment was discontinued and it was decided to perform an exploratory laparotomy. Free intra-abdominal liquid and 4 sites of intussusception were found at 20, 30, 70 and 150 centimeters up from the ileocecal valve (Figure 2). All 4 intussusception sites presented an intramural lesion. Post-transplant lymphoproliferative disorder was suspected, and a biopsy of one of the lesions was taken. In the absence of bowel ischemia and to avoid extensive bowel resection, only manual desinvagination was performed. Histopathological analysis later revealed a low-grade tubulovillous adenoma.\n\nTwelve days later, the patient presented a new episode of bowel obstruction, with a CT scan showing 1 intussusception. It also demonstrated progression of the pulmonary infection. The patient was taken again to the operating room, and a recurrence of the intussusception at the proximal site was found. Segmental resection was theoretically indicated, but, due to hemodynamic instability secondary to septic shock requiring vasoactive support, it was decided to refrain from respective surgery and to proceed again with a manual reduction of the invagination. Following surgery, the patient showed no clinical improvement. She progressed toward multiple organ failure (MOF) and eventually died 6 days after second surgery. Autopsy revealed multiple tubulovillous adenomas. It also showed massive necrosis of the pancreas graft, with thrombosis of the pancreatic artery. Finally, a pulmonary adenocarcinoma was found in the left lower lobe, with multiple bilateral pulmonary metastases and lymphangitic carcinomatosis.\n\nDiscussion\nEtiology\nAI is an unusual cause of intestinal obstruction. The mean age is 50 years, without a sex predominance [2]. It is the result of an organic cause in up to 90% of cases and idiopathic in about 10% [1,4,16]. It can appear on every part of the gastrointestinal tract, but seems to occur more frequently at the junction between freely moving and retroperitoneally fixed segments or segments fixed by adhesions [2,9,16]. Idiopathic intussusceptions are mostly found in those regions, especially at the ileocecal junction [4,14].\n\nAlthough some studies showed an equal distribution between small and large bowel, a predominance of small bowel intussusception is found (60% to 81%) [1,4,8,12].\n\nA malignant origin is found in about 1/3 of small-bowel intussusceptions and 2/3 of large-bowel intussusceptions [17, 18]. Malignant lesions in the small bowel are usually secondary lesions, while in the large bowel, they are almost always primaries [2].\n\nMany benign or malignant lesions can cause AI. Etiologies are summarized in Figure 3.\n\nClinical presentation and investigation\nIn contrast to children, clinical presentation in adults is generally nonspecific and insidious. Patients usually complain of abdominal pain, constipation, and vomiting, and, less frequently, melena or abdominal mass [7, 18]. In case of malignancy, symptoms like weight loss, asthenia, and hematochezia can also be present [9]. Acute abdominal pain can occur, mostly in case of peritonitis resulting from necrosis and perforation. Finally, intussusception can be asymptomatic and is more frequently discovered with the increasing use of abdominal CT scans.\n\nDiagnosis is rarely made based on patient history and clinical findings. Abdominal ultrasound is a useful tool to diagnose intussusception, especially in children. The characteristic findings include the “target” and “doughnut” signs on the transverse view and the “pseudo-kidney” sign on the lateral view [4,7,18]. Abdominal ultrasound is relatively inexpensive and widely available but operator-dependent, and the presence of air in the distended bowels can lead to difficult interpretation and poor image quality.\n\nCT scan is the most accurate study, with a positive result in 70% to 100% of cases. The classic features are the “target” or “sausage-shaped” sign [1,3,4,7,16,18]. CT scans can identify the precise localization of the intussusception, as well as showing potential intraluminal masses or positive lymph nodes. Free fluid or air and signs of ischemia such as wall thickening and lack of enhancement of the bowel wall can also be easily seen. Radiological studies reported that an intussusception length <4 cm and a diameter <3.2 cm are more likely to resolve with conservative treatment [20,21]. On the contrary, 6 factors were found to be associated with an underlying cause: male sex, colonic involvement, visualization of a pathological lead point, abdominal pain, distal bowel diameter ≥27 mm, and a wall thickness ≥3 mm [22].\n\nManagement\nMany factors influence the management of AI: patient characteristics, age, small versus large bowel, emergency situations versus chronic presentation, and incidental findings.\n\nAlthough treatment by contrast or air insufflation is the treatment of choice in the pediatric population, it is not indicated in adults [6]. Surgery is considered as the primary treatment of AI in symptomatic patients. The surgical approach can be open or minimally invasive, depending on emergency situations, surgeon experience or preference, and localization [6].\n\nIn case of large-bowel intussusception, a surgical approach should be chosen because of the risk of malignancy [7,23]. Depending on the perioperative findings, oncological resection may be performed, and perioperative histology assessment can help in the decision [6]. The intussusception should not be reduced because of the risks of vascular and intra-abdominal tumor cells dissemination and increased risks of perforation or anastomotic complications due to the weakened bowel wall [2,4,6].\n\nThe management of symptomatic small bowel intussusception in adults is more controversial. Patient history, clinical presentation, and radiological findings are essential to make the most appropriate therapeutic decision. In the absence of any sign of complications or in case of an incidental finding, conservative treatment is recommended. A radiological examination must be carried out within 5 to 7 days to ensure resolution of the intussusception. In this case, a low-dose CT scan is the best choice [22].\n\nIf surgery is indicated, patients without any previous surgery should be treated by manual reduction before resection, to minimize the length of the resected segment. In case of multiple intussusceptions, a perioperative biopsy should be performed to identify the etiology and to avoid extensive bowel resection, which can result in a short-bowel syndrome. For example, multiple polyps can be seen in Peutz-Jeghers syndrome and can be responsible for repeated intussusceptions; a combination of polypectomy and limited bowel resection is the best approach in this situation [6].\n\nIn patients with a history of abdominal surgery, a “watch and wait approach” is acceptable since adhesions can cause the intussusception. If symptoms do not resolve spontaneously, surgery is the treatment of choice.\n\nIn all cases, if clinical history and/or radiological findings show signs of complications (e.g., acute abdominal pain, weight loss, asthenia, free intra-abdominal air or fluid, and lack of parietal enhancement), surgery has to be considered. If an oncological etiology is suspected, and if clinical presentation allows it, a complete oncological assessment should be carried out. To help physicians in patient management, we developed a decision tree (Figure 4).\n\nPatients receiving immunosuppressive treatment are at higher risk of developing malignancies. The most common cancers seen in immunosuppressed transplant recipients are non-melanoma skin cancer and non-Hodgkin lymphoma. Several other types of malignancies have higher relative risks. Lung cancer, as seen in the present case, also has a significantly higher incidence in immunosuppressed patients, with a relative risk of 1.4 [24]. Tubulovillous adenomas have not been associated with immunosuppressive treatment, but have the potential to progress to adenocarcinoma in the colon [25].\n\nIn the present case, we faced multiple intussusceptions in an immunocompromised patient. In the absence of ischemia, because the patient was in severe sepsis with a high risk of anastomotic leakage, and in view of the length of intestine involved, bowel resection was avoided. The histological assessment performed perioperatively showed no sign of malignancy but did show several adenomas. The patient had a recurrence, but because of her general condition, resection and anastomosis would have been too risky. The most likely cause of death was the pulmonary insufficiency on bilateral pneumonia and the advanced lung cancer. The autopsy also showed necrosis of the pancreatic graft with thrombosis of the artery. Despite this discovery, the patient had preserved pancreatic graft function, and, notably, no exogenous insulin treatment was required. This was most probably the result of the hypercoagulable state secondary to septic shock.\n\nIt is unlikely that the intussusceptions were the reason for MOF; therefore, it is unlikely that a more aggressive approach during the first surgery would have improved the outcome. On the contrary, the poor hemodynamic status of the patient combined with multiple bowel resections/anastomosis would have put the patient at a high risk of complications.\n\nConclusions\nIntussusception is a rare condition in adults, with various clinical presentations. Abdominal CT scan is the imaging modality of choice. There is currently no clinical or scientific evidence indicating a preferred treatment. Therefore, each case should be assessed individually. The presented case confirms that adult intussusception is rarely a spontaneous disease and that the therapeutic strategy should be planned accordingly.\n\nThe authors thank the staff of the Intensive Care Unit of Geneva University Hospital for their help with this case.\n\nDepartment and Institution where work was done\n\nGeneva University Hospital, Geneva, Switzerland\n\nConflict of interest\n\nNone.\n\nFigure 1. Sagittal (A), coronal (B), and transverse (C, D) views of abdominal CT showing the 4 intestinal intussusceptions, marked by black arrows. The classical “doughnut sign” can be seen on the sagittal and transverse views.\n\nFigure 2. Intraoperative photo of the 4 intestinal intussusceptions marked with 4 forceps.\n\nFigure 3. Adult intussusception etiologies.\n\nFigure 4. Proposed decision tree for management of adult patients with intussusception in small and large bowel.\n==== Refs\nReferences:\n1. Azar T Berger DL Adult intussusception Ann Surg 1997 226 2 134 38 9296505 \n2. Marsicovetere P Ivatury SJ White B Holubar SD Intestinal intussusception: Etiology, diagnosis, and treatment Clin Colon Rectal Surg 2017 30 1 30 39 28144210 \n3. Begos DG Sandor A Modlin IM The diagnosis and management of adult intussusception Am J Surg 1997 173 2 88 94 9074370 \n4. Eisen LK Cunningham JD Aufses AH Jr Intussusception in adults: Institutional review J Am Coll Surg 1999 188 4 390 95 10195723 \n5. Lai J Ramai D Murphy T Kasher F Transient adult jejunojejunal intussusception: A case of conservative management vs . surgery Gastroenterology Res 2017 10 6 369 71 29317946 \n6. Potts J Al Samaraee A El-Hakeem A Small bowel intussusception in adults Ann R Coll Surg Engl 2014 96 1 11 14 24417823 \n7. Kim JW Lee BH Park SG Factors predicting malignancy in adult intussusception: An experience in university-affiliated hospitals Asian J Surg 2018 41 1 92 97 28131633 \n8. Marinis A Yiallourou A Samanides L Intussusception of the bowel in adults: A review World J Gastroenterol 2009 15 4 407 11 19152443 \n9. Aydin N Roth A Misra S Surgical versus conservative management of adult intussusception: Case series and review Int J Surg Case Rep 2016 20 142 46 26859872 \n10. Lindor RA Bellolio MF Sadosty AT Adult intussusception: Presentation, management, and outcomes of 148 patients J Emerg Med 2012 43 1 1 6 22244289 \n11. Shenoy S Adult intussusception: A case series and review World J Gastrointest Endosc 2017 9 5 220 27 28572876 \n12. Hanan B Diniz TR da Luz MM Intussusception in adults: A retrospective study Colorectal Dis 2010 12 6 574 78 19486100 \n13. Grulich AE van Leeuwen MT Falster MO Vajdic CM Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: A meta-analysis Lancet 2007 370 9581 59 67 17617273 \n14. Honjo H Mike M Kusanagi H Kano N Adult intussusception: A retrospective review World J Surg 2015 39 1 134 38 25192846 \n15. Wassmer CH Abbassi Z Ris F Berney T Intussusception in an immuno-compromised patient: Case report and review of the literature. ESSR Abstracts Eur Surg Res 2019 60 Suppl. 2 214 \n16. Maghrebi H Makni A Rhaiem R Adult intussusceptions: Clinical presentation, diagnosis and therapeutic management Int J Surg Case Rep 2017 33 163 66 28327421 \n17. Barussaud M Regenet N Briennon X Clinical spectrum and surgical approach of adult intussusceptions: A multicentric study Int J Colorectal Dis 2006 21 8 834 39 15951987 \n18. Renzulli P Candinas D Idiopathic small-bowel intussusception in an adult CMAJ 2010 182 3 E148 19969561 \n19. Zubaidi A Al-Saif F Silverman R Adult intussusception: A retrospective review Dis Colon Rectum 2006 49 10 1546 51 16990978 \n20. Lvoff N Breiman RS Coakley FV Distinguishing features of self-limiting adult small-bowel intussusception identified at CT Radiology 2003 227 1 68 72 12668740 \n21. Rea JD Lockhart ME Yarbrough DE Approach to management of intussusception in adults: A new paradigm in the computed tomography era Am Surg 2007 73 11 1098 105 18092641 \n22. Tan HL Koh YX Taufik M A clinical scoring system to predict the clinical sequelae of computed tomography diagnosed intussusception World J Surg 2018 42 3 682 87 28916884 \n23. Goh BK Quah HM Chow PK Predictive factors of malignancy in adults with intussusception World J Surg 2006 30 7 1300 4 16773257 \n24. Collett D Mumford L Banner NR Comparison of the incidence of malignancy in recipients of different types of organ: A UK Registry audit Am J Transplant 2010 10 8 1889 96 20659094 \n25. Kalimuthu SN Chelliah A Chetty R From traditional serrated adenoma to tubulovillous adenoma and beyond World J Gastrointest Oncol 2016 8 12 805 9 28035250\n\n",
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"mesh_terms": "D000236:Adenoma; D000367:Age Factors; D001344:Autopsy; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007443:Intussusception; D008875:Middle Aged; D009102:Multiple Organ Failure; D011014:Pneumonia; D012772:Shock, Septic",
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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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"reactionmeddraversionpt": "23.0",
"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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},
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] |
{
"abstract": "Opportunistic infection and reactivation of latent infection has been reported with use of monoclonal TNF alpha antibodies used for treatment of severe rheumatoid arthritis. We present a case of peritoneal tuberculosis (TB) causing renal failure secondary to ureteral constriction in a patient who had been treated with infliximab for rheumatoid arthritis. We suggest that physicians should be aware of the increased risk of false negative and false positive TST and IGRA among patients treated with monoclonal TNF alpha antibodies and should regularly look for usual and unusual symptoms of TB in this patient population.",
"affiliations": "Department of Medicine, Maimonides Medical Center , NY , USA .",
"authors": "Sharma|Abhishek|A|;Dubey|Divyanshu|D|;Janga|Kalyan|K|;Greenberg|Sheldon|S|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.3109/0886022X.2014.917389",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0886-022X",
"issue": "36(6)",
"journal": "Renal failure",
"keywords": "Monoclonal TNF alpha antibodies; renal failure; tuberculosis",
"medline_ta": "Ren Fail",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D000069285:Infliximab; D014395:Peritonitis, Tuberculous; D014517:Ureteral Obstruction",
"nlm_unique_id": "8701128",
"other_id": null,
"pages": "948-50",
"pmc": null,
"pmid": "24960622",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of peritoneal TB causing renal failure in a patient with rheumatoid arthritis and initial negative PPD after treatment with infliximab.",
"title_normalized": "a case of peritoneal tb causing renal failure in a patient with rheumatoid arthritis and initial negative ppd after treatment with infliximab"
}
|
[
{
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}
],
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"reaction": [
{
"reactionmeddrapt": "Peritoneal tuberculosis",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ureteric stenosis",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal failure",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "1"
}
],
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},
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"literaturereference": "SHARMA A, DUBEY D, JANGA K, GREENBERG S. A CASE OF PERITONEAL TB CAUSING RENAL FAILURE IN A PATIENT WITH RHEUMATOID ARTHRITIS AND INITIAL NEGATIVE PPD AFTER TREATMENT WITH INFLIXIMAB. RENAL FAILURE 2014;36(6):948-950.",
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"qualification": "1",
"reportercountry": "US"
},
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"receiptdate": "20140819",
"receivedate": "20140709",
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},
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}
] |
{
"abstract": "Cupriavidus gilardii is a rare cause of human infection. We report a muscular abscess on the right thigh caused by this organism in a renal transplant recipient, who had suffered a septic shock associated with an extensive cellulitis caused by Streptococcus pyogenes. The patient was successfully treated with surgical drainage and intravenous ciprofloxacin for 13 days. This is the first time that C. gilardii is isolated from a human abscess. C. gilardii should be considered as a cause of human infection, especially in immunocompromised patients. Infection caused by this organism may be underdiagnosed because the identification is very difficult.",
"affiliations": "Sección de Microbiología, Hospital Universitario de Guadalajara, Guadalajara, Spain. Electronic address: [email protected].;Sección de Microbiología, Hospital Universitario de Guadalajara, Guadalajara, Spain.;Servicio de Bacteriología, Centro Nacional de Microbiología, Majadahonda, Madrid, Spain.;Servicio de Bacteriología, Centro Nacional de Microbiología, Majadahonda, Madrid, Spain.",
"authors": "Tena|Daniel|D|;Losa|Cristina|C|;Medina|María José|MJ|;Sáez-Nieto|Juan Antonio|JA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-8893",
"issue": "79(1)",
"journal": "Diagnostic microbiology and infectious disease",
"keywords": "Cupriavidus gilardii; Cupriavidus species; Immunocompromised patient; Muscular abscess; Renal transplant",
"medline_ta": "Diagn Microbiol Infect Dis",
"mesh_terms": "D000328:Adult; D049921:Cupriavidus; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D016659:Psoas Abscess; D066027:Transplant Recipients",
"nlm_unique_id": "8305899",
"other_id": null,
"pages": "108-10",
"pmc": null,
"pmid": "24582579",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Muscular abscess caused by Cupriavidus gilardii in a renal transplant recipient.",
"title_normalized": "muscular abscess caused by cupriavidus gilardii in a renal transplant recipient"
}
|
[
{
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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": [
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cellulitis streptococcal",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Septic shock",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Muscle abscess",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TENA D, LOSA C, MEDINA MJ, SAEZ-NIETO JA. MUSCULAR ABSCESS CAUSED BY CUPRIAVIDUS GILARDII IN A RENAL TRANSPLANT RECIPIENT.. DIAGN MICROBIOL INFECT DIS.. 2014?79:108-10",
"literaturereference_normalized": "muscular abscess caused by cupriavidus gilardii in a renal transplant recipient",
"qualification": "3",
"reportercountry": "ES"
},
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"receiptdate": "20180125",
"receivedate": "20180125",
"receiver": {
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"receivertype": "6"
},
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"safetyreportid": 14442223,
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},
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"transmissiondate": "20180509"
}
] |
{
"abstract": "Denosumab is a fully human antibody to receptor activator of nuclear factor kappa-B ligand (RANKL), and it is administered every 6 months in women with postmenopausal osteoporosis (PMO) at high risk for fracture. Adverse effects of denosumab include musculoskeletal pain, hypercholesterolaemia, symptomatic hypocalcaemia, osteonecrosis of the jaw and cutaneous events such as angioedema, cellulitis and pustular dermatitis. While the possibility of vasculitis was mentioned in the product Monograph as well as in the WHO Newsletter, this is the first case, to our knowledge, of cytoplasmic-ANCA (c-ANCA) associated vasculitis officially published in the literature. 1 2 The pathogenic mechanisms behind drug-induced vasculitis remain to be defined and appear to be multifactorial. Once suspicion for drug-induced vasculitis arises, the offending agent should be discontinued and immunosuppressive therapy should be initiated according to the severity of organ involvement to inhibit progression to severe, irreversible disease. As new medications continue to be developed, the number of agents causing drug-induced vasculitis is expected to increase.",
"affiliations": "University of Miami Miller School of Medicine at Holy Cross Hospital, Fort Lauderdale, Florida, USA.;University of Miami Miller School of Medicine at Holy Cross Hospital, Fort Lauderdale, Florida, USA.;University of Miami Miller School of Medicine at Holy Cross Hospital, Fort Lauderdale, Florida, USA.;University of Miami Miller School of Medicine at Holy Cross Hospital, Fort Lauderdale, Florida, USA.",
"authors": "Sanchez|Alexandra|A|;Lozier|Matthew|M|;Adkinson|Brian Cody|BC|;Ilaiwy|Amro|A|http://orcid.org/0000-0001-9407-9220",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-228336",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(3)",
"journal": "BMJ case reports",
"keywords": "drug interactions; unwanted effects / adverse reactions; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D005260:Female; D006801:Humans; D015663:Osteoporosis, Postmenopausal",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30826782",
"pubdate": "2019-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22271809;22279412;25935915",
"title": "c-ANCA vasculitis after initiation of denosumab.",
"title_normalized": "c anca vasculitis after initiation of denosumab"
}
|
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},
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"abstract": "BACKGROUND\nDuchenne muscular dystrophy (DMD), which is caused by a mutation/deletion in the dystrophin gene on the X-chromosome, is the most common type of neuromuscular disorder in pediatrics. Skeletal muscle weakness progressively develops in DMD patients and usually leads to respiratory failure in the early adolescent years. Cardiac muscle is frequently affected in DMD patients, which leads to a high burden of cardiomyopathy and heart failure. In the era of improved respiratory care, cardiac deaths are becoming the major cause of mortality in DMD patients.\n\n\nMETHODS\nWe report the case of a 15-year-old boy who presented to the hospital due to recurrent orthopnea for 6 mo and palpitations for 4 mo. He was diagnosed with progressive muscular dystrophy at the age of 3 years and was confined to a wheelchair at 12 years. He was prescribed diuretics and digoxin at the outpatient clinic; however, his symptoms did not resolve. Sacubitril/valsartan was added 1 mo prior to presentation, but he experienced recurrent episodes of palpitations. The electrocardiogram showed atrial tachycardia with a heart rate of 201 bpm, and he was then hospitalized. Hypotension was found following the administration of sacubitril/valsartan tablets; he could not tolerate even a small dose, always developing tachyarrhythmia. His symptoms were relieved after discontinuing sacubitril/valsartan, and his heart rate was controlled by a small dose of metoprolol tartrate and digoxin. Atrial tachycardia spontaneously converted in this patient, and his symptoms attenuated in the following 6 mo, without palpitation episodes.\n\n\nCONCLUSIONS\nBlood pressure should be closely monitored in DMD patients with advanced heart failure when taking sacubitril/valsartan.",
"affiliations": "Department of Cardiology, Zhejiang Provincial Key Laboratory of Cardiovascular Disease Diagnosis and Treatment, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China.;Department of Cardiology, Zhejiang Provincial Key Laboratory of Cardiovascular Disease Diagnosis and Treatment, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China. [email protected].",
"authors": "Li|Jia-Min|JM|;Chen|Han|H|",
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"country": "United States",
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"doi": "10.12998/wjcc.v7.i23.4098",
"fulltext": "\n==== Front\nWorld J Clin CasesWJCCWorld Journal of Clinical Cases2307-8960Baishideng Publishing Group Inc jWJCC.v7.i23.pg409810.12998/wjcc.v7.i23.4098Case ReportRecurrent hypotension induced by sacubitril/valsartan in cardiomyopathy secondary to Duchenne muscular dystrophy: A case report Li Jia-Min Department of Cardiology, Zhejiang Provincial Key Laboratory of Cardiovascular Disease Diagnosis and Treatment, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, ChinaChen Han Department of Cardiology, Zhejiang Provincial Key Laboratory of Cardiovascular Disease Diagnosis and Treatment, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China. [email protected] contributions: Li JM and Chen H were the patient’s physicians; they also reviewed the literature and contributed to drafting the manuscript. Chen H was responsible for revising the manuscript for important intellectual content. All authors issued final approval for the version to be submitted.\n\nSupported by Natural Science Foundation of Zhejiang Province, No. LQ16H020004.\n\nCorresponding author: Han Chen, MD, PhD, Doctor, Department of Cardiology, Zhejiang Provincial Key Laboratory of Cardiovascular Disease Diagnosis and Treatment, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou 310009, Zhejiang Province, China. [email protected]\n\nTelephone: +86-571-87315198 Fax: +86-571-87022776\n\n6 12 2019 6 12 2019 7 23 4098 4105 20 6 2019 17 11 2019 20 11 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.2019This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nDuchenne muscular dystrophy (DMD), which is caused by a mutation/deletion in the dystrophin gene on the X-chromosome, is the most common type of neuromuscular disorder in pediatrics. Skeletal muscle weakness progressively develops in DMD patients and usually leads to respiratory failure in the early adolescent years. Cardiac muscle is frequently affected in DMD patients, which leads to a high burden of cardiomyopathy and heart failure. In the era of improved respiratory care, cardiac deaths are becoming the major cause of mortality in DMD patients.\n\nCASE SUMMARY\nWe report the case of a 15-year-old boy who presented to the hospital due to recurrent orthopnea for 6 mo and palpitations for 4 mo. He was diagnosed with progressive muscular dystrophy at the age of 3 years and was confined to a wheelchair at 12 years. He was prescribed diuretics and digoxin at the outpatient clinic; however, his symptoms did not resolve. Sacubitril/valsartan was added 1 mo prior to presentation, but he experienced recurrent episodes of palpitations. The electrocardiogram showed atrial tachycardia with a heart rate of 201 bpm, and he was then hospitalized. Hypotension was found following the administration of sacubitril/valsartan tablets; he could not tolerate even a small dose, always developing tachyarrhythmia. His symptoms were relieved after discontinuing sacubitril/valsartan, and his heart rate was controlled by a small dose of metoprolol tartrate and digoxin. Atrial tachycardia spontaneously converted in this patient, and his symptoms attenuated in the following 6 mo, without palpitation episodes.\n\nCONCLUSION\nBlood pressure should be closely monitored in DMD patients with advanced heart failure when taking sacubitril/valsartan.\n\nSacubitril/valsartanDuchenne muscular dystrophyHeart failureHypotensionCase report\n==== Body\nCore tip: A 15-year-old boy with Duchenne muscular dystrophy presented to the hospital due to recurrent orthopnea for 6 mo. He was diagnosed with heart failure and was prescribed oral diuretics and digoxin at the outpatient clinic, but his symptoms did not resolve. Sacubitril/valsartan was added to his therapeutic regimen 1 mo before presentation, but resulted in recurrent hypotension and palpitation episodes until discontinuation of this medication. Although sacubitril/valsartan has been shown to be beneficial for heart failure with a reduced ejection fraction, hypotension is a common side effect of this medication, and blood pressure should be closely monitored in Duchenne muscular dystrophy patients with advanced heart failure.\n\nINTRODUCTION\nDuchenne muscular dystrophy (DMD) is the most common congenital neuromuscular disorder in children. As an X-linked recessive disorder, it is caused by a lack of dystrophin, due to a mutation or deletion of one or more exons in the X-chromosome. The prevalence of DMD in newborns ranges from 1.59 to 1.95 in every 10000 live births[1]. Children suffering from DMD usually present with myasthenia, then gradually lose their motor function, and finally develop respiratory failure. In addition to respiratory complications, cardiac muscles can also be affected in DMD patients, leading to a high prevalence of cardiomyopathy and heart failure in this population. Cardiac enlargement and diverse arrhythmia (mostly supraventricular arrhythmia) are frequently found in DMD patients[2,3].\n\nRenin-angiotensin system (RAS) inhibitors, beta-adrenergic blockers (β-blockers) and mineralocorticoid receptor antagonists (MRAs) were considered the cornerstone of heart failure treatment until recently, when their use was rivaled by angiotensin receptor-neprilysin inhibitors (ARNIs)[4]. Sacubitril/valsartan is the first available ARNI on the market, and it inhibits neprilysin, elevates natriuretic peptide levels, dilates blood vessels and promotes urinary sodium excretion. It has been proven to be a potent medication in improving the cardiac performance and prognosis of heart failure patients with reduced ejection fraction[5]. The PARADIGM-HF trial included 8442 heart failure patients with New York Heart Association (NYHA) class II-IV disease, comparing sacubitril/valsartan with the angiotensin-converting enzyme inhibitor (ACEI) enalapril and demonstrated that ARNI reduced mortality and hospitalization more than ACEI in heart failure with reduced ejection fraction (HFrEF) patients[6]. The 2016 AHA/ACC guidelines state that ARNI is recommended for patients with chronic HFrEF to reduce morbidity and mortality[6], and it is also recommended by the European Society of Cardiology with class I recommendation and level B evidence[7]. Nevertheless, the application of ARNI in NYHA class IV patients remains controversial as only 60 patients with baseline NYHA class IV were included in the PARADIGM-HF trial. Severe hypotension/cardiogenic shock was reported in a heart failure patient with NYHA class IV after initiation of ARNI[8]; however, improvements in the NYHA functional class and 6-min walking test were also found in NYHA class IV patients taking ARNI[9,10]. Here, we report a boy with DMD and NYHA class IV disease who suffered recurrent hypotension after taking sacubitril/valsartan.\n\nCASE PRESENTATION\nChief complaints\nA 15-year-old boy presented to the Emergency Department of our hospital complaining of recurrent orthopnea and palpitations.\n\nHistory of present illness\nThe patient started to experience orthopnea 6 mo prior to presentation. The orthopnea episodes recurred with increased frequency, and he started to have palpitation episodes 4 mo prior to presentation. He was prescribed oral diuretics and digoxin at the outpatient clinic, although his symptoms did not resolve. Sacubitril/valsartan was added to his therapeutic regimen 1 mo before presentation; however, the palpitations and orthopnea episodes became even more frequent. Six hours prior to presentation, he experienced persistent palpitations and shortness of breath.\n\nHistory of past illness\nAt the age of 3 years, the patient was found to have significantly elevated serum aspartate aminotransferase (AST) and creatine kinase (CK) levels when he had a check-up for an unknown fever. His peak serum CK level was > 20000 U/L, and gastrocnemius biopsy revealed swelling and dystrophy of the skeletal muscle, with partial replacement of muscle by fat and fibrotic tissue. A clinical diagnosis of muscular dystrophy was established after genetic testing of dystrophin showed a deficiency at exons 48, 49, 50 and 51. He was regularly followed at the children’s hospital and treated with nutrients and steroids; however, the medication did not alter his disease progression. He had difficulty running and developed toe walking 5 years prior to presentation and required hand assistance to push himself into an upright position when arising from the floor (termed the Gower’s sign) 4 years previously. In the past 3 years, he has been completely confined to a wheelchair. Although lasting for no more than 2 min, he experienced chest tightness several times in the past 3 years, especially when he developed a cold or became tired.\n\nPersonal and family history\nThe patient’s mother gave birth to him at the age of 36 years. The patient learned to walk at 15 mo, and his language development was consistent with his peers. The patient’s mother was proven to be the carrier of the dystrophin gene defects.\n\nPhysical examination upon admission\nThe patient’s body temperature was 37.4°C, heart rate was 202 bpm, respiratory rate was 19 breaths per minute and blood pressure was 97/78 mmHg. The breath sounds were normal, and no wheeze or rales were heard in both lungs. The heart rhythm was irregular, and no obvious murmurs were auscultated. On percussion, the cardiac borders were enlarged on both sides. The muscle strength of the upper extremities was grade 4 at the distal part and grade 2 at the proximal part, while the muscle strength of the lower extremities was grade 0, with apparent gastrocnemius hypertrophy.\n\nLaboratory examinations\nThe patient’s laboratory findings revealed a serum CK level of 3374 U/L, CK-MB level of 75 U/L and cardiac troponin I (cTnI) level of 0.168 ng/mL. The alanine aminotransferase level was 245 U/L, the AST level was 170 U/L, and the creatinine level was 16 μmol/L.\n\nImaging examinations\nElectrocardiograms recorded in the Emergency Department revealed a fast heart rate (Figure 1) in the form of atrial tachycardia with Wenckebach block, and the patient was then hospitalized for further observation and treatment. Echocardiogram (Figure 2) and cardiac magnetic resonance images (Figure 3) are shown below.\n\nFigure 1 Electrocardiogram recorded at the Emergency Department. The electrocardiogram shows atrial tachycardia with Wenckebach block, Q waves in leads I, V5 and V6, and large R waves in leads V1 and V2.\n\nFigure 2 Echocardiogram of the patient. A: Parasternal long axis view; B: Apical four-chamber view. Whole heart enlargement with cardiac dysfunction was found with mild mitral regurgitation, mild to moderate tricuspid regurgitation and moderate pulmonary hypertension (PASP = 51 mmHg). The left ventricular ejection fraction was 23% as calculated using Simpson’s Formula.\n\nFigure 3 Cardiac magnetic resonance imaging of the patient. A, B: Long-axis view of the heart, in diastole (A) and systole (B); C, D: With late gadolinium enhancement imaging, the short-axis view (C) and long-axis view (D) demonstrated multi-segmental abnormal enhancement at lateral, anterolateral and part of the inferior wall of the left ventricle.\n\nFINAL DIAGNOSIS\nThe final diagnosis of the presented case was DMD, dilated cardiomyopathy, NYHA class IV disease, and atrial tachycardia with Wenckebach block.\n\nTREATMENT\nSacubitril/valsartan was stopped due to recurrent hypotension. Intravenous cedilanid (lanatoside C) 0.2 mg and oral metoprolol tartrate 6.25 mg twice daily were introduced to control the ventricular rate. Within 2 h of admission, the patient felt relief of his symptoms, and an electrocardiogram showed that he was in sinus rhythm (Figure 4) with a heart rate of 113 bpm. The dosage of metoprolol tartrate was increased to 6.25 mg every 8 h for better rate control. However, the patient was intolerant of metoprolol tartrate due to hypotensive episodes. Oral administration of amiodarone 0.2 g once daily controlled the heart rhythm.\n\nFigure 4 Electrocardiogram at the time of symptom relief. Electrocardiogram shows sinus rhythm, right heart hypertrophy, Q waves in leads I, V5 and V6, and large R waves in leads V1 and V2.\n\nOUTCOME AND FOLLOW-UP\nThe patient was observed in the hospital for 5 d and maintained sinus rhythm before discharge. He was still intolerant of sacubitril/valsartan and metoprolol tartrate after several attempts, ending in hypotension. He remained in sinus rhythm and was free from orthopnea and palpitations at the 6-month follow-up, with oral administration of amiodarone, which had been reduced to 0.1 g once daily 2 mo after discharge.\n\nDISCUSSION\nDystrophin, a protein encoded by the dystrophin gene on chromosome Xp21.1, is located in skeletal muscle and cardiac muscle cells and connects membrane elements with the cytoskeleton[11]. A deficiency of dystrophin leads to DMD and Becker muscular dystrophy, as well as X-linked dilated cardiomyopathy[12,13]. Although the distribution and regulatory mechanism of dystrophin have been extensively studied in skeletal muscle cells, the physiological role of dystrophin in cardiac muscle has not been fully elucidated. Clinical observation has revealed a high incidence of cardiac involvement in patients with muscular dystrophy. Dilated cardiomyopathy, arrhythmias and congestive heart failure are commonly found in DMD patients, and end-stage heart failure is becoming the main cause of death in the DMD population[14,15]. Early diagnosis of cardiac impairment is challenging in these patients because they usually lose their ambulatory capacity in the early adolescent years, and symptoms of cardiac insufficiency such as shortness of breath might also be mixed with symptoms of respiratory failure, which makes the early detection of cardiac dysfunction even more difficult.\n\nRAS inhibitors, including ACEI and angiotensin receptor blockers (ARBs), β-blockers and MRAs, have been proven to reverse left ventricular remodeling and improve the outcome of patients with systolic heart failure. However, there are limited data on the effects of these medications in DMD patients with heart failure. Ogata et al[16] studied the combination of ACEI and β-blockers in a cohort of 52 DMD patients who had begun treatment for heart failure, and these medications showed beneficial effects on the long-term survival of DMD patients with left ventricular dysfunction[16]. However, Blain et al tested the combination of ACEI and β-blockers in an mdx mouse model of DMD and found that these medications did not confer any advantage in DMD cardiomyopathy. El-Aloul et al[17] summarized the studies on pharmacological therapy for the prevention and management of cardiomyopathy in DMD patients and found modest improvements in LV systolic dysfunction on either monotherapy or combination therapy with ACEI, ARB or β-blockers. However, data regarding the optimal pharmacological regimens for delaying the onset of cardiomyopathy in DMD patients and when to initiate therapy to prevent or treat heart failure are largely insufficient and lacking[17].\n\nThe ARNI sacubitril/valsartan, which has been tested in the PARADIGM-HF Trial (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), is the state-of-the-art medication for heart failure treatment[18]. Sacubitril/valsartan is the only available ARNI on the market. The substantial improvement by ARNI compared to ACEI, in addition to optimal treatment, results in a class I guideline recommendation for patients with chronic HFrEF to reduce morbidity and mortality[6]. The idea of administering ARNIs in DMD patients with heart failure seems appealing, but we must consider that teenagers under 18 years and patients with symptomatic hypotension were excluded from the PARADIGM-HF Trial, which might be the usual case among the DMD population. In addition, patients with NYHA class II accounted for approximately 70% of all the participants in the PARADIGM-HF Trial, while patients with NYHA class IV accounted for less than 1% of those in the PARADIGM-HF Trial, and most of the DMD patients were not suitable for cardiac function evaluation according to the NYHA criteria based on their loss of ambulation. Although the guidelines of the United States and Europe recommend the administration of sacubitril/valsartan in NYHA class II-IV patients, analysis of real-world eligibility data suggests that only 20%-40% of HFrEF patients will be eligible for sacubitril/valsartan initiation based on current guidelines[19]. ARNIs inhibit the RAS and enhance the activity of natriuretic peptides and bradykinin, thus demonstrating an effect on lowering blood pressure[20]. As predicted, hypotension was more prevalent in patients with sacubitril/valsartan than with enalapril in the PARADIGM-HF Trial[21]. During the run-in stage of the PARADIGM-HF Trial, baseline low blood pressure, low estimated glomerular filtration rate, and higher N-terminal pro-brain natriuretic peptide levels were associated with a higher risk for noncompletion. However, it was reported that patients with lower systolic blood pressure (SBP) at randomization were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP[22]. It is debatable whether hypotension is beneficial or detrimental to cardiac output and organ perfusion, but it will always be important for us to monitor blood pressure during the uptitration period of sacubitril/valsartan in heart failure patients with reduced ejection fraction. Hsiao et al[23] reported a case with prolonged first-dose hypotension induced by sacubitril/valsartan. In this case, the patient experienced recurrent intolerable hypotension episodes shortly after taking sacubitril/valsartan, even with a quarter of a 50-mg (sacubitril 24 mg/valsartan 26 mg) tablet. This might be related to the poor cardiac reserve in this patient and implies a more advanced stage than we thought in this particular population with heart failure.\n\nCheeran et al[24] studied the predictors of death in adults with DMD-associated cardiomyopathy, and found that a lower body mass index, a lower maximum inspiratory pressure and an elevated NT-proBNP level were risk factors for a poorer outcome. Early intervention for cardiac dysfunction in DMD patients, especially at the time of preserved ejection fraction, might postpone the process of left ventricular remodeling and improve the cardiac outcomes in these patients. A recent multicenter, randomized double-blind placebo-controlled study reported the effect and safety of combined treatment with an ACEI and a β-blocker in a German cohort of DMD patients with preserved left ventricular function. Thirty-eight patients from 10 sites were centrally randomized into the intervention group (combined treatment with enalapril and metoprolol) and a placebo control group. The results showed that the administration of ACEI and β-blocker delayed the progression of intrinsic cardiomyopathy to left ventricular failure in DMD patients with preserved left ventricular function, although this did not reach statistical significance[25]. Further studies should be conducted to determine the effect of ARNIs in DMD patients with preserved left ventricular function.\n\nCONCLUSION\nIt is challenging to evaluate cardiac function in heart failure patients with DMD according to the NYHA criteria, mainly due to their limited ambulatory capacity. Although clinical trials have revealed that sacubitril/valsartan greatly improve cardiac performance in patients with reduced heart failure, hypotension is a common side effect of this medication. We hereby advise close monitoring of blood pressure after sacubitril/valsartan administration in severe DMD patients with heart failure. Further studies on the administration of sacubitril/valsartan in DMD patients with reduced or preserved left ventricular ejection fraction are of crucial importance.\n\nInformed consent statement: Informed written consent was obtained from the patient and families for publication of this report and any accompanying images.\n\nConflict-of-interest statement: The authors declare no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have carefully read the CARE Checklist (2016), and the manuscript was prepared according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: June 26, 2019\n\nFirst decision: November 12, 2019\n\nArticle in press: November 20, 2019\n\nSpecialty type: Medicine, Research and Experimental\n\nCountry of origin: China\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B, B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Bamoshmoosh M, Pastromas S, Ueda H S-Editor: Dou Y L-Editor: Webster JR E-Editor: Wu YXJ\n==== Refs\n1 Ryder S Leadley RM Armstrong N Westwood M de Kock S Butt T Jain M Kleijnen J The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review Orphanet J Rare Dis 2017 12 79 28446219 \n2 Perloff JK Cardiac rhythm and conduction in Duchenne's muscular dystrophy: a prospective study of 20 patients J Am Coll Cardiol 1984 3 1263 1268 6707378 \n3 Villa CR Czosek RJ Ahmed H Khoury PR Anderson JB Knilans TK Jefferies JL Wong B Spar DS Ambulatory Monitoring and Arrhythmic Outcomes in Pediatric and Adolescent Patients With Duchenne Muscular Dystrophy J Am Heart Assoc 2015 5 \n4 Docherty KF McMurray JJV Angiotensin receptor-neprilysin inhibitors: A new paradigm in heart failure with reduced ejection fraction Int J Cardiol 2019 281 179 185 29891240 \n5 Krittanawong C Kitai T Pharmacogenomics of angiotensin receptor/neprilysin inhibitor and its long-term side effects Cardiovasc Ther 2017 35 \n6 Yancy CW Jessup M Bozkurt B Butler J Casey DE Jr Colvin MM Drazner MH Filippatos G Fonarow GC Givertz MM Hollenberg SM Lindenfeld J Masoudi FA McBride PE Peterson PN Stevenson LW Westlake C 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America J Am Coll Cardiol 2016 68 1476 1488 27216111 \n7 Ponikowski P Voors AA Anker SD Bueno H Cleland JG Coats AJ Falk V González-Juanatey JR Harjola VP Jankowska EA Jessup M Linde C Nihoyannopoulos P Parissis JT Pieske B Riley JP Rosano GM Ruilope LM Ruschitzka F Rutten FH van der Meer P Authors/Task Force Members; Document Reviewers 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC Eur J Heart Fail 2016 18 891 975 27207191 \n8 Rawal HA Kocheril AG Sacubitril/Valsartanstive Heart Failure: Cardiogenic Shock Case Rep Cardiol 2018 2018 8231576 29862089 \n9 Rodil Fraile R Malafarina V Tiberio López G Sacubitril-valsartan in heart failure and multimorbidity patients ESC Heart Fail 2018 5 956 959 30039930 \n10 Beltrán P Palau P Domínguez E Faraudo M Núñez E Guri O Mollar A Sanchis J Bayés-Genís A Núñez J Sacubitril/valsartan and short-term changes in the 6-minute walk test: A pilot study Int J Cardiol 2018 252 136 139 29249422 \n11 Fayssoil A Abasse S Silverston K Cardiac Involvement Classification and Therapeutic Management in Patients with Duchenne Muscular Dystrophy J Neuromuscul Dis 2017 4 17 23 28269790 \n12 Koenig M Beggs AH Moyer M Scherpf S Heindrich K Bettecken T Meng G Müller CR Lindlöf M Kaariainen H de la Chapellet A Kiuru A Savontaus ML Gilgenkrantz H Récan D Chelly J Kaplan JC Covone AE Archidiacono N Romeo G Liechti-Gailati S Schneider V Braga S Moser H Darras BT Murphy P Francke U Chen JD Morgan G Denton M Greenberg CR Wrogemann K Blonden LA van Paassen MB van Ommen GJ Kunkel LM The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion Am J Hum Genet 1989 45 498 506 2491009 \n13 Towbin JA Hejtmancik JF Brink P Gelb B Zhu XM Chamberlain JS McCabe ER Swift M X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus Circulation 1993 87 1854 1865 8504498 \n14 Kamdar F Garry DJ Dystrophin-Deficient Cardiomyopathy J Am Coll Cardiol 2016 67 2533 2546 27230049 \n15 D'Amario D Amodeo A Adorisio R Tiziano FD Leone AM Perri G Bruno P Massetti M Ferlini A Pane M Niccoli G Porto I D'Angelo GA Borovac JA Mercuri E Crea F A current approach to heart failure in Duchenne muscular dystrophy Heart 2017 103 1770 1779 28668906 \n16 Ogata H Ishikawa Y Ishikawa Y Minami R Beneficial effects of beta-blockers and angiotensin-converting enzyme inhibitors in Duchenne muscular dystrophy J Cardiol 2009 53 72 78 19167641 \n17 El-Aloul B Altamirano-Diaz L Zapata-Aldana E Rodrigues R Malvankar-Mehta MS Nguyen CT Campbell C Pharmacological therapy for the prevention and management of cardiomyopathy in Duchenne muscular dystrophy: A systematic review Neuromuscul Disord 2017 27 4 14 27815032 \n18 McMurray JJ Packer M Desai AS Gong J Lefkowitz MP Rizkala AR Rouleau JL Shi VC Solomon SD Swedberg K Zile MR PARADIGM-HF Investigators and Committees Angiotensin-neprilysin inhibition versus enalapril in heart failure N Engl J Med 2014 371 993 1004 25176015 \n19 Yandrapalli S Andries G Biswas M Khera S Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives Vasc Health Risk Manag 2017 13 369 382 29042791 \n20 Bruno RM Taddei S Sacubitril/valsartan and low blood pressure in heart failure with reduced ejection fraction Eur Heart J 2017 38 1144 1146 28158388 \n21 Vardeny O Claggett B Kachadourian J Pearson SM Desai AS Packer M Rouleau J Zile MR Swedberg K Lefkowitz M Shi V McMurray JJV Solomon SD Incidence, Predictors, and Outcomes Associated With Hypotensive Episodes Among Heart Failure Patients Receiving Sacubitril/Valsartan or Enalapril: The PARADIGM-HF Trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) Circ Heart Fail 2018 11 e004745 29643067 \n22 Böhm M Young R Jhund PS Solomon SD Gong J Lefkowitz MP Rizkala AR Rouleau JL Shi VC Swedberg K Zile MR Packer M McMurray JJV Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF Eur Heart J 2017 38 1132 1143 28158398 \n23 Hsiao FC Chu PH Prolonged First-Dose Hypotension Induced by Sacubitril/Valsartan Acta Cardiol Sin 2018 34 96 98 29375230 \n24 Cheeran D Khan S Khera R Bhatt A Garg S Grodin JL Morlend R Araj FG Amin AA Thibodeau JT Das S Drazner MH Mammen PPA Predictors of Death in Adults With Duchenne Muscular Dystrophy-Associated Cardiomyopathy J Am Heart Assoc 2017 6 \n25 Dittrich S Graf E Trollmann R Neudorf U Schara U Heilmann A von der Hagen M Stiller B Kirschner J Pozza RD Müller-Felber W Weiss K von Au K Khalil M Motz R Korenke C Lange M Wilichowski E Pattathu J Ebinger F Wiechmann N Schröder R German Competence Network for Congenital Heart Defects and the Treat-NMD Neuromuscular Network Investigators list of additional local Investigators and co-workers of the German Competence Network for Congenital Heart Defects and the Treat-NMD Neuromuscular Network Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial Orphanet J Rare Dis 2019 14 105 31077250\n\n",
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"keywords": "Case report; Duchenne muscular dystrophy; Heart failure; Hypotension; Sacubitril/valsartan",
"medline_ta": "World J Clin Cases",
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"pages": "4098-4105",
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"references": "8504498;29891240;28269790;30039930;27815032;28158398;2491009;28489317;19167641;27207191;26722125;29042427;29862089;29042791;31077250;27216111;27230049;29249422;25176015;29643067;28446219;6707378;28668906;29375230;28158388",
"title": "Recurrent hypotension induced by sacubitril/valsartan in cardiomyopathy secondary to Duchenne muscular dystrophy: A case report.",
"title_normalized": "recurrent hypotension induced by sacubitril valsartan in cardiomyopathy secondary to duchenne muscular dystrophy a case report"
}
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"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DIGOXIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": "209261",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ORTHOPNOEA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "1",
"drugrecurrence": [
{
"drugrecuraction": "Hypotension"
}
],
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "26",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VALSARTAN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SACUBITRIL"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ORTHOPNOEA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "1",
"drugrecurrence": [
{
"drugrecuraction": "Hypotension"
}
],
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "24",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SACUBITRIL"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": "209261",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PALPITATIONS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "1",
"drugrecurrence": [
{
"drugrecuraction": "Hypotension"
}
],
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VALSARTAN."
}
],
"patientagegroup": null,
"patientonsetage": "15",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Tachyarrhythmia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Atrial tachycardia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Palpitations",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHEN H, LI J. RECURRENT HYPOTENSION INDUCED BY SACUBITRIL/VALSARTAN IN CARDIOMYOPATHY SECONDARY TO DUCHENNE MUSCULAR DYSTROPHY: A CASE REPORT. WORLD J CLIN CASES. 2019 DEC 06?7(3):4098-105. DOI:10.12998/WJCC.V7.I23.4098",
"literaturereference_normalized": "recurrent hypotension induced by sacubitril valsartan in cardiomyopathy secondary to duchenne muscular dystrophy a case report",
"qualification": "1",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20200206",
"receivedate": "20200206",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17374473,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200409"
}
] |
{
"abstract": "Although foam sclerotherapy to varicose veins is now a popular treatment because of its high efficacy and safety, some neurologic complications have recently been reported. Presently, the effectiveness and safety of intravenous recombinant tissue-type plasminogen activator therapy to stroke following foam sclerotherapy remain unclear. Here, we report the case of a 68-year-old woman whose ischemic symptoms following foam sclerotherapy were treated by intravenous recombinant tissue-type plasminogen activator. After she was admitted, the venous thrombosis in her right soleus vein and a patent foramen ovale causing the right-to-left shunt were revealed. Thus, we diagnosed the ischemic symptoms were due to paradoxical embolism following foam sclerotherapy. After intravenous recombinant tissue-type plasminogen activator therapy, there was no complication and the outcome was good. Our case suggests the effectiveness and the safety of intravenous recombinant tissue-type plasminogen activator therapy to paradoxical embolism following foam sclerotherapy.",
"affiliations": "Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan. Electronic address: [email protected].;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.;Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.",
"authors": "Matsuzono|Kosuke|K|;Arai|Naoto|N|;Suzuki|Masayuki|M|;Kim|Younhee|Y|;Ozawa|Tadashi|T|;Mashiko|Takafumi|T|;Shimazaki|Haruo|H|;Koide|Reiji|R|;Matsuura|Tohru|T|;Fujimoto|Shigeru|S|",
"chemical_list": "D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D012597:Sclerosing Solutions; D000077423:Polidocanol; D011092:Polyethylene Glycols; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2018.01.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "27(6)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "paradoxical embolism; patent foramen ovale; polidocanol; rt-PA; sclerotherapy",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D019320:Embolism, Paradoxical; D005260:Female; D005343:Fibrinolytic Agents; D054092:Foramen Ovale, Patent; D006801:Humans; D000077423:Polidocanol; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012597:Sclerosing Solutions; D015911:Sclerotherapy; D020521:Stroke; D010959:Tissue Plasminogen Activator; D014648:Varicose Veins; D020246:Venous Thrombosis",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "e110-e112",
"pmc": null,
"pmid": "29402614",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tissue Plasminogen Activator to Treat a Stroke after Foam Sclerotherapy in a Woman with a Patent Foramen Ovale.",
"title_normalized": "tissue plasminogen activator to treat a stroke after foam sclerotherapy in a woman with a patent foramen ovale"
}
|
[
{
"companynumb": "JP-MERZ NORTH AMERICA, INC.-17MRZ-00311",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EZETIMIBE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "EZETIMIBE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "POLIDOCANOL"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "021201",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION",
"drugdosagetext": "SEVEN SESSIONS OF TREATMENT",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "VARICOSE VEIN",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ASCLERA"
}
],
"patientagegroup": null,
"patientonsetage": "68",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hypoaesthesia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Venous thrombosis limb",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Paradoxical embolism",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cerebral infarction",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Decreased nasolabial fold",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201704"
}
},
"primarysource": {
"literaturereference": "MATSUZONO K. TISSUE PLASMINOGEN ACTIVATOR TO TREAT A STROKE AFTER FOAM SCLEROTHERAPY IN A WOMAN WITH A PATENT FORAMEN OVALE.. JOURNAL OF STROKE AND CEREBROVASCULAR DISEASES, 2018. 2018?.",
"literaturereference_normalized": "tissue plasminogen activator to treat a stroke after foam sclerotherapy in a woman with a patent foramen ovale",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "DE",
"receiptdate": "20180223",
"receivedate": "20171019",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14109225,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180508"
}
] |
{
"abstract": "BACKGROUND\nTo evaluate the efficacy and toxicity of irinotecan and oxaliplatin plus 5-fluorouracil (FU) and leucovorin (FOLFIRINOX) as second-line therapy in metastatic pancreatic adenocarcinoma (MPA).\n\n\nMETHODS\nWe retrospectively analyzed the medical records of 27 patients with MPA treated with FOLFIRINOX as second-line therapy between January 2003 and November 2009 in our hospital. The recommended schedule was oxaliplatin 85 mg/m(2) on day 1 + irinotecan 180 mg/m(2) on day 1 + leucovorin 400 mg/m(2) on day 1 followed by FU 400 mg/m(2) as a bolus on day 1 and 2,400 mg/m(2) as 46-hour continuous infusion biweekly.\n\n\nRESULTS\nThe median age of the 27 patients (13 males and 14 females) was 63 years (45-83). All patients had progressive disease after first-line chemotherapy by gemcitabine. A total of 167 cycles were administered, with a median number of 6 cycles (1-29) per patient. One toxic death occurred (sepsis). Tolerance of treatment was acceptable, and the relative dose density delivered per patient was 92.8% for oxaliplatin, 89.1% for irinotecan and 96.4% for FU. Grade 3-4 neutropenia occurred in 55.6% of the patients, including 1 febrile neutropenia. The other toxicities were manageable. Regarding efficacy, 22 of the 27 patients were evaluable (WHO and RECIST criteria). Five patients had partial responses and 12 stable disease, resulting in an overall disease control rate of 63%. Median time to progression was 5.4 months (0.7-25.48), and median event-free survival was 3 months (0.5-24.9). Median overall survival was 8.5 months (0-26). A clinical benefit was reported for 55% of the patients.\n\n\nCONCLUSIONS\nThese results confirmed the good safety profile and the efficacy of the FOLFIRINOX regimen as second-line treatment of MPA.",
"affiliations": "Department of Medical Oncology, Centre Hospitalier Universitaire, Groupe Hospitalier Henri Mondor-Albert Chenevier, Assistance Publique-Hôpitaux de Paris et Université Paris XII, 51 Avenue du Maréchal de Lattre de Tassigny, Créteil, France. [email protected]",
"authors": "Assaf|Elias|E|;Verlinde-Carvalho|Muriel|M|;Delbaldo|Catherine|C|;Grenier|Julien|J|;Sellam|Zineb|Z|;Pouessel|Damien|D|;Bouaita|Linda|L|;Baumgaertner|Isabelle|I|;Sobhani|Iradj|I|;Tayar|Claude|C|;Paul|Muriel|M|;Culine|Stéphane|S|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000077146:Irinotecan; C056507:gemcitabine; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000329803",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "80(5-6)",
"journal": "Oncology",
"keywords": null,
"medline_ta": "Oncology",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D017024:Chemotherapy, Adjuvant; D003841:Deoxycytidine; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D012189:Retrospective Studies; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "301-6",
"pmc": null,
"pmid": "21778770",
"pubdate": "2011",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "5-fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma.",
"title_normalized": "5 fluorouracil leucovorin combined with irinotecan and oxaliplatin folfirinox as second line chemotherapy in patients with metastatic pancreatic adenocarcinoma"
}
|
[
{
"companynumb": "FR-CIPLA LTD.-2016FR08930",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INFUSION",
"drugdosagetext": "85 MG/M2, ON DAY 1, 2 HOUR INFUSION",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "85",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "OXALIPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INFUSION",
"drugdosagetext": "180 MG/M2, ON DAY 1, 90 MINUTE INFUSION, 1 HOUR AFTER END OF OXALIPLATIN INFUSION",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "180",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IRINOTECAN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"drugadministrationroute": "040",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INFUSION",
"drugdosagetext": "400 MG/M2, ON DAY 1, AFTER IRINOTECAN INFUSION",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "400",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUOROURACIL."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INFUSION",
"drugdosagetext": "2400 MG/M2, AS A 46 HOUR CONTINUOS INFUSION BIWEEKLY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "2400",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUOROURACIL."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATROPINE"
},
"drugadditional": "3",
"drugadministrationroute": "058",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "0.25 MG, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CHOLINERGIC SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": ".25",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ATROPINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "GEMCITABINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "400 MG/M2, ON DAY 1, 2 HOUR INFUSION",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PANCREATIC CARCINOMA METASTATIC",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "400",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEUCOVORIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Disease progression",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neuropathy peripheral",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
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{
"abstract": "Fungal infections have an important role in organ transplant recipients, and in some cases can be lethal. Blastomycosis is rare in kidney transplantation. We present a case of cutaneous blastomycosis in a kidney transplant recipient in Tunisia, a country outside the known endemic countries. This case, with the very uncommon and unexpected diagnosis of blastomycosis, demonstrates the diversity of infections in transplant recipients and reflects the importance of histologic and serologic tests in the immunocompromised patient.",
"affiliations": "Department of Nephrology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia.;Department of Nephrology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia. Electronic address: [email protected].;Department of Dermatology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia.;Department of Nephrology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia.;Department of Nephrology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia.;Department of Pathology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia.;Department of Nephrology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia.;Department of Pathology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia.;Department of Nephrology, Fattouma Bourguiba Hospital, Monastir, Tunisia; University Faculty of Medicine, Monastir, Tunisia.",
"authors": "Ben Salem|M|M|;Hamouda|M|M|;Mohamed|M|M|;Aloui|S|S|;Letaief|A|A|;Moussa|A|A|;Skhiri|H|H|;Zakahama|A|A|;Ben Dhia|N|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.06.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "49(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D001758:Blastomyces; D001759:Blastomycosis; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D008297:Male; D011183:Postoperative Complications; D014416:Tunisia",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1583-1586",
"pmc": null,
"pmid": "28838445",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Blastomyces dermatitidis in a Renal Transplant Recipient: A Case Report.",
"title_normalized": "blastomyces dermatitidis in a renal transplant recipient a case report"
}
|
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"drugstartdateformat": null,
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "44",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Blastomycosis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BEN SALEM M, HAMOUDA M, MOHAMED M, ALOUI S ET. AL.. BLASTOMYCES DERMATITIDIS IN A RENAL TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2017?49(7):1583-1586",
"literaturereference_normalized": "blastomyces dermatitidis in a renal transplant recipient a case report",
"qualification": "1",
"reportercountry": "TN"
},
"primarysourcecountry": "TN",
"receiptdate": "20190102",
"receivedate": "20190102",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15780978,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "TN-ACCORD-058990",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "065416",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MYCOPHENOLIC ACID."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "091195",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "2",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "44",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Blastomycosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BEN SALEM M, HAMOUDA M, MOHAMED M, ALOUI S, LETAIEF A, MOUSSA A ET AL. BLASTOMYCES DERMATITIDIS IN A RENAL TRANSPLANT RECIPIENT: A CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2017;49(7):1583-1586.",
"literaturereference_normalized": "blastomyces dermatitidis in a renal transplant recipient a case report",
"qualification": "1",
"reportercountry": "TN"
},
"primarysourcecountry": "TN",
"receiptdate": "20170928",
"receivedate": "20170928",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14018989,
"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": "To examine indications for, duration of use, and rate of adverse drug events (ADE) attributable to anticonvulsant initiation, as adjudicated by expert review of electronic health records (EHR) of older adults.\n\n\n\nWe identified a cohort of community dwelling Medicare beneficiaries with linked EHR (aged 65+, continuously enrolled with a large health system/until death between 2012 and 2014, n = 20 945) and drew a stratified EHR review sample (n = 1534). An expert reviewed all records to adjudicate anticonvulsant use, years of use, indication for use, and evidence of ADEs attributable to anticonvulsant initiation. After excluding patients with insufficient EHR data (n = 37; 2%), we reconstructed the cohort using inverse probability weights to resemble the original cohort of eligible beneficiaries (n = 20 380). Among incident users of a single anticonvulsant, we estimated the rate of ADEs and described the type and severity of ADEs.\n\n\n\nOverall, 12% (n = 2469) of eligible beneficiaries used at least one anticonvulsant in the 2012 to 2014 period (4% [n = 757] incident users, 8% [n = 1712] prevalent users). Incident users were most frequently prescribed gabapentin (n = 461/757, 61%), benzodiazepines (n = 122/757, 16%), and levetiracetam (n = 74/757, 10%); the most common indication was pain relief (n = 214; 28%) followed by epilepsy (n = 53; 7%). Among incident users, the overall ADE rate was 10/100 person-years (95% CI 4-20/100 person-years), of which 29% (n = 28/97) were life threatening (eg, somnolence). Most ADEs among incident monotherapy users were nervous system related (68%, n = 66/97).\n\n\n\nMany older adult community dwelling traditional Medicare beneficiaries had clinically significant ADEs likely attributable to the initiation of anticonvulsant therapy, which was begun for a range of indications.",
"affiliations": "Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.;Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts.;Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.;Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts.",
"authors": "Moura|Lidia M V R|LMVR|0000-0002-1191-1315;Smith|Jason R|JR|0000-0001-9764-5849;Yan|Zhiyu|Z|;Blacker|Deborah|D|;Schwamm|Lee H|LH|;Newhouse|Joseph P|JP|;Hernandez-Diaz|Sonia|S|0000-0003-1458-7642;Hsu|John|J|",
"chemical_list": "D000927:Anticonvulsants",
"country": "England",
"delete": false,
"doi": "10.1002/pds.5139",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-8569",
"issue": "30(1)",
"journal": "Pharmacoepidemiology and drug safety",
"keywords": "Aged, anticonvulsants, neurology, outcome assessment, patient safety",
"medline_ta": "Pharmacoepidemiol Drug Saf",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D004827:Epilepsy; D006801:Humans; D006278:Medicare; D014481:United States",
"nlm_unique_id": "9208369",
"other_id": null,
"pages": "28-36",
"pmc": null,
"pmid": "33009718",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19679449;30762723;9846778;1971862;28276060;15955935;15824914;20690786;26953296;19800848;21533517;14511391;22810319;10403221;20840443;21632214;12199723;25684224;26529160;16848658;21904096;28276062;25955736;30564781;22507695;24575970;26850976;19802824;10908898;16207524;22544296;27552848;31185130;25556909;16682577",
"title": "Patterns of anticonvulsant use and adverse drug events in older adults.",
"title_normalized": "patterns of anticonvulsant use and adverse drug events in older adults"
}
|
[
{
"companynumb": "US-UCBSA-2020041841",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "EPILEPSY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVETIRACETAM."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "OFF LABEL USE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVETIRACETAM."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adverse event",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MOURA LMVR, SMITH JR, YAN Z, BLACKER D, SCHWAMM LH, NEWHOUSE JP, ET AL. PATTERNS OF ANTICONVULSANT USE AND ADVERSE DRUG EVENTS IN OLDER ADULTS. PHARMACOEPIDEMIOL DRUG SAF. 2020",
"literaturereference_normalized": "patterns of anticonvulsant use and adverse drug events in older adults",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20201023",
"receivedate": "20201023",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 18419226,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210114"
}
] |
{
"abstract": "Liver transplant is now considered to be a successful treatment modality for early hepatocellular carcinoma. In addition, advances in immunosuppressive therapy have greatly prolonged posttransplant survival of patients with hepatocellular carcinoma. However, both the posttransplant physiologic condition and immunosuppressive therapy affect the patient's natural immunity, resulting in accumulating and more problematic complications. Three years after a male patient with hepatocellular carcinoma underwent living-donor liver transplant, he presented with esophageal metastasis from recurrence of hepatocellular carcinoma. This is an extremely rare complication, perhaps with an ominous prognosis, and, to the best of our knowledge, the first such case to be published in the English literature.",
"affiliations": "From the Department of Thoracic Surgery, China Medical University Hospital, Taichung, Taiwan and the School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.",
"authors": "Chen|Jian-Xun|JX|;Jeng|Long-Bin|LB|;Lin|Yu-Sen|YS|;Lu|Ting-Yu|TY|;Kao|Pei-Yu|PY|;Fang|Hsin-Yuan|HY|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2014.0179",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "14(5)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D006528:Carcinoma, Hepatocellular; D016099:Endoscopy, Gastrointestinal; D004938:Esophageal Neoplasms; D017809:Fatal Outcome; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D009364:Neoplasm Recurrence, Local; D049268:Positron-Emission Tomography; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "571-574",
"pmc": null,
"pmid": "26325233",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Mimicking Esophageal Cancer After Liver Transplant for Hepatocellular Carcinoma: A Rare Posttransplant Metastasis.",
"title_normalized": "a mimicking esophageal cancer after liver transplant for hepatocellular carcinoma a rare posttransplant metastasis"
}
|
[
{
"companynumb": "TW-MYLANLABS-2016M1053006",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "090596",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1MG EVERY 12 HOURS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hepatocellular carcinoma",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Metastases to oesophagus",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHEN J-X, JENG L-B, LIN Y-S, LU T-Y, KAO P-Y, FANG H-Y. A MIMICKING ESOPHAGEAL CANCER AFTER LIVER TRANSPLANT FOR HEPATOCELLULAR CARCINOMA: A RARE POSTTRANSPLANT METASTASIS. EXP-CLIN-TRANSPLANT 2016;14(5):571-574.",
"literaturereference_normalized": "a mimicking esophageal cancer after liver transplant for hepatocellular carcinoma a rare posttransplant metastasis",
"qualification": "3",
"reportercountry": "TW"
},
"primarysourcecountry": "TW",
"receiptdate": "20161207",
"receivedate": "20161207",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13007198,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170207"
}
] |
{
"abstract": "OBJECTIVE\nTo investigate the efficacy and toxicity of bortezomib of different doses in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma (MM).\n\n\nMETHODS\n23 patients with relapsed or refractory MM, 10 males and 13 females, aged 65 (42-86), were randomized to 2 groups: low dose group receiving intravenous 1.0 mg/m2 bortezomib (n=10) on days 1, 4, 6, and 11 (twice weekly) combined with dexamethasone 20 mg/d on days 1-4, with 3 weeks as a course of treatment, and (20 standard dose group: receiving intravenous 1.3 mg/m2 bortezomib (n=13) combined with dexamethasone. The patients were followed up for 9.5 (3-15) months. The effect was determined using modified European Group for Blood and Marrow Transplantation (EBMT) criteria.\n\n\nRESULTS\nThe complete response (CR) + partial response (PR) rate of the 1.0 mg/m2 bortezomib group was 70.0%, not significantly different from that of the 1.3 mg/m2 bortezomib group (61.5%, P > 0.05). The relief rate (CR + near CR rate) of the 1.0 mg/m2 bortezomib group was 20.0% not significantly different from that of the 1.3 mg/m2 bortezomib group (38.5%, P > 0.05). Only 1 case of adverse event over the grade 3 of National Cancer Institute Common Terminology Criteria for Adverse Events occurred in the 1.3 mg/m2 bortezomib group. Five cases of infectious fever and 2 cases of treatment-associated death occurred in the 1.3 mg/m2 bortezomib group.\n\n\nCONCLUSIONS\nBortezomib at the dose of 1.3 mg/m2 is more effective in treatment of relapsed or refractory MM than that at the dose of 1.3 mg/m2 and has more side effects.",
"affiliations": "Institute of Hematology of People's Hospital, Peking University, Beijing 100044, China.",
"authors": "Bao|Li|L|;Lu|Xi-jing|XJ|;Zhang|Xiao-hui|XH|;Huang|Xiao-jun|XJ|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0376-2491",
"issue": "88(26)",
"journal": "Zhonghua yi xue za zhi",
"keywords": null,
"medline_ta": "Zhonghua Yi Xue Za Zhi",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D003907:Dexamethasone; D003967:Diarrhea; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005221:Fatigue; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D011446:Prospective Studies; D011719:Pyrazines; D016896:Treatment Outcome",
"nlm_unique_id": "7511141",
"other_id": null,
"pages": "1829-31",
"pmc": null,
"pmid": "19040018",
"pubdate": "2008-07-08",
"publication_types": "D003160:Comparative Study; D004740:English Abstract; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effects of bortezomib at different doses in combination with dexamethasone in treatment of relapsed or refractory multiple myeloma: a comparative study.",
"title_normalized": "effects of bortezomib at different doses in combination with dexamethasone in treatment of relapsed or refractory multiple myeloma a comparative study"
}
|
[
{
"companynumb": "CN-TAKEDA-2016MPI007723",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "021602",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "1.3 MG/M2, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PLASMA CELL MYELOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1.3",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VELCADE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "40 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PLASMA CELL MYELOMA",
"drugintervaldosagedefinition": "804",
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"abstract": "BACKGROUND\nWhen opportunistic infections occur, patients with inflammatory bowel disease (IBD) commonly display a significantly increased rate of morbidity and mortality. With increasing use of immunosuppressive agents and biological agents, opportunistic infections are becoming a hot topic in the perspective of drug safety in IBD patients. Despite the well-established role of opportunistic infections in the prognosis of IBD patients, there are few epidemiological data investigating the incidence of opportunis-tic infections in IBD patients in China. Besides, the risk factors for opportunistic infection in Chinese IBD patients remain unclear.\n\n\nOBJECTIVE\nTo predict the incidence of opportunistic infections related to IBD in China, and explore the risk factors for opportunistic infections.\n\n\nMETHODS\nA single-center, prospective study of IBD patients was conducted. The patients were followed for up to 12 mo to calculate the incidence of infections. For each infected IBD patient, two non-infected IBD patients were selected as controls. A conditional logistic regression analysis was used to assess associations between putative risk factors and opportunistic infections, which are represented as odds ratios (OR) and 95% confidence intervals (CIs).\n\n\nRESULTS\nSeventy (28.11%) out of 249 IBD patients developed opportunistic infections. Clostridium difficile infections and respiratory syncytial virus infections were found in 24 and 16 patients, respectively. In a univariate analysis, factors such as the severity of IBD, use of an immunosuppressant or immunosuppressants, high levels of fecal calprotectin, and C-reactive protein or erythrocyte sedimentation rate were individually related to a significantly increased risk of opportunistic infection. Multivariate analysis indicated that the use of any immunosuppressant yielded an OR of 3.247 (95%CI: 1.128-9.341), whereas the use of any two immunosuppressants yielded an OR of 6.457 (95%CI: 1.726-24.152) for opportunistic infection. Interestingly, when immunosuppressants were used in combination with infliximab (IFX) or 5-aminosalicylic acid, a significantly increased risk of opportunistic infection was also observed. The relative risk of opportunistic infection was greatest in IBD patients with severe disease activity (OR = 9.090; 95%CI: 1.532-53.941, relative to the remission stage). However, the use of IFX alone did not increase the risk of opportunistic infection.\n\n\nCONCLUSIONS\nFactors such as severe IBD, elevated levels of fecal calprotectin, and the use of immunosuppressive medications, especially when used in combination, are major risk factors for opportunistic infections in IBD patients. The use of IFX alone does not increase the risk of opportunistic infection.",
"affiliations": "Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China.;Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China. [email protected].;Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China.;Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China.;Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China.",
"authors": "Gong|Shan-Shan|SS|;Fan|Yi-Hong|YH|;Han|Qing-Qing|QQ|;Lv|Bin|B|;Xu|Yi|Y|",
"chemical_list": "D007166:Immunosuppressive Agents; D039841:Leukocyte L1 Antigen Complex; D019804:Mesalamine; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v25.i18.2240",
"fulltext": "\n==== Front\nWorld J GastroenterolWorld J. GastroenterolWJGWorld Journal of Gastroenterology1007-93272219-2840Baishideng Publishing Group Inc jWJG.v25.i18.pg224010.3748/wjg.v25.i18.2240Observational StudyNested case-control study on risk factors for opportunistic infections in patients with inflammatory bowel disease Gong Shan-Shan Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, ChinaFan Yi-Hong Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China. [email protected] Qing-Qing Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, ChinaLv Bin Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, ChinaXu Yi Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, ChinaAuthor contributions: Gong SS conducted clinical observation, analyzed the data, and wrote the paper; Fan YH designed the research and revised the paper; Han QQ collected the data; Xu Y and Lv B conducted literature search and provided valuable suggestions for this study; all authors have read and approved the final manuscript.\n\nSupported by: National Natural Science Foundation of China, No. 81473506; Natural Science Foundation of Zhejiang Province, No. LY16H290001 and No. LY17H290009; Project of Department of Construction of Zhejiang Province, No. WKJ-ZJ-1531; and Zhejiang TCM Science and Technology Project, No. 2016ZB047 and No. 2017ZA056.\n\nCorresponding author: Yi-Hong Fan, MD, PhD, Associate Professor, Chief Doctor, Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, No. 54, Youdian Road, Shangcheng District, Hangzhou 310006, Zhejiang Province, China. [email protected]\n\nTelephone: +86-571-87608001 Fax: +86-571-87608001\n\n14 5 2019 14 5 2019 25 18 2240 2250 22 2 2019 11 3 2019 29 3 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.2019This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nWhen opportunistic infections occur, patients with inflammatory bowel disease (IBD) commonly display a significantly increased rate of morbidity and mortality. With increasing use of immunosuppressive agents and biological agents, opportunistic infections are becoming a hot topic in the perspective of drug safety in IBD patients. Despite the well-established role of opportunistic infections in the prognosis of IBD patients, there are few epidemiological data investigating the incidence of opportunis-tic infections in IBD patients in China. Besides, the risk factors for opportunistic infection in Chinese IBD patients remain unclear.\n\nAIM\nTo predict the incidence of opportunistic infections related to IBD in China, and explore the risk factors for opportunistic infections.\n\nMETHODS\nA single-center, prospective study of IBD patients was conducted. The patients were followed for up to 12 mo to calculate the incidence of infections. For each infected IBD patient, two non-infected IBD patients were selected as controls. A conditional logistic regression analysis was used to assess associations between putative risk factors and opportunistic infections, which are represented as odds ratios (OR) and 95% confidence intervals (CIs).\n\nRESULTS\nSeventy (28.11%) out of 249 IBD patients developed opportunistic infections. Clostridium difficile infections and respiratory syncytial virus infections were found in 24 and 16 patients, respectively. In a univariate analysis, factors such as the severity of IBD, use of an immunosuppressant or immunosuppressants, high levels of fecal calprotectin, and C-reactive protein or erythrocyte sedimentation rate were individually related to a significantly increased risk of opportunistic infection. Multivariate analysis indicated that the use of any immunosuppressant yielded an OR of 3.247 (95%CI: 1.128-9.341), whereas the use of any two immunosuppressants yielded an OR of 6.457 (95%CI: 1.726-24.152) for opportunistic infection. Interestingly, when immunosuppressants were used in combination with infliximab (IFX) or 5-aminosalicylic acid, a significantly increased risk of opportunistic infection was also observed. The relative risk of opportunistic infection was greatest in IBD patients with severe disease activity (OR = 9.090; 95%CI: 1.532-53.941, relative to the remission stage). However, the use of IFX alone did not increase the risk of opportunistic infection.\n\nCONCLUSION\nFactors such as severe IBD, elevated levels of fecal calprotectin, and the use of immunosuppressive medications, especially when used in combination, are major risk factors for opportunistic infections in IBD patients. The use of IFX alone does not increase the risk of opportunistic infection.\n\nNested case-control studyOpportunistic infectionsInflammatory bowel disease\n==== Body\nCore tip: When opportunistic infections occur, patients with inflammatory bowel disease (IBD) commonly display a significantly increased rate of morbidity and mortality. With increasing use of immunosuppressive agents and biological agents, opportunistic infections are becoming a hot topic in the perspective of drug safety in IBD patients. Despite the well-established role of opportunistic infections in the prognosis of IBD patients, there are few epidemiological data investigating the incidence of opportunistic infections in IBD patients in China. Besides, the risk factors for opportunistic infections in Chinese IBD patients remain unclear.\n\nINTRODUCTION\nOpportunistic infection refers to any infection caused by a weakened immune system and typically does not occur in people with normal immune function[1]. When they occur, patients presenting with opportunistic infections commonly display a significantly increased rate of morbidity and mortality. With increasing use of immunosuppressive agents and biological agents, opportunistic infections are becoming a hot topic in the perspective of drug safety in patients with inflammatory bowel disease (IBD). Studies have shown that opportunistic infections are closely related to the recurrence of IBD[2,3]. Severe opportunistic infection was observed in 3% of IBD patients, significantly increasing their mortality[4]. According to the consensus of The European Crohn’s and Colitis Organization on opportunistic infections in IBD, IBD patients taking glucocorticoids, immunomodulators, and biologic therapies are all at an increased risk of opportunistic infection. Malnutrition and old age are also key risk factors for opportunistic infections[5]. A multicenter prospective study conducted in Japan followed 570 patients with IBD for one year and observed 52 (9.1%) cases of opportunistic infection. Further analysis found that being over 50 years of age and the use of immunosuppressive agents are contributing risk factors for opportunistic infections in patients with IBD[6]. A study conducted by Tourner et al[7] also concluded that immunosuppressive medications and increased patient age are related with an increased risk of opportunistic infections in IBD patients. On the other hand, positive prevention, early diagnosis, and timely control of opportunistic infections are the current focuses for improving the prognosis of IBD patients.\n\nDespite the well-established role of opportunistic infections in the prognosis of IBD patients, there are few epidemiological data investigating the incidence of opportunistic infections in IBD patients in China. The level of fecal calprotectin (FC) is a commonly used diagnostic measure for patients with IBD as its levels generally increase in patients with IBD. It is generally accepted that FC levels are a stable and reliable measure of IBD severity with a high sensitivity and specificity. However, the relationship between FC levels and the incidence of opportunistic infections in IBD has never been studied.\n\nTherefore, this study sought to investigate the relationship between IBD and opportunistic infections from a cohort of patients with IBD using a nested case-control method. Specifically, we sought to predict the incidence of oppor-tunistic infections in patients with IBD in China, and determine the relationship between FC and opportunistic infection, with an aim to provide a scientific basis for the effective prevention and control of opportunistic infections in patients with IBD.\n\nMATERIALS AND METHODS\nResearch design and patient groups\nThis study involving 301 IBD patients [139 with ulcerative colitis (UC) and 162 with Crohn’s disease (CD)] enrolled from January to December 2017. The probability of an opportunistic infection was calculated during a one-year follow-up period. Common opportunistic infections in patients with IBD include viral infections (herpes viruses, human papillomavirus, influenza virus, and JC virus), bacterial infections (tuberculosis, nocardia, Clostridium difficile, pneumococcus, legionella, and listeriosis), fungal infections (histoplasmosis, cryptococcosis, Pneumocystis jirovecii infection, aspergillosis, and candidiasis), and parasite infections (Strongyloides stercoralis)[8]. Patients were screened for opportunistic infection before enrollment to exclude those currently infected. Infection was based on laboratory results, in which viral IgM positivity and DNA copy were diagnosed as viral infection. The diagnosis of tuberculosis was based on the detection of Tubercle bacillus. Clostridium difficile was detected by PCR. Positive fecal cultures of mold and candida were diagnosed as fungal infections. Clinical visits were conducted once a month. Clinical follow-up and laboratory examinations [including routine blood examination, C-reactive protein (CRP), hepatic and renal function, FC, infection indicators, etc.] were conducted once a month. In addition, disease activity was assessed at each follow-up. Truelove and Witts disease severity classification criteria[9] and CD activity index (CDAI)[10] were used to evaluate the disease activity of patients with UC and CD, respectively. These diagnoses and disease activity index were admitted by the attending physician.\n\nThis study was approved by the ethics committee of First Affiliated Hospital of Zhejiang Chinese Medical University, and patients under the age of 16 were admitted to our study with the consent from their parents or guardians.\n\nCase-control study\nIBD patients with opportunistic infections were selected as the case group. For each case, two uninfected patients were chosen as controls and were matched according to age (at an interval of 10 years; ≤ 19, 20-29, 30-39,40-49, and ≥ 50 years).\n\nData collection\nThe demographic characteristics of patients were collected, including age, gender, course of the disease, current smoking habits, previous bowel surgery, comorbidity, disease activity, the type of IBD, and current medications. All patients were diagnosed with UC or CD based on the previously criteria[11].\n\nStatistical analysis\nDemographic characteristics were analyzed by the t-test. The univariate and multivariate analyses were performed with SPSS version 23 (SPSS, Tokyo, Japan).\n\nRESULTS\nIBD patients’ demographic and clinical features\nA total of 301 IBD patients were enrolled in this study, 52 of whom were lost to follow-up. Of the remaining 249 patients, 119 had UC and 130 had CD. The patients’ ages ranged from 12 to 78 years (mean age, 45.24 years). During one year of follow-up, we found 70 IBD patients who developed an opportunistic infection (Table 1). The incidence of opportunistic infections was 28.11%. Clostridium difficile infection was found to be the most common opportunistic infection in patients with IBD (9.64%), followed by respiratory syncytial virus infection (6.43%). Fifteen (6.02%) and eleven (4.42%) patients were infected with Epstein-Barr virus and Fungal, respectively. One patient developed active tuberculosis.\n\nTable 1 Opportunistic infections in inflammatory bowel disease patients evaluated between January 1, 2017 and December 31, 2018\n\nOrganism\tNumber of UC patients\tNumber of CD patients\t\nMycobacterium tuberculosis\t1\t0\t\nEpstein-Barr virus\t10\t5\t\nCytomegalovirus\t3\t1\t\nHepatotropic virus\t0\t1\t\nClostridium difficile\t11\t13\t\nAdenovirus\t0\t3\t\nSyncytial virus\t5\t11\t\nCoxsaccie virus\t1\t2\t\nHerpes simplex virus\t3\t2\t\nHerpes zoster\t0\t1\t\nMold\t6\t3\t\nCandida albicans\t2\t0\t\nStreptococcus\t1\t2\t\nThree patients were co-infected with Epstein-Barr virus (EBV) and respiratory syncytial virus (S virus). Two patients were co-infected with EBV and mold. One patient was co-infected with EBV and Clostridium difficile (CDI). One patient was co-infected with EBV and cytomegalovirus (CMV). One patient was co-infected with EBV and herpes simplex virus (HSV). One patient was co-infected with EBV, S virus, and Coxsaccie virus (C virus). One patient was co-infected with mold and CDI. One patient was co-infected with adenovirus and S virus. One patient was co-infected with adenovirus and C virus. One patient was co-infected with CDI and C virus. One patient was co-infected with CDI and S virus. One patient was co-infected with CDI, mold, and Streptococcus. UC: Ulcerative colitis; CD: Crohn’s disease.\n\nThere were 70 patients in the case group, including 33 UC patients and 37 CD patients. In contrast, the control group consisted of 140 patients, including 66 UC patients and 74 CD patients. Selected demographic and clinical characteristics of cases and controls are provided in Table 2. There were no statistically significant differences between the two groups in age, gender, type of IBD, duration of IBD, duration of medication use, prior surgery or smoking history. The data of the two groups were well balanced and comparable.\n\nTable 2 Demographic and clinical features of inflammatory bowel disease patients with (cases) and without (controls) opportunistic infection\n\n\tCases (n = 70)\tControls (n = 140)\tP-value\t\nMedian age\t45.67 ± 15.79\t44.13 ± 14.21\t0.45\t\nGender\t\t\t0.11\t\nMale\t39\t89\t\t\nFemale\t31\t51\t\nType of IBD\t\t\t0.82\t\nUC\t33\t66\t\t\nProctitis\t4\t24\t\nLeft-sided\t7\t15\t\nExtensive\t22\t27\t\nCD\t37\t74\t\nIleitis (L1)\t9\t23\t\nColitis (L2)\t6\t3\t\nIleocolitis (L3)\t17\t26\t\nUpper gastrointestinal tract (L4)\t1\t4\t\nL1 + L4\t0\t5\t\nL2 + L4\t0\t2\t\nL3 + L4\t4\t11\t\nDuration of IBD (yr)\t6.42 ± 6.01\t5.12 ± 4.04\t0.28\t\nDuration of medication (yr)\t2.73 ± 2.02\t2.54 ± 2.11\t0.71\t\nPrior surgery\t25\t41\t0.31\t\nSmoking\t2\t13\t0.11\t\nL1; Ileitis; L2: Colitis; L3: Ileocolitis; L4: Upper gastrointestinal tract; IBD: Inflammatory bowel disease; UC: Ulcerative colitis; CD: Crohn’s disease.\n\nSevere disease activity is a risk factor for opportunistic infections in IBD patients\nPatients’ gender, age, type of IBD, duration of medication, course of the disease, history of prior surgery, and smoking habits were not related to increased risk of opportunistic infections, according to the univariate analysis. However, severe disease activity in IBD patients was related to an increased rate of opportunistic infections (P < 0.001, OR = 18.404; 95%CI: 3.833-88.375). Multivariate analysis also indicated that severe IBD was the greatest risk factor for opportunistic infections (P < 0.001, OR = 18.404; 95%CI: 3.833-88.375).\n\nElevated level of FC is a risk factor for opportunistic infections in IBD patients\nIn our study, FC higher than normal levels (>200 µg/g) was related to an increased risk of opportunistic infections both in our univariate analysis (P < 0.001, OR = 4.431; 95%CI: 2.265-8.667) and multivariate analysis (P = 0.023, OR = 2.467; 95%CI: 1.133-5.373).\n\nImmunosuppressive medications, especially when used in combination, are risk factors for opportunistic infections in IBD patients\nCompared with the use of 5-aminosalicylic acid (5-ASA), the use of infliximab (IFX) or 5-ASA+ IFX was not related to the incidence of opportunistic infections in our univariate analysis (Table 3) and multivariate analysis. On the contrary, the use of any immunosuppressant (steroids, azathioprine, tacrolimus, thalidomide, or methotrexate) was related to a significantly increased odd for opportunistic infection, compared with the use of 5-ASA both in univariate analysis (P < 0.047, OR = 2.668; 95%CI: 1.012-7.033) (Table 3) and multivariate analysis (P = 0.029, OR = 3.235; 95%CI: 1.125-9.306) (Figure 1). Especially when two or more immunosuppressants were used in combination, it represented the second largest risk factor for opportunistic infections in both univariate analysis (P < 0.001, OR = 10.375; 95%CI: 2.948-36.508) (Table 3) and multivariate analysis (P = 0.006, OR = 6.462; 95%CI: 1.727-24.172) (Figure 1). In addition, the use of 5-ASA and any immunosuppressant(s) or IFX with any immunosuppressant(s) was related to significantly increased infection rates both in univariate analysis (P < 0.01) (Table 3) and multivariate analysis (P < 0.05) (Figure 1).\n\nFigure 1 Risk factors for opportunistic infection in inflammatory bowel disease patients (multivariate analysis). 5-ASA: 5-aminosalicylic acid; IS: Immunosuppressant (steroids, thiopurine, thalidomide, tacrolimus, or methotrexate); FC: Fecal calprotectin; CRP: C-reaction protein; ESR: Erythrocyte sedimentation rate; ULN: Upper limit of normal; CI: Confidence interval. P-values and 95% confidence intervals (CIs) for mild, moderate, and severe disease were compared with remission. P-values and 95%CIs for any immunosuppressant (IS), any two IS, infliximab, 5-aminosalicylic acid (5-ASA) + any IS, and infliximab + any IS were compared with 5-ASA.\n\nTable 3 Risk factors for opportunistic infection in inflammatory bowel disease patients (univariate analysis)\n\n\tCases (n = 70)\tControls (n = 140)\tP-value\tOdds ratio\t95%CI\t\nDisease activity\t\t\t\t\t\t\nRemission\t25\t85\tReference\t\nMildly active\t20\t40\t0.145\t1.673\t0.837-3.345\t\nModerate\t14\t13\t0.004\t3.604\t1.505-8.626\t\nSevere\t11\t2\t<0.001\t18.404\t3.833-88.375\t\nTreatment\t\t\t\t\t\t\n5-ASA\t20\t83\tReference\t\nAny IS\t8\t12\t0.047\t2.668\t1.012-7.033\t\nAny two IS\t10\t4\t<0.001\t10.375\t2.948-36.508\t\nInfliximab\t13\t24\t0.109\t1.992\t0.857-4.632\t\n5-ASA + any IS\t11\t9\t0.002\t5.072\t1.853-13.887\t\nInfliximab + any IS\t9\t7\t0.003\t5.336\t1.773-16.058\t\nFC > ULN\t57\t69\t<0.001\t4.431\t2.265-8.667\t\nCRP > ULN\t26\t18\t<0.001\t3.98\t1.994-7.944\t\nESR > ULN\t25\t18\t<0.001\t3.744\t1.87-7.494\t\n5-ASA: 5-aminosalicylic acid; IS: Immunosuppressant (steroids, thiopurine, thalidomide, tacrolimus, or methotrexate); FC: Fecal calprotectin; CRP: C-reaction protein; ESR: Erythrocyte sedimentation rate; ULN: Upper limit of normal; CI: Confidence interval.\n\nHigh levels of CRP and erythrocyte sedimentation rate (ESR) are not related to a significantly increased risk of opportunistic infection\nOur univariate analysis showed that high levels of CRP (OR = 3.98; 95%CI: 1.994-7.944) and ESR (OR = 3.744; 95%CI: 1.87-7.494) were related to an increased risk of opportunistic infections (Table 3). However, the results of multivariate analysis did not confirm this finding (Figure 1).\n\nDISCUSSION\nIn our study, we prospectively predicted the occurrence of opportunistic infections in IBD patients. A total of 70 (28.11%) of the 249 patients developed opportunistic infections. Currently, there are few epidemiological data on the rate of opportunistic infection in IBD patients in China. In a study performed at Ruijin Hospital affiliated to Shanghai Jiao Tong University, of 130 patients with IBD, 12.3% developed CD infection[12]. In another study, positive serum IgG for cytomegalovirus (CMV) was found in 73% of UC patients in Wuhan, China and 89% of CD patients, and the rate in the healthy population was 50.69%[13]. Data from Peking Union Medical College Hospital indicated that the CMV infection rate in UC patients undergoing surgical operations was 46.2%[14], compared to 36.7% among refractory UC patients in Tianjin[15]. A multicenter prospective study conducted in Japan included 570 IBD patients who were followed for one year, and the authors observed 52 cases (9.1%) of opportunistic infection[7]. Separately, a national study in France found that the incidence of opportunistic infections in IBD patients was 7.9% after five years of follow-up[16]. The high incidence of opportunistic infection in IBD patients in China may be related to the level of economic development and the abuse of antibiotics. In most regions of China, expensive biological agents are not covered by medical insurance, which limits their extensive use in China. However, most immunosuppre-ssants, such as steroids and azathioprine, are cheap and are accepted by the majority of IBD patients. China is known to be one of the countries with the worst rates of antibiotic abuse in the world. It is estimated that China produced 248000 tons of antibiotics in 2013[17], and the per capita consumption of antibiotics was 10 times that of the United States[18]. The direct consequence of abuse of antibiotics is widespread bacterial drug resistance, which results in an increased rate and severity of opportunistic infections.\n\nInfection with Clostridium difficile, an anaerobic, gram-positive bacillus, is the most common nosocomial infection which was most commonly observed in the IBD patients in our study (9.64%). IBD patients are at an increased risk for infection with Clostridium difficile[19-23]. Compared with those with IBD alone, patients with Clostridium difficile and IBD had longer hospital stay, requiring colon surgery intervention[24,25]. The use of antibiotics is closely related to Clostridium difficile associated diarrhea. Antimicrobials may disrupt the normal gastrointestinal flora, leading decreased colonization resistance and allowing toxigenic strains of Clostridium difficile to cause diseases. The abuse of antibiotics in China is serious. In addition, IBD patients are often treated with antibiotics for IBD deterioration or immunosuppressive complications, so Clostridium difficile infection can easily occur. Clostridium difficile is an increasing problem in immunocompromised patients, which can lead to higher rates of colectomy and mortality[26]. Clostridium difficile infection initiates with disruption of normal colonic microbiota, for which IBD patients are at high risk, conferring them an additional risk of Clostridium difficile infection[27,28]. In our pooled analysis, Clostridium difficile has the highest infection rate among opportunistic infections in IBD patients due to the extensive use of antibiotics and immunosuppressive agents.\n\nOur study found that disease severity was also a risk factor for opportunistic infections in IBD patients. Previously, the relationship between disease activity and the incidence of opportunistic infections was not clear. We speculate that when IBD patients progress to late-stage disease, a nonspecific inflammatory reaction is initiated in the gut mucosa, promoting pathogen invasion. The invasion of pathogens subsequently aggravates intestinal inflammation, creating a positive feedback loop. Furthermore, the increased energy consumption and low immunity state induced by inflammation diminish IBD patients’ ability to resist external pathogens, leading to further opportunistic infection.\n\nA reliable measure of long-term outcome is paramount in predicting the course of the disease, responsiveness to treatment, potential for complications, and need for hospitalization and/or surgery[29]. Many studies have shown that mucosal healing is the best predictor of positive long-term outcomes[30-33]. Endoscopy is currently regarded as the gold standard test for the assessment of mucosal healing[34]. However, its invasive nature and high cost make it an unfeasible modality for frequent monitoring. Calprotectin is an abundant calcium-binding protein, which is derived mainly from neutrophils and a lesser extent monocytes and reactive macrophages. FC is a sensitive marker of intestinal inflammation in IBD, as its concentration reflects the migration of neutrophils into the intestinal cavity[35]. Thus, FC has emerged as a novel diagnostic tool to detect and monitor intestinal inflammation and reflect disease activity in IBD. Measurements for FC are simple, rapid, specific, sensitive, and inexpensive compared to its counterparts[36,37]. Along with CRP, ESR, and FC, our study discovered that elevated FC was a risk factor for opportunistic infections in IBD patients. One explanation for this finding may be that the level of FC serves as an indicator for intestinal inflammation and therefore, disease activity. This makes FC level a more sensitive and specific marker than CRP and ESR. When the level of FC in IBD patients is elevated, it suggests that intestinal inflammation has occurred and the disease is in an active stage, conferring the patient to opportunistic infections.\n\nIn our study, immunosuppressive agents included methotrexate, 6-mercaptopurine, azathioprine, thalidomide, tacrolimus and steroids. From this study, we have found that the use of immunosuppressive medications alone increased the risk of an opportunistic infection about 3.247-fold. When any two immunosuppressive medications were used in conjunction, the risk was increased greatly to about 6.457-fold. This result from our study is consistent with recent results in the literature[7,8,38,39]. Additionally, it was determined that when immunosuppressive medications were combined with 5-ASA or IFX, the risk of opportunistic infection was increased greatly to about 4 to 5 folds. This conclusion is consistent with the findings reported by Tourner et al[7], Lawrance et al[40], and Kirchgesner et al[16].\n\nThe relationship between biologics and opportunistic infections has not been clearly established. Some studies[41-44] indicated that biologics increase the incidence of opportunistic infections, while others do not support this conclusion[45,46]. In our study, we found no association between the use of IFX alone and the increased risk of opportunistic infections. One possible explanation is that IFX may not cause opportunistic infections within the one-year period of the study (shorter than the previous five-year period)[7].\n\nDespite the important findings, this study had several limitations. First, the sample size of our study was small. A larger sample size would have allowed for more accurate estimation of the incidence of opportunistic infections and increase in reliability of risk factors in Chinese IBD patients. Second, our study was a single-center clinical study, which cannot represent the situation of IBD patients in China as a whole.\n\nIn conclusion, severe disease activity, elevated levels of FC, and immunosup-pressive medications, especially when used in combination, are risk factors for opportunistic infections in IBD patients. The use of IFX alone has nothing to do with opportunistic infections. With the increasing use of immunosuppressants in IBD and the advocacy of combination therapy, patients and physicians need to pay attention to and prevent opportunistic infections. As the genetic background, living environment, lifestyle, and diet of IBD patients in China are different from those in Western countries, our study of opportunistic infection could provide vital information for clinicians and IBD patients in China and other countries.\n\nARTICLE HIGHLIGHTS\nResearch background\nOpportunistic infection refers to any infection caused by a weakened immune system and typically does not occur in people with normal immune function. When they occur, patients presenting with opportunistic infections commonly display a significantly increased rate of morbidity and mortality. A number of studies have been conducted in Western countries and Japan to investigate the incidence of and risk factors for opportunistic infection in inflammatory bowel disease (IBD) patients. Currently, there are few epidemiological data on the rate of opportunistic infection in IBD patients in China. The risk factors for opportunistic infection in Chinese IBD patients remain unclear.\n\nResearch motivation\nThe main topics in our study are to predict the incidence of opportunistic infections related to IBD in China, and explore the risk factors for opportunistic infections. The key problems to be solved is to ensure compliance of enrolled IBD patients. The significance of solving these problems for future research in this field is to more accurately predict the incidence of and risk factors for opportunistic infections.\n\nResearch objectives\nThe main objectives in our study were to predict the incidence of opportunistic infections related to IBD in China, and explore the risk factors for opportunistic infections. The realized objectives include that the incidence of opportunistic infection in IBD patients in China is higher than that in Western countries and factors such as severe IBD, elevated levels of fecal calprotectin, and the use of immunosuppressive medications, especially when used in combination, are major risk factors for opportunistic infections in IBD patients, according to our single-center study. The significance of realizing these objectives for future research in this field is to alert patients and physicians to pay attention to and prevent opportunistic infections. Meanwhile, our study can provide important information for clinicians and IBD patients in China and other countries.\n\nResearch methods\nThe research design that was adopted to realize the objectives is observational study and nested case-control study. Observational study is to observe and record the characteristics of research objects in a natural state, and describe and compare the results. In our study, the patients were followed for up to 12 mo to identify the incidence of infections. In nested case-control studies, cases and controls come from the same cohort, so the selection bias in effect estimation is reduced and comparability is good. For each infected IBD patient, two non-infected IBD patients were selected as controls in our study.\n\nResearch results\nOur study found that the incidence of opportunistic infection in IBD patients in China is higher than that in Western countries and factors such as severe IBD, elevated levels of fecal calprotectin, and the use of immunosuppressive medications, especially when used in combination, are major risk factors for opportunistic infections in IBD patients. Meanwhile, the use of infliximab alone does not increase the risk of opportunistic infection. Our findings remind patients and physicians to pay attention to and prevent opportunistic infections. As the genetic background, living environment, lifestyle, and diet of IBD patients in China are different from patients in Western countries, our study of opportunistic infection could provide important information for clinicians and IBD patients in China and other countries. The following problems remain to be solved: (1) Our study was a single-center clinical study, which cannot represent the situation of IBD patients in China as a whole; and (2) the sample size of this study for both ulcerative colitis and Crohn’s disease patients was small. A larger sample size would have allowed for more precise estimation of the incidence of opportunistic infections and increase in reliability of risk factors in Chinese IBD patients.\n\nResearch conclusions\nThe new findings of this study are that the incidence of opportunistic infection in IBD patients in China is higher than that in Western countries, according to our single-center study, and factors such as severe IBD, elevated levels of fecal calprotectin, and the use of immunosuppressive medications, especially when used in combination, are major risk factors for opportunistic infections in IBD patients. Meanwhile, the use of infliximab alone does not increase the risk of opportunistic infection. The original insights into the current knowledge that this study offered is when opportunistic infection occurs, patients commonly display a significantly increased rate of morbidity and mortality. Therefore, prevention and identification of opportunistic infections are critical. The implications of this study for clinical practice in the future is patients and physicians need to pay attention to and prevent opportunistic infections.\n\nResearch perspectives\nFrom this study, we can conclude that the incidence of opportunistic infection in IBD patients in China is higher than that in Western countries, and doctors should pay attention to and prevent the incidence of opportunistic infections. The future research direction is to conduct a multi-center study to evaluate the incidence of opportunistic infection in Chinese IBD patients, and more accurately screen out the risk factors leading to the occurrence of opportunistic infection in Chinese IBD patients, so as to effectively prevent the occurrence of opportunistic infection.\n\nManuscript source: Unsolicited manuscript\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: China\n\nPeer-review report classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): D\n\nGrade E (Poor): 0\n\nInstitutional review board statement: This study was approved by the institutional review board of First Affiliated Hospital of Zhejiang Chinese Medical University.\n\nInformed consent statement: Informed consent was obtained from each patient.\n\nConflict-of-interest statement: The authors have declare no conflicts of interest.\n\nData sharing statement: No additional data are available.\n\nSTROBE statement: The manuscript was prepared according to the STROBE checklist.\n\nPeer-review started: February 22, 2019\n\nFirst decision: March 5, 2019\n\nArticle in press: March 30, 2019\n\nP-Reviewer: Day AS, Perse M, Seicean A S-Editor: Ma RY L-Editor: Wang TQ E-Editor: Zhang YL\n==== Refs\n1 Bryant PA Baddley JW Opportunistic Infections in Biological Therapy, Risk and Prevention Rheum Dis Clin North Am 2017 43 27 41 27890172 \n2 Mylonaki M Langmead L Pantes A Johnson F Rampton DS Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool Eur J Gastroenterol Hepatol 2004 16 775 778 15256979 \n3 Axelrad JE Joelson A Nobel YR Lawlor G Green PHR Lichtiger S Lebwohl B Enteric Infection in Relapse of Inflammatory Bowel Disease: The Utility of Stool Microbial PCR Testing Inflamm Bowel Dis 2017 23 1034 1039 28511200 \n4 Siegel CA Review article: explaining risks of inflammatory bowel disease therapy to patients Aliment Pharmacol Ther 2011 33 23 32 21083583 \n5 Rahier JF Magro F Abreu C Armuzzi A Ben-Horin S Chowers Y Cottone M de Ridder L Doherty G Ehehalt R Esteve M Katsanos K Lees CW Macmahon E Moreels T Reinisch W Tilg H Tremblay L Veereman-Wauters G Viget N Yazdanpanah Y Eliakim R Colombel JF European Crohn's and Colitis Organisation (ECCO) Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease J Crohns Colitis 2014 8 443 468 24613021 \n6 Naganuma M Kunisaki R Yoshimura N Takeuchi Y Watanabe M A prospective analysis of the incidence of and risk factors for opportunistic infections in patients with inflammatory bowel disease J Gastroenterol 2013 48 595 600 23053426 \n7 Toruner M Loftus EV Jr Harmsen WS Zinsmeister AR Orenstein R Sandborn WJ Colombel JF Egan LJ Risk factors for opportunistic infections in patients with inflammatory bowel disease Gastroenterology 2008 134 929 936 18294633 \n8 Dave M Purohit T Razonable R Loftus EV Jr Opportunistic infections due to inflammatory bowel disease therapy Inflamm Bowel Dis 2014 20 196 212 24051931 \n9 Truelove SC Witts LJ Cortisone in ulcerative colitis; final report on a therapeutic trial Br Med J 1955 2 1041 1048 13260656 \n10 Best WR Becktel JM Singleton JW Kern F Jr Development of a Crohn's disease activity index. 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"fulltext_license": "CC BY-NC",
"issn_linking": "1007-9327",
"issue": "25(18)",
"journal": "World journal of gastroenterology",
"keywords": "Inflammatory bowel disease; Nested case-control study; Opportunistic infections",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002681:China; D004359:Drug Therapy, Combination; D005243:Feces; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D015212:Inflammatory Bowel Diseases; D000069285:Infliximab; D039841:Leukocyte L1 Antigen Complex; D008297:Male; D019804:Mesalamine; D008875:Middle Aged; D009894:Opportunistic Infections; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "2240-2250",
"pmc": null,
"pmid": "31143074",
"pubdate": "2019-05-14",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "1248701;13260656;15256979;17471545;17530704;17681162;17905821;18294633;18484669;18513271;19255850;19340881;19818785;21039834;21083583;21198703;22298971;23053426;23374225;23649185;23856361;24051931;24184171;24560869;24613021;24821849;25961663;26176396;26199993;26879017;27189910;27215924;27890172;28502260;28511200;29655835;30277409;30342711;30668662;30701842;30704158;30728954;8244101",
"title": "Nested case-control study on risk factors for opportunistic infections in patients with inflammatory bowel disease.",
"title_normalized": "nested case control study on risk factors for opportunistic infections in patients with inflammatory bowel disease"
}
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] |
{
"abstract": "The authors present three cases of carbon monoxide poisoning (two suicides and one accident) from the autopsy material of the Institute of Legal Medicine at Basel, which are unusual with regard to the circumstances at the scene of death, the method of suicide and the post-mortem findings: Suicide of a 27-year-old male by burning charcoal in the bathroom, documentation of the suicide and previous attempted suicides on a tablet PC. Suicide of a 27-year-old male by carbon monoxide chemically, produced by dehydration of formic acid with sulphuric acid and inhalation of the gas through a breathing mask. Accidental carbon monoxide poisoning of a 34-year-old male by car exhaust fumes in an open garage. Difficult establishment of the diagnosis in the post-mortem examination due to unspecific colour of livores and varnished fingernails.",
"affiliations": null,
"authors": "Hecht|Lars|L|;Dittmann|Volker|V|;Dussy|Franz|F|;Gerlach|Kathrin|K|",
"chemical_list": "D000082:Acetaminophen",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9225",
"issue": "233(5-6)",
"journal": "Archiv fur Kriminologie",
"keywords": null,
"medline_ta": "Arch Kriminol",
"mesh_terms": "D000059:Accidents; D000082:Acetaminophen; D000328:Adult; D001344:Autopsy; D002249:Carbon Monoxide Poisoning; D056486:Chemical and Drug Induced Liver Injury; D017809:Fatal Outcome; D005753:Gastric Mucosa; D006801:Humans; D008099:Liver; D008297:Male; D013405:Suicide; D013557:Switzerland",
"nlm_unique_id": "0002256",
"other_id": null,
"pages": "192-202",
"pmc": null,
"pmid": "25004621",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Unusual findings in carbon monoxide-related deaths.",
"title_normalized": "unusual findings in carbon monoxide related deaths"
}
|
[
{
"companynumb": "CH-ACTAVIS-2014-22052",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
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"drugadministrationroute": "065",
"drugauthorizationnumb": "74978",
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"drugdosageform": "Unk",
"drugdosagetext": "10 G",
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"drugindication": "SUICIDE ATTEMPT",
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"medicinalproduct": "IBUPROFEN (UNKNOWN)"
},
{
"actiondrug": null,
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"activesubstancename": "ACETAMINOPHEN"
},
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"drugadministrationroute": "065",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "Unk",
"drugdosagetext": "40 G IN 5 DAYS; 12 G; 20 G; 16 G",
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"drugindication": "SUICIDE ATTEMPT",
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"medicinalproduct": "PARACETAMOL (UNKNOWN)"
},
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"activesubstancename": "ASPIRIN"
},
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"drugdosagetext": "6 (AS REPORTED)",
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"drugindication": "SUICIDE ATTEMPT",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ACETYLSALICYLIC ACID (UNKNOWN)"
}
],
"patientagegroup": null,
"patientonsetage": "27",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Chronic gastritis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Somnolence",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HECHT L, DITTMANN V, DUSSY F, GERLACH K. [UNUSUAL FINDINGS IN CARBON MONOXIDE-RELATED DEATHS]. ARCH KRIMINOL. 2014;233(5-6):192-202. GERMAN.",
"literaturereference_normalized": "unusual findings in carbon monoxide related deaths",
"qualification": "1",
"reportercountry": "CH"
},
"primarysourcecountry": "CH",
"receiptdate": "20141017",
"receivedate": "20141017",
"receiver": {
"receiverorganization": "FDA",
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},
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"safetyreportid": 10524609,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150528"
}
] |
{
"abstract": "BACKGROUND\nIt has been reported that tri-weekly Abraxane therapy has better outcomes in recurrent breast cancer than tri-weekly Cremophor-based taxol therapy, and that cyclophosphamide combined with taxane shows an enhanced antitumor effect. We conducted a phase II clinical trial of preoperative chemotherapy with a combination of TRI-ABC.\n\n\nMETHODS\nFrom September 2011 to September 2013, 4 cycles of preoperative chemotherapy with TRI-ABC followed by 4 cycles of FEC were administered in patients with resectable breast cancer. In patients with HER2-positive breast cancer, tri-weekly Trastuzumab was administered with TRI-ABC. The primary end point was the pathological complete response (pCR) rate in the breasts and lymph nodes.\n\n\nRESULTS\nThe treatment outcomes and safety were evaluated in 54 patients who received at least 1 dose of chemotherapy. All patients underwent radical surgery, and the overall pCR rate of 37% (20 of 54) was achieved. The pCR rates according to each subtype were 8% (2 of 24) in hormone receptor (HR)-positive HER2-negative breast cancer, 56% (5 of 9) in HR-positive HER2-positive breast cancer, 63% (5 of 8) in HR-negative HER2-positive breast cancer, and 62% (8 of 13) in triple-negative breast cancer. Multivariate analysis revealed that HR negativity and HER2 positivity were predictive factors of pCR. Clinical response was observed in 49 patients (91%). The safety profile was acceptable.\n\n\nCONCLUSIONS\nPreoperative chemotherapy with TRI-ABC followed by FEC showed high efficacy and excellent safety. Further clinical studies should be conducted to compare the efficacy of TRI-ABC followed by FEC with conventional taxane-anthracycline regimens.",
"affiliations": "Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima-City, Hiroshima, Japan.;Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima-City, Hiroshima, Japan.;Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima-City, Hiroshima, Japan.;Department of Surgery, Onomichi General Hospital, Onomichi-City, Hiroshima, Japan.;Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima-City, Hiroshima, Japan.;Department of Gastrointestinal, Breast, and Transplantation Surgery, Hiroshima Prefectural Hospital, Hiroshima-City, Hiroshima, Japan.;Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima-City, Hiroshima, Japan.;Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima-City, Hiroshima, Japan. Electronic address: [email protected].",
"authors": "Shigematsu|Hideo|H|;Kadoya|Takayuki|T|;Masumoto|Norio|N|;Sasada|Tatsunari|T|;Emi|Akiko|A|;Ohara|Masahiro|M|;Kajitani|Keiko|K|;Okada|Morihito|M|",
"chemical_list": "D000068196:Albumin-Bound Paclitaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1526-8209",
"issue": "15(2)",
"journal": "Clinical breast cancer",
"keywords": "Abraxane; Breast cancer; Cyclophosphamide; Preoperative chemotherapy",
"medline_ta": "Clin Breast Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000068196:Albumin-Bound Paclitaxel; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy",
"nlm_unique_id": "100898731",
"other_id": null,
"pages": "110-6",
"pmc": null,
"pmid": "25454688",
"pubdate": "2015-04",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "The efficacy and safety of preoperative chemotherapy with triweekly abraxane and cyclophosphamide followed by 5-Fluorouracil, epirubicin, and cyclophosphamide therapy for resectable breast cancer: a multicenter clinical trial.",
"title_normalized": "the efficacy and safety of preoperative chemotherapy with triweekly abraxane and cyclophosphamide followed by 5 fluorouracil epirubicin and cyclophosphamide therapy for resectable breast cancer a multicenter clinical trial"
}
|
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{
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},
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},
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"literaturereference": "SHIGEMATSU H, KADOYA T, MASUMOTO N, SASADA T, EMI A, OHARA M, KAJITANI K AND OKADA M. THE EFFICACY AND SAFETY OF PREOPERATIVE CHEMOTHERAPY WITH TRIWEEKLY ABRAXANE AND CYCLOPHOSPHAMIDE FOLLOWED BY 5-FLUOROURACIL, EPIRUBICIN, AND CYCLOPHOSPHAMIDE THERAPY FOR RESECTABLE BREAST CANCER: A MULTICENTER CLINICAL TRIAL. CLINICAL BREAST CANCER 2015 APR 01;15 (2):110-116.",
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},
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},
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},
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{
"abstract": "We present a case report of a patient with diffuse skin and systemic Kaposi's sarcoma (KS), 1 year after renal transplantation. A concomitant Pyrenochaeta romeroi granuloma of the right hallux was diagnosed and illustrated an important immunodysfunction in our patient. Four months after reduction in immunosuppression and switch to everolimus, a total regression of the KS was observed. Reduction in the immunosuppression and treatment with terbinafine cleared the P. romeroi infection, while lowering immunosuppression and changing the type of immunosuppressive therapy were important steps in the successful management of the KS. In recent years, evidence of the antitumor effects of everolimus is increasing: total regression of KS in combination with renal function preservation in renal graft recipients is possible with mammalian target of rapamycin (mTOR) inhibitor-based regimens. In addition, with increasing numbers of human immunodeficiency virus-positive transplant recipients, mTOR inhibitors may play a more crucial role in the management of KS.",
"affiliations": "Department of Nephrology, UZ Leuven, Leuven, Belgium.",
"authors": "Detroyer|D|D|;Deraedt|K|K|;Schöffski|P|P|;Hauben|E|E|;Lagrou|K|K|;Naesens|M|M|;Delforge|M L|ML|;Kuypers|D|D|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12357",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Kaposi's sarcoma; Kaposi's sarcoma herpesvirus; Pyrenochaeta romeroi; immunosuppression; mTOR inhibitor; renal transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D003881:Dermatomycoses; D057915:Drug Substitution; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008113:Liver Neoplasms; D009173:Mycophenolic Acid; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "303-7",
"pmc": null,
"pmid": "25645490",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Resolution of diffuse skin and systemic Kaposi's sarcoma in a renal transplant recipient after introduction of everolimus: a case report.",
"title_normalized": "resolution of diffuse skin and systemic kaposi s sarcoma in a renal transplant recipient after introduction of everolimus a case report"
}
|
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"patientagegroup": null,
"patientonsetage": "27",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Wound infection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Chronic allograft nephropathy",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Transplant rejection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Kaposi^s sarcoma",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DETROYER D, DERAEDT K, SCHOEFFSKI P, HAUBEN E, LAGROU K, NAESENS M ET.AL.. RESOLUTION OF DIFFUSE SKIN AND SYSTEMIC KAPOSI^S SARCOMA IN A RENAL TRANSPLANT RECIPIENT AFTER INTRODUCTION OF EVEROLIMUS: A CASE REPORT.. TRANSPLANT INFECTIOUS DISEASE. 2015?17(2):303-7",
"literaturereference_normalized": "resolution of diffuse skin and systemic kaposi s sarcoma in a renal transplant recipient after introduction of everolimus a case report",
"qualification": "3",
"reportercountry": "BE"
},
"primarysourcecountry": "BE",
"receiptdate": "20200131",
"receivedate": "20200131",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17357365,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200409"
}
] |
{
"abstract": "Fingolimod is an oral sphingosine-1-phosphate receptor modulator which causes lymphocyte sequestration in lymph nodes and is approved for relapsing multiple sclerosis. The Therapeutic Goods Administration of Australia is aware of only one case where fingolimod preceded immune thrombocytopenic purpura (ITP) by 5 weeks. Here we report three such cases.None were on any medications known to cause ITP and routine investigations were unremarkable. All cases were treated with immunosuppression. Case 1 successfully weaned prednisolone after fingolimod cessation whereas case 2 weaned slowly while continuing fingolimod therapy. Case 3 had more refractory ITP and re-exposure to fingolimod worsened thrombocytopenia.There was a temporal association between fingolimod exposure and ITP however dose-effect association and pathogenesis remain less clear.In conclusion, our cases highlight that clinicians should be aware of the possible association between ITP and fingolimod.",
"affiliations": "Department of Haematology, Monash Health, Clayton, Victoria, Australia.;Department of Haematology, Monash Health, Clayton, Victoria, Australia.;Department of Haematology, Monash Health, Clayton, Victoria, Australia.;Department of Clinical Haematology, Monash University, Melbourne, Victoria, Australia.",
"authors": "Yuen|Hiu Lam Agnes|HLA|http://orcid.org/0000-0001-8349-6782;Brown|Susan|S|;Chan|Noel|N|;Grigoriadis|George|G|",
"chemical_list": "D005938:Glucocorticoids; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D011961:Receptors, Fc; D049349:Receptors, Lysosphingolipid; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; D011239:Prednisolone; D000068876:Fingolimod Hydrochloride; C488777:romiplostim",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220590",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Drugs And Medicines; Haematology (incl Blood Transfusion); Neurology (drugs And Medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001792:Blood Platelets; D019468:Disease Management; D005260:Female; D000068876:Fingolimod Hydrochloride; D005938:Glucocorticoids; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D008875:Middle Aged; D009103:Multiple Sclerosis; D000069442:Natalizumab; D011239:Prednisolone; D016553:Purpura, Thrombocytopenic, Idiopathic; D011961:Receptors, Fc; D049349:Receptors, Lysosphingolipid; D011993:Recombinant Fusion Proteins; D013926:Thrombopoietin; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28893804",
"pubdate": "2017-09-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11967257;14283879;16869934;17553484;18588683;20089952;20089954;20131303;23148237;23817558;24976291;27308307",
"title": "Immune thrombocytopenic purpura associated with fingolimod.",
"title_normalized": "immune thrombocytopenic purpura associated with fingolimod"
}
|
[
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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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"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "2"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2013"
}
},
"primarysource": {
"literaturereference": "YUEN H,BROWN S,CHAN N,GRIGORIADIS G. IMMUNE THROMBOCYTOPENIC PURPURA ASSOCIATED WITH FINGOLIMOD. BMJ CASE REPORTS 2017?.",
"literaturereference_normalized": "immune thrombocytopenic purpura associated with fingolimod",
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"reportercountry": "AU"
},
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},
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},
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"transmissiondate": "20180509"
},
{
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},
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"abstract": "OBJECTIVE\nTrastuzumab-emtansine is an antibody-drug conjugate developed to decrease off-target toxicity. According to the product label, reactions secondary to extravasation are mild or moderate.\n\n\nMETHODS\nWe report on a 51-year-old woman who developed epidermal necrosis after extravasation of trastuzumab-emtansine, which required surgical intervention. Six weeks later, the lesions were healed with residual hyperpigmentation.\n\n\nCONCLUSIONS\nWe describe the course of a case of severe toxicity following trastuzumab-emtansine extravasation. We provide treatment recommendations and recommend amending the information on the product label on extravasation.",
"affiliations": "Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands.;Department of Plastic Surgery, St Antonius Hospital, Nieuwegein, The Netherlands.;Department of Internal Medicine, St Antonius Hospital, Nieuwegein, The Netherlands.;Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands.",
"authors": "Sallevelt|Bastiaan T G M|BTGM|https://orcid.org/0000-0003-4687-4048;Teunis|Teun|T|;Agterof|Mariette J|MJ|;van den Broek|Marcel P H|MPH|",
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"fulltext": "\n==== Front\nJ Clin Pharm Ther\nJ Clin Pharm Ther\n10.1111/(ISSN)1365-2710\nJCPT\nJournal of Clinical Pharmacy and Therapeutics\n0269-4727 1365-2710 John Wiley and Sons Inc. Hoboken \n\n10.1111/jcpt.13148\nJCPT13148\nCase Report\nCase Reports\nExtravasation of an antibody‐drug conjugate: A case report of epidermal necrosis after trastuzumab‐emtansine extravasation\nSALLEVELT et al.Sallevelt Bastiaan T. G. M. PharmDhttps://orcid.org/0000-0003-4687-4048\n1\n\n2\[email protected] Teunis Teun MD, PhD\n3\n Agterof Mariette J. MD, PhD\n4\n van den Broek Marcel P. H. PharmD, PhD\n1\n \n1 \nDepartment of Clinical Pharmacy\nSt Antonius Hospital\nNieuwegein\nThe Netherlands\n\n\n2 \nDepartment of Clinical Pharmacy\nUniversity Medical Center Utrecht\nUtrecht\nThe Netherlands\n\n\n3 \nDepartment of Plastic Surgery\nSt Antonius Hospital\nNieuwegein\nThe Netherlands\n\n\n4 \nDepartment of Internal Medicine\nSt Antonius Hospital\nNieuwegein\nThe Netherlands\n\n* Correspondence\n\nBastiaan T. G. M. Sallevelt, Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.\n\nEmail: [email protected]\n\n15 5 2020 \n8 2020 \n45 4 10.1111/jcpt.v45.4832 835\n17 1 2020 15 2 2020 03 4 2020 © 2020 The Authors. Journal of Clinical Pharmacy and Therapeutics published by John Wiley & Sons Ltd\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nWhat is known and objective\nTrastuzumab‐emtansine is an antibody‐drug conjugate developed to decrease off‐target toxicity. According to the product label, reactions secondary to extravasation are mild or moderate.\n\nCase summary\nWe report on a 51‐year‐old woman who developed epidermal necrosis after extravasation of trastuzumab‐emtansine, which required surgical intervention. Six weeks later, the lesions were healed with residual hyperpigmentation.\n\nWhat is new and conclusion\nWe describe the course of a case of severe toxicity following trastuzumab‐emtansine extravasation. We provide treatment recommendations and recommend amending the information on the product label on extravasation.\n\nThis report describes the course of severe skin toxicity following trastuzumab‐emtansine extravastion and provides treatment recommendations.\n\n\nantibody‐drug conjugatechemotherapyepidermal necrosisextravasationoncologytrastuzumab‐emtansine source-schema-version-number2.0cover-dateAugust 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:27.07.2020\n\n\nSallevelt \nBTGM \n, \nTeunis \nT \n, \nAgterof \nMJ \n, \nvan den Broek \nMPH \n. Extravasation of an antibody‐drug conjugate: A case report of epidermal necrosis after trastuzumab‐emtansine extravasation\n. J Clin Pharm Ther . 2020 ;45 :832 –835\n. 10.1111/jcpt.13148 \n32412114 \n\n\n\nFunding information\n\n\nThis research received no specific grant from any funding agency in the public, commercial or not‐for‐profit sectors.\n==== Body\n1 WHAT IS KNOWN AND OBJECTIVES\nTrastuzumab‐emtansine is indicated for patients with HER2‐positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane. Trastuzumab‐emtansine is an antibody‐drug conjugate (ADC) and consists of trastuzumab, a humanized IgG1‐antibody linked with a covalent bond to a highly cytotoxic maytansine derivate (DM1), which disrupts microtubule function by binding near the vinca alkaloid binding side. The toxic agent DM1 is 20‐200 times more potent compared with systemically administered taxanes and vinca alkaloids. As a result, parenteral administration of DM1 alone is restricted due to severe side effects and poor efficacy. Therefore, DM1 is only registered as an antibody‐drug conjugate. The DM1‐trastuzumab conjugate promotes selectivity of the cytotoxic agent for HER2‐overexpressing tumour cells. This increases intracellular delivery of DM1 to malignant cells with HER2‐overexpression and decreases off‐target exposure. Upon binding to HER2, trastuzumab‐emtansine undergoes receptor‐mediated internalization and subsequent lysosomal degradation, resulting in release of intracellular DM1‐containing cytotoxic catabolites.\n1\n\n\n\nExtravasation is an accidental leakage of intravenously administered drug into the tissue around the vein. Complications caused by extravasation depend on many factors such as the irritant or vesicant properties of the drug itself, composition of the drug formulation (eg pH, tonicity and emulsifiers), the pharmacological properties of the drug (eg vasoconstriction) and the volume of extravasation. The product label of trastuzumab‐emtansine states that reactions secondary to extravasation observed in clinical studies were usually mild or moderate and comprised erythema, tenderness, skin irritation, pain or swelling at the infusion site. Furthermore, no specific treatment recommendations are mentioned for trastuzumab‐emtansine extravasation.\n1\n Although the label does not warn for severe toxic effects of extravasation, we report a case of a patient that developed severe epidermal necrosis after extravasation, which required surgical intervention.\n\n2 CASE DESCRIPTION\nWe report on a 51‐year‐old woman who was treated for oestrogen receptor (ER)‐negative, progesterone receptor (PR)‐negative and HER2 positive breast cancer. She was diagnosed with supraclavicular lymph metastasis for which she initially received a combination of docetaxel, carboplatin, trastuzumab and pertuzumab. After mastectomy, she continued with trastuzumab in combination with radiotherapy. Unfortunately, progression of disease with leptomeningeal metastasis was shown on MRI, and oral treatment with lapatinib and capecitabine was initiated. The patient discontinued oral treatment because of further progression and was switched to trastuzumab‐emtansine infusions. Trastuzumab‐emtansine was administered on day one of a 21‐day cycle, as intravenous infusions via peripheral access. The weight‐based dosage of 3.6 mg/kg was diluted with 250 mL of normal saline.\n\nAt the end of the infusion of the second cycle, extravasation of trastuzumab‐emtansine was noticed by the oncology nurse while disconnecting the infusion line. As the infusion access was covered by the patient's clothes, the patient had not noticed the extravasation during infusion. At the time of discovery, the patient had a slightly erythematous, painless swelling. According to the size of the swelling, it was assumed that the total infusion volume had been administered subcutaneously. According to local protocol, the oncologist and hospital pharmacist were consulted to discuss whether supportive treatment was indicated.\n\nIt was decided to choose an observational approach, substantiated by statements in the product label about relatively mild reactions and a lack of (known) specific treatment strategies after trastuzumab‐emtansine extravasations. However, one case of delayed epidermal necrosis after extravasation was reported, but no treatment strategies were provided.\n2\n Therefore, the patient was instructed to elevate the affected arm in order to prevent further swelling, was informed about a possible delayed response and was instructed to contact her oncologist as soon as cutaneous symptoms (swelling, erythema and pain) worsened.\n\nThe next day, the patient experienced an increase in pain and erythema at the site of extravasation. There was no increase in swelling or skin temperature. Pain could be sufficiently managed with acetaminophen. We contacted the patient every other day to monitor the extravasation. After a week, the patient attended our oncology outpatient clinic. The erythema was expanded to a larger area. After consulting plastic surgery, watchful waiting was continued as the skin was intact and the extravasation was too long ago to consider other treatments (eg local hyaluronidase injection or liposuction). Four days later, the patient developed blisters and the skin turned somewhat darker. The blisters were removed, and the affected area was treated with silver sulphadiazine to prevent infection. The darker discoloration did not progress to full‐thickness necrosis. Six weeks after the event, the lesion healed with residual hyperpigmentation of skin. The development of cutaneous symptoms over time is presented in Figure 1.\n\nFIGURE 1 Development of symptoms after extravasation of trastuzumab‐emtansine over time from the start of infusion (day 1) until 6 wk after administration. [Colour figure can be viewed at wileyonlinelibrary.com]\n\n3 WHAT IS NEW AND CONCLUSION\nTo our knowledge, this is the first case report that describes a detailed course of cutaneous trastuzumab‐emtansine extravasation over time—illustrated by photos—and provides recommendations for clinicians how to manage trastuzumab‐emtansine extravasations.\n\nShafaee et al also reported a case of trastuzumab‐emtansine extravasation. A 55‐year‐old woman developed similar symptoms.\n2\n In this patient, no pain or swelling was noted at the end of infusion. After 9 hours, a swelling and tenderness were present at the infusion site. Two days later, large clear fluid‐filled blisters developed with eventual rupture and serosanguinous discharge. Treatment existed of pain control requiring opioids. The lesion slowly healed in 4 weeks with residual hyperpigmentation, but without permanent sensory changes. This only other case report confirms that the worst symptoms develop with a delay of several hours to days. However, no clear treatment recommendations for trastuzumab‐emtansine extravasations were provided. These two cases illustrate that severe toxic reactions can develop after trastuzumab‐emtansine extravasation.\n\nThere are theoretically three mechanisms that could contribute to local cytotoxicity after extravasation of trastuzumab‐emtansine: (a) proteolysis by intracellular lysosomes after HER2‐mediated internalization by cutaneous cells; (b) uptake by local cells of the reticuloendothelial system (RES‐cells) followed by proteolysis; or (c) chemical degradation of the ADC in situ. According to literature, HER‐2/neu protein is present on cell membranes of skin tissue, suggesting that internalization by cutaneous HER2 is possible.\n3\n, \n4\n In addition, RES cells such as macrophages are found in skin tissue and thus may attribute to local toxicity by facilitating proteolysis of trastuzumab‐emtansine.\n5\n In situ chemical degradation of the non‐cleavable, stable thioether bond between trastuzumab and DM1 seems to be very unlikely.\n1\n\n\n\nIn addition to general recommendations for drug extravasations such as liquid aspiration and the use of agent‐specific antidotes (eg dexrazoxane for anthracyclines), treatment options can be roughly divided into a ‘spread and dilute’ or ‘concentrate and condensate’ approach. A warm compress, administration of subcutaneous hyaluronidase or vasodilatants (eg nitroglycerin and phentolamine) will promote agent dispersion, whereas cold dressings will decrease the spread into adjacent skin tissue by vasoconstriction.\n6\n For the treatment of trastuzumab‐emtansine extravasation, no specific treatment recommendations are mentioned by the product label or in literature. Although the intracellular action of emtansine (DM1) is similar to vinca alkaloids, the treatment strategy for extravasation of vinca alkaloids with hyaluronidase\n7\n cannot be extrapolated to trastuzumab‐emtansine as the pharmacokinetic profile is determined by trastuzumab pharmacokinetics. The pharmacokinetics of the trastuzumab‐emtansine conjugate has only been studied as an intravenous infusion. However, trastuzumab as a monoclonal antibody is also available as a 600 mg subcutaneous injection. This subcutaneous formulation contains recombinant human hyaluronidase in order to facilitate distribution to plasma. Despite the use of co‐formulated hyaluronidase in subcutaneous injections, it takes 3 days to reach peak plasma concentrations (Tmax) with a high inter‐individual variation (1‐14 days) due to transport via de lymphatic system.\n8\n Treatment with hyaluronidase after subcutaneous extravasation of trastuzumab‐emtansine will therefore not be able to provide a distribution to plasma, but will likely promote spreading of the agent into adjacent cutaneous tissue. Dilution of emtansine over a larger area will not decrease its toxicity, because of the extremely high potency of the payload. As a result, concentrating the agent to minimize the affected area, for example with a cold compress, seems to be a safer strategy. If blisters develop, a plastic surgeon should be consulted to consider surgical removal and monitor for full‐thickness necrosis and subsequent treatment if necessary.\n\nIn conclusion, we recommend a non‐operative treatment after trastuzumab‐emtansine extravasation, including pain control, elevation of the affected limb and close patient monitoring. Cooling may be considered to decrease the spread of fluid into adjacent skin tissue, thereby possibly reducing the size of the affected area. Due to the extravascular pharmacokinetics of trastuzumab and the cytotoxic potency of emtansine, administration of hyaluronidase is not expected to be helpful since it will only enlarge the affected cutaneous area.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTION\nAuthorship eligibility is based on the four ICMJE authorship criteria. All authors certify that they have participated sufficiently in the work to take public responsibility for the content. We have not received substantial contributions from non‐authors.\n\nPATIENT CONSENT FOR PUBLICATION\nObtained.\n==== Refs\nREFERENCES\n1 \nRoche GmbH \n. Kadcyla (Trastuzumab‐Emtansine) EMEA/H/C/002389. Summary of product characteristics\n (updated 2018). www.ema.europa.eu/en/medicines/human/EPAR/kadcyla. Accessed November 05, 2019.\n2 \n\nShafaee \nMN \n, \nSalahudeen \nAA \n, \nValero \nV \n. Skin necrosis after ado‐trastuzumab emtansine extravasation\n. J Oncol Pract . 2017 ;13 (8 ):555 ‐556\n.28678590 \n3 \n\nKrähn \nG \n, \nLeiter \nU \n, \nKaskel \nP \n, et al. Coexpression patterns of EGFR, HER2, HER3 and HER4 in non‐melanoma skin cancer\n. Eur J Cancer . 2001 ;37 (2 ):251 ‐259\n.11166154 \n4 \n\nPress \nMF \n, \nCordon‐Cardo \nC \n, \nSlamon \nDJ \n. Expression of the HER‐2/neu proto‐oncogene in normal human adult and fetal tissues\n. Oncogene . 1990 ;5 (7 ):953 ‐962\n.1973830 \n5 \n\nYanez \nDA \n, \nLacher \nRK \n, \nAurobind Vidyarthi \nA \n, \nColegio \nOR \n. The role of macrophages in skin homeostasis\n. Pflugers Arch . 2017 ;469 (3–4 ):455 ‐463\n.28233123 \n6 \n\nGoutos \nI \n, \nCogswell \nLK \n, \nGiele \nH \n. Extravasation injuries: a review\n. J Hand Surg Eur . 2014 ;39 (8 ):808 ‐818\n.\n7 \n\nBertelli \nG \n, \nDini \nD \n, \nForno \nGB \n, et al. Hyaluronidase as an antidote to extravasation of Vinca alkaloids: clinical results\n. J Cancer Res Clin Oncol . 1994 ;120 :505 ‐506\n.8207052 \n8 \nRoche GmbH \n. Herceptin (Trastuzumab) EMEA/H/C/000278. Summary of product characteristics\n (updated 2019). https://www.ema.europa.eu/en/medicines/human/EPAR/herceptin. Accessed November 05, 2019).\n\n",
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"issn_linking": "0269-4727",
"issue": "45(4)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "antibody-drug conjugate; chemotherapy; epidermal necrosis; extravasation; oncology; trastuzumab-emtansine",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000080044:Ado-Trastuzumab Emtansine; D000970:Antineoplastic Agents; D004817:Epidermis; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D008875:Middle Aged; D009336:Necrosis",
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"title": "Extravasation of an antibody-drug conjugate: A case report of epidermal necrosis after trastuzumab-emtansine extravasation.",
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{
"abstract": "Pancreatic cancer is one of the most lethal cancers. To improve its prognosis, conversion surgery for initially unresectable advanced pancreatic cancer (UAPC) after chemotherapy has been reported in recent years.\n\n\nMETHODS\nA retrospective analysis of the patients with initially UAPC underwent conversion surgery after the first-line modified FOLFIRINOX (mFX) was conducted at a single tertiary care center between January 2014 and March 2020.\n\n\nRESULTS\nAmong 79 patients with UAPC who had mFX, 8 patients with a median age of 63 years, including 5 males (3 with locally advanced and 5 metastatic lesions), underwent conversion surgery after a median of 20 cycles of mFX. Conversion surgery was performed in 10.1% of patients (8/79) and surgical resection was successful in all with R0 resection. Postoperative major adverse events were seen in 2 patients, but no perioperative deaths were recognized. Recurrence was confirmed in 3 patients, and these 3 patients died due to cancer recurrence in 17.7, 30.6 and 57.8 months after mFX initiation. 5 patients were still alive without recurrence. The median OS in the patients who underwent conversion surgery was estimated as 65.9 months and was significantly longer than that of the patients without conversion surgery or that in the patients who had a partial response for mFX but did not have conversion surgery. The median follow-up period for the patients who had conversion surgery was 35.2 months.\n\n\nCONCLUSIONS\nConversion surgery achieved long-term survival in patients with UAPC who were treated with the first-line mFX, although controversy still remained.",
"affiliations": "First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan.;First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan.;First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan.;First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan.;First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan.;Department of Digestive Surgery, Gifu University Hospital, Gifu 501-1194, Japan.;First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan.",
"authors": "Mita|Naoki|N|;Iwashita|Takuji|T|0000-0003-4978-1787;Ichikawa|Hironao|H|;Iwasa|Yuhei|Y|;Uemura|Shinya|S|;Murase|Katsutoshi|K|;Shimizu|Masahito|M|0000-0002-1151-2058",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/jcm10132848",
"fulltext": "\n==== Front\nJ Clin Med\nJ Clin Med\njcm\nJournal of Clinical Medicine\n2077-0383\nMDPI\n\n34199125\n10.3390/jcm10132848\njcm-10-02848\nArticle\nClinical Outcomes of Conversion Surgery after FOLFIRINOX in Patients with Unresectable Advanced Pancreatic Cancer: A Retrospective Cohort Study at a Single Center\nMita Naoki 1\nhttps://orcid.org/0000-0003-4978-1787\nIwashita Takuji 1*\nIchikawa Hironao 1\nIwasa Yuhei 1\nUemura Shinya 1\nMurase Katsutoshi 2\nhttps://orcid.org/0000-0002-1151-2058\nShimizu Masahito 1\nFujiwara Kenji Academic Editor\nAshley Stanley W. Academic Editor\n1 First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu 501-1194, Japan; [email protected] (N.M.); [email protected] (H.I.); [email protected] (Y.I.); [email protected] (S.U.); [email protected] (M.S.)\n2 Department of Digestive Surgery, Gifu University Hospital, Gifu 501-1194, Japan; [email protected]\n* Correspondence: [email protected]; Tel.: +81-58-2306308; Fax: +81-58-2306310\n27 6 2021\n7 2021\n10 13 284830 5 2021\n24 6 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/).\nPancreatic cancer is one of the most lethal cancers. To improve its prognosis, conversion surgery for initially unresectable advanced pancreatic cancer (UAPC) after chemotherapy has been reported in recent years. Methods: A retrospective analysis of the patients with initially UAPC underwent conversion surgery after the first-line modified FOLFIRINOX (mFX) was conducted at a single tertiary care center between January 2014 and March 2020. Results: Among 79 patients with UAPC who had mFX, 8 patients with a median age of 63 years, including 5 males (3 with locally advanced and 5 metastatic lesions), underwent conversion surgery after a median of 20 cycles of mFX. Conversion surgery was performed in 10.1% of patients (8/79) and surgical resection was successful in all with R0 resection. Postoperative major adverse events were seen in 2 patients, but no perioperative deaths were recognized. Recurrence was confirmed in 3 patients, and these 3 patients died due to cancer recurrence in 17.7, 30.6 and 57.8 months after mFX initiation. 5 patients were still alive without recurrence. The median OS in the patients who underwent conversion surgery was estimated as 65.9 months and was significantly longer than that of the patients without conversion surgery or that in the patients who had a partial response for mFX but did not have conversion surgery. The median follow-up period for the patients who had conversion surgery was 35.2 months. Conclusion: Conversion surgery achieved long-term survival in patients with UAPC who were treated with the first-line mFX, although controversy still remained.\n\nadjuvant surgery\nneoadjuvant therapy\npreoperative therapy\npancreatic ductal adenocarcinoma\n==== Body\n1. Introduction\n\nPancreatic cancer is the fourth leading cause of cancer-related deaths in Japan, with more than 35,000 deaths annually, increasing its proportion in cancer-related deaths over time [1]. Moreover, pancreatic cancer is often diagnosed at an advanced stage with locally advanced and/or metastatic lesions, wherein 10–20% of patients are candidates for surgical resection; despite this, the procedure is the only treatment to achieve complete cure of this disease [2]. It is due to these situations that the prognosis of pancreatic cancer patients is considered poor as compared to other malignant diseases, with an overall five-year survival rate of only 8.5% [1].\n\nIn cases of unresectable advanced pancreatic cancer, chemotherapy or chemoradiotherapy (CRT) has been the mainstay of treatment, with gemcitabine (GEM) as its standard medication since the late 1990s. Recently, two regimens, FOLFIRINOX (FX; a combination of 5-fluorouracil, oxaliplatin, irinotecan and leucovorin) and GEM plus nab-paclitaxel (GnP) have shown better outcomes than GEM alone in terms of overall survival (OS), progression-free survival (PFS) and response rate (RR). However, the survival benefit is still limited, and the median OS of patients who underwent these new regimens was reported to be within one year [3,4]. To improve pancreatic cancer prognosis, the concept of conversion surgery recently emerged and is surgery for pancreatic cancer, which is initially considered as unresectable advanced one, as a result of significant response to chemotherapy or CRT [5,6,7,8,9,10,11]. However, the efficacy and safety of conversion surgery have not been well studied yet. We then conducted this study to evaluate our experience with conversion surgery following FX regimen for unresectable advanced pancreatic cancer.\n\n2. Methods\n\n2.1. Study Design and Patient Selection\n\nThis was a retrospective study conducted at a single tertiary care center (Gifu University Hospital, Gifu, Japan). Between January 2014 and March 2020, a total of 79 patients with unresectable advanced pancreatic cancer, including locally advanced and metastatic cancer, underwent FX as the first-line chemotherapy at GUH. All patients had pathologically proven pancreatic adenocarcinomas before chemotherapy. In our center, modified FX (mFX; IV oxaliplatin at 85 mg/m2 for 2 h, IV leucovorin at 400 mg/m2 for 2 h, IV irinotecan at 150 mg/m2 for 90 min and IV fluorouracil (5-FU) at 2400 mg/m2 over 46 h) has been the first-line regimen for unresectable pancreatic cancer since January 2014, which is followed by gemcitabine plus nab-paclitaxel as the second-line therapy [12,13]. Of the 79 patients, 8 underwent conversion surgery, and their medical records were retrospectively analyzed in this study. The consent for participation of patients in this study was obtained through an opt-out methodology. The study was conducted in accordance with the human and ethical principles of the Helsinki guidelines, and the study protocol was approved by the Institutional Review Board of Gifu University Hospital with the approved number of 2020-148.\n\n2.2. Assessment of Resectability\n\nInitial and final assessment for resectability of pancreatic cancer were evaluated based on findings of dynamic contrast-enhanced computed tomography (CT) either combined with or without dynamic contrast-enhanced magnetic resonance imaging (MRI), endoscopic ultrasound and positron emission tomography (PET) with CT. For the final assessment for resectability in the patients with metastatic lesions, CT, MRI and PET-CT were at least performed for a thorough evaluation. Tumor resectability was determined after discussion by physicians, surgeons and radiologists on a case-by-case basis while referring to the Classification of Pancreatic Cancer by Japan Pancreas Society (4th English Edition) [14]. Pancreatic cancer was essentially deemed unresectable when the following findings were recognized: Metastatic lesion was recognized, or there were major vessel involvements, contacting with the superior mesenteric artery (SMA), celiac artery (CA) or common hepatic artery (CHA) more than 180 degrees, occluding the portal vein (PV) or the superior mesenteric vein (SMV), involving PV or SMV broadly, or involving the aorta. For peritoneal dissemination, the diagnosis was made during initial surgery before mFX and the staging laparoscopy or laparotomy was performed at the time of conversion surgery.\n\n2.3. First-Line Chemotherapy and Assessment of Clinical Outcomes\n\nAll patients enrolled in this study underwent mFX as first-line chemotherapy, and none of them underwent CRT. Efficacy of mFX was assessed by comparing CT scans before and after treatment. Conversion surgery indications were also well discussed at a multidisciplinary conference by physicians, surgeons and radiologists on a case-by-case basis.\n\nDifferent assessments were used for the following outcomes: Response Evaluation Criteria in Solid Tumors (RECIST) was used for radiologic tumor response evaluation; National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 was used for chemotherapy-related adverse event scoring; the Clavien-Dindo classification was applied used for postoperative complications [15]; the Classification of Pancreatic Cancer (4th English Edition) was used for pathological diagnosis and classification [14], and Evan’s grading system was used for assessing the pathologic effect of preoperative therapy [16].\n\n2.4. Study Outcomes and Statistical Analysis\n\nThe primary outcome of this study was to evaluate the outcomes of conversion surgery among the cohort underwent mFX for unresectable advanced pancreatic cancer. The secondary outcomes were the rate of conversion surgery and comparison of OS in patients who underwent conversion surgery to the patients who could not.\n\nOS was calculated from the date of mFX initiation to the date of death. The relative dose intensity was calculated as the ratio of the amount of drug that was administered to the amount of standard regimen of mFX until conversion surgery. The OS was estimated using the Kaplan-Meier method and calculated with the corresponding 95% confidence interval (CI). All statistical analyses were performed using JMP 14.0 (SAS Institute, Inc., Cary, NC, USA).\n\n3. Results\n\n3.1. Patient and Tumor Characteristics\n\nIn this case, 79 patients [median age of 64 year-old (range 38–74); 44 men] underwent mFX for unresectable advanced pancreatic cancer due to local advancement in 20 patients (25.1%) and metastasis in 59 patients (74.9%). Best responses for mFX were partial response in 27 patients (34.2%), stable disease in 32 patients (40.5%) and progressive disease in 20 patients (25.3%). Conversion surgery after the first-line mFX was performed in 8 patients with a resection rate of 10.1%. (Table 1 and Figure 1) The baseline characteristics of the 8 patients including 5 males and 3 females with a median age of 63-year-old (range: 57–72) and are shown in Table 2. The primary tumor site was found to be at the pancreatic head in 4 patients and at the body or tail in the remaining four. The unresectable factors were due to metastatic lesions in 5 patients (3 in the liver, 2 in the peritoneum) and locally advanced lesions in 3 patients (1 in the SMV, 1 in the aorta, and 1 in both the SMA and SMV).\n\n3.2. Preoperative Therapy\n\nDetailed information on the preoperative mFX is shown in Table 3. The median duration and cycle were 10.7 months (range: 4.5–23.9) and 20 cycles (range: 6–47), respectively. Grade ≥ 3 chemotherapy-related adverse events were recognized in all patients, including neutropenia in 8 patients and peripheral sensory neuropathy in 1 patient, and the median CA19–9 level was 2921 U/mL (range: 171–10424 U/mL) at peak and 30 U/mL (range: 12–177) after preoperative treatment. The unresectable factors were evaluated using cross-sectional imaging, including contrast-enhanced CT, MRI and PET-CT, to decide indication for conversion surgery, and disappeared in 7 patients. However, in the remaining one (patient #6), major vessel tumor invasion improved, but the perivascular high-density area remained slightly on contrast-enhanced CT.\n\n3.3. Surgical Outcomes and Pathological Findings\n\nRegarding the operative procedure for the 8 patients, pancreatoduodenectomy (PD) was performed in 4 patients, distal pancreatectomy (DP) in 3 patients and DP with en bloc celiac axis resection in 1 patient. The median operative time and blood losses were 438 min (range: 220–880) and 648 mL (range: 100–1840), respectively. Gastroduodenal artery pseudoaneurysm rupture and pancreatic fistula occurred in the same patient (Patient #6), and intractable chylous ascites occurred in another (Patient #7), both manifesting as major postoperative complications (Clavien-Dindo class ≥ IIIa). The median hospital stay length was 26.5 days (range: 15–50), and the R0 resection rate was 100%. Regarding the pathological treatment effect based on the Evans grading system [16], Grade IIa was achieved in 2 patients (25%), Grade IIb in 4 patients (50%) and Grade IV in 2 patients (25%) (Table 4).\n\n3.4. Adjuvant Chemotherapy and Postoperative Outcomes\n\nAdjuvant chemotherapy was administered in 7 patients (mFX in 4, combination drug of tegafur, gimeracil and oteracil [S1] in 3), and the remaining patient (Patient #6) did not undergo any further treatment. Recurrence was confirmed in 3 (Patient #1, #2 and #7; 37.5%) of the 8 patients. Specifically, Patient #1 had liver metastasis recurrence, Patient #2 recurrence in the remnant pancreas and Patient #7 had lung metastasis recurrence in 8.5, 20.1 and 24.1 months after conversion surgery, respectively. These 3 patients (Patient #1, #2 and #7) were dead in 17.7, 57.8 and 30.6 months after conversion surgery (24.9, 65.9 and 35.1 months from the beginning of mFX), respectively. Overall, 5 patients were still alive without recurrence. (Table 5) The median OS in the patients who underwent conversion surgery was estimated as 65.9 months (95% CI, 24.9–95.9) and was significantly longer than that in all patients without conversion surgery (median OS of 14.6 months; 95% CI, 11.8–17.2) (Figure 2) or that in the patients who had the best response of PR but did not have conversion surgery (median OS of 18.3 months; 95% CI, 12.0–25.2) (Figure 3). The median follow-up period for the patients who had conversion surgery was 35.2 months (range: 24.9–65.9).\n\n4. Discussion\n\nThe term “conversion surgery” was used to describe surgical resection following chemotherapy for initially unresectable advanced pancreatic cancer in this study. There have been several terminologies to be used for similar treatment strategies, such as “adjuvant surgery,” surgical resection after “neoadjuvant therapy,” or “preoperative therapy” [7]. Natsume et al. further described that “adjuvant surgery” should be used for planned surgeries that are sequentially performed after preoperative neoadjuvant therapy, and “conversion surgery” should be used for unplanned surgeries that are performed as a result of “strategy conversion” due to an unexpected strong anticancer effect with non-surgical therapy [6]. In this study, all 8 patients were considered as non-candidates for surgery before first-line mFX initiation, thus the term “conversion surgery” was considered suitable in this study.\n\nAt our institution, mFX was performed as the first-line chemotherapy for unresectable advanced pancreatic cancers, including locally advanced and metastatic cancer, if the patient’s condition allows for it (PS of 0–1 and age of ≤75 years). This treatment strategy enabled evaluation of uniform preoperative therapy using mFX and its treatment effect for conversion surgery. In this study, the conversion surgery rate was 10.1% (8/79) following mFX for unresectable advanced pancreatic cancer. There are several reports on conversion surgery for initially unresectable pancreatic cancer after FX. A retrospective study including 101 locally advanced pancreatic cancer patients by Sadot et al. [17] reported that 31 patients (31%) underwent conversion surgery, and 16 of them (55%) achieved an R0 resection after FX with or without radiation therapy. Another report by Lee et al. [18] also performed a retrospective analysis of 64 patients with locally advanced pancreatic cancer and showed a resection rate of 23% (15/64) and an R0 resection rate of 73% (11/15) after FX with or without radiation therapy. A direct comparison of the conversion surgery rates cannot be performed, since the unresectable factors and procedure indications would be different between studies and institutions. Despite this, the development of more effective chemotherapies, such as FX, for pancreatic cancer has created a new concept of treatment strategy termed “conversion surgery” in a certain number of unresectable pancreatic cancer patients.\n\nAn indication for conversion surgery is patients in whom margin-negative resection could be achieved, although an accurate resectability assessment remains limited based on current imaging modalities. Therefore, its surgical indication seems to be diverse depending on the institution. In some institutions, surgical exploration was offered to evaluate resectability as a more reliable procedure in patients with no progression after chemotherapy [19]. Another indication was that conversion surgery was recommended in patients who were expected to undergo margin-negative resection based on the clinical response [19]. Moreover, the most common indication seems to be decided by clinical response on imaging studies and decreased serum CA19-9 levels [19]. At our institution, the basic indication for conversion surgery is that curative resection could be achieved based on findings of imaging studies, although this is not absolute. In Patient #6, a remarkable response in tumor size and serum CA 19-9 levels was observed, although CT still showed circumferential slightly high-density area around the SMA. However, we decided to perform surgical resection after a multidisciplinary assessment by physicians, surgeons and radiologists, and a discussion with the patient. The final pathological evaluation of the resected specimen only showed a dense desmoplastic change without any viable tumor cells, indicating a complete chemotherapy response (Figure 4). Considering the fibrotic change did not disappear even with CR to mFX in this case, a multidisciplinary assessment is important, because, again, an assessment of resectability based on imaging study is limited. As for an indication of conversion surgery for metastatic one, a more careful assessment might be required. A retrospective cohort study by Tanaka et al. evaluated predictive resectability factors in 101 metastatic pancreatic cancer patients scheduled for surgery after FX, showing a shrinkage rate of the primary tumor of more than 50% (odds ratio [OR]: 13.0, 95% CI: 1.0–162.0, p = 0.04) and post-chemotherapy serum CA19-9 level of <150 U/mL (OR: 10.3, 95% CI: 1.4–76.3, p = 0.02), which were both significant predictive factors for resectability on multivariate analysis [20]. In this study, among 5 out of 8 patients who underwent conversion surgery for metastatic pancreatic cancer, conversion surgery was decided based on the disappearance of metastatic lesions on imaging studies including CT, MRI and PET-CT. During the study period, 3 patients have not had a recurrence, although 2 patients died because of cancer recurrence (Figure 5). Given all these, at this moment, the indication of conversion surgery for pancreatic cancer should be decided by a comprehensive assessment of the tumor response to chemotherapy based on imaging studies and the serum levels of relevant tumor markers, although further evaluations of its indication are required, especially for metastatic pancreatic cancer.\n\nThe optimal preoperative therapy duration also remains controversial. A multicenter retrospective cohort study comparing surgery with non-surgery after a long-term favorable response to non-surgical anti-cancer treatment, which was based on gemcitabine or S1, in initially unresectable pancreatic cancer patients by Satoi et al. performed a subgroup analysis based on the time from initial treatment to surgical resection [21]. On multivariate analysis, their results showed a significantly favorable OS in patients who underwent surgery over 240 days after the initial treatment (hazard ratio: 0.332, 95%CI: 0.150–0.734, p = 0.006). Considering the higher response and adverse event rates of FX, we are not sure whether that optimal duration (more than 240 days) could be applicable for FX as well, although a longer duration of chemotherapy may be related to better patient selection. In a retrospective cohort study by Tanaka et al. evaluating predictive resectability factors in 101 metastatic pancreatic cancer patients scheduled for surgery after FX, preoperative FX duration was not a significant predictive factor for longer OS [20]. In our study, 3 patients (Patients #1, #2 and #7) died due to tumor recurrence, although we could not evaluate optimal FX duration for conversion surgery due to the small cohort size. The optimal duration of FX for conversion surgery should also be evaluated in future larger studies.\n\nRegarding the survival benefit of conversion surgery, 5 out of 8 patients were still alive, the median OS in the patients who underwent conversion surgery was estimated as 65.9 months (95% CI, 24.9–95.9) and was significantly longer than that in all patients without conversion surgery. Our previous Phase II study evaluating mFX in 31 unresectable advanced pancreatic cancer patients showed a median OS of 14.9 months (95%CI: 9.9–19.2) [12]. Considering these results, long-term survival was achieved in the patients who underwent conversion surgery; however, the question as to whether conversion surgery contributed to improving the prognosis of patients is unclear. In other words, it is possible that the patients who underwent conversion surgery had a better prognosis than those who received chemotherapy only since these patients should be remarkable responders to preoperative therapy. A multicenter retrospective cohort study comparing surgery with non-surgery after a long-term favorable response to non-surgical anti-cancer treatment in initially unresectable pancreatic cancer patients further found a significantly better overall survival in the conversion surgery group as compared to the control group (median OS: 39.7 months vs. 20.8 months; p < 0.0001) [21]. Moreover, Natsume et al. analyzed the survival benefit of conversion surgery by limiting the cohort to responder patients for the first-line therapy, reporting that the survival rate was better in patients who underwent conversion surgery than in those who did not (median OS: not reached vs. 562 days, p < 0.001) [6]. In our study as well, the median OS in the patients who underwent conversion surgery was significantly longer than that in the patients who had the best response of PR but did not have conversion surgery (65.9 vs. 18.3 months). These results are supporting the survival benefits of conversion surgery in patients with unresectable advanced pancreatic cancer, although the benefit cannot be completely confirmed. Further studies are needed to evaluate the survival benefit of conversion surgery as well.\n\nThe major limitation of our study was that the study included a small number of patients who underwent conversion surgery at a single center. Due to small cohort size, the outcomes could not be separately evaluated between locally advanced and metastatic advanced pancreatic cancer, although these two conditions might be different. An insufficient follow-up period was also another limitation. However, the strength of our study was that all preoperative treatments were performed with a unified regimen (mFX) by a single dedicated team of specialized pancreaticobiliary physicians.\n\nIn conclusion, long-term survival was achieved in initially unresectable advanced pancreatic cancer patients, including those with locally advanced and metastatic cancer, treated with the first-line mFX followed by conversion surgery. Despite these findings, optimal treatment regimen, optimal preoperative treatment duration and optimal surgery indications remain controversial. Therefore, further large-scale studies are required to evaluate these points.\n\nAcknowledgments\n\nWe express our sincere gratitude to everyone who was related to this study.\n\nAuthor Contributions\n\nN.M. and T.I. wrote the manuscript. N.M., T.I., H.I., Y.I., S.U., K.M. and M.S. managed the patients. T.I. took the correspondence. 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\nThe study was conducted according to the guidelines of the Helsinki guidelines, and approved by the Institutional Review Board of Gifu University Hospital (the approved number of 2020-148 and date of approval of 2 September 2020).\n\nInformed Consent Statement\n\nThe consent for participation of patients in this study was obtained through an opt-out methodology.\n\nConflicts of Interest\n\nN.M., T.I., H.I., Y.I., S.U., K.M. and M.S. have nothing to declare.\n\nAbbreviations\n\nmFX, modified FOLFIRINOX; CRT, chemoradiotherapy; GEM, gemcitabine; GnP, gemcitabine plus nab-paclitaxel; OS, overall survival; PFS, progression free survival; RR, response rate; SMA, superior mesenteric artery; CA, celiac artery; CHA, common hepatic artery; SMV, superior mesenteric vein; CT, computed tomography; RECIST, response evaluation criteria in solid tumors; MRI, magnetic resonance imaging; PET-CT, positron emission tomography CT; PD, pancreatoduodenectomy; DP, distal pancreatectomy; pCR, pathological complete response.\n\nFigure 1 Patient flow.\n\nFigure 2 In Kaplan-Meier analysis, the median overall survival (OS) in the patients who underwent conversion surgery was estimated as 65.9 months (95% CI, 24.9–95.9) and was significantly longer than that in all patients without conversion surgery (median OS of 14.6 months; 95% CI, 11.8–17.2) (Log-Rand test of p < 0.001).\n\nFigure 3 In Kaplan-Meier analysis, the median overall survival (OS) in the patients who underwent conversion surgery was estimated as 65.9 months (95% CI, 24.9–95.9) and was significantly longer than that in the patients who had the best response of partial response but did not have conversion surgery (median OS of 18.3 months; 95% CI, 12.0–25.2) (Log-Rand test of p = 0.0002).\n\nFigure 4 Computed tomography (CT) findings of Patient #6. (A): CT findings before chemotherapy showed that the pancreatic head tumor involved the superior mesenteric artery (SMA) (white arrow). (B): CT findings before conversion surgery. The high-density area surrounding the SMA (white arrow) remained slightly, although the tumor itself disappeared. (C): Pathological findings of the resected tumor showed mainly predominant fibrous tissue with fatty degeneration, mucus pool and remaining Langerhans islands, without any viable tumor cells (hematoxylin and eosin staining). These pathological findings were considered as Evan’s grade of IV.\n\nFigure 5 Computed tomography (CT) findings of Patient #1. (A): CT showed multiple metastatic lesions (white arrow) in the liver before chemotherapy. (B): All liver metastasis disappeared on CT after chemotherapy. (C): Cancer recurrence in the liver (white arrow) was confirmed 8.5 months after conversion surgery.\n\njcm-10-02848-t001_Table 1 Table 1 Basic characteristic of all 79 patients.\n\nAge, Years\tMedian (Range)\t64 (38–74)\t\nSex\tn (%)\tmen\t44 (55.7)\t\nMetastasis\tn (%)\tyes\t59 (74.7)\t\nBest response based on imaging studies\tn (%)\tCR\t0\t\nPR\t27 (34.2)\t\nSD\t32 (40.5)\t\nPD\t20 (25.3)\t\nConversion surgery\tn (%)\t\t8 (10.1)\t\nCR, complete response; PR, partial response; SD, stable disease; PD progressive disease.\n\njcm-10-02848-t002_Table 2 Table 2 Basic characteristic of patients underwent conversion surgery.\n\nPatient No.\tAge (years)\tGender\tSite of Primary Tumor\tUnresectable Factor\t\n1\t63\tMale\tTail\tM (HEP)\t\n2\t72\tMale\tHead\tLA (SMV)\t\n3\t59\tMale\tBody\tM (PER)\t\n4\t63\tFemale\tBody\tM (HEP)\t\n5\t58\tMale\tHead\tLA (Ao)\t\n6\t57\tFemale\tHead\tLA (SMA, SMV)\t\n7\t63\tMale\tBody\tM (PER)\t\n8\t63\tFemale\tHead\tM (HEP)\t\nM, metastatic lesion (HEP, liver; PER, Peritoneal); LA, locally advanced lesion; (SMV, superior mesenteric vein; Ao, aorta; SMA, superior mesenteric artery).\n\njcm-10-02848-t003_Table 3 Table 3 Details and effects of preoperative chemotherapy.\n\nPatient No.\tDuration (Months)\n(Cycles)\tTreatment Effect\n(RECIST)\tAdverse Events\n(≥Grade 3)\tCA19–9(U/mL)\nPeak/after Chemotherapy\tRelative Dose Intensity (%)\tFindings of\nUnresectable Factor\t\nL-OHP\tCPT-11\t5-FU\tLV\t\n1\t7.1 (10)\tPR\tNeutropenia G4\t6529 / 32\t42.9\t56.2\t68.1\t68.1\tM\n(HEP/Multi)\tdisappeared\t\n2\t8.0 (13)\tPR\tPeripheral sensory neuropathy G3\t1462 / 55\t59.6\t74.5\t85.0\t85.0\tLA\n(SMV)\tdisappeared\t\n3\t23.9 (47)\tPR\tNeutropenia G3\t250 / 13\t65.1\t79.8\t86.8\t87.7\tM\n(PER/Multi)\tdisappeared\t\n4\t23.3 (31)\tPR\tNeutropenia G4\t4379 / 81\t42.8\t56.4\t69.9\t68\tM\n(HEP/Multi)\tdisappeared\t\n5\t6.8 (11)\tPR\tNeutropenia G4\t171 / 12\t71.8\t81.4\t83.4\t83.0\tLA\n(Ao)\tdisappeared\t\n6\t13.3 (27)\tPR\tNeutropenia G4\t5431 / 20\t60.9\t89.7\t92.7\t92.2\tLA\n(SMA, SMV)\timproved\t\n7\t4.5 (6)\tPR\tNeutropenia G3\t370 / 177\t50.2\t53.3\t65\t66\tM\n(PER/Multi)\tdisappeared\t\n8\t24.0 (36)\tPR\tNeutropenia G4\t10424 / 27\t41.7\t56.5\t65.7\t66.4\tM\n(HEP/Multi)\tdisappeared\t\nRECIST, response evaluation criteria in solid tumors; L-OHP, oxaliplatin; CPT-11, irinotecan; 5-FU, fluorouracil; LV, leucovorin; PR, partial response; G, grade; M, metastatic lesion (HEP, liver; PER, Peritoneal); Multi, multiple metastasis sites; LA, locally advanced lesion (SMV, superior mesenteric vein; Ao, aorta; SMA, superior mesenteric artery).\n\njcm-10-02848-t004_Table 4 Table 4 Surgical outcomes and pathological findings.\n\nPatient No.\tOperative Procedure\tOperative Time (min)\tBlood Loss (ml)\tMajor Complications\tHospital Stay (Days)\tpTNM\tResidual Tumor\tTumor Viability\n(Evans)\t\n1\tDP\t220\t100\t-\t20\tpT2N0M0,\nstageIB\tR0\tIIb\t\n2\tPD\t520\t710\t-\t50\tpT2N1M0,\nstageIIB\tR0\tIIb\t\n3\tDP\t445\t1840\t-\t22\tpT3N0M0,\nstageIIA\tR0\tIIa\t\n4\tDP\t350\t290\t-\t19\tpT3N0M0,\nstageIIA\tR0\tIIb\t\n5\tPD\t500\t685\t-\t31\tpT3N0M0,\nstageIIA\tR0\tIIb\t\n6\tPD\t880\t1790\tGDA pseudoaneurysm rupture\nPancreatic fistula\t47\tpCR\tR0\tIV\t\n7\tDP-CAR\t360\t330\t-\t15\tpT3N1M0,\nstageIIB\tR0\tIIb\t\n8\tPD\t430\t610\tChylous ascites\t41\tpCR\tR0\tIV\t\nDP, distal pancreatectomy; PD, pancreatoduodenectomy; DP-CAR, distal pancreatectomy with en bloc celiac axis resection; GDA, gastroduodenal artery; pCR, pathologically complete response.\n\njcm-10-02848-t005_Table 5 Table 5 Adjuvant Chemotherapy and postoperative outcomes.\n\nPatient No.\tAdjuvant Chemotherapy\tRecurrence Site/Time to Recurrence from CS (Month)\tFinal Outcome\tOS (Months)\nfrom Initial Treatment\n[from Surgery]\t\n1\tmFX\tLiver/8.5\tDeath\t24.9 [17.7]\t\n2\tS1\tRemnant pancreas/20.1\tDeath\t65.9 [57.8]\t\n3\tmFX\tNo\tAlive\t40.9 [16.7]\t\n4\tmFX\tNo\tAlive\t35.2 [12.0]\t\n5\tmFX\tNo\tAlive\t26.1 [19.3]\t\n6\tNo\tNo\tAlive\t27.3 [13.9]\t\n7\tS1\tLung/24.1\tDeath\t35.1 [30.6]\t\n8\tS1\tNo\tAlive\t26.7 [12.6]\t\nOS, overall survival; mFX, modified FOLFIRINOX; S1, the combination drug of tegafur, gimeracil and oteracil; CS, conversion surgery; D/A, dead/alive.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Foundation for Promotion of Cancer Research Cancer Statistics in Japan, 2019 Available online: https://ganjoho.jp/en/professional/statistics/brochure/2019_en.html (accessed on 20 May 2021)\n2. Vincent A. Herman J. Schulick R. Hruban R.H. Goggins M. Pancreatic Cancer Lancet 2011 378 607 620 10.1016/S0140-6736(10)62307-0 21620466\n3. Conroy T. Desseigne F. Ychou M. Bouché O. Guimbaud R. Bécouarn Y. Adenis A. Raoul J.-L. Gourgou-Bourgade S. de la Fouchardière C. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer N. Engl. J. Med. 2011 364 1817 1825 10.1056/NEJMoa1011923 21561347\n4. Von Hoff D.D. Ervin T. Arena F.P. Chiorean E.G. Infante J. Moore M. Seay T. Tjulandin S.A. Ma W.W. Saleh M.N. Increased Survival in Pancreatic Cancer with Nab-Paclitaxel plus Gemcitabine N. Engl. J. Med. 2013 369 1691 1703 10.1056/NEJMoa1304369 24131140\n5. Sapam S. Sohei O. Yanagimoto H. Yamamoto T. Toyokawa H. Hirooka S. Yamaki S. Role of Adjuvant Surgery in Initially Unresectable Pancreatic Cancer after Long-Term Chemotherapy or Chemoradiation Therapy: Survival Benefit? J. Hepato Biliary Pancreat. Sci. 2014 21 695 702\n6. Natsume S. Shimizu Y. Senda Y. Hijioka S. Matsuo K. Ito S. Komori K. Conversion Surgery Only for Highly Selected Patients with Unresectable Pancreatic Cancer: A Satisfactory Outcome in Exchange for a Lower Resection Rate Surg. Today 2019 49 670 677 10.1007/s00595-019-01776-y 30730003\n7. Yoshitomi H. Takano S. Furukawa K. Takayashiki T. Kuboki S. Conversion Surgery for Initially Unresectable Pancreatic Cancer: Current Status and Unresolved Issues Surg. Today 2019 49 894 906 10.1007/s00595-019-01804-x 30949842\n8. Kato K. Kondo S. Hirano S. Tanaka E. Shichinohe T. Tsuchikawa T. Matsumoto J. Adjuvant Surgical Therapy for Patients with Initially-Unresectable Pancreatic Cancer with Long-Term Favorable Responses to Chemotherapy J. Hepato Biliary Pancratic Sci. 2011 18 712 716 10.1007/s00534-011-0391-8 21455748\n9. Nitsche U. Wenzel P. Siveke J.T. Braren R. Holzapfel K. Schlitter A.M. Stöß C. Kong B. Esposito I. Erkan M. Resectability After First-Line FOLFIRINOX in Initially Unresectable Locally Advanced Pancreatic Cancer: A Single-Center Experience Ann. Surg. Oncol. 2015 22 1212 1220 10.1245/s10434-015-4851-2 26350368\n10. Bickenbach K.A. Gonen M. Tang L.H. O’Reilly E. Goodman K. Brennan M.F. D’Angelica M.I. DeMatteo R.P. Fong Y. Jarnagin W.R. Downstaging in Pancreatic Cancer: A Matched Analysis of Patients Resected Following Systemic Treatment of Initially Locally Unresectable Disease Ann. Surg. Oncol. 2012 19 1663 1669 10.1245/s10434-011-2156-7 22130621\n11. Furuse J. Shibahara J. Sugiyama M. Development of Chemotherapy and Significance of Conversion Surgery after Chemotherapy in Unresectable Pancreatic Cancer J. Hepato Biliary Pancreatic Sci. 2018 25 261 268 10.1002/jhbp.547 29651809\n12. Yoshida K. Iwashita T. Uemura S. Maruta A. A Multicenter Prospective Phase II Study of First-Line Modified FOLFIRINOX for Unresectable Advanced Pancreatic Cancer Oncotarget 2017 8 111346 111355 10.18632/oncotarget.22795 29340058\n13. Mita N. Iwashita T. Uemura S. Yoshida K. Iwasa Y. Ando N. Iwata K. Okuno M. Mukai T. Shimizu M. Second-Line Gemcitabine Plus Nab-Paclitaxel for Patients with Unresectable Advanced Pancreatic Cancer after First-Line FOLFIRINOX Failure J. Clin. Med. 2019 8 761 10.3390/jcm8060761 31146420\n14. Japan Pancreas Society Classification of Pancreatic Carcinoma (4th English Edition) Kanehara Co. Tokyo, Japan 2017\n15. Dindo D. Demartines N. Clavien P.A. Classification of Surgical Complications: A New Proposal with Evaluation in a Cohort of 6336 Patients and Results of a Surgery Ann. Surg. 2004 240 205 213 10.1097/01.sla.0000133083.54934.ae 15273542\n16. Evans D.B. Rich T.A. Byrd D.R. Cleary K.R. Connelly J.H. Levin B. Charnsangavej C. Fenoglio C.J. Ames F.C. 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{
"abstract": "BACKGROUND\nAmyloidosis and fibrillary glomerulonephritis (FGN) share similar electron microscopic signatures including random arrangement of fibrils. However, distinction between the 2 can often be made using Congo Red staining.\nHere we describe a unique case of FGN, which stained positive for Congo Red, as well as DnaJ heat shock protein family (Hsp40) member B9 which is more specific for FGN. The patient presented with acute kidney injury and severe proteinuria.\n\n\nMETHODS\nCongophilic FGN.\n\n\nMETHODS\nSix-month course of mycophenolate mofetil and prednisone.\n\n\nRESULTS\ncomplete resolution of acute kidney injury and proteinuria TAKE HOME LESSONS:: To our knowledge, this is the first reported case of successful treatment of this rare condition using mycophenolate mofetil and prednisone.",
"affiliations": "Division of Kidney Diseases and Hypertension, Alpert Medical School of Brown University, Providence, RI, United States.",
"authors": "Gandhi|Pulkit|P|;Tang|Jie|J|",
"chemical_list": "D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D009173:Mycophenolic Acid; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000021101",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\nMD-D-19-07226\n10.1097/MD.0000000000021101\n21101\n5200\nResearch Article\nClinical Case Report\nSuccessful treatment of a unique case of congophilic fibrillary glomerulonephritis\nA case reportGandhi Pulkit MD Tang Jie MD, MPH∗ Saranathan. Maya Division of Kidney Diseases and Hypertension, Alpert Medical School of Brown University, Providence, RI, United States.\n∗ Correspondence: Jie Tang, Division of Kidney Diseases and Hypertension, Brown University Warren Alpert Medical School, Providence, RI, United States (e-mail: [email protected]).\n10 7 2020 \n10 7 2020 \n99 28 e2110116 9 2019 15 5 2020 4 6 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nAmyloidosis and fibrillary glomerulonephritis (FGN) share similar electron microscopic signatures including random arrangement of fibrils. However, distinction between the 2 can often be made using Congo Red staining.\n\nPatient concerns:\nHere we describe a unique case of FGN, which stained positive for Congo Red, as well as DnaJ heat shock protein family (Hsp40) member B9 which is more specific for FGN. The patient presented with acute kidney injury and severe proteinuria.\n\nDiagnosis:\nCongophilic FGN.\n\nInterventions:\nSix-month course of mycophenolate mofetil and prednisone.\n\nOutcomes:\ncomplete resolution of acute kidney injury and proteinuria\n\nTake home lessons:\nTo our knowledge, this is the first reported case of successful treatment of this rare condition using mycophenolate mofetil and prednisone.\n\nKeywords\namyloidosisCongo red stainfibrillary glomerulonephritisOPEN-ACCESSTRUE\n==== Body\nKey Points\n1. The final diagnosis of congophilic FGN was based on the pathological findings, as well as positive Congo Red & DNAJB9 stains.\n\n2. Congo red positivity can rarely be seen in FGN in addition to amyloidosis. In such cases, DNAJB9 stain should be used to identify FGN.\n\n3. A treatment regimen consists of MMF and prednisone may be considered in congophilic FGN.\n\n\n\n1 Introduction\nGlomerular diseases can be associated with fibrillar deposits in the glomerular basement membrane and mesangium. Congo Red staining has traditionally been used to distinguish between fibrillary glomerulonephritis (FGN) which is typically Congo Red negative, and amyloidosis which is Congo Red positive.[1]\n\nFGN is a rare glomerular disease, seen in approximately 1% of native kidney biopsies.[2] Most cases are idiopathic, although some are thought to be secondary to hepatitis C infection, paraproteinemia, or autoimmune diseases. The diagnosis is based on the typical morphological features seen on electron microscopy (EM). Patients usually present with renal insufficiency, hematuria and proteinuria, which can be in nephrotic range.[3] On EM, fibril deposits can be seen either in mesangium, glomerular basement membrane, or both. Fibrils can vary in size, usually ranging between 16 to 24 nm, which is larger than those described in amyloidosis (4–11 nm).[2] Under immunofluorescence, it can stain positive for Immunoglobulin G (IgG), complement component 3 (C3), Kappa And Lambda light chains.[3] Certain IgG subclasses, such as IgG4, are seen more often than others.[2] In general, FGN has a poor prognosis despite therapeutic interventions. Existing evidence showed that 43% of patients had persistent renal dysfunction, and 44% progressed to end-stage renal disease (ESRD) over an average of 4.3 years of follow-up.[4]\n\nHere, we describe a rare case of FGN, which stained positive for Congo Red and DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9). The patient responded well to a 6-month combined regimen of mycophenolate mofetil (MMF) and prednisone with complete remission.\n\n2 Case presentation\nA 58–year-old Caucasian male with medical history of hepatitis C status post treatment with Harvoni in 2015 with negative viral PCR in September 2016, well controlled type 2 diabetes mellitus (HbA1c 5.2%), well controlled hypertension (blood pressure 130's/50's), chronic kidney disease stage III with a baseline creatinine of 1.4 mg/dL and random urine albumin-to-creatinine ratio of 627 to 877 mg/g, presented as an outpatient consult for rising serum creatinine. The serum creatinine rose to 3.2 mg/dL over a period of 3 months. His 24 hour urine showed significant proteinuria, measured at 2682 mg. He did not report family history of kidney problems. Social history was unrevealing. He did not present with any systemic signs or symptoms. Systolic blood pressure ranged between 140 to 160's while in clinic. Physical examination did not reveal any pulmonary or cardiovascular abnormalities. There was neither skin rash nor joint effusions. Edema was graded at 1+ bilaterally in his lower extremities. Urine sediment showed microscopic hematuria, with some dysmorphic features. Serologic studies showed elevated Kappa/Lambda ratio at 2.52, but no paraprotein per serum and 24-hour urine protein electrophoresis. He had normal C3 & 4 levels, negative antinuclear and anti-neutrophil cytoplasmic antibodies, and his hepatitis B viral surface antigen and hepatitis C viral antibody were also unremarkable. Erythrocyte sedimentation rate was 37. His age-appropriate cancer screening was unrevealing. Kidney ultrasound showed normal sized kidneys with scattered cysts and normal appearing parenchyma.\n\nThe patient underwent renal biopsy, which showed mesangioproliferative glomerulonephritis, with both mesangial and subendothelial fibrillary deposits (Fig. 1, Image A). The fibrils measured 14.8 nm in diameter and were Congo Red positive (Fig. 1, Image B). Immunofluorescence were positive for polytypic IgG (predominant IgG4) (Fig. 1, Image C) and C3. Staining for serum amyloid A was negative. There were equal and trace reactivities of Kappa and Lambda light chain in the glomeruli and tissue background (Fig. 1, Image D& E). Lastly, there were advanced chronic changes noted in the parenchyma, including global and segmental glomerulosclerosis (52% of glomeruli) and significant interstitial fibrosis (60% of the cortex).\n\nFigure 1 Images of kidney biopsy. A. Electron microscopy (80000X) showing fibril deposits; B. Congo red stain under light microscopy; C. Immunofluorescence stain for IgG (400X); D. E Immunofluorescence stain for Kappa and Lambda light chains respectively (400X); F. DNAJB9 stain under light microscopy.\n\nConsidering atypical findings on renal biopsy including larger than expected fibril size of 14.8 nm (usually < 10 nm in amyloidosis), negative amyloid protein A staining, and lack of clinical evidence of extrarenal amyloidosis, we decided to send his specimen for a special DNAJB9 stain (Fig. 1, image F) which is a biomarker specific for FGN.[5] In the meantime, he was started on MMF 1 gram twice daily and oral prednisone 40 mg daily (0.5 mg/kg/d) for a total of 6 months with a slow taper of prednisone afterwards in light of clinical factors favoring a diagnosis of FGN, despite the positive Congo Red stain. His serum creatinine trended down from 3.2 to 1.5 mg /dL in next 6 months, and his proteinuria improved to baseline with repeat random urine albumin-to-creatinine ratio reduced to 431 mg/g. His DNAJB9 stain later came back positive.\n\n3 Discussion\nFGN is a rare but well recognized pathological entity. It belongs to a group of glomerular diseases known as fibrillary glomerulopathies, which also include amyloidosis. FGN has the unique ultrastructural feature of haphazardly arranged, straight fibrils in the mesangium and/or along the glomerular basement membrane. The slightly larger fibrils and Congo Red negative deposits distinguish FGN from amyloidosis. This histological distinction using Congo Red is important clinically because while the treatment for amyloidosis often involves chemotherapy and autologous stem cell transplantation,[6] the treatment for FGN relies on immunosuppression.[7]\n\nHowever, rare congophilic FGN has been recently reported by a group of Mayo investigators and was observed in the case we presented. Alexander et al examined kidney biopsy specimens containing Congo Red–positive glomerular deposits from 2010 to 2017. Some were originally referred for amyloid typing. After comprehensive analysis, a total of 18 specimens were found to be unusual examples of FGN. They accounted for 4% of FGN in which Congo Red staining was performed. There was a male predominance, and a higher incidence of concomitant monoclonal gammopathy was observed. However, there appeared to be no differences in serum creatinine, and incidence of hematuria or nephrotic syndrome at presentation, when compared to traditional FGN. EM showed the typical randomly oriented nonbranching fibrils in the mesangium and glomerular basement membranes with fibril sizes ranging from 11 to 18 nm.[8] The techniques used to confirm a diagnosis of FGN were liquid chromatography–assisted tandem mass spectrometry of microdissected tissue sections and DNAJB9 immunohistochemistry.\n\nDNAJB9 is a protein involved in the stress response of endoplasmic reticulum and is found to be highly concentrated in the glomerular capillary and mesangium of patients with FGN. DNAJB9 staining has not been seen in other glomerular diseases including amyloidosis or in healthy subjects, and therefore is a marker for FGN with a reported 100% sensitivity and 100% specificity.[5,9,10]\n\nOur patient is a unique case of an already rare congophilic FGN, which to our knowledge, is the first reported case of successful treatment of this rare condition. In general, renal survival in traditional FGN is poor, with over 40% of patients reached ESRD within 4.3 years according to a case series.[4] Aside from kidney transplantation, there is currently no proven effective therapy for FGN. As in the traditional Condo Red-negative FGN, the response to treatment and renal prognosis also appears to be poor in congophilic FGN. Thus far, the only reported clinical data on these congophilic cases have come from the Mayo series. According to the authors, clinical follow-up was available in 16 out of 18 patients. Mean duration of follow-up was 23 (range, 4–56) months. Five (31%) progressed to ESRD and the remaining 11 (69%) had decreased kidney function, with persistent proteinuria and hematuria. No patient had normalization of serum creatinine level or > 50% decrease in proteinuria on follow up, except for one who with remission of proteinuria but worsening serum creatinine level.[8] The immunosuppressive regimen included steroids alone, cyclophosphamide, azathioprine, rituximab alone or in combination with steroids.[8] The fact that our patient showed impressive response to the treatment with MMF and prednisone is encouraging, and future larger scale studies would be needed to examine the efficacy of this treatment regimen.\n\nAuthor contributions\nConceptualization: Jie Tang.\n\nData curation: Pulkit Gandhi, Jie Tang.\n\nInvestigation: Jie Tang.\n\nProject administration: Jie Tang.\n\nResources: Jie Tang.\n\nSupervision: Jie Tang.\n\nValidation: Jie Tang.\n\nWriting – original draft: Pulkit Gandhi, Jie Tang.\n\nWriting – review & editing: Jie Tang.\n\nAbbreviations: C3 = complement component 3, DNAJB9 = DnaJ heat shock protein family (Hsp40) member B9, EM = electron microscopy, ESRD = end-stage renal disease, FGN = fibrillary glomerulonephritis, IgG = immunoglobulin G, MMF = mycophenolate mofetil.\n\nHow to cite this article: Gandhi P, Tang J. Successful treatment of a unique case of congophilic fibrillary glomerulonephritis: a case report. Medicine. 2020;99:28(e21101).\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nThe authors have no funding and conflicts of interests to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Alpers CE Rennke HG Hopper J Jr \nFibrillary glomerulonephritis: an entity with unusual immunofluorescence features\n. Kidney Int \n1987 ;31 :781 –9\n.3106698 \n[2] Iskandar SS Falk RJ Jennette JC \nClinical and pathologic features of fibrillary glomerulonephritis\n. Kidney Int \n1992 ;42 :1401 –7\n.1474772 \n[3] Yang GC Nieto R Stachura I \nUltrastructural immunohistochemical localization of polyclonal IgG, C3, and amyloid P component on the Congo red-negative amyloid-like fibrils of fibrillary glomerulopathy\n. Am J Pathol \n1992 ;141 :409 –19\n.1497092 \n[4] Nasr SH Valeri AM Cornell LD \nFibrillary glomerulonephritis: a report of 66 cases from a single institution\n. Clin J Am Soc Nephrol \n2011 ;6 :775 –84\n.21441134 \n[5] Nasr SH Vrana JA Dasari S \nDNAJB9 is a specific immunohistochemical marker for fibrillary glomerulonephritis\n. Kidney Int Rep \n2018 ;3 :56 –64\n.29340314 \n[6] Skinner M Sanchorawala V Seldin DC \nHigh-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study\n. Ann Intern Med \n2004 ;140 :85 –93\n.14734330 \n[7] Javaugue V Karras A Glowacki F \nLong-term kidney disease outcomes in fibrillary glomerulonephritis: a case series of 27 patients\n. Am J Kidney Dis \n2013 ;62 :679 –90\n.23759297 \n[8] Alexander MP Dasari S Vrana JA \nCongophilic fibrillary glomerulonephritis: a case series\n. Am J Kidney Dis \n2018 ;72 :325 –36\n.29866458 \n[9] Andeen NK Yang HY Dai DF \nDnaJ homolog subfamily B member 9 is a putative autoantigen in fibrillary GN\n. J Am Soc Nephrol \n2018 ;29 :231 –9\n.29097624 \n[10] Dasari S Alexander MP Vrana JA \nDnaJ heat shock protein family B member 9 Is a novel biomarker for fibrillary GN\n. J Am Soc Nephrol \n2018 ;29 :51 –6\n.29097623\n\n",
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"mesh_terms": "D001706:Biopsy; D003937:Diagnosis, Differential; D004791:Enzyme Inhibitors; D005921:Glomerulonephritis; D005938:Glucocorticoids; D006801:Humans; D007678:Kidney Glomerulus; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009173:Mycophenolic Acid; D011241:Prednisone",
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"title": "Successful treatment of a unique case of congophilic fibrillary glomerulonephritis: A case report.",
"title_normalized": "successful treatment of a unique case of congophilic fibrillary glomerulonephritis a case report"
}
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"literaturereference": "GANDHI P, TANG J.. SUCCESSFUL TREATMENT OF A UNIQUE CASE OF CONGOPHILIC FIBRILLARY GLOMERULONEPHRITIS: A CASE REPORT.. MEDICINE (BALTIMORE). 2020?99(28):E21101",
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"abstract": "The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer has changed dramatically with the introduction and widespread use of HER2-targeted therapies. There is, however, relatively limited real-world information about the effectiveness and safety of trastuzumab emtansine (T-DM1) in Hong Kong Chinese patients. We assessed the efficacy and toxicity profiles among local patients with HER2-positive advanced breast cancer who had received T-DM1 therapy in the second-line setting and beyond.\n\n\n\nThis retrospective study involved five local centres that provide service for over 80% of the breast cancer population in Hong Kong. The study period was from December 2013 to December 2015. Patients were included if they had recurrent or metastatic histologically confirmed HER2+ breast cancer who had progressed after at least one line of anti-HER2 therapy including trastuzumab. Patients were excluded if they received T-DM1 as first-line treatment for recurrent or metastatic HER2+ breast cancer. Patient charts including biochemical and haematological profiles were reviewed for background information, T-DM1 response, and toxicity data. Adverse events were documented during chemotherapy and 28 days after the last dose of medication.\n\n\n\nAmong 37 patients being included in this study, 28 (75.7%) had two or more lines of anti-HER2 agents and 26 (70.3%) had received two or more lines of palliative chemotherapy. Response assessment revealed that three (8.1%) patients had a complete response, eight (21.6%) a partial response, 11 (29.7%) a stable disease, and 12 (32.4%) a progressive disease; three patients could not be assessed. The median duration of response was 17.3 (95% confidence interval, 8.4-24.8) months. The clinical benefit rate (complete response + partial response + stable disease, ≥12 weeks) was 37.8% (95% confidence interval, 22.2%-53.5%). The median progression-free survival was 6.0 (95% confidence interval, 3.3- 9.8) months and the median overall survival had not been reached by the data cut-off date. Grade 3 or 4 toxicities included thrombocytopaenia (13.5%), raised alanine transaminase (8.1%), anaemia (5.4%), and hypokalaemia (2.7%). No patient died as a result of toxicities.\n\n\n\nIn patients with HER2-positive advanced breast cancer who have been heavily pretreated with anti-HER2 agents and cytotoxic chemotherapy, T-DM1 is well tolerated and provided a meaningful progression-free survival of 6 months and an overall survival that has not been reached. Further studies to identify appropriate patient subgroups are warranted.",
"affiliations": "Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong.;Department of Clinical Oncology, Queen Mary Hospital, Pokfulam, Hong Kong.;Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong.;Department of Clinical Oncology, Queen Elizabeth Hospital, Jordan, Hong Kong.;Department of Clinical Oncology, Tuen Mun Hospital, Tuen Mun, Hong Kong.;Comprehensive Clinical Trials Unit, Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong.;Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong.;Department of Clinical Oncology, Tuen Mun Hospital, Tuen Mun, Hong Kong.;Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.;Department of Clinical Oncology, Queen Elizabeth Hospital, Jordan, Hong Kong.;Department of Clinical Oncology, Prince of Wales Hospital, Shatin, Hong Kong.;Department of Clinical Oncology, Queen Elizabeth Hospital, Jordan, Hong Kong.",
"authors": "Yeo|W|W|;Luk|M Y|MY|;Soong|I S|IS|;Yuen|T Ys|TY|;Ng|T Y|TY|;Mo|F Kf|FK|;Chan|K|K|;Wong|S Y|SY|;Tsang|J|J|;Leung|C|C|;Suen|J Js|JJ|;Ngan|R Kc|RK|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D008453:Maytansine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine",
"country": "China",
"delete": false,
"doi": "10.12809/hkmj176808",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-2708",
"issue": "24(1)",
"journal": "Hong Kong medical journal = Xianggang yi xue za zhi",
"keywords": "Breast neoplasms; Trastuzumab",
"medline_ta": "Hong Kong Med J",
"mesh_terms": "D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D005260:Female; D006723:Hong Kong; D006801:Humans; D008453:Maytansine; D008875:Middle Aged; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D016019:Survival Analysis; D000068878:Trastuzumab",
"nlm_unique_id": "9512509",
"other_id": null,
"pages": "56-62",
"pmc": null,
"pmid": "29326401",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2-positive breast cancer.",
"title_normalized": "efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2 positive breast cancer"
}
|
[
{
"companynumb": "HK-ROCHE-2073134",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ADO-TRASTUZUMAB EMTANSINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "125427",
"drugbatchnumb": "UNKNOWN",
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"drugindication": "HER-2 POSITIVE BREAST CANCER",
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"medicinalproduct": "TRASTUZUMAB EMTANSINE"
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Hypokalaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sepsis",
"reactionmeddraversionpt": "22.0",
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},
{
"reactionmeddrapt": "Hypoalbuminaemia",
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},
{
"reactionmeddrapt": "Nausea",
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},
{
"reactionmeddrapt": "Dyspepsia",
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},
{
"reactionmeddrapt": "Peripheral sensory neuropathy",
"reactionmeddraversionpt": "22.0",
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},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "22.0",
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},
{
"reactionmeddrapt": "Blood alkaline phosphatase increased",
"reactionmeddraversionpt": "22.0",
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},
{
"reactionmeddrapt": "Stomatitis",
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},
{
"reactionmeddrapt": "Decreased appetite",
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},
{
"reactionmeddrapt": "Rash",
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},
{
"reactionmeddrapt": "Hypoaesthesia",
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},
{
"reactionmeddrapt": "Blood creatinine increased",
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},
{
"reactionmeddrapt": "Myalgia",
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},
{
"reactionmeddrapt": "Hyperbilirubinaemia",
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},
{
"reactionmeddrapt": "Leukopenia",
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},
{
"reactionmeddrapt": "Fatigue",
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},
{
"reactionmeddrapt": "Blood urea increased",
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},
{
"reactionmeddrapt": "Hyponatraemia",
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},
{
"reactionmeddrapt": "Ejection fraction decreased",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Alanine aminotransferase increased",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aspartate aminotransferase increased",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Malaise",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YEO W, LUK M, SOONG I, YUEN T, NG T, MO F, CHAN K, WONG S, TSANG J, LEUNG C, SUEN J AND NGAN R. EFFICACY AND TOLERABILITY OF TRASTUZUMAB EMTANSINE IN ADVANCED HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2-POSITIVE BREAST CANCER. HONG KONG MEDICAL JOURNAL 2018 JAN 12?24 (1):56-62.",
"literaturereference_normalized": "efficacy and tolerability of trastuzumab emtansine in advanced human epidermal growth factor receptor 2 positive breast cancer",
"qualification": "1",
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"primarysourcecountry": "HK",
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "Here, we present possible death caused by Mycobacterium gordonae infection in a patient with angioimmunoblastic T-cell lymphoma. Our patient was severely immunocompromised in whom we suspect to an infection, but we did not have isolates until she died. After she died, we received a positive sputum culture of M. gordonae. We conclude that when having severely immunocompromised patients with suspicion of infection but without isolates we should always consider the saprophytic mycobacteria. These mycobacteria require a long period of isolation, but patients with these mycobacteria are potentially curable if appropriate treatment is applied for a sufficiently long period.",
"affiliations": "Department of Hematology and Oncology, General Hospital Dr. Josip Benčević, Andrije Štampara 42, Slavonski Brod 35000, Croatia.;Department of Hematology and Oncology, General Hospital Dr. Josip Benčević, Andrije Štampara 42, Slavonski Brod 35000, Croatia.;Department of Hematology and Oncology, General Hospital Dr. Josip Benčević, Andrije Štampara 42, Slavonski Brod 35000, Croatia.",
"authors": "Holik|Hrvoje|H|;Ljubičić|Ivana Vučinić|IV|;Coha|Božena|B|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.4103/ijmy.ijmy_37_17",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2212-5531",
"issue": "6(2)",
"journal": "International journal of mycobacteriology",
"keywords": null,
"medline_ta": "Int J Mycobacteriol",
"mesh_terms": "D000368:Aged; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016399:Lymphoma, T-Cell; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria",
"nlm_unique_id": "101615660",
"other_id": null,
"pages": "199-201",
"pmc": null,
"pmid": "28559527",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Death caused by possible unrecognized (too Late Recognized) Mycobacterium gordonae infection in a patient with angioimmunoblastic T-cell lymphoma.",
"title_normalized": "death caused by possible unrecognized too late recognized mycobacterium gordonae infection in a patient with angioimmunoblastic t cell lymphoma"
}
|
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{
"abstract": "Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.",
"affiliations": "Dr.RMLIMS, Department of Nephrology, Vibhuti Khand, Gomti Nagar, Lucknow, 226010, India.;Dr.RMLIMS, Department of Nephrology, Vibhuti Khand, Gomti Nagar, Lucknow, 226010, India.;Dr.RMLIMS, Department of Pathology, Vibhuti Khand, Gomti Nagar, Lucknow, 226010, India.",
"authors": "Chandra|Abhilash|A|http://orcid.org/0000-0002-9055-4351;Rao|Namrata|N|http://orcid.org/0000-0002-5733-4218;Malhotra|Kiran Preet|KP|http://orcid.org/0000-0002-4400-9168",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "Brazil",
"delete": false,
"doi": "10.1590/2175-8239-JBN-2019-0123",
"fulltext": "\n==== Front\nJ Bras Nefrol\nJ Bras Nefrol\njbn\nJornal Brasileiro de Nefrologia\n0101-2800 2175-8239 Sociedade Brasileira de Nefrologia \n\n32353102\n10.1590/2175-8239-JBN-2019-0123\nCase Report\nRenal tuberculosis in an imatinib-treated chronic myeloid leukemia\nTuberculose renal em paciente com leucemia mieloide crônica tratado com imatinibe http://orcid.org/0000-0002-9055-4351Chandra Abhilash 1 http://orcid.org/0000-0002-5733-4218Rao Namrata 1 http://orcid.org/0000-0002-4400-9168Malhotra Kiran Preet 2 \n1 Dr.RMLIMS, Department of Nephrology, Vibhuti Khand, Gomti Nagar, Lucknow, 226010, India.\n\n2 Dr.RMLIMS, Department of Pathology, Vibhuti Khand, Gomti Nagar, Lucknow, 226010, India.\nCorrespondence to: Namrata Rao. E-mail: [email protected]\nCONFLICT OF INTEREST\n\n\nThis project did not receive financial support from anywhere. Authors have no conflict of interest to declare.\n\n\nAUTHORS’ CONTRIBUTION\n\n\nAll authors have contributed in the manuscript preparation as per International Committee of Medical Journal Editors (ICMJE) recommendations.\n\n\n27 4 2020 \nJul-Sep 2020 \n42 3 366 369\n05 7 2019 27 1 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.ABSTRACT\nImatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.\n\nRESUMO\nO imatinibe, um inibidor da atividade da tirosina-quinase da proteína BCR-ABL, faz parte do padrão de tratamento para leucemia mieloide crônica (LMC). Por conta de seu efeito imunomodulador, o imatinibe afeta a função dos linfócitos T de várias maneiras ao inibir a sua ativação e proliferação induzidas por antígenos. Linfócitos T e macrófagos antígeno-específicos são vitais para a proteção contra o Mycobacterium tuberculosis. O presente artigo relata um caso de tuberculose renal associada a terapia com imatinibe na fase de manutenção da LMC. Com nefrite intersticial granulomatosa e positividade para DNA de M. tuberculosis na biópsia renal, o paciente foi tratado com sucesso com terapia antituberculínica. O presente caso corrobora a hipótese de que a terapia com imatinibe na LMC aumenta a suscetibilidade à tuberculose, exigindo vigilância rigorosa para permitir sua detecção e tratamento precoces.\n\nKeywords:\nImatinib MesylateTuberculosisLeukemia, Myelogenous, Chronic, BCR-ABL PositivePalavras-chave:\nMesilato de ImatinibTuberculoseLeucemia Mielogênica Crônica BCR-ABL Positiva\n==== Body\nINTRODUCTION\nChronic myeloid leukemia (CML) is a myeloproliferative disorder. In CML, chromosomal translocation of the Bcr gene to Abl gene produces the Bcr-Abl fusion protein. Imatinib, a widely used drug in the treatment of CML, inhibits constitutive tyrosine kinase activity of Bcr-Abl protein.\n\nTuberculosis (TB) remains one of the biggest health issues in India. The incidence of TB in India is one of the highest in the world: 2.15 million TB cases were notified in India in the year 2018 1. Poor immune status is one of the important risk factors for developing the disease. Other known risk factors include old age, male sex, diabetes mellitus, chronic obstructive airway disease, end stage renal disease 2, chronic liver disease, and certain malignancies. Association of TB with CML is not consistent. Silva et al. reported a very low prevalence of TB in CML patients as compared to other hematological malignancies (2.2%) 3.\n\nHere, we present a case of CML with disseminated TB presenting with features of renal dysfunction and minimal pulmonary symptoms where the used therapeutic drug, imatinib, was a contributing factor.\n\nCASE\nA 29-year-old male was diagnosed as having BCR-ABL-positive CML, and imatinib mesylate therapy was initiated (400 mg/day) about two years ago (age 27 yrs.). Three months post-initiation, the imatinib dosage was increased to 600 mg/day. The patient responded well to the therapy. BCR-ABL/ABL ratio (%) showed a gradual decline from 60.36% at the start of therapy to 0.08% at the time of presentation. During therapy, he developed anorexia and nausea that persisted for 2 months prompting his physician to perform a thorough evaluation. By investigation results he was found to be anemic (Hb-9g/dL). Total leucocyte and platelet counts were normal. Serum creatinine had risen to a value of 1.99 mg/dL from a baseline of 1.1. Serologic test results for human immunodeficiency virus and hepatitis B and C virus were negative, and liver function tests were normal. Urine examination showed 1+ proteinuria with 20-25 rbc/hpf and 4-5 wbc/hpf. With these findings, he was referred to the department of Nephrology. In view of deteriorating renal functions, proteinuria, and active urinary sediments he was taken for a renal biopsy, which revealed granulomatous interstitial nephritis (Figures 1 and 2). No CD117 or myeloperoxidase positive cells were seen in the interstitium (Figures 2 and 3). Finding from Ziehl-Neelsen stain was negative for AFB and Mantoux test was negative. Renal tissue PCR was positive for tubercular DNA. A urine sample was subjected to BACTEC Mycobacteria Growth Indicator Tube [MGIT] culture, which turned out to be positive. A thorax CT scan was done to look for a primary source of TB, which revealed an area of collapse and consolidation in the posterior segment of the right upper lobe and lateral segment of the right middle lobe. The apico-posterior segment of the left upper lobe showed cavitary changes. Multiple enlarged para-aortic, precarinal, and subcarinal lymph nodes were also seen. In spite of the prominent findings in the CT scan, the patient had no symptoms pertaining to his respiratory system. Also, there was no complaint of fever or significant weight loss. He was never before evaluated for latent TB nor had any history of treatment for tuberculosis in the past. Anti-tubercular therapy comprising of isoniazid, rifampicin, pyrazinamide, and ethambutol was initiated. This was followed by symptomatic improvement, and serum creatinine settled to a value of 1.3 mg/dL. Imatinib therapy was continued at a dose of 600 mg/day. Antitubercular therapy was continued for a total of six months.\n\n\nFigure 1 Section from renal biopsy showing two unremarkable and one sclerosed glomerulus. Moderate lymphocytic infiltrate is seen in the interstitium with a granuloma (arrow) and a Langhan's giant cell (asterisk). Periodic Acid Schiff, x200 magnification.\n\n\n\n\nFigure 2 Section from renal biopsy without any CD117-positive cell in the interstitium (diaminobenzidine, x100 magnification).\n\n\n\n\nFigure 3 Section from renal biopsy without any myeloperoxidase-positive cell in the interstitium (diaminobenzidine, x100 magnification).\n\n\n\nDISCUSSION\nThe relationship between CML and TB is not very clear. While some studies have reported a higher incidence of TB in CML,4 others have not found strong evidence of a relationship 3. Possibly, different study designs and regional variations of disease incidence have contributed to the different outcomes.\n\nBeing the first line of treatment in CML, imatinib has other immunological implications as well, including an immunomodulatory effect and T cell function modulation in a number of ways. It inhibits antigen-induced T cell activation and proliferation, and inhibits phosphorylation of zap70, a member of the tyrosine kinase family thereby interfering in T cell receptor-related signaling cascade. Cytokine production is also impaired 5. In addition, imatinib has been shown to cause accumulation of cells in G0/G1 phase of the cell cycle and inhibit delayed type hypersensitivity, thereby leading to a rise in number of infections 6. However, these effects have been found to be reversible on discontinuation of the drug 6. Imatinib also impairs the function of antigen-presenting dendritic cells along with recall response of specific memory CD8T cell 7. Reduction of immunoglobulin levels are also seen in patients treated with imatinib. This effect is more pronounced in those with better cytogenetic response, which could be due to B cell dysfunction associated with ABL inhibition by imatinib 8.\n\nConsidering the fact that our patient had responded well to imatinib and was on maintenance therapy, the predisposing factor behind his active TB could well have been the drug itself by the above detailed mechanisms.\n\nTB is either acquired through transmission from a person with active disease or activation of a latent infection. The above immune changes brought by imatinib can provide fertile ground for active TB through either route. Although similar cases of TB have been reported with imatinib therapy in CML 9\n,\n10\n, to the best of our knowledge renal involvement has never been reported so far. Daniels et al. 9 reported three such cases. Two had pulmonary TB while one presented as a paravertebral mass. The dose of imatinib in these cases varied from 400 to 800 mg/day. Similar to our case, all these responded well to anti-tuberculous therapy (ATT). Another case of meningeal tuberculoma in a patient with CML on imatinib 400 mg/day was reported by Pravin Salunke et al. 11.\n\nThe dose required to inhibit T cell proliferation was found to be 400 mg by Dietz et al. 6, which is actually lower than what our patient was taking. This could be one of the reasons behind his susceptibility to TB infection and anergy to Mantoux test. Reduction in the maintenance dosage of imatinib is also a viable option in those who achieve good response in the early phase of the treatment 12\n,\n13. This strategy might help negate some of the overt side effects of the drug. As rifampicin is a CYP3A4 inducer, the dose of imatinib needs to be increased by approximately 50% 14. However, in our case imatinib was continued at the same dose of 600 mg/day on account of the low level of CML disease status.\n\nGranulomatous interstitial nephritis has been found to be associated with antibiotics, analgesics, and infections like tuberculosis, fungal infections, sarcoidosis, and granulomatosis with polyangiitis 15. In our case, positivity of tissue PCR for tubercular DNA, positive urine culture for Mycobacterium tuberculosis and good response to therapy clearly indicated the tubercular cause of granulomas in the renal tissue. Absence of CD117 and myeloperoxidase-positive cells in the interstitium rules out the possibility of myelogenous cause of the reported interstitial nephritis. Similar findings in cases of renal tuberculosis have also been reported by Daher et al. 16.\n\nCONCLUSION\nThis case raises the hypothesis that imatinib therapy in CML can increase the susceptibility to infections including TB, probably by affecting the acquired immunity through its influence on specific T cells. Assessment of the risk of TB infection prior to imatinib therapy can help in preventing the disease. Atypical clinical presentation of TB infection in such cases necessitates high degree of suspicion, particularly in endemic regions.\n==== Refs\nREFERENCES\n1 Ministry of Health and Family Welfare (IND) TB India Report 2018: Central of Tuberculosis Division - Government of India Internet India Ministry of Health 2018 https://tbcindia.gov.in \n2 Hu HY Wu CY Huang N Chou YJ Chang YC Chu D Increased risk of tuberculosis in patients with end-stage renal disease: a population-based cohort study in Taiwan, a country of high incidence of end-stage renal disease Epidemiol Infect 1 2014 142 1 191 199 23510593 \n3 Silva FA Matos JO Mello FCQ Nucci M Risk factors for and attributable mortality from tuberculosis in patients with hematologic malignances Haematologica 2005 90 8 1110 1115 16079111 \n4 Liu CJ Hong YC Teng CJ Hung MH Hu YW Ku FC Risk and impact of tuberculosis in patients with chronic myeloid leukemia: a nationwide population-based study in Taiwan Int J Cancer 4 2015 136 8 1881 1887 25208807 \n5 Seggewiss R Loré K Greiner E Magnusson MK Price DA Douek DC Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner Blood 3 2005 105 6 2473 2479 15572591 \n6 Dietz AB Souan L Knutson GJ Bulur PA Litzow MR Vuk-Pavlovic S Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo Blood 8 2004 104 4 1094 1099 15100154 \n7 Sinai P Berg RE Haynie JM Egorin MJ Ilaria RL Junior Forman J Imatinib mesylate inhibits antigen-specific memory CD8 T cell responses in vivo J Immunol 2007 178 2028 2037 17277106 \n8 Steegmann JL Moreno G Aláez C Osorio S Granda A Cámara R Chronic myeloid leukemia patients resistant to or intolerant of interferon alpha and subsequently treated with imatinib show reduced immunoglobulin levels and hypogammaglobulinemia Haematologica 7 2003 88 7 762 768 12857554 \n9 Daniels JM Vonk-Noordegraaf A Janssen JJ Postmus PE Van Altena R Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia Eur Respir J 3 2009 33 3 670 672 19251803 \n10 Ghadyalpati N Prabhash K Menon H Nair R Banavali S Noronha V Tuberculosis infection in chronic myeloid leukemia (CML) patients treated with imatinib J Clin Oncol 2010 28 15 Suppl 1 6594 6594 \n11 Salunke P Gupta K Singla N Singh H Singh P Mukherjee KK Meningeal tuberculoma mimicking chloroma in a patient with chronic myeloid leukemia on imatinib. Neurol India 2011 59 628 630 21891950 \n12 Petzer AL Fong D Lion T Dyagil I Masliak Z Bogdanovic A High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients - final analysis of a randomized, multicenter, phase III trial Haematologica 10 2012 97 10 1562 1569 22511495 \n13 Faber E Divoká M Skoumalová I Novák M Marešová I Mičová K A lower dosage of imatinib is sufficient to maintain undetectable disease in patients with chronic myeloid leukemia with long-term low-grade toxicity of the treatment Leuk Lymphoma 2 2016 57 2 370 375 26022524 \n14 Sorà F Matteis S Di Mario A Maiuro G Laurenti L Chiusolo P Antituberculosis therapy and imatinib for chronic myeloid leukemia Clin Infect Dis 11 2006 43 9 1224 1224 \n15 Shan S Carter-Monroe N Atta MG Granulomatous interstitial nephritis Clin Kidney J 2015 8 5 516 523 26413275 \n16 Ede FD Silva GB Junior Barros EJ Renal tuberculosis in the modern era Am J Trop Med Hyg 1 2013 88 1 54 64 23303798\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0101-2800",
"issue": "42(3)",
"journal": "Jornal brasileiro de nefrologia : 'orgao oficial de Sociedades Brasileira e Latino-Americana de Nefrologia",
"keywords": null,
"medline_ta": "J Bras Nefrol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D010879:Piperazines; D011743:Pyrimidines; D014398:Tuberculosis, Renal",
"nlm_unique_id": "9426946",
"other_id": null,
"pages": "366-369",
"pmc": null,
"pmid": "32353102",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17277106;26413275;15572591;21891950;19251803;26022524;25208807;23303798;22511495;12857554;23510593;16079111;17029152;15100154",
"title": "Renal tuberculosis in an imatinib-treated chronic myeloid leukemia.",
"title_normalized": "renal tuberculosis in an imatinib treated chronic myeloid leukemia"
}
|
[
{
"companynumb": "IN-SHILPA MEDICARE LIMITED-SML-IN-2021-00059",
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{
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},
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"medicinalproduct": "IMATINIB, UNKNOWN"
},
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Renal tuberculosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tubulointerstitial nephritis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disseminated tuberculosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "CHANDRA A, RAO N, MALHOTRA K. RENAL TUBERCULOSIS IN AN IMATINIB TREATED CHRONIC MYELOID LEUKEMIA. THE BRAZILIAN JOURNAL OF NEPHROLOGY. 2020 JAN 27?42(3):366?369. DOI:10.1590/2175?8239?JBN?2019?0123",
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},
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}
] |
{
"abstract": "Blister formation and eccrine sweat gland necrosis have been recognized to occur in states of impaired consciousness and were first reported following barbiturate intoxication. Their etiology is complex and cannot simply be explained by pressure effects. Now that barbiturates are less frequently used, clinicians are likely to be less aware of the phenomenon of coma blister formation; however, newer drugs have also been associated with the occurrence of coma blisters. We describe 2 new associations of coma blisters and anticonvulsants in children. In the first child, blisters recurred on multiple occasions along with obtundation and edema. Our aims are to alert clinicians to the occurrence of coma blisters in children sedated on anticonvulsant medications and to report the new finding of recurrent coma blisters.",
"affiliations": "Department of Paediatric Neurology, Newcastle General Hospital, Newcastle Upon Tyne, United Kingdom. [email protected]",
"authors": "Basu|Anna|A|;Brown|Sara|S|;Kirkham|Nigel|N|;Ramesh|Venkateswaran|V|;Leech|Suzy|S|;Devlin|Anita|A|",
"chemical_list": "D000927:Anticonvulsants",
"country": "United States",
"delete": false,
"doi": "10.1177/0883073809332771",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "24(8)",
"journal": "Journal of child neurology",
"keywords": null,
"medline_ta": "J Child Neurol",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D001768:Blister; D002648:Child; D004487:Edema; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "1021-5",
"pmc": null,
"pmid": "19359256",
"pubdate": "2009-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Coma blisters in 2 children on anticonvulsant medication.",
"title_normalized": "coma blisters in 2 children on anticonvulsant medication"
}
|
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},
{
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}
],
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"reaction": [
{
"reactionmeddrapt": "Bronchiolitis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Swelling face",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Seizure",
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},
{
"reactionmeddrapt": "Somnolence",
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},
{
"reactionmeddrapt": "Coma blister",
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},
{
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},
{
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}
],
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},
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{
"abstract": "Methemoglobinemia can result in severe hypoxia. It has been frequently reported during the use of inhaled nitric oxide, but can occur where nitrate containing medications are used. Glyceryl trinitrate (GTN) patches have been used in the treatment of digital and limb ischemia in prematurely born infants. Little is known about the pharmacokinetics of GTN when incorporated into patches. Studies of other topical forms of nitroglycerine have shown a wide range of absorption. It is likely that the increased permeability of the prematurely born infant's skin would facilitate absorption. We describe the use of GTN patches in two very prematurely born infants used to treat limb/digit ischemia. This resulted in methemoglobinemia and resultant increase in their supplementary oxygen requirements. Removal of the patches was associated with a reduction in their methemoglobin levels and the supplementary oxygen requirements back to baseline levels. In conclusion, routine monitoring of methemoglobin levels should be undertaken when GTN patches are used in very prematurely born infants.",
"affiliations": "Neonatal Intensive Care Centre, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.;Neonatal Intensive Care Centre, King's College Hospital NHS Foundation Trust, London, United Kingdom.;MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.;Neonatal Intensive Care Centre, St George's Hospital NHS Foundation Trust, London, United Kingdom.;MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, United Kingdom.",
"authors": "Mintoft|Alison|A|;Williams|Emma|E|;Harris|Christopher|C|;Kennea|Nigel|N|;Greenough|Anne|A|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1055/s-0038-1669945",
"fulltext": "\n==== Front\nAJP RepAJP Rep10.1055/s-00000169AJP Reports2157-69982157-7005Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. 10.1055/s-0038-1669945180020Case ReportMethemoglobinemia during the Use of Glyceryl Trinitrate Patches in Neonates: Two Case Reports Mintoft Alison MRCPCH1Williams Emma MRCPCH2Harris Christopher MRCPCH34Kennea Nigel PhD5Greenough Anne MD(Cantab)3461 Neonatal Intensive Care Centre, Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom2 Neonatal Intensive Care Centre, King's College Hospital NHS Foundation Trust, London, United Kingdom3 MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London, United Kingdom4 Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom5 Neonatal Intensive Care Centre, St George's Hospital NHS Foundation Trust, London, United Kingdom6 NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London, London, United KingdomAddress for correspondence Anne Greenough, MD(Cantab) Neonatal Intensive Care Unit, King's College Hospital4th Floor Golden Jubilee Wing, Denmark Hill, London SE5 9RSUnited [email protected] 2018 15 10 2018 8 4 e227 e229 28 3 2018 26 7 2018 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.Methemoglobinemia can result in severe hypoxia. It has been frequently reported during the use of inhaled nitric oxide, but can occur where nitrate containing medications are used. Glyceryl trinitrate (GTN) patches have been used in the treatment of digital and limb ischemia in prematurely born infants. Little is known about the pharmacokinetics of GTN when incorporated into patches. Studies of other topical forms of nitroglycerine have shown a wide range of absorption. It is likely that the increased permeability of the prematurely born infant's skin would facilitate absorption. We describe the use of GTN patches in two very prematurely born infants used to treat limb/digit ischemia. This resulted in methemoglobinemia and resultant increase in their supplementary oxygen requirements. Removal of the patches was associated with a reduction in their methemoglobin levels and the supplementary oxygen requirements back to baseline levels. In conclusion, routine monitoring of methemoglobin levels should be undertaken when GTN patches are used in very prematurely born infants.\n\nKeywords\nmethemoglobinemiapretermglyceryl trinitrateischemia\n==== Body\nMethemoglobinemia is formed as a result of the oxidization of iron from its ferrous (Fe\n2+\n) to ferric (Fe\n3+\n) state and can occur following exposure not only to inhaled nitric oxide (iNO) but also nitrite containing medications. Methemoglobinemia has been frequently reported in infants treated with iNO.\n1\nThe levels of methemoglobinemia relate to the iNO levels used.\n1\nMethemoglobin has a higher oxygen-binding capacity than hemoglobin and thus affected infants can suffer severe hypoxia. Ischemia can be caused by a combination of vascular damage and concomitant vasoconstriction.\n2\nGlyceryl trinitrate (GTN) patches are used in the treatment of ischemic digits and limbs in neonates\n2\n3\nand in adults.\n4\nGTN is converted to NO in the vascular smooth muscle, and this activates guanylate cyclase and increases the levels of cyclic guanosine monophosphate (cGMP);\n5\ncGMP causes relaxation of the vascular smooth muscle in the affected artery and dilation of the collateral circulation.\n2\nGTN patches, however, remain unlicensed for use in neonates and little is known about the pharmacokinetics of GTN when used in patch formation in prematurely born neonates. Methemoglobinemia is not listed as a side effect of the use of GTN patches. The absorption of nitroglycerin from topical ointments has been shown to be variable in infants. GTN patches vary in size and dose. A 10-cm\n2\npatch typically contains 40 mg of nitroglycerin and is designed to release this at 0.2 mg/h; however, in one study of seven infants, an application of 1 mg in an ointment resulted in blood levels of between 0.03 and 3.36 ng/mL.\n6\nThe skin of prematurely born infants has increased permeability compared with term born infants which might lead to greater absorption of topical treatments.\n7\nWe present two cases of methemoglobinemia which occurred during the use of GTN patches to treat ischemic digits and limbs of very prematurely born infants. In both cases, 9 cm\n2\npatches were used which contained 18.7 mg GTN.\n\n\nCase 1\n\nAn infant with a birth weight of 650 g was born at 24 weeks of gestational age following the onset of spontaneous preterm labor. During initial resuscitation, it was noted that the lower limbs of the infant were dusky and this did not resolve despite improving the blood pressure levels by administering volume replacement and inotropes. One GTN patch was applied to each lower limb over the area of the posterior tibial arteries. These were left in place as the infant was stabilized and transferred to the local tertiary unit. A radial arterial line was inserted the following day, day 2 after birth. The thumb and forefinger distal to the radial arterial line became poorly perfused shortly after insertion and a further GTN patch was applied to the hand. This was in addition to the two patches in situ on the feet. The oxygen requirement was noted to rise from an inspired oxygen fraction (FiO\n2\n) of 0.21 to 0.4 within 6 hours of application of the third patch. The infant's inspired oxygen concentration was altered as necessary to keep the oxygen saturation levels between 92 and 95%. Serial capillary blood gases showed an increase in methemoglobinemia from 1.1% prearterial line insertion to 8.4% over 6 hours. In total, three patches had been applied over the 48-hour period. All patches were immediately removed and the methemoglobinemia level fell to less than 1% within 2 hours. There was a corresponding reduction in the oxygen requirement to the level prior to the application of the patch. Perfusion of the hand and lower limbs completely recovered.\n\n\nCase 2\n\nAn infant with a birth weight of 617 g was born at 24 weeks of gestational age via a vaginal delivery following premature rupture of membranes 1 week previously. After initial resuscitation, the infant was transferred to a tertiary neonatal unit. Umbilical arterial access was not obtained and a right posterior tibial arterial line was inserted on day 2 after birth. The following day, it was noted that it was difficult to sample from the arterial line and to obtain an adequate blood pressure trace. The toes and foot were cool to touch and blanched white on examination. The arterial line was removed and a GTN patch immediately applied and replaced daily. The toes on the right foot became necrotic on day 7 and, following consultation with the vascular team, two GTN patches were applied to the foot, one proximally and one posteriorly to the point where the arterial line had been inserted. The patches were changed twice daily. Over the following 24 hours, the infant's supplementary oxygen requirement increased from an FiO\n2\nof 0.23 to an FiO\n2\nof 0.70. The infant's inspired oxygen concentration was altered as necessary to keep the oxygen saturation levels between 92 and 95%. At that time, it was noted that the methemoglobin level was 14.5%. The GTN patches were immediately removed. A total of 10 patches had been used during the previous 5 days and 5 of those patches had been sited in 24 hours prior to removal of the patches. Over the following 24 hours, the methemoglobin level fell from the highest level of 23.3 to 2.5%, with a corresponding reduction in the oxygenation index (mean airway pressure × FiO\n2\n × 100 divided by PaO\n2\n, kPa), from 24 to 8. The tips of the toes that were necrotic sloughed off after several weeks, but no amputation was required.\n\n\nDiscussion\n\nWe have demonstrated GTN patch use in very prematurely born infants can result in methemoglobinemia. In both infants, this was associated with an increase in their inspired oxygen requirement. In the first case, the ischemia completely resolved, but in the second resolution was incomplete and as a consequence, the toes became necrotic. In both cases due to the development of the methemoglobinemia, the patches were removed prematurely, which may have reduced their efficacy. Previous case reports have suggested a treatment duration of 28 days.\n2\n\n\n\nIt is not clear whether the methemoglobinemia was the cumulative effect of all the patches applied or after a certain number of patches a threshold was reached. It is known, however, that prematurely born infants have lower levels of methemoglobin reductase which makes them more susceptible to methemoglobinemia.\n8\n9\nOnce the patches were removed, the methemoglobin levels decreased and the supplementary oxygen requirement returned to the level prior to treatment with the patches. Thus, we suggest the use of the GTN patches resulted in the methemoglobinemia. As a consequence, we recommend if GTN patches are used in a very prematurely born infant, frequent assessment of methemoglobin levels should be undertaken.\n\n\nConflict of Interest None.\n==== Refs\nReferences\n1 Hamon I Gauthier-Moulinier H Grelet-Dessioux E Storme L Fresson J Hascoet J M Methaemoglobinaemia risk factors with inhaled nitric oxide therapy in newborn infants Acta Paediatr 2010 99 10 1467 1473 20456277 \n2 Vasquez P Burd A Mehta R Hiatt M Hegyi T Resolution of peripheral artery catheter-induced ischemic injury following prolonged treatment with topical nitroglycerin ointment in a newborn: a case report J Perinatol 2003 23 04 348 350 12774147 \n3 Varughese M Koh T H Successful use of topical nitroglycerine in ischaemia associated with umbilical arterial line in a neonate J Perinatol 2001 21 08 556 558 11774020 \n4 Boyce L Dhukaram V Transdermal glyceryl trinitrate in the treatment of ischemia following toe deformity correction: a case series Foot Ankle Int 2014 35 11 1226 1230 25125514 \n5 Ignarro L J Cirino G Casini A Napoli C Nitric oxide as a signaling molecule in the vascular system: an overview J Cardiovasc Pharmacol 1999 34 06 879 886 10598133 \n6 Guran P Beal G Brion N Advenier C Topical nitroglycerin as an aid to insertion of peripheral venous catheters in neonates J Pediatr 1989 115 06 1025 \n7 Pinsker J E McBayne K Edwards M Jensen K Crudo D F Bauer A J Transient hypothyroidism in premature infants after short-term topical iodine exposure: an avoidable risk? Pediatr Neonatol 2013 54 02 128 131 23590958 \n8 Kravitz H Elegant L D Kaiser E Kagan B M Methemoglobin values in premature and mature infants and children AMA J Dis Child 1956 91 01 1 5 13275111 \n9 Haymond S Cariappa R Eby C S Scott M G Laboratory assessment of oxygenation in methemoglobinemia Clin Chem 2005 51 02 434 444 15514101\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2157-7005",
"issue": "8(4)",
"journal": "AJP reports",
"keywords": "glyceryl trinitrate; ischemia; methemoglobinemia; preterm",
"medline_ta": "AJP Rep",
"mesh_terms": null,
"nlm_unique_id": "101569862",
"other_id": null,
"pages": "e227-e229",
"pmc": null,
"pmid": "30345159",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": "13275111;23590958;2511291;10598133;15514101;11774020;12774147;20456277;25125514",
"title": "Methemoglobinemia during the Use of Glyceryl Trinitrate Patches in Neonates: Two Case Reports.",
"title_normalized": "methemoglobinemia during the use of glyceryl trinitrate patches in neonates two case reports"
}
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{
"abstract": "OBJECTIVE\nTo report a case of Corynebacterium striatum endocarditis that was treated successfully with daptomycin plus rifampin following an unsuccessful attempt at vancomycin desensitization and failure of linezolid therapy.\n\n\nMETHODS\nA 46-year-old woman with hemodialysis-dependent chronic renal failure was admitted for a graft-related infection. She presented with C. striatum endocarditis that was treated with daptomycin plus rifampin due to a history of allergies to vancomycin and beta-lactam antibiotics and failure of linezolid therapy. The patient received daptomycin and rifampin for a total of 6 weeks. Three months after completion of treatment, no recurrence of endocarditis was evident.\n\n\nCONCLUSIONS\nDaptomycin is a lipopeptide antibiotic, with rapid bactericidal activity. It has demonstrated efficacy in animal models of staphylococcal, streptococcal, and enterococcal endocarditis. Case reports of its activity in methicillin-resistant Staphylococcus aureus endocarditis have also been documented.\n\n\nCONCLUSIONS\nDaptomycin, which has shown in vitro activity against C. striatum, may be a viable treatment option for patients with C. striatum endocarditis who are either allergic or refractory to traditional antibiotics.",
"affiliations": "Department of Pharmaceutical Services, Newark Beth Israel Medical Center, Newark, NJ 07112-2027, USA. [email protected]",
"authors": "Shah|Monica|M|;Murillo|Jeremias L|JL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017576:Daptomycin; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1345/aph.1G242",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "39(10)",
"journal": "The Annals of pharmacotherapy",
"keywords": null,
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D003352:Corynebacterium; D003354:Corynebacterium Infections; D017576:Daptomycin; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004697:Endocarditis, Bacterial; D005260:Female; D006801:Humans; D008875:Middle Aged; D012293:Rifampin; D016896:Treatment Outcome",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1741-4",
"pmc": null,
"pmid": "16144879",
"pubdate": "2005-10",
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"abstract": "Autoimmune hepatitis (AIH) is a disease of unknown aetiology with drug-induced AIH being the most complex and not fully understood type. We present the case of a 57-year-old female patient with acute icteric hepatitis after interferon-beta-1b (IFNβ-1b) administration for multiple sclerosis (MS). Based on liver autoimmune serology, histology and appropriate exclusion of other liver diseases, a diagnosis of AIH-related cirrhosis was established. Following discontinuation of IFNβ-1b, a complete resolution of biochemical activity indices was observed and the patient remained untreated on her own decision. However, 3 years later, after a course of intravenous methylprednisolone for MS, a new acute transaminase flare was recorded which subsided again spontaneously after 3 weeks. Liver biopsy and elastography showed significant fibrosis regression (F2 fibrosis). To our knowledge, this is the first report showing spontaneous cirrhosis regression in an IFNβ-1b-induced AIH-like syndrome following drug withdrawal, suggesting that cirrhosis might be reversible if the offending fibrogenic stimulus is withdrawn.\nAutoimmune hepatitis (AIH) is a very heterogeneous liver disease of unknown aetiology, with drug-induced AIH being the most complex and not fully understood type.Intravenous methylprednisolone pulse administration may reactivate or unmask previously unrecognised or misdiagnosed AIH and therefore liver autoimmune serology should be sought for every patient with acute or chronic hepatitis in the absence of viral, metabolic, genetic and alcoholic causes of liver disease.Spontaneous regression of cirrhosis, although controversial, may occur if the offending fibrogenic stimuli are immediately withdrawn as shown in this case of IFNβ-1b-induced AIH.",
"affiliations": "Department of Gastroenterology, University Hospital of Patras, Greece.;Department of Gastroenterology, University Hospital of Patras, Greece.;Department of Pathology, University Hospital of Patras, Greece.;Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece.",
"authors": "Kalafateli|Maria|M|;Triantos|Christos|C|;Tsamandas|Athanasios|A|;Dalekos|George N|GN|",
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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 10.12890/2016_000396396-1-2754-1-10-20160420ArticlesSpontaneous Cirrhosis Regression in an IFN-beta-induced AIH-like Syndrome Following Drug Withdrawal: Art of Facts or Artifacts? Kalafateli Maria 1Triantos Christos 1Tsamandas Athanasios 2Dalekos George N. 3\n1 Department of Gastroenterology, University Hospital of Patras, Greece\n2 Department of Pathology, University Hospital of Patras, Greece\n3 Department of Medicine and Research Laboratory of Internal Medicine, School of Medicine, University of Thessaly, Larissa, Greece2016 20 4 2016 3 4 00039621 1 2016 30 1 2016 © EFIM 20162016This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseAutoimmune hepatitis (AIH) is a disease of unknown aetiology with drug-induced AIH being the most complex and not fully understood type. We present the case of a 57-year-old female patient with acute icteric hepatitis after interferon-beta-1b (IFNβ-1b) administration for multiple sclerosis (MS). Based on liver autoimmune serology, histology and appropriate exclusion of other liver diseases, a diagnosis of AIH-related cirrhosis was established. Following discontinuation of IFNβ-1b, a complete resolution of biochemical activity indices was observed and the patient remained untreated on her own decision. However, 3 years later, after a course of intravenous methylprednisolone for MS, a new acute transaminase flare was recorded which subsided again spontaneously after 3 weeks. Liver biopsy and elastography showed significant fibrosis regression (F2 fibrosis). To our knowledge, this is the first report showing spontaneous cirrhosis regression in an IFNβ-1b-induced AIH-like syndrome following drug withdrawal, suggesting that cirrhosis might be reversible if the offending fibrogenic stimulus is withdrawn.\n\nLEARNING POINTS\nAutoimmune hepatitis (AIH) is a very heterogeneous liver disease of unknown aetiology, with drug-induced AIH being the most complex and not fully understood type.\n\nIntravenous methylprednisolone pulse administration may reactivate or unmask previously unrecognised or misdiagnosed AIH and therefore liver autoimmune serology should be sought for every patient with acute or chronic hepatitis in the absence of viral, metabolic, genetic and alcoholic causes of liver disease.\n\nSpontaneous regression of cirrhosis, although controversial, may occur if the offending fibrogenic stimuli are immediately withdrawn as shown in this case of IFNβ-1b-induced AIH.\n\nAutoimmune hepatitiscirrhosisdrug-induced liver injuryinterferon-betamultiple sclerosis\n==== Body\nINTRODUCTION\nAutoimmune hepatitis (AIH) is an acute or chronic liver disease of unknown aetiology that mainly affects women and is characterized by circulating autoantibodies, interface hepatitis on liver histology, favourable response to immunosuppression and hypergammaglobulinaemia even in the absence of cirrhosis[1,2]. The disease can sometimes demonstrate quite dramatic disease fluctuations with periods of apparent spontaneous remission, acute flares and/or smouldering disease[1,2].\n\nOf the several diagnostic challenges associated with this disease, the issue of drug-induced AIH is the most complex and is not fully understood. There seem to be three scenarios: (a) drug-induced liver injury (DILI) with a strong immune component mimicking AIH; (b) AIH mimicking DILI due to drug exposure in recent weeks and spontaneous improvement after cessation of drug exposure; and (c) AIH triggered by an offending drug (DILI-induced AIH)[2]. On the other hand, although cirrhosis is widely regarded as an irreversible end stage of chronic liver disease, there is recent evidence supporting the possibility of its reversibility or significant regression in cases of effective treatment of the underlying conditions[3]. In this context, some reports have already shown the reversibility of fibrosis and cirrhosis in AIH patients after favourable response to immunosuppression. However, to our knowledge spontaneous cirrhosis regression in DILI-induced AIH-like syndrome following drug withdrawal has not been reported so far.\n\nCASE REPORT\nA 57-year-old Caucasian female with a history of multiple sclerosis (MS) under interferon-beta-1b (IFNβ-1b) treatment for the previous 2 years was admitted because of acute icteric hepatitis accompanied by flatulence and considerable fatigue. On admission, she had no fever but she was jaundiced, while the remaining physical examination was unrevealing. She denied ever consumption of herbal agents and/or dietary supplements, intravenous or nasal illicit drugs, or alcohol use.\n\nTotal bilirubin (5 mg/dL), direct bilirubin (2.8 mg/dL), AST (474 IU/L), ALT (597 IU/L), γ-GT (144 IU/L) and INR (1.36), were elevated, whereas complement component C4 was characteristically low (13.6 mg/dL; low limit of normal 18 mg/dL). The remaining haematological, virological and biochemical parameters including IgG levels, were within normal limits. Abdominal ultrasonography was also normal. Liver autoimmune serology by indirect immunofluorescence on in-house freshly frozen rodent substrate that includes kidney, liver and stomach according to our standard protocols[1,4], revealed anti-nuclear antibodies (ANA) titre 1:80 (positive titre ≥1:40) and smooth muscle antibodies (SMA) titre 1:320 (positive titre ≥1:40). Additional testing for liver/kidney microsomal antibodies type 1 (anti-LKM1) and type 3 (anti-LKM3), liver cytosol antibodies and antibodies against soluble liver antigens/liver pancreas (anti-SLA/LP) by Western immunoblot using in-house rat liver microsomal and cytosolic extracts showed profound reactivity for anti-LKM3 and anti-SLA/LP antibodies. Liver biopsy revealed interface hepatitis with moderate portal inflammation consisting of lymphocytes and plasma cells, hepatocyte swelling and mild cholangiolar hyperplasia but without inflammatory lymphocytic infiltrate of the bile ducts and incomplete and complete cirrhotic nodules with obvious extensive portal to portal and portal to central bridging fibrosis (Fig. 1 A,B).\n\nBased on liver autoimmune serology (presence of ANA, SMA, anti-LKM3 and anti-SLA/LP), the histological findings and appropriate exclusion of other liver diseases, a diagnosis of DILI-induced (IFNβ-1b-induced) AIH-related cirrhosis was established[2]. IFNβ-1b was immediately discontinued and a combination treatment schedule of prednisolone (1 mg/kg/day) along with azathioprine (1 mg/kg/day) was advised, but the patient refused treatment as following discontinuation of IFNβ-1b, a complete resolution of biochemical activity indices was observed.\n\nThe patient recovered completely and was discharged in very good health with permanent discontinuation of IFNβ-1b and close follow-up by liver ultrasound at 6-month intervals for hepatocellular carcinoma (HCC) screening, regular screening for complications, and close monitoring of AST, ALT and IgG every 3–6 months including follow-up liver biopsy if ALT and/or IgG levels increased or fluctuated[2].\n\nThree years later, a new episode of acute flare of transaminases (AST 123 IU/L, ALT 264 IU/L) was recorded after a course of intravenous methylprednisolone pulses (1 g/day for 3 consecutive days) for MS exacerbation, which again completely subsided spontaneously after 3 weeks. A second liver biopsy at this time along with transient elastography showed significant regression of fibrosis compared to the first biopsy 3 years previously. Liver histology again showed moderate interface hepatitis, hepatocellular rosette formation, hepatocyte swelling and mild cholangiolar hyperplasia. However, neither incomplete nor complete cirrhotic nodules were seen apart from the presence of focal portal to portal bridging fibrosis (stage 2 according to the Ishak staging system) (Fig. 1 C,D). In line with the histological findings (Ishak fibrosis stage 2/6, inflammation grade 8/18), a treatment schedule was recommended to the patient with corticosteroids in combination with azathioprine but the patient again refused any intervention.\n\nDISCUSSION\nThe present case raises the following major points: (a) DILI-induced AIH is an intriguing and complex disorder, which can manifest clinically in different phenotypes across the spectrum of the disease; (b) AIH should never be excluded only because of normal IgG levels; (c) spontaneous biochemical remission despite histological evidence of persisting inflammatory activity in AIH, though infrequent, does exist; (d) treatment with intravenous methylprednisolone pulses could potentially reactivate or unmask previously unrecognised or misdiagnosed AIH; and, most importantly, (e) liver cirrhosis might be regressed if the offending fibrogenic stimuli are immediately withdrawn as shown in this case by the spontaneous cirrhosis regression following IFNβ-1b withdrawal confirmed by both liver biopsy and elastography to avoid sampling error. Indeed, although historically liver biopsy has been the only accepted method to evaluate the severity of hepatic fibrosis in patients with liver disease, the procedure is associated not only with sampling error problems because a liver biopsy sample represents only 1/50,000th of total liver volume, but also with other problems because of intra- and inter-observer variability in assessing fibrosis stage. In contrast, transient elastography effectively samples an area of liver stiffness that is approximately of 1 cm in diameter and 2 cm long, leading to a volume 100 times larger than that of a standard liver biopsy specimen and therefore results in more precise assessment of liver fibrosis. Unfortunately, due to a firm diagnosis after the first liver biopsy (IFNβ-1b-induced AIH-related cirrhosis), at that time we did not perform transient elastography which we could have compared with that performed 3 years later and possibly demonstrated a considerable change in liver stiffness.\n\nLiver dysfunction in MS could be due to many factors such as fatty infiltration, viral infection and DILI, and sometimes the autoimmune process. On the other hand, AIH is associated with a variety of autoimmune conditions including MS[1,2]. In particular, MS patients who are being treated with IFNβ or corticosteroid pulses because of a supposed ‘reconstitution’ of the immune system during interpulse periods, seem to carry a higher risk for autoimmune reactions including either DILI-induced AIH or genuine AIH[1,2].\n\nOf the three DILI/AIH scenarios, DILI-induced AIH seems the most likely in our case, although the presence of cirrhosis at the first liver biopsy suggests that genuine AIH may have already been present and IFNβ-1b and/or pulse corticosteroid administration simply provoked and worsened the disease phenotype.\n\nSpontaneous biochemical remission of the disease would not be unexpected as this is consistent with the fluctuating nature of AIH[1,2]. Such spontaneous apparently biochemical remission is a critical issue that may sometimes result in delay and/or underestimation of AIH diagnosis. This disease behaviour may sometimes explain the presence of previously established cirrhosis in almost one third of patients at the time of initial diagnosis[1,2].\n\nConcerning the absence of hypergammaglobulinaemia in our patient, it should be emphasised that although high levels of serum IgG are found in approximately 85% of AIH patients[1,2,4], this prevalence tends to be lower in those patients with acute onset of disease, a higher proportion of whom (25%–39%) have been reported to have normal IgG levels[2].\n\nFinally, for almost two centuries liver cirrhosis, the name of which is derived from the Greek word κίρρος [kirrhos] meaning tawny, has been considered an irreversible end stage of chronic liver disease. However, this issue is currently a matter of debate as cirrhosis itself comprises a broad spectrum of stages such as pre-cirrhosis or incipient cirrhosis, early cirrhosis, fully developed cirrhosis, advanced cirrhosis and decompensated cirrhosis[3]. If cirrhosis reversibility does actually exist, it most likely does not affect all cirrhosis stages equally. Indeed, the incipient stage and the early cirrhotic stage are the better candidates for reversibility. In light of this, our case perhaps represents early stage cirrhosis, although there was collagen type I accumulation in the connective tissue matrix, which is less frequent compared to collagen type III in early cirrhotic stages. Nevertheless, it should be emphasized that our patient could probably have had an even better outcome with complete resolution of fibrosis and a normal or near normal second liver biopsy if apart from immediate discontinuation of IFNβ, she had not refused the suggested immunosuppression which, according to the recent EASL guidelines, should be offered to all patients with active disease in order to achieve complete biochemical and histological resolution of AIH[2].\n\nIn conclusion, to our knowledge, this is the first report suggesting spontaneous cirrhosis regression in an IFNβ-induced AIH-like syndrome following drug withdrawal. Although this of course is not, and should not be, standard management for AIH cases, our report indicates that liver cirrhosis might be reversible if the offending fibrogenic stimulus is immediately withdrawn.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 (A) Masson’s trichrome ×20.\n\n(B) Masson’s trichrome ×200. Representative microphotographs from the first biopsy which was 2.2 cm long and contained incomplete and complete cirrhotic nodules and 14 PT, and also showed extensive portal to portal and portal to central bridging fibrosis. There is a thick diaphragm of connective tissue (thickness 0.75 mm, green arrows) implying the presence of a cirrhotic nodule (modified Hepatic Activity Index stage 5–6). Collagen type I accumulation in the PT and fibrous septa was counted as 73.8±11.8. Blue areas represent collagen type I.\n\n(B, C) Representative microphotographs from the second biopsy performed 3 years later which was 2.8 cm long and contained 22 PT. There is portal to portal bridging fibrosis. Green arrows point to thin diaphragms of connective tissue (C: thickness 0.08 mm. D: thickness 0.02 mm). Modified Hepatic Activity Index stage 2 and inflammation grade 8/18.\n\nPT: portal tract.\n==== Refs\nREFERENCES\n1 Zachou K Muratori P Koukoulis GK Granito A Gatselis N Fabbri A Review article: autoimmune hepatitis - current management and challenges Aliment Pharmacol Ther 2013 38 887 913 24010812 \n2 EASL Clinical Practice Guidelines: Autoimmune hepatitis J Hepatol 2015 63 971 1004 26341719 \n3 Hytiroglou P Snover DC Alves V Balabaud C Bhathal PS Bioulac-Sage P Beyond “cirrhosis”: a proposal from the International Liver Pathology Study Group Am J Clin Pathol 2012 137 5 9 22180471 \n4 Zachou K Gatselis N Papadamou G Rigopoulou EI Dalekos GN Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naive patients J Hepatol 2011 55 636 646 21238519\n\n",
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"issue": "3(4)",
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"keywords": "Autoimmune hepatitis; cirrhosis; drug-induced liver injury; interferon-beta; multiple sclerosis",
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"title": "Spontaneous Cirrhosis Regression in an IFN-beta-induced AIH-like Syndrome Following Drug Withdrawal: Art of Facts or Artifacts?",
"title_normalized": "spontaneous cirrhosis regression in an ifn beta induced aih like syndrome following drug withdrawal art of facts or artifacts"
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"medicinalproduct": "METHYLPREDNISOLONE."
}
],
"patientagegroup": null,
"patientonsetage": "57",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Autoimmune hepatitis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KALAFATELI M, TRIANTOS C, TSAMANDAS A, DALEKOS GN. SPONTANEOUS CIRRHOSIS REGRESSION IN AN IFN-BETA-INDUCED AIH-LIKE SYNDROME FOLLOWING DRUG WITHDRAWAL: ART OF FACTS OR ARTIFACTS?. EUR J CASE REP INTERN MED (DOI: 10.12890/2016_000396). 2016;3:4",
"literaturereference_normalized": "spontaneous cirrhosis regression in an ifn beta induced aih like syndrome following drug withdrawal art of facts or artifacts",
"qualification": "3",
"reportercountry": "GR"
},
"primarysourcecountry": "GR",
"receiptdate": "20170117",
"receivedate": "20170117",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13122465,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnessother": 1,
"transmissiondate": "20170428"
}
] |
{
"abstract": "The use of non-steroidal anti-inflammatory drugs like diclofenac in the third trimester of pregnancy can cause severe side effects, in particular oligohydramnios, premature closure of ductus arteriosus, and fetal kidney damage. However, the treatment with non-steroidal anti-inflammatory drugs until gestational week 28 is accepted as relatively safe. Here we describe two retrospectively reported cases of early-onset oligohydramnios associated with long-term diclofenac exposure of at least 150mg per day. The pathological findings were detected at gestational weeks 22 and 23, respectively. Amniotic fluid turned to normal after discontinuation of diclofenac in both cases, suggesting causality. Although early-onset oligohydramnios is a rare complication, caution for long-term diclofenac use in high doses is recommended even before gestational week 28.",
"affiliations": "Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Germany. Electronic address: [email protected].;Department of Obstetrics and Gynecology, University of Rostock, Rostock, Germany.;Obstetrics and Gynecology, Center for Prenatal Diagnosis Kudamm-199, Berlin, Germany.;Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Germany.;Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Germany.;Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité-Universitätsmedizin Berlin, Germany.",
"authors": "Scherneck|Stephan|S|;Schöpa|Franziska Lilli|FL|;Entezami|Michael|M|;Kayser|Angela|A|;Weber-Schoendorfer|Corinna|C|;Schaefer|Christof|C|",
"chemical_list": "D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D014147:Tramadol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "58()",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": "Adverse drug effects; Diclofenac; NSAID; Oligohydramnios; Pregnancy",
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001172:Arthritis, Rheumatoid; D004008:Diclofenac; D004334:Drug Administration Schedule; D057915:Drug Substitution; D005260:Female; D005865:Gestational Age; D006801:Humans; D050498:Live Birth; D016104:Oligohydramnios; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D059285:Pregnancy, Twin; D012307:Risk Factors; D012585:Sciatica; D014147:Tramadol; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "61-4",
"pmc": null,
"pmid": "26318712",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Reversible oligohydramnios in the second trimester of pregnancy in two patients with long-term diclofenac exposure.",
"title_normalized": "reversible oligohydramnios in the second trimester of pregnancy in two patients with long term diclofenac exposure"
}
|
[
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{
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"activesubstance": {
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"medicinalproduct": "PREDNISOLONE."
},
{
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},
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{
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},
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},
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},
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"medicinalproduct": "SULFASALAZINE."
},
{
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},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "OMEPRAZOLE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Talipes",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Foetal growth restriction",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SCHERNECK S, SCHOPA F, ENTEZAMI M, KAYSER A, WEBER-SCHOENDORFER C, SCHAEFER C. REVERSIBLE OLIGOHYDRAMNIOS IN THE SECOND TRIMESTER OF PREGNANCY IN TWO PATIENTS WITH LONG-TERM DICLOFENAC EXPOSURE. REPRODUCTIVE TOXICOLOGY. 2015;58:61-64.",
"literaturereference_normalized": "reversible oligohydramnios in the second trimester of pregnancy in two patients with long term diclofenac exposure",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20170719",
"receivedate": "20170719",
"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171127"
},
{
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"fulfillexpeditecriteria": "1",
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"patient": {
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{
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"activesubstancename": "OMEPRAZOLE"
},
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"drugindication": "PROPHYLAXIS AGAINST GASTROINTESTINAL ULCER",
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"medicinalproduct": "OMEPRAZOLE."
},
{
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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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"reaction": [
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Oligohydramnios",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SCHERNECK S, SCHOPA F, ENTEZAMI M, KAYSER A, WEBER-SCHOENDORFER C, SCHAEFER C. REVERSIBLE OLIGOHYDRAMNIOS IN THE SECOND TRIMESTER OF PREGNANCY IN TWO PATIENTS WITH LONG-TERM DICLOFENAC EXPOSURE. REPRODUCTIVE TOXICOLOGY. 2015;58:61-64.",
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"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
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},
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},
"serious": 1,
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"transmissiondate": "20171127"
},
{
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},
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"medicinalproduct": "OMEPRAZOLE."
},
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"reaction": [
{
"reactionmeddrapt": "Foetal growth restriction",
"reactionmeddraversionpt": "20.1",
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},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SCHERNECK S, SCHOPA F, ENTEZAMI M, KAYSER A, WEBER-SCHOENDORFER C, SCHAEFER C. REVERSIBLE OLIGOHYDRAMNIOS IN THE SECOND TRIMESTER OF PREGNANCY IN TWO PATIENTS WITH LONG-TERM DICLOFENAC EXPOSURE. REPRODUCTIVE TOXICOLOGY. 2015;58:61-64.",
"literaturereference_normalized": "reversible oligohydramnios in the second trimester of pregnancy in two patients with long term diclofenac exposure",
"qualification": "3",
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},
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},
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},
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}
] |
{
"abstract": "A 68-year-old woman was receiving chemotherapy and endocrine therapy for right breast cancer postoperative pulmonary metastasis and local lymph node recurrence. However, she developed interstitial pneumonia 12 weeks after initiating treatment with everolimus and exemestane. Treatment with everolimus and exemestane was discontinued and steroid pulse therapy was initiated; however, she required ventilator management because of the severity of the pneumonia. The patient's condition improved 9 days after ventilator management. Everolimus-induced interstitial pneumonia is often mild, but it can be severe in rare cases. In our case, everolimus-induced diffuse alveoli damage was successfully treated with ventilator management.",
"affiliations": "Dept. of Surgery, Baba Memorial Hospital.",
"authors": "Kinoshita|Haruhito|H|;Teraoka|Hitoshi|H|;Hasegawa|Tsuyoshi|T|;Nakamoto|Kentaro|K|;Kashiwagi|Shinichiro|S|;Hirakawa|Kosei|K|;Ohira|Masaichi|M|",
"chemical_list": "D000730:Androstadienes; D000068338:Everolimus",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000730:Androstadienes; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000068338:Everolimus; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D009364:Neoplasm Recurrence, Local; D011014:Pneumonia",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2370-2372",
"pmc": null,
"pmid": "33468964",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Metastatic Breast Cancer That Recovered from Diffuse Alveolar Damage Associated with Everolims.",
"title_normalized": "a case of metastatic breast cancer that recovered from diffuse alveolar damage associated with everolims"
}
|
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}
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"literaturereference": "KINOSHITA H, TERAOKA H, HASEGAWA T, NAKAMOTO K, KASHIWAGI S, HIRAKAWA K, OHIRA M. A CASE OF METASTATIC BREAST CANCER THAT RECOVERED FROM DIFFUSE ALVEOLAR DAMAGE ASSOCIATED WITH EVEROLIMS. GAN TO KAGAKU RYOHO. 2020 DEC?47(13):2370?2372.",
"literaturereference_normalized": "a case of metastatic breast cancer that recovered from diffuse alveolar damage associated with everolims",
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},
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},
{
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},
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},
{
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"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
},
{
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}
],
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},
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"literaturereference": "KINOSHITA H, TERAOKA H, HASEGAWA T, NAKAMOTO K, KASHIWAGI S, HIRAKAWA K, ET AL. A CASE OF METASTATIC BREAST CANCER THAT RECOVERED FROM DIFFUSE ALVEOLAR DAMAGE ASSOCIATED WITH EVEROLIMS. GAN TO KAGAKU RYOHO. 2020?47(13):2370?2372",
"literaturereference_normalized": "a case of metastatic breast cancer that recovered from diffuse alveolar damage associated with everolims",
"qualification": "3",
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},
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}
] |
{
"abstract": "Anaesthesia induction and meticulous airway management is important in a patient with anterior mediastinal mass. It is all the more challenging if this is encountered in infants. We report a comrehensive successful management of an infant with huge anterior mediastinal mass who was anaesthesized for diagnosis initially followed by surgical resection of the tumor.",
"affiliations": "Department of Anesthesiology, Sancheti Hospital, Pune, Maharashtra, India.;Department of Anaesthesiology, Shusurut Jadhav Kinder Chirurgie Paediatric Hospital, Vishrambaug, Sangli, Maharashtra, India.;Department of Surgery, Shusurut Jadhav Kinder Chirurgie Paediatric Hospital, Vishrambaug, Sangli, Maharashtra, India.;Department of Anaesthesiology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana, India.",
"authors": "Diwan|Sandeep|S|;Patil|Sunil|S|;Jadhav|Sudhakar|S|;Nair|Abhijit S|AS|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/sja.SJA_788_18",
"fulltext": "\n==== Front\nSaudi J AnaesthSaudi J AnaesthSJASaudi Journal of Anaesthesia1658-354X0975-3125Wolters Kluwer - Medknow India SJA-13-24610.4103/sja.SJA_788_18Case ReportComprehensive perioperative management of an infant with huge mediastinal mass Diwan Sandeep Patil Sunil 1Jadhav Sudhakar 2Nair Abhijit S. 3Department of Anesthesiology, Sancheti Hospital, Pune, Maharashtra, India1 Department of Anaesthesiology, Shusurut Jadhav Kinder Chirurgie Paediatric Hospital, Vishrambaug, Sangli, Maharashtra, India2 Department of Surgery, Shusurut Jadhav Kinder Chirurgie Paediatric Hospital, Vishrambaug, Sangli, Maharashtra, India3 Department of Anaesthesiology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana, IndiaAddress for correspondence: Dr. Sandeep Diwan, Department of Anesthesiology, Sancheti Hospital, Pune - 411 005, Maharashtra, India. E-mail: [email protected] 2019 13 3 246 248 Copyright: © 2019 Saudi Journal of Anesthesia2019This 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.Anaesthesia induction and meticulous airway management is important in a patient with anterior mediastinal mass. It is all the more challenging if this is encountered in infants. We report a comrehensive successful management of an infant with huge anterior mediastinal mass who was anaesthesized for diagnosis initially followed by surgical resection of the tumor.\n\nAnaesthesiainfantmediastinal masssurgery\n==== Body\nIntroduction\nAnesthesia management of an infant with a mediastinal is extremely challenging. We report a case where we successfully managed an 8-month-old child with mediastinal mass twice; initially, for a diagnostic computed tomography (CT) scan and later for a definitive surgery involving excision of mediastinal lesion.\n\nCase Report\nWe report a case of an 8-month, 7-kg male child delivered at term via cesarean section. The parents consulted a pediatrician as they noticed recent-onset excessive crying in supine position followed by cyanosis. Chest radiograph revealed a huge mass in the right hemithorax displacing mediastinum to the left in anteroposterior (AP) view and compressing the entire tracheobronchial tree in lateral view [Figure 1a and b]. After optimizing the child with salbutamol nebulisation and steroids, CT scan was planned. The child was afebrile, tachypnoeic (respiratory rate, 40–45/min), heart rate was 130–140/min, pulses well felt in all extremities with no radiofemoral delay. On auscultation, air entry was almost absent in right hemithorax except at the base with normal heart sounds. Oxygen saturation (SPO2) on room air was 94–95%.\n\nFigure 1 (a) Chest X-ray AP view showing mass occupying entire right hemithorax. (b) Chest X-ray lateral view showing compression of entire tracheobronchial tree. (c) CT chest axial tracheal bronchial compression seen. Arrow shows mediastinal displacement to left due to tumor. (d) Right thoracotomy performed exposing the mass, shown with red arrow\n\nAfter obtaining an informed high risk consent, CT chest was planned under monitored anesthesia care with sedation. Intravenous (IV) access with 24-G cannula was secured by the pediatrician. Appropriate sized endotracheal tubes, supraglottic airways, laryngoscope, drugs for resuscitation (adrenaline, atropine) were kept ready in the console. After confirming a nil by mouth (NBM) status, we administered 1 mg/kg ketamine IV (7 mg) in mother's arm for sedation and scanning was started in prone position. Oxygen supplementation via face mask at 5 L/min was started with the child breathing spontaneously throughout. Procedure was uneventful. CT scan revealed a huge mediastinal mass which was not compressing the tracheobronchial tree as scan was done in the prone position [Figure 1c]. Surgical excision was planned under general anesthesia (GA) after counselling family members. Risks of bleeding, cardiopulmonary issues, and prolonged ICU stay were explained in detail. After obtaining a high-risk consent, the surgery was posted after 2 days.\n\nOn the day of the surgery, 25 mg hydrocortisone was injected IV 30 min prior to induction. Premedication was done with 0.05 mg glycopyrrolate and 1 mg/kg ketamine. The child was shifted to the OR in prone position and standard monitors (ECG, NIBP, SpO2) were attached. Surgeons were ready for emergency thoracotomy and a 3-mm rigid bronchoscope was also ready in an event of severe desaturation resulting from mass effect. GA was induced with oxygen: nitrous oxide with isoflurane which led to several episodes of desaturation (lowest of 82%), which improved with assisted ventilation. After 10 min, the child was intubated with 3-mm internal diameter flexometallic endotracheal tube. Ventilation was assisted and air entry confirmed on auscultation; 2 μg/kg fentanyl was administered IV. The child was then positioned for a right thoracotomy in left lateral position which led to increased airway resistance and desaturation (lowest SPO2 of 70%). Immediately a thoracotomy was done with assisted ventilation and the mass was pulled away from tracheobronchial tree which led to improvement in ventilation and oxygenation.\n\nDuring excision, there were several occasions of inability to inflate the lung due to compression of the tip of ETT and the mass distorting the trachea lumen. Eventually, a complete excision was possible [Figure 1d]. Neuromuscular blockade (NMB) was achieved with atracurium 0.5 mg/kg body weight once the mass was resected. Right thoracic paravertebral block with 3 ml 0.25% bupivacaine was administered for the postoperative pain relief. NMB was reversed with IV neostigmine 0.05 mg/kg and 0.01 mg/kg atropine followed by tracheal extubation in OR. The infant was shifted to the ICU with oxygen via face mask. Child received paracetamol syrup 200 mg every 8 hours orally for postoperative analgesia and 2 mg dexamethasone every 8 hours for 24 hours. The entire postoperative course was uneventful and the child was discharged after 5 days.\n\nDiscussion\nAdministering anesthesia to a child with anterior mediastinal mass is extremely challenging. Severe cardiovascular and/or respiratory collapse may occur during induction of anesthesia and can have undesirable outcomes despite expeditious use of all appropriate resuscitative manoeuvres. Anesthesiologist should review the CT scan in detail and try to understand the compression that the mass is causing, as it can help in planning anesthesia. A discussion with the surgeon and radiologist can give a lot of information. Adequacy of ventilation during GA and the tracheal cross-sectional area can be estimated from the CT scan. The presence or extent of symptoms does not correlate well with the degree of tracheal narrowing shown by CT scan except for orthopnea.[1] Less than 50% of the normal predicted tracheal cross-sectional area is associated with significant anesthetic complications.\n\nA 35% decrease in the diameter of tracheobronchial lumen is associated with respiratory symptoms. A greater than 50% decrease may be associated with complete airway obstruction during induction or emergence from GA.[2] Clinical presentation of childhood mediastinal masses is often nonspecific or incidental. Patients can be asymptomatic and can go undetected. In such cases, ambulatory anesthesia for even a lymph node biopsy may prove fatal.[3] Severe cardiovascular and/or respiratory collapse may occur following induction of anesthesia in a patient with critical mediastinal mass syndrome (CMMS).[4] The outcome may be fatal despite expeditious use of all appropriate resuscitative manoeuvres. CMMS in infants are identified by factors such as anterior mass, lymphoma, superior vena cava syndrome, vessel compression or displacement, pericardial, and pleural effusion. Cardiac tamponade and superior venacaval syndrome are known complications of anterior mediastinal masses.[5] Tumor enveloping the heart and infiltrating the pericardium can lead to refractory cardiovascular collapse under GA.[6]\n\nPreoperative cardiac assessment by ECG and echocardiography in such infants can provide lot of information. Availability of femoro-femoral cardiopulmonary bypass in symptomatic patients before induction of GA in these patients is suggested.[7] In cannot ventilate situation, an immediate laryngoscopy and splinting of trachea or an emergency bronchoscopy to counteract the mass effect on the tracheobronchial tree is recommended.[8] An elective postoperative ventilation for 12–24 h usually helps in stabilizing the pulmonary functions.\n\nConclusion\nA thorough clinical examination, understanding of scans and rapid decision making is important while managing a child with mediastinal mass coming for surgery. Situations aggravating and relieving respiratory compromise should be elicited. Surgical team should be ready for a rapid thoracotomy if there is total tracheobronchial obstruction during induction to relieved compression. The child should be managed in a dedicated pediatric unit with backup for ICU care and ventilation.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patients parents have given their consent for his/her/their images and other clinical information to be reported in the journal. The patients family understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Blank RS de Souza DG Anesthetic management of patients with an anterior mediastinal mass: Continuing professional development Can J Anaesth 2011 58 853 9 860-7 21779948 \n2 Azizkhan RG Dudgeon DL Buck JR Colombani PM Yaster M Nichols D Life threatening airway obstruction as a complication to the management of mediastinal masses in children J Pediatr Surg 1985 20 816 22 4087108 \n3 Viswanathan S Campbell CE Cork RC Asymptomatic undetected mediastinal mass: A death during ambulatory anesthesia J Clin Anesth 1995 7 151 5 7598925 \n4 Lam JC Chui CH Jacobsen AS Tan AM Joseph VT When is a mediastinal mass critical in a child? An analysis of 29 patients Pediatr Surg Int 2004 20 180 4 15064964 \n5 Northrip DN Bohman BK Tsueda K Total airway occlusion and superior vena cava syndrome in a child with an anterior mediastinal tumor Anesth Analg 1986 65 1079 82 3752559 \n6 Juanpere S Cañete N Ortuño P Martínez S Sanchez G Bernado L A diagnostic approach to the mediastinal masses Insights Imaging 2012 4 29 52 23225215 \n7 Slinger P Karsli C Management of the patient with a large anterior mediastinal mass: Recurring myths Curr Opin Anaesthesiol 2007 20 1 3 17211158 \n8 Pelton JJ Ratner IA A technique of airway management in children with obstructed airway due to tumor Ann Thorac Surg 1989 48 301 2 2764625\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "13(3)",
"journal": "Saudi journal of anaesthesia",
"keywords": "Anaesthesia; infant; mediastinal mass; surgery",
"medline_ta": "Saudi J Anaesth",
"mesh_terms": null,
"nlm_unique_id": "101500601",
"other_id": null,
"pages": "246-248",
"pmc": null,
"pmid": "31333373",
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"title": "Comprehensive perioperative management of an infant with huge mediastinal mass.",
"title_normalized": "comprehensive perioperative management of an infant with huge mediastinal mass"
}
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{
"abstract": "At the autopsy of a 25-year-old man who had died from combined morphine and cocaine intoxication, depositions of metallic mercury were incidentally found in the myocardium of the right ventricular septum and posterior wall. Deposits, toxicologically identified as mercury, were also found radiologically and histologically in the lungs. All these deposits were probably the result of intravenous injections of mercury many months previously, as is known to be done occasionally by addicts. Judging by the histological picture the greatest proportion of the mercury collected in the right ventricular cavity after injection, a smaller amount by embolization in the small pulmonary arteries. The mercury spheres which came to lie in the right ventricle then penetrated into the myocardium, moving outward and causing a chronic and partly transmural inflammatory response.",
"affiliations": "Institut für Gerichtliche Medizin, Universität Tübingen.",
"authors": "Haffner|H T|HT|;Erdelkamp|J|J|;Göller|E|E|;Schweinsberg|F|F|;Schmidt|V|V|",
"chemical_list": "D003932:Heroin; D008628:Mercury; D003042:Cocaine",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-2008-1063756",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "116(36)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000328:Adult; D001344:Autopsy; D003042:Cocaine; D003932:Heroin; D006801:Humans; D007275:Injections, Intravenous; D008168:Lung; D008297:Male; D008628:Mercury; D008630:Mercury Poisoning; D009206:Myocardium; D019966:Substance-Related Disorders",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "1342-6",
"pmc": null,
"pmid": "1884673",
"pubdate": "1991-09-06",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Morphological and toxicological findings after intravenous injection of metallic mercury.",
"title_normalized": "morphological and toxicological findings after intravenous injection of metallic mercury"
}
|
[
{
"companynumb": "DE-PFIZER INC-2020386012",
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{
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"literaturereference": "HAFFNER, H.. MORPHOLOGICAL AND TOXICOLOGICAL FINDINGS AFTER INTRAVENOUS INJECTION OF METALLIC MERCURY. DEUTSCHE MEDIZINISCHE WOCHENSCHRIFT. 1991?116 (36):1342-1346",
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{
"abstract": "Dexmedetomidine, an α2-adrenergic agonist, can be used to perform mild to moderate sedation in critically ill patients. In this case series, 9 cardiovascular intensive care unit patients with hyperthermia during dexmedetomidine administration, suggestive of drug fever, are presented. Hyperthermia (>38.5°C) occurred 6 (4-10) hours (median [interquartile range]) after dexmedetomidine initiation at a dose of 1.0 (0.8-1.3) μg/kg/h and was resolved 3 (1-8) hours after discontinuation of dexmedetomidine. All patients were screened for infectious and noninfectious causes of hyperthermia, and the findings were analyzed by 2 adverse drug reaction (ADR) assessment methods-the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) Causality Assessment and the Naranjo ADR scale. This resulted in a \"probable\" ADR in all 9 patients (WHO) and a \"probable\" and \"possible\" ADR in 1 and 8 patients (Naranjo), respectively. This case series supports published case reports, suggesting that dexmedetomidine administration may be associated with the occurrence of clinically relevant hyperthermia. The underlying mechanisms and risk factors are uncertain and require further research.",
"affiliations": "From the Intensive Care Unit for Cardiovascular Surgery, Institute of Anaesthesiology, University of Zurich, and University Hospital Zurich, Zurich, Switzerland.;From the Intensive Care Unit for Cardiovascular Surgery, Institute of Anaesthesiology, University of Zurich, and University Hospital Zurich, Zurich, Switzerland.;Unit of General Internal Medicine, Hirslanden Clinic, Zurich, Switzerland.;From the Intensive Care Unit for Cardiovascular Surgery, Institute of Anaesthesiology, University of Zurich, and University Hospital Zurich, Zurich, Switzerland.;From the Intensive Care Unit for Cardiovascular Surgery, Institute of Anaesthesiology, University of Zurich, and University Hospital Zurich, Zurich, Switzerland.;From the Intensive Care Unit for Cardiovascular Surgery, Institute of Anaesthesiology, University of Zurich, and University Hospital Zurich, Zurich, Switzerland.",
"authors": "Krüger|Bernard D|BD|;Kurmann|Judith|J|;Corti|Natascia|N|;Spahn|Donat R|DR|;Bettex|Dominique|D|;Rudiger|Alain|A|",
"chemical_list": "D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine",
"country": "United States",
"delete": false,
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"journal": "Anesthesia and analgesia",
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"abstract": "Infective endocarditis in neonates can be fatal. Adjunctive rifampin therapy might be effective as salvage therapy in critically ill patients with Staphylococcus aureus native valve endocarditis (NVE). We present a case of a full-term neonate with NVE who had a favorable clinical outcome after adding rifampin to standard therapy.",
"affiliations": "Department of Pediatrics Umm Al Qura University Makkah Saudi Arabia.;Medical College of Umm Al Qura University Makkah Saudi Arabia.;Department of Pediatrics Security Forces Hospital Makkah Saudi Arabia.;Department of Pediatrics Security Forces Hospital Makkah Saudi Arabia.;Department of Pediatrics Umm Al Qura University Makkah Saudi Arabia.;Department of Pediatrics Security Forces Hospital Makkah Saudi Arabia.;Department of Pediatrics Security Forces Hospital Makkah Saudi Arabia.;Department of Pediatrics Umm Al Qura University Makkah Saudi Arabia.;Department of Pediatrics Security Forces Hospital Makkah Saudi Arabia.",
"authors": "Almatrafi|Mohammed A|MA|https://orcid.org/0000-0003-1520-5482;Alsahaf|Nouf|N|;Alsharif|Elaf J|EJ|;Sayed|Jamal A|JA|;Telmesani|Abdulwahab M A|AMA|;Alidrisi|Dhuha|D|;Mohammed|Alkhayat|A|;Mosalli|Rafat|R|;Albaihani|Ahmed|A|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4902\nCCR34902\nCase Report\nCase Reports\nAdjunctive rifampin therapy for native valve Staphylococcus aureus endocarditis in a neonate: A case report and literature review\nALMATRAFI et al.\nAlmatrafi Mohammed A. https://orcid.org/0000-0003-1520-5482\n1 2 [email protected]\n\nAlsahaf Nouf 3\nAlsharif Elaf J. 2\nSayed Jamal A. 2\nTelmesani Abdulwahab M. A. 1 2\nAlidrisi Dhuha 2\nMohammed Alkhayat 2 4\nMosalli Rafat 1\nAlbaihani Ahmed 2\n1 Department of Pediatrics Umm Al Qura University Makkah Saudi Arabia\n2 Department of Pediatrics Security Forces Hospital Makkah Saudi Arabia\n3 Medical College of Umm Al Qura University Makkah Saudi Arabia\n4 Department of Pediatric Cardiology, Maternity and Children Hospital Makkah Saudi Arabia\n* Correspondence\nMohammed A. Almatrafi, Department of Pediatrics, Umm Al Qura University, Makkah, Saudi Arabia.\nEmail: [email protected]\n\n04 10 2021\n10 2021\n9 10 10.1002/ccr3.v9.10 e0490220 8 2021\n19 9 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nInfective endocarditis in neonates can be fatal. Adjunctive rifampin therapy might be effective as salvage therapy in critically ill patients with Staphylococcus aureus native valve endocarditis (NVE). We present a case of a full‐term neonate with NVE who had a favorable clinical outcome after adding rifampin to standard therapy.\n\nAdding rifampin in a critically ill neonate with native valve Staphylococcus aureus endocarditis might be effective and lifesaving. Further studies are needed to determine rifampin's effect on neonatal Staphylococcus aureus native valve endocarditis.\n\ninfective endocarditis\nneonatal\nrifampin\nsource-schema-version-number2.0\ncover-dateOctober 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.8 mode:remove_FC converted:04.10.2021\nAlmatrafiMA, AlsahafN, AlsharifEJ, et al. Adjunctive rifampin therapy for native valve Staphylococcus aureus endocarditis in a neonate: A case report and literature review. Clin Case Rep. 2021;9 :e04902. 10.1002/ccr3.4902\n==== Body\npmc1 BACKGROUND\n\nInfective endocarditis (IE) is an uncommon infection of the endothelial surface lining the heart and its associated structures.1, 2 These infections are life‐threatening, with reported mortality rates as high as 10%.1, 2 The pathogenesis of IE involves fibrin‐platelet deposits on damaged or denuded endothelium caused by abnormal cardiac structures or turbulence leading to the formation of nonbacterial thrombotic endocarditis (NBTE).3 NBTE acts as an excellent nidus of infection for circulating bacteria and fungi. Staphylococcus aureus and fungi are the most common isolated microorganisms in neonatal IE.4\n\nPrevious research has established that IE is less common in children than adults in recent years. An annual incidence rate for IE estimated between 0.05 and 0.12 cases per 1000 pediatric admissions. The exact incidence of IE in neonates is unknown; however, a recent multicenter study concluded that around 7% of pediatric IE was diagnosed during the neonatal period. Prematurity, structural cardiac defects, cardiac surgeries, and central venous catheters are well‐established risk factors for neonatal IE.5, 6, 7\n\nOnce blood cultures have been obtained, appropriate empirical antimicrobial therapy should be initiated. The optimal course of therapy and the duration are determined by the clinical response, the identified pathogen, and antimicrobial susceptibility.5, 8 Congestive heart failure, valvular dysfunction, embolic phenomena, and persistent bacteremia despite appropriate antibiotic therapy may indicate surgical intervention.5, 8\n\nWe report a case of a full‐term male who presented with fulminant sepsis, multiorgan failure, and native valve endocarditis secondary to methicillin‐susceptible Staphylococcus aureus (MSSA). He had a favorable clinical outcome after combination therapy with intravenous oxacillin, gentamicin, and rifampin.\n\n2 CASE PRESENTATION\n\nA late preterm baby boy of 36 weeks +5 days born to a 26‐year‐old G2P1 via spontaneous vaginal delivery was admitted to the neonatal intensive care unit (NICU) for persistent hypoglycemia secondary to transient hyperinsulinemia. The patient required a high dextrose infusion through an umbilical venous catheter (UVC) up to day 10 of life. On day 11, the patient developed respiratory distress and lethargy. On examination, the patient appeared very ill‐looking, with respiratory distress and generalized anasarca. The abdomen was tense and distended, with an erythematous indurated skin rash around the umbilicus stump at the UVC insertion site. A sepsis work‐up including blood culture and urine culture was collected, and the patient started on meropenem (20 mg/kg/dose every 8 h) plus vancomycin (15 mg/kg/dose every 8 h) empirically for neonatal sepsis and omphalitis.\n\nInitial laboratory results showed marked leucocytosis (39 × 10e3/μL), with a predominant neutrophil count (80%), anemia (8.4 g/dL), and profound thrombocytopenia (16 × 10e3/μL). The hepatic panel revealed normal liver enzymes (AST 32.7 unit/L, ALT 24.7 unit/L), hypoalbuminemia (2.3 g/L), and direct hyperbilirubinemia (total bilirubin 24.7 mg/dL, direct 22.2 mg/dL). The coagulation profile was notable for prolonged INR (2.4), PT (31.8 s), and aPTT (45 s). Initial renal function tests were within the normal limits for the patient age group. Blood culture grew methicillin‐susceptible staph aureus (MSSA) and Escherichia coli (E. coli). The following day, a new grade III systolic murmur appeared in his cardiac examination, and his oxygen requirement had significantly increased to the point where he required mechanical ventilation and was eventually placed on high‐frequency oscillatory ventilation. He received numerous blood transfusions, platelet transfusions, fresh frozen plasma, and an albumen infusion for disseminated intravascular coagulopathy and hypoalbuminemia.\n\nAn echocardiography showed a mass (0.8 * 1 cm) attached to the septum protruding to the left atrium with vegetation (Figure 1), and his chest X‐ray showed bilateral reticular densities of both lung fields, raising the possibility of showering septic emboli (Figure 2). Although the patient's E. coli bacteremia cleared very quickly, his blood culture for MSSA remained positive. The antibiotic therapy was changed to oxacillin (50 mg/kg/dose every 6 h) and gentamicin (5 mg/kg/dose every 24 h) for more targeted therapy for MSSA endocarditis, and cefotaxime (50 mg/kg/dose every 8 h) for E. coli bacteremia and presumed meningitis as LP was not obtained, given the patient's clinical instability.\n\nFIGURE 1 (A) Transthoracic ECHO revealed a large mass measuring 0.8 * 1 cm attached to the right interatrial septum and protruding into the left atrium. (B) A follow‐up ECHO after five days showed the progression of the vegetation size to 1.3 * 1.6 cm. (C) Significant regression in the size of the vegetation to 1.2 * 1 cm after adding rifampin. (D) Within 3 weeks of receiving combined antimicrobial therapy with rifampin, the vegetations were completely resolved without valvular dysfunction\n\nFIGURE 2 X‐ray of the chest showing bilateral reticulonodular opacities in both lung fields\n\nDespite the patient's appropriate therapy for MSSA endocarditis, he continued to have positive blood cultures for MSSA and enlarging vegetations (1.3 * 1.6 cm) (Figure 1). The patient was not a candidate for surgical intervention with his compromised respiratory status and multiple organ failure. Rifampin (10 mg/kg/day every 24 h) was added to his regimen for its excellent tissue penetration and as a last resort therapy for his uncontrolled infection. Shortly after starting rifampin, his MSSA bacteremia took a longer time to grow in his blood culture. Eventually, the patient's clinical status improved with antibiotic therapy of oxacillin, gentamicin, and rifampin, which was evident in the cleared bacteremia and gradual reduction in the size of the vegetations (Figure 1). On day 28 of life, his ECHO was negative for vegetations (Figure 1). The patient received 2 weeks of gentamicin and rifampin from the first negative culture. Rifampin was discontinued early, and oxacillin was switched to cefazoline (130 mg/kg/day every 8 h) because of liver toxicity (ALT 990, AST 1300). The patient completed 6 weeks of antibiotic therapy from the first negative blood culture and was discharged in a stable condition.\n\n3 DISCUSSION\n\nInfective endocarditis (IE) is associated with significant morbidity and mortality.5 It is commonly caused by Staphylococcus aureus, coagulase‐negative Staphylococci, and Candida species in neonates.5 Clinical manifestations of infectious endocarditis vary and may include a new or changing heart murmur, respiratory distress, clinical sepsis, and an embolic phenomenon.6\n\nClinical and laboratory signs of infection in the presence of UVC raised the suspicion of IE in this case. IE was diagnosed based on the presence of two major Duke criteria: multiple positive bacterial cultures for the IE typical microorganism, and echocardiographic evidence of a mass and vegetative lesions.\n\nThe American Heart Association (AHA) current standard of care for methicillin‐susceptible Staphylococcus aureus (MSSA) endocarditis in a native valve or other native cardiac tissue is four to 6 weeks of intravenous antistaphylococcal penicillin (nafcillin/oxacillin), with the optional use of gentamycin for first 3–5 days. Cefazolin is an alternative in patients with penicillin‐allergic reactions. Vancomycin is used for patients who are unable to tolerate β‐lactam antibiotic drugs. Patients with methicillin‐resistant Staphylococcus aureus (MRSA) endocarditis are treated with vancomycin for a minimum of 6 weeks. Rifampin is recommended as an adjunctive treatment in staphylococcal endocarditis involving a prosthetic valve.5\n\nThis case report discusses rather unusual management of infective endocarditis in a neonate as there are no guidelines that particularly address the use of rifampin in MSSA endocarditis involving a native valve. Rifampin is a highly lipid‐soluble bactericidal agent that can achieve high intracellular concentration with excellent biofilms and tissue penetration.9 Therefore, current guidelines for prosthetic valve endocarditis and hardware‐associated osteomyelitis secondary to staphylococcal infections support the adjunctive use of rifampin.5, 10 Rifampin is associated with various adverse effects, including gastrointestinal symptoms, hepatotoxicity, nephrotoxicity, thrombocytopenia, hemolysis, anaphylaxis, and increased risk of drug interactions.\n\nThere has been conflicting data regarding the adjunctive use of rifampin in staphylococcal bacteremia in both adults and children. In the multicenter, randomized controlled trial (ARREST), adjunctive rifampin had no overall benefit compared with standard treatment for Staphylococcus aureus bacteremia in adults.12 Additionally, a recent meta‐analysis concluded that adding rifampin to the treatment of Staphylococcus aureus bacteremia in adults with deep infections did not result in a reduction in the rate of bacteriologic failure, relapse, or death.13\n\nData on the adjunctive use of rifampin in neonatal endocarditis secondary to Staphylococcus aureus are scarce. Tan et al. reported successful use of intravenous rifampin with vancomycin for ten neonates with persistent staphylococcal bacteremia.14 Within 24 h of initiating rifampin, eight of ten neonates in the study had sterile blood culture, one neonate within 48 h, and one neonate within 5 days.14 Among the study's notable observations were the absence of significant adverse effects of rifampin in this age group.14 O'Callaghan C and McDougall reported four cases of neonatal IE caused by Staphylococcus aureus. Two patients had complete clinical recovery when rifampin was added to their regimen, with the caveat that one patient had rifampin for a brief period.15\n\nIn our case, chest X‐ray findings were consistent with septic emboli and persistent bacteremia for more than 7 days and enlarging vegetation despite appropriate antimicrobial therapy are all indications for surgical intervention. However, due to his unstable general condition, he was not a candidate for surgery. Rifampin was added to his regimen as salvage therapy to control his infection. Soon after initiating rifampin, our patient's overall clinical status, as well as radiological and microbiological data, improved significantly.\n\n4 CONCLUSION\n\nThis report, along with previous reports, suggests that rifampin may be clinically effective as adjunctive therapy in critically ill neonates with native valve Staphylococcus aureus endocarditis. Elevated hepatic transaminases could be interpreted as an adverse effect of rifampin in neonates, as demonstrated in this case. Although we believe our patient's increase in liver enzymes was multifactorial, it is critical to weigh the risks and benefits before initiating rifampin in neonates.\n\nCONFLICTS OF INTEREST\n\nThe authors declare no conflict of interests.\n\nAUTHOR CONTRIBUTIONS\n\nMA led and designed the study, wrote, contributed to the literature search, reviewed, and edited the manuscript. NA and EA participated in the manuscript writing, literature search, and data collection. JS, AT, DA, and AM contributed to the interpretation of data and manuscript revisions. RM and AA critically revised the manuscript. All authors approved the final manuscript.\n\nETHICAL APPROVAL\n\nI testify that my article was submitted to the Clinical Case Reports Journal.\n\nTitle: Adjunctive Rifampin Therapy for Native Valve Staphylococcus aureus Endocarditis in a Neonate: A Case Report and Literature Review. This material has not been published in whole or in part elsewhere.\n\nThe manuscript is not currently being considered for publication in another journal.\n\nI have been personally and actively involved in substantive work leading to the revised manuscript and will hold themselves jointly and individually responsible for its content.\n\nCONSENT\n\nInformed consent was obtained from the parents of this patient.\n\nACKNOWLEDGEMENTS\n\nWe thank Dr Eman Labah and Dr Angham Almakki (Microbiology Department at the Security Forces Hospital) for their support and assistance during the clinical evaluation and management of this patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe data supporting the findings of this study are available within this article.\n==== Refs\nREFERENCES\n\n1 DayMD, GauvreauK, ShulmanS, NewburgerJW. Characteristics of children hospitalized with infective endocarditis. Circulation. 2009;119 (6 ):865‐870.19188508\n2 NiwaK, NakazawaM, TatenoS, YoshinagaM, TeraiM. Infective endocarditis in congenital heart disease: Japanese national collaboration study. Heart. 2005;91 (6 ):795‐800.15894782\n3 WilsonW, TaubertKA, GewitzM, et al. Prevention of infective endocarditis. Circulation. 2007;116 (15 ):1736‐1754.17446442\n4 DuperrilM, RapinS, VuillardC, RayetI, PaturalH. Case report: Staphylococcus aureus endocarditis in 2 premature newborns. Medicine (Baltimore). 2019;98 (1 ):e13549.30608383\n5 BaltimoreRS, GewitzM, BaddourLM, et al. Infective endocarditis in childhood: 2015 update. Circulation. 2015;132 (15 ):1487‐1515.26373317\n6 FerrieriP, GewitzMH, GerberMA, et al. Unique features of infective endocarditis in childhood. Circulation. 2002;105 (17 ):2115‐2126.11980694\n7 OelbergDG. Neonatal endocarditis–neither rare nor fatal. Clin Pediatr. 1998;37 (12 ):747‐748.\n8 O'BrienSE. Infective endocarditis in children. In: Armsby C, ed.: Uptodate 2019: https://www.uptodate.com/contents/infective‐endocarditis‐in‐children. Accessed July 28, 2021.\n9 MandellGL, VestTK. Killing of intraleukocytie Staphylococcus aureus by Rifampin: in‐vitro and in‐vivo studies. J Infect Dis. 1972;125 (5 ):486‐490.5023643\n10 PerlrothJ, KuoM, TanJ, BayerAS, MillerLG. Adjunctive use of rifampin for the treatment of staphylococcus aureus infections: a systematic review of the literature. Arch Intern Med. 2008;168 (8 ):805‐819.18443255\n11 GrossetJ, LeventisS. Adverse effects of rifampin. Rev Infect Dis. 1983;5 (Suppl 3 ):S440‐S450.6356277\n12 ThwaitesGE, ScarboroughM, SzubertA, et al. Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double‐blind, placebo‐controlled trial. Lancet. 2018;391 (10121 ):668‐678.29249276\n13 MaH, ChengJ, PengL, GaoY, ZhangG, LuoZ. Adjunctive rifampin for the treatment of Staphylococcus aureus bacteremia with deep infections: a meta‐analysis. PLoS ONE. 2020;15 (3 ):e0230383.32191760\n14 TanTQ, MasonEOJr, OuCN, KaplanSL. Use of intravenous rifampin in neonates with persistent staphylococcal bacteremia. Antimicrob Agents Chemother. 1993;37 (11 ):2401‐2406.8285624\n15 O'CallaghanC, McDougallP. Infective endocarditis in neonates. Arch Dis Child. 1988;63 (1 ):53‐57.3279917\n\n",
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"title": "Adjunctive rifampin therapy for native valve Staphylococcus aureus endocarditis in a neonate: A case report and literature review.",
"title_normalized": "adjunctive rifampin therapy for native valve staphylococcus aureus endocarditis in a neonate a case report and literature review"
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{
"abstract": "BACKGROUND\nOsimertinib is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor. Elevated serum creatine kinase level is an uncommon adverse event associated with osimertinib treatment for lung cancer.\n\n\nMETHODS\nWe report a previously healthy 56-year-old woman who developed elevated serum creatine kinase levels during osimertinib monotherapy for epidermal growth factor receptor mutation-positive lung adenocarcinoma.\nDuring treatment, she experienced leg cramps and her serum creatine kinase levels increased, peaking at 989 U/l. Further investigation revealed no evidence of cardiotoxicity or myositis; thus, osimertinib-induced myopathy was assumed to be the cause of her elevated serum creatine kinase levels. We successfully managed both lung cancer and osimertinib-induced myopathy using 1-week pauses of osimertinib therapy without dose reduction.\n\n\nCONCLUSIONS\nShort-term suspension of osimertinib without dose reduction may be a reasonable option for osimertinib-induced myopathy.",
"affiliations": "Department of Respiratory Medicine, 36809Kobe Red Cross Hospital, Japan.;Department of Pharmacy, 36809Kobe Red Cross Hospital, Japan.;Department of Neurology, 36809Kobe Red Cross Hospital, Japan.;Department of Respiratory Medicine, 36809Kobe Red Cross Hospital, Japan.",
"authors": "Sugimoto|Hiroshi|H|https://orcid.org/0000-0002-2053-8858;Matsumoto|Satoshi|S|;Tsuji|Yukio|Y|;Sugimoto|Keisuke|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/10781552211042271",
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"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Lung cancer; creatine kinase; epidermal growth factor receptor-tyrosine kinase inhibitor; myotoxicity; osimertinib",
"medline_ta": "J Oncol Pharm Pract",
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"nlm_unique_id": "9511372",
"other_id": null,
"pages": "10781552211042271",
"pmc": null,
"pmid": "34605320",
"pubdate": "2021-10-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Elevated serum creatine kinase levels due to osimertinib: A case report and review of the literature.",
"title_normalized": "elevated serum creatine kinase levels due to osimertinib a case report and review of the literature"
}
|
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},
{
"reactionmeddrapt": "Blood creatine phosphokinase increased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Muscle spasms",
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}
],
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},
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{
"abstract": "A 74-year-old woman with gross hematuria for 3 months was referred to our hospital. Contrast-enhanced computed tomographic scan showed a mass on the upper-right renal calyx, and retrograde pyelography showed stenoses from the renal pelvis to the renal calyx infundibulum. We performed an endoscopic biopsy, which led to a diagnosis of urothelial cancer. Therefore, she underwent total right nephroureterectomy, and pathological examination revealed a clear cell variant of invasive urothelial carcinoma. Irradiation was performed mainly on the renal arteriovenous stump 2 months postoperatively; subsequently, three courses of combination chemotherapy comprising gemcitabine plus cisplatin (GC) were administered. Port-site recurrence and pelvic recurrence were observed 22 months after the operation, and GC therapy and pembrolizumab were administered. However she died 36 months after the operation. The clear cell variant of invasive urothelial carcinoma of the upper urethra is rarely reported. Moreover, since this was a very rare case, we have included a literature review in our report.",
"affiliations": "The Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.;The Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.;The Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.;The Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.;The Department of Urology, Saiseikai Yokohamashi Nanbu Hospital.",
"authors": "Ishibashi|Yukari|Y|;Yamaguchi|Katsuya|K|;Hayashi|Yutaro|Y|;Onuki|Tatsuaki|T|;Suzuki|Koutaro|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.14989/ActaUrolJap_67_7_313",
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"issn_linking": "0018-1994",
"issue": "67(7)",
"journal": "Hinyokika kiyo. Acta urologica Japonica",
"keywords": null,
"medline_ta": "Hinyokika Kiyo",
"mesh_terms": "D000368:Aged; D002295:Carcinoma, Transitional Cell; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D007682:Kidney Pelvis; D009364:Neoplasm Recurrence, Local; D000074682:Nephroureterectomy; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0421145",
"other_id": null,
"pages": "313-316",
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"pmid": "34353012",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clear Cell Variant of Invasive Urothelial Carcinoma of the Renal Pelvis: A Case Report.",
"title_normalized": "clear cell variant of invasive urothelial carcinoma of the renal pelvis a case report"
}
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{
"abstract": "Acute liver failure has a high mortality and its most frequent cause in Spain is viral infection. In this article, we present a case of fulminant liver failure. The failure is secondary to an idiosyncratic reaction to ibuprofen, an entity included in the DRESS syndrome. This syndrome plays a key role in the differential diagnosis of acute liver failure, since its unfortunate course often requires liver transplantation as the only useful therapeutic weapon. This case illustrates the need for an efficient coordination between hospitals as a key factor for improving the prognosis.",
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"authors": "Roales-Gómez|Valentín|V|;Molero|Aída Isabel|AI|;Pérez-Amarilla|Inmaculada|I|;Casabona-Francés|Sergio|S|;Rey-Díaz-Rubio|Enrique|E|;Catalán|Mercedes|M|;Vanaclocha|Francisco|F|;Colina|Francisco|F|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen",
"country": "Spain",
"delete": false,
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"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": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D063926:Drug Hypersensitivity Syndrome; D006801:Humans; D007052:Ibuprofen; D017114:Liver Failure, Acute; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D055815:Young Adult",
"nlm_unique_id": "9007566",
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"pages": "482-6",
"pmc": null,
"pmid": "25490169",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "DRESS syndrome secondary to ibuprofen as a cause of hyperacute liver failure.",
"title_normalized": "dress syndrome secondary to ibuprofen as a cause of hyperacute liver failure"
}
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{
"abstract": "Immunosuppressives have been used in multiple sclerosis (MS) since 1966. Today, we have many treatments for the relapsing forms of the disease, including 8 US Food and Drug Administration-approved therapies, with more soon to be introduced. Given the current treatment landscape what place do immunosuppressants have in combating MS? Trial work and our experience suggest that immunosuppressives still have an important role in treating MS. Cyclophosphamide finds use in treating patients with severe, inflammatory relapsing remitting MS or those suffering from a fulminant attack. We tend to employ mycophenolate mofetil as an add-on to injectable therapy for patients experiencing breakthrough activity. Some progressive (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) patients may stabilize after treatment with either cyclophosphamide or mycophenolate. We rarely employ mitoxantrone because of potential cardiac or carcinogenic effects. We prefer to use cyclophosphamide or mycophenolate mofetil in preference to methotrexate because evidence of efficacy is limited for this drug. We have less experience with azathioprine, but it may be an alternative for patients with limited options who are unable to tolerate conventional therapies.",
"affiliations": "Department of Neurology, Brigham and Women's Hospital, Center for Neurologic Disease and Partners MS Center, Harvard Medical School, Boston, MA, USA.",
"authors": "Stankiewicz|James M|JM|;Kolb|Hadar|H|;Karni|Arnon|A|;Weiner|Howard L|HL|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D008942:Mitoxantrone; D009173:Mycophenolic Acid; D001379:Azathioprine; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1007/s13311-012-0172-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-7479",
"issue": "10(1)",
"journal": "Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics",
"keywords": null,
"medline_ta": "Neurotherapeutics",
"mesh_terms": "D000328:Adult; D001379:Azathioprine; D003520:Cyclophosphamide; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008727:Methotrexate; D008942:Mitoxantrone; D009103:Multiple Sclerosis; D009173:Mycophenolic Acid",
"nlm_unique_id": "101290381",
"other_id": null,
"pages": "77-88",
"pmc": null,
"pmid": "23271506",
"pubdate": "2013-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "9710434;19439721;9683547;1672870;15645351;19465443;9048709;11805267;10618696;19439723;3276298;16193896;20532907;10496187;5906182;6157011;21180633;19204263;8649558;21865410;6834081;18855101;14759636;11347331;7473491;8909421;8815753;8602705;18074075;8388090;2838768;9104732;6605824;21547093;1783915;393355;15252268;6143013;7165996;8229034;65452;2950845;11475443;19752302;17870094;14582767;17943809;22091259;22591293;2957983;17222119;12504397;6294517;11511721;10025593;15940386;22402204;1671468;14017935;2025981;20925435;2387697;8338289;4631348;14698862;7818255;17920546;7639809;2899660;20439849;18541787;8469348;11511139;11569905",
"title": "Role of immunosuppressive therapy for the treatment of multiple sclerosis.",
"title_normalized": "role of immunosuppressive therapy for the treatment of multiple sclerosis"
}
|
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{
"abstract": "To investigate the clinical efficacy of combination of mouse nerve growth factor (NGF) and nimodipine in the treatment of neonatal intracranial hemorrhage (NICH) and its effect on plasma platelet-activating factor (PAF), C-type natriuretic peptide (CNP), matrix metalloproteinase-2 (MMP-2), and neurological function.\n\n\n\nA total of 90 infants with severe ICH admitted to our hospital from December 2016 to December 2018 were enrolled for retrospective study. According to different treatment schemes, they were assigned into 2 groups: group A (n=40) treated with mouse NGF plus nimodipine; group B (n=50) treated with nimodipine. The recovery time, serum indexes (PAF, MMP-2, CNP), neurological function (neonatal behavioral neurological assessment (NBNA) score), complications, and total effective rate of patients were recorded, and the satisfaction degree of family members was statistically analyzed.\n\n\n\nPatients in group A showed shorter recovery time, down-regulated PAF and MMP-2, evidently up-regulated CNP, and significantly increased NBNA score after one/two weeks of treatment, as well as fewer complications, higher total effective rate and higher satisfaction of family members.\n\n\n\nTo sum up, the combination of mouse NGF and nimodipine achieves good clinical efficacy in NICH, which down-regulates plasma PAF and MMP-2, up-regulates CNP, and improves neurological function. Therefore, it is suitable for clinical promotion.",
"affiliations": "Pharmacy Department, Rizhao People's Hospital, Rizhao, China. [email protected].",
"authors": "Pei|L-N|LN|;Liu|X-H|XH|;Zhang|H|H|;Zhu|J|J|;Gao|Z|Z|;Bi|M-Z|MZ|",
"chemical_list": "D010972:Platelet Activating Factor; D020098:Natriuretic Peptide, C-Type; D009553:Nimodipine; D020932:Nerve Growth Factor; D020778:Matrix Metalloproteinase 2",
"country": "Italy",
"delete": false,
"doi": "10.26355/eurrev_202101_24387",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1128-3602",
"issue": "25(1)",
"journal": "European review for medical and pharmacological sciences",
"keywords": null,
"medline_ta": "Eur Rev Med Pharmacol Sci",
"mesh_terms": "D000818:Animals; D006801:Humans; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D007273:Injections, Intramuscular; D020300:Intracranial Hemorrhages; D020778:Matrix Metalloproteinase 2; D051379:Mice; D020098:Natriuretic Peptide, C-Type; D020932:Nerve Growth Factor; D009553:Nimodipine; D010972:Platelet Activating Factor; D012189:Retrospective Studies",
"nlm_unique_id": "9717360",
"other_id": null,
"pages": "215-221",
"pmc": null,
"pmid": "33506910",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical efficacy of mouse nerve growth factor plus nimodipine in neonatal intracranial hemorrhage and its effect on plasma PAF, CNP, MMP-2, and neurological function.",
"title_normalized": "clinical efficacy of mouse nerve growth factor plus nimodipine in neonatal intracranial hemorrhage and its effect on plasma paf cnp mmp 2 and neurological function"
}
|
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"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HAEMORRHAGE INTRACRANIAL",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "NIMODIPINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Intracranial pressure increased",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PEI L?N, LIU X?H, ZHANG H, ZHU J, GAO Z, BI M?Z. CLINICAL EFFICACY OF MOUSE NERVE GROWTH FACTOR PLUS NIMODIPINE IN NEONATAL INTRACRANIAL HEMORRHAGE AND ITS EFFECT ON PLASMA PAF, CNP, MMP?2, AND NEUROLOGICAL FUNCTION. EUR. REV. MED. PHARMACOL. SCI.. 2021?25:1:215?221",
"literaturereference_normalized": "clinical efficacy of mouse nerve growth factor plus nimodipine in neonatal intracranial hemorrhage and its effect on plasma paf cnp mmp 2 and neurological function",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20210621",
"receivedate": "20210621",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19443951,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210717"
},
{
"companynumb": "CN-ARBOR PHARMACEUTICALS, LLC-CN-2021ARB000733",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIMODIPINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "203340",
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"drugenddateformat": null,
"drugindication": "HAEMORRHAGE INTRACRANIAL",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "NIMODIPINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PEI L?N, LIU X?H, ZHANG H, ZHU J, GAO Z, BI M?Z. CLINICAL EFFICACY OF MOUSE NERVE GROWTH FACTOR PLUS NIMODIPINE IN NEONATAL INTRACRANIAL HEMORRHAGE AND ITS EFFECT ON PLASMA PAF, CNP, MMP?2, AND NEUROLOGICAL FUNCTION. EUR. REV. MED. PHARMACOL. SCI.. 2021?25:1:215?221",
"literaturereference_normalized": "clinical efficacy of mouse nerve growth factor plus nimodipine in neonatal intracranial hemorrhage and its effect on plasma paf cnp mmp 2 and neurological function",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20210618",
"receivedate": "20210618",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19439243,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210717"
},
{
"companynumb": "CN-ARBOR PHARMACEUTICALS, LLC-CN-2021ARB000725",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIMODIPINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "203340",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HAEMORRHAGE INTRACRANIAL",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "NIMODIPINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Apnoea",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PEI L?N, LIU X?H, ZHANG H, ZHU J, GAO Z, BI M?Z. CLINICAL EFFICACY OF MOUSE NERVE GROWTH FACTOR PLUS NIMODIPINE IN NEONATAL INTRACRANIAL HEMORRHAGE AND ITS EFFECT ON PLASMA PAF, CNP, MMP?2, AND NEUROLOGICAL FUNCTION. EUR. REV. MED. PHARMACOL. SCI.. 2021?25:1:215?221",
"literaturereference_normalized": "clinical efficacy of mouse nerve growth factor plus nimodipine in neonatal intracranial hemorrhage and its effect on plasma paf cnp mmp 2 and neurological function",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20210618",
"receivedate": "20210618",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19439233,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210717"
}
] |
{
"abstract": "Drug-induced aseptic meningitis (DIAM) represents a diagnostic challenge since clinical and cerebrospinal fluid (CSF) findings may be indistinguishable from a bacterial meningitis. Intravenous immunoglobulin (IVIg) are commonly used in a variety of diseases, including inflammatory and autoimmune disorders. Although usually well-tolerated, various adverse effects have been reported. DIAM is a serious neurological side effect of IVIg therapy: albeit rare (0.067% of all IVIg infusions), the condition represents an important diagnostic challenge and should be considered by physicians. Here we report a case of an aseptic meningitis induced by IVIg therapy in a child with acute Epstein-Barr virus (EBV) infection and thrombocytopenia.",
"affiliations": "Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy.;Department of Pediatrics, Sapienza University of Rome, Italy.;Department of Pediatrics, Sapienza University of Rome, Italy.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy.;Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy.",
"authors": "Vassalini|Paolo|P|;Ajassa|Camilla|C|;Di Ruscio|Valentina|V|;Morace|Alessandra|A|;Vergari|Jacopo|J|;Tosato|Cecilia|C|;Savelloni|Giulia|G|;Mastroianni|Claudio M|CM|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1124-9390",
"issue": "27(2)",
"journal": "Le infezioni in medicina",
"keywords": null,
"medline_ta": "Infez Med",
"mesh_terms": "D000208:Acute Disease; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008582:Meningitis, Aseptic; D013921:Thrombocytopenia",
"nlm_unique_id": "9613961",
"other_id": null,
"pages": "194-197",
"pmc": null,
"pmid": "31205046",
"pubdate": "2019-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aseptic meningitis induced by intravenous immunoglobulins in a child with acute Epstein-Barr virus infection and thrombocytopenia.",
"title_normalized": "aseptic meningitis induced by intravenous immunoglobulins in a child with acute epstein barr virus infection and thrombocytopenia"
}
|
[
{
"companynumb": "IT-BEH-2019104170",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "1",
"drugadministrationroute": "042",
"drugauthorizationnumb": "125201",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "400 MILLIGRAM/KILOGRAM",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "EPSTEIN-BARR VIRUS INFECTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosagenumb": "400",
"drugstructuredosageunit": "007",
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"medicinalproduct": "HUMAN IMMUNOGLOBULIN (INN)"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": "125201",
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"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "THROMBOCYTOPENIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "HUMAN IMMUNOGLOBULIN (INN)"
}
],
"patientagegroup": "3",
"patientonsetage": "4",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Meningitis aseptic",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "No adverse event",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nuchal rigidity",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VASSALINI P, AJASSA C, DI RUSCIO V, MORACE A, VERGARI J, TOSATO C ET AL. ASEPTIC MENINGITIS INDUCED BY INTRAVENOUS IMMUNOGLOBULINS IN A CHILD WITH ACUTE EPSTEIN-BARR VIRUS INFECTION AND THROMBOCYTOPENIA. LE INFEZIONI IN MEDICINA. 2019?27(2):194-197",
"literaturereference_normalized": "aseptic meningitis induced by intravenous immunoglobulins in a child with acute epstein barr virus infection and thrombocytopenia",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20190925",
"receivedate": "20190715",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16570870,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191004"
},
{
"companynumb": "IT-SHIRE-IT201933181",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": "1255960",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "EPSTEIN-BARR VIRUS INFECTION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HUMAN NORMAL IMMUNOGLOBULIN"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "1",
"drugadministrationroute": "042",
"drugauthorizationnumb": "1255960",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "400 MILLIGRAM/KILOGRAM",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "THROMBOCYTOPENIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "400",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HUMAN NORMAL IMMUNOGLOBULIN"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional product use issue",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Meningitis aseptic",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nuchal rigidity",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VASSALINI, P? AJASSA, C? DI RUSCIO, V? MORACE, A? VERGARI, J ET AL.. ASEPTIC MENINGITIS INDUCED BY INTRAVENOUS IMMUNOGLOBULINS IN A CHILD WITH ACUTE EPSTEIN-BARR VIRUS INFECTION AND THROMBOCYTOPENIA. LE INFEZIONI IN MEDICINA. 2019?27(2):194-197",
"literaturereference_normalized": "aseptic meningitis induced by intravenous immunoglobulins in a child with acute epstein barr virus infection and thrombocytopenia",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20191015",
"receivedate": "20191015",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16921763,
"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": "Disease recurrence occurs in 20% to 40% of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are treated with chemotherapy and tyrosine kinase inhibitors (TKIs). In the current study, the authors report the incidence, treatment, and outcome after first disease recurrence in young and older adults treated in the ALL Ph08 trial (ClinicalTrials.gov identifier NCT01491763).\n\n\n\nPatients aged 18 to 55 years with de novo Ph+ ALL were treated with imatinib concurrently with standard-dose induction and consolidation therapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) when possible. In patients with first disease recurrence, the authors analyzed the type of recurrence, timing, location, presence of kinase domain mutations, type of treatment, and outcomes.\n\n\n\nOf the 125 patients, 28 patients (22%) developed disease recurrence before (4 patients) or after (24 patients) HSCT, with the recurrences being molecular in 11 patients (39%) and overt in 17 patients (61%). T315I was the most common mutation noted at the time of disease recurrence. Change in TKI was the most frequent treatment for patients with molecular disease recurrence whereas rescue chemotherapy and TKI change followed by second allo-HSCT when possible were performed for the most part in patients with overt disease recurrence. A total of 20 patients (71%) achieved response. The median disease-free survival (DFS) and overall survival (OS) were 8.5 months and 15.3 months, respectively. A trend for better DFS and OS was observed in patients with molecular recurrence compared with those with overt recurrence (median of 16.9 months vs 6.3 months [P = .05] and 28.7 months vs 11.5 months [P = .05] for DFS and OS, respectively).\n\n\n\nDisease recurrence was frequent in young and older adults with Ph+ ALL who were treated with imatinib and chemotherapy with HSCT. Although the majority of patients responded to rescue therapy, their outcomes were poor, especially with regard to overt disease recurrence.",
"affiliations": "Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain.;Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain.;Department of Hematology, Hospital of the Virgen de la Victoria, Malaga, Spain.;Department of Hematology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain.;Department of Hematology, Hospital of Sant Pau, Barcelona, Spain.;Department of Hematology, ICO-Hospital Duran i Reynals, L'Hospitalet de Llobregat, Catalonia, Spain.;Department of Hematology, Le Fe University and Polytechnic Hospital, Valencia, Spain.;Department of Hematology, Carlos Haya Hospital, Malaga, Spain.;Department of Hematology, Virgen del Rocio University Hospital, Seville, Spain.;Department of Hematology, Central Hospital of Asturias, Oviedo, Spain.;Department of Hematology, General University Hospital of Alicante, Alicante, Spain.;Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain.;Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain.;Department of Hematology, Son Espases Hospital, Palma de Mallorca, Spain.;Department of Hematology, ICO-Hospital Joan XXIII, Tarragona, Spain.;Department of Hematology, Reina Sofia Hospital, Cordoba, Spain.;Department of Hematology, Lucus Augusti Hospital, Lugo, Spain.;Department of Hematology, del Mar Hospital, Barcelona, Spain.;Department of Hematology, Clinical Hospital, Valencia, Spain.;Department of Hematology, Morales Meseguer University General Hospital, Murcia, Spain.;Department of Hematology, Donostia University Hospital, San Sebastian, Spain.;Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain.;Department of Hematology, Fuenlabrada University Hospital, Madrid, Spain.;Department of Hematology, La Zarzuela Hospital, Madrid, Spain.;Department of Hematology, Arnau de Vilanova Hospital, Lleida, Spain.;Department of Hematology, University Hospital of Salamanca, Salamanca, Spain.;Department of Clinical Hematology, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Autonomous University of Barcelona, Badalona, Spain.",
"authors": "Ribera|Josep-Maria|JM|0000-0003-1042-6024;García|Olga|O|;Moreno|María-José|MJ|;Barba|Pere|P|;García-Cadenas|Irene|I|;Mercadal|Santiago|S|;Montesinos|Pau|P|0000-0002-3275-5593;Barrios|Manuel|M|;González-Campos|José|J|;Martínez-Carballeira|Daniel|D|;Gil|Cristina|C|;Ribera|Jordi|J|;Vives|Susana|S|;Novo|Andrés|A|;Cervera|Marta|M|;Serrano|Josefina|J|;Lavilla|Esperanza|E|;Abella|Eugenia|E|;Tormo|Mar|M|;Amigo|María-Luz|ML|;Artola|María-Teresa|MT|;Genescà|Eulalia|E|;Bravo|Pilar|P|;García-Belmonte|Daniel|D|;García-Guiñón|Antoni|A|;Hernández-Rivas|Jesús-María|JM|;Feliu|Evarist|E|;|||",
"chemical_list": "D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.32156",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "125(16)",
"journal": "Cancer",
"keywords": "Philadelphia chromosome-positive acute lymphoblastic leukemia; clinical disease recurrence; molecular disease recurrence; outcome",
"medline_ta": "Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000068877:Imatinib Mesylate; D015994:Incidence; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "2810-2817",
"pmc": null,
"pmid": "31012967",
"pubdate": "2019-08-15",
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"title": "Incidence and outcome after first molecular versus overt recurrence in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia included in the ALL Ph08 trial from the Spanish PETHEMA Group.",
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}
|
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"drugindication": "ACUTE LYMPHOCYTIC LEUKAEMIA",
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{
"reactionmeddrapt": "Recurrent cancer",
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},
{
"reactionmeddrapt": "Acute lymphocytic leukaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "RIBERA J, GARCIA O, MORENO M, BARBA P, GARCIA-CADENAS I, MERCADAL S ET AL.. INCIDENCE AND OUTCOME AFTER FIRST MOLECULAR VERSUS OVERT RECURRENCE IN PATIENTS WITH PHILADELPHIA CHROMOSOME- POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA INCLUDED IN THE ALL PH08 TRIAL FROM THE SPANISH PETHEMA GROUP. CANCER. 2019?0:1-8",
"literaturereference_normalized": "incidence and outcome after first molecular versus overt recurrence in patients with philadelphia chromosome positive acute lymphoblastic leukemia included in the all ph08 trial from the spanish pethema group",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20190919",
"receivedate": "20190919",
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},
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},
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}
] |
{
"abstract": "Human immunodeficiency virus (HIV) causes a spectrum of immunodysfunction, the most severe of which is the acquired immunodeficiency syndrome (AIDS). We have followed the course of psoriasis in 13 patients over 2 1/2 years in a population of more than 1000 HIV-positive individuals. Four patients had a history of mild psoriasis that became severe and uncontrollable as symptoms of immunodeficiency developed. Psoriasis and HIV positivity, AIDS-related complex, or AIDS simultaneously developed in nine patients. In addition to psoriasis, Reiter's syndrome (arthritis, urethritis, and conjunctivitis) developed in one patient in the first group and three patients in the second group. Opportunistic infections, especially candidiasis and Staphylococcus, drugs, and an altered immune system may contribute to the development or flare of psoriasis in these patients. The appearance of severe psoriasis (especially in a patient with other risk factors for HIV) should prompt evaluation for HIV, and may be a poor prognostic indicator in HIV-positive patients, since nine of our 13 patients have died. Immunosuppressive therapy with methotrexate is contraindicated in this group of patients. Newer forms of drug therapy including etretinate show promising results for the management of AIDS-associated psoriasis.",
"affiliations": "Department of Dermatology, University of Texas Health Sciences Center, Houston.",
"authors": "Duvic|M|M|;Johnson|T M|TM|;Rapini|R P|RP|;Freese|T|T|;Brewton|G|G|;Rios|A|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-987X",
"issue": "123(12)",
"journal": "Archives of dermatology",
"keywords": null,
"medline_ta": "Arch Dermatol",
"mesh_terms": "D000386:AIDS-Related Complex; D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D016918:Arthritis, Reactive; D006679:HIV Seropositivity; D006801:Humans; D008297:Male; D009894:Opportunistic Infections; D011379:Prognosis; D011565:Psoriasis; D012867:Skin",
"nlm_unique_id": "0372433",
"other_id": null,
"pages": "1622-32",
"pmc": null,
"pmid": "3688903",
"pubdate": "1987-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired immunodeficiency syndrome-associated psoriasis and Reiter's syndrome.",
"title_normalized": "acquired immunodeficiency syndrome associated psoriasis and reiter s syndrome"
}
|
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},
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] |
{
"abstract": "OBJECTIVE\nTo investigate the efficacy and safety of sildenafil added to inhaled nitric oxide (iNO) for newborn infants with persistent pulmonary hypertension of newborn (PPHN) or hypoxic respiratory failure (HRF) at risk of PPHN.\n\n\nMETHODS\nPart A of a multinational, randomized, double-blind, placebo-controlled trial. Infants ≤96 hours' old, >34 weeks of gestation, receiving iNO (10-20 ppm on ≥50% FiO2) for PPHN or HRF at risk of PPHN, and oxygen index >15 to <60, were randomized (1:1) to intravenous (IV) sildenafil (loading: 0.1 mg/kg, over 30 minutes; maintenance: 0.03 mg/kg/h) or placebo, for up to 14 days. Coprimary end points were treatment failure rate (day 14/discharge) and time on iNO without treatment failure. Secondary end points included time on ventilation and oxygenation measures.\n\n\nRESULTS\nOf 87 infants screened, 29 were randomized to IV sildenafil and 30 to placebo; 13 discontinued treatment (sildenafil, n = 6; placebo: n = 7), including 3 deaths (sildenafil: n = 2; placebo: n = 1). Treatment failure rates did not differ with sildenafil (27.6%) vs placebo (20.0%; P = .4935). Mean time on iNO was not different with sildenafil (4.1 days) vs placebo (4.1 days; P = .9850). No differences were noted in secondary end points. Most common adverse events (AEs) with sildenafil (≥10% infants) were hypotension (n = 8/29), hypokalemia (n = 7/29), anemia, drug withdrawal syndrome (n = 4/29, each), and bradycardia (n = 3/29). One serious AE (hypotension) was considered treatment-related.\n\n\nCONCLUSIONS\nIV sildenafil added to iNO was not superior to placebo in infants with PPHN or HRF at risk of PPHN. A review of AEs did not identify any pattern of events indicative of a safety concern with IV sildenafil. Infants will have developmental follow-up (Part B). TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT01720524.",
"affiliations": "Pediatric and Neonatal Intensive Care, Great Ormond Street Hospital for Children, London, United Kingdom. Electronic address: [email protected].;Global Biometrics and Data Management, Pfizer Inc, La Jolla, CA.;Department of Neonatology, Karolinska Institute and University Hospital, Stockholm, Sweden.;Pfizer Inc, Collegeville, PA.;Pfizer Inc, Collegeville, PA.;Pfizer Inc, New York, NY.;Rady Children's Hospital and University of California San Diego, San Diego, CA.",
"authors": "Pierce|Christine M|CM|;Zhang|Min H|MH|;Jonsson|Baldvin|B|;Iorga|Dinu|D|;Cheruvu|Narayan|N|;Balagtas|Cecile C|CC|;Steinhorn|Robin H|RH|",
"chemical_list": "D045462:Endothelium-Dependent Relaxing Factors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000068677:Sildenafil Citrate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpeds.2021.05.051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3476",
"issue": "237()",
"journal": "The Journal of pediatrics",
"keywords": "PPHN; infant; inhaled nitric oxide; placebo; sildenafil citrate; treatment failure",
"medline_ta": "J Pediatr",
"mesh_terms": "D000280:Administration, Inhalation; D004311:Double-Blind Method; D045462:Endothelium-Dependent Relaxing Factors; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male; D009569:Nitric Oxide; D010547:Persistent Fetal Circulation Syndrome; D000068677:Sildenafil Citrate; D014665:Vasodilator Agents",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "154-161.e3",
"pmc": null,
"pmid": "34052232",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Efficacy and Safety of IV Sildenafil in the Treatment of Newborn Infants with, or at Risk of, Persistent Pulmonary Hypertension of the Newborn (PPHN): A Multicenter, Randomized, Placebo-Controlled Trial.",
"title_normalized": "efficacy and safety of iv sildenafil in the treatment of newborn infants with or at risk of persistent pulmonary hypertension of the newborn pphn a multicenter randomized placebo controlled trial"
}
|
[
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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": "PIERCE C, ZHANG M, JONSSON B, IORGA D, ET.AL. EFFICACY AND SAFETY OF IV SILDENAFIL IN THE TREATMENT OF NEWBORN INFANTS WITH, OR AT RISK OF PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN): A MULTICENTER, RANDOMIZED, PLACEBO?CONTROLLED TRIAL. THE JOURNAL OF PEDIATRICS. 2021?UNK:UNK",
"literaturereference_normalized": "efficacy and safety of iv sildenafil in the treatment of newborn infants with or at risk of persistent pulmonary hypertension of the newborn pphn a multicenter randomized placebo controlled trial",
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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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}
] |
{
"abstract": "Dear Editor, Scleroderma associated with neoplasia is rare, with only a small number of cases reported. We describe 4 patients with paraneoplastic scleroderma who were treated at the I. Department of Dermatovenereology, St. Anna Hospital, during the period between 2004 and 2014. The patients were diagnosed with cholangiogenic carcinoma, endometrial carcinoma, prostatic adenocarcinoma, and adenoma of the suprarenal gland. In the case of concurrent scleroderma and tumor, four situations may occur: they can develop independently of each other; scleroderma may be induced by the tumor; the tumor can develop in the scleroderma; or the tumor can be induced by immunosuppressive therapy. Sclerotization of the skin was described in association with lung cancer, carcinoid, plasma cell dyscrasia, cancer of the ovary, cervix, breast, esophagus, stomach, nasopharynx, melanoma, and sarcoma (1,2,5,7,10). Symptoms may be induced by substances secreted by the tumor (hormones, cytokines, etc.) (9). Tumorous cells further induce cytotoxic and autoantibody response. Scleroderma is characterized by immunological dysregulation, vasculopathy, and hyperproduction of the extracellular matrix by activated fibroblasts. Endothelial, inflammatory, and mesenchymal cells produce cytokines, chemokines, and growth factors e.g. Interleukin-1 (IL1), Interleukin-6 (IL6), tumor necrosis factor alpha (TNF α), collagen alpha 1, connective tissue growth factor (CTGF) (3), and basic fibroblast growth factor (bFGF). This factor is also produced by lung cancer cells (4). The clinical picture of scleroderma and paraneoplastic scleroderma is similar. Diffuse thickening of the skin and/or sclerodermatous plaques can be seen. The histological picture is consistent with scleroderma. Capillaroscopy changes, antinuclear antibodies (ANA), sclerodactyly, and Raynaud phenomenon suggest the diagnosis of systemic scleroderma (SS) (4). Our patients did not fulfill enough of the criteria for SS. Both diffuse and localized scleroderma was seen in 3 patients and generalized localized scleroderma in one case. All patients had a histological picture consistent with scleroderma, negative ANA and ENA antibodies (Table 1, Figure 1). A 66-year-old woman presented with a 10 months history of sclerodermatous plaques on her neck, trunk, and upper and lower extremities. The skin on her breasts and cheeks was diffusely indurated. Examination showed thrombocytopenia, elevated transaminases, Cancer antigen 19-9 (Ca 19-9), thyroid stimulating hormone (TSH), and anti-thyroid peroxidase antibodies, dysmotility of the lower part of esophagus, hepatosplenomegaly, cholecystolithiasis, and benign polyps of colon. She was given prednisone 40 mg/day but did not return for follow up. After 6 months she was diagnosed with cholangiogenic carcinoma with metastatic disease and died shortly afterwards. A 74-year-old woman had localized scleroderma on the trunk for three years. She was treated with procaine penicillin for positive borrelia Immunoglobulin M (IgM) antibodies. Her condition worsened suddenly with confluent scleroderma plaques on her trunk, extremities, and genital region, and vasoneurosis on her lower extremities; she was started on prednisone 35 mg/day. Examination revealed endometrial cancer. The patient underwent a hysterectomy, adnexectomy, and radiotherapy with curative effect. Scleroderma patches softened with residual hyperpigmentation, and prednisone was stopped two years later. A 80-year-old man had a month-long history of diffuse thickening and toughening of the skin on the forearms and lower legs and scleroderma patches on the thighs and shins. Examination revealed prostate adenocarcinoma, and therapy with antiandrogen bicalutamide and prednisone 15 mg/day was started. Two years after the diagnosis he continues with bicalutamide treatment, prednisone 5 mg q.a.d. and has residual toughening of the skin on his lower legs. A 62-year-old woman with seronegative rheumatoid arthritis presented with diffusely tough skin on her extremities and trunk, present for 2 months. Examination revealed cervicitis with a benign endometric polyp, cholecystolithiasis, borderline pulmonary hypertension, and a hormonally inactive suprarenal adenoma. She was given prednisone 40 mg/day and penicillamine with effect. In the 3rd year of therapy she has residual induration of her lower legs and a scleroderma plaque in the lumbar region. She is monitored for her suprarenal adenoma. Two patients had scleroderma at the same time as a malignant tumor; in one patient the localized scleroderma worsened rapidly at the time of the tumor diagnosis, and in one patient a clinically silent adenoma was found. Adrenal tissue can secrete molecules such as serotonine or bFGF involved in fibroplasia (3,6). One patient died of a metastatic disease, two patients after the successful treatment of the tumor, and the patient with suprarenal adenoma experienced softening of the skin and regression of scleroderma. Although paraneoplastic scleroderma is often classified as a pseudoscleroderma, we regard neoplasia as a distinct triggering impulse for scleroderma. Recently, an association between RNA polymerase I/III antibodies in systemic scleroderma and cancer was suggested (8). Such studies may confirm the true link between scleroderma and malignancy. These patients are characterized by older age, sudden onset, diffuse thickening of the skin, and/or generalized morphea with a concurrent neoplastic process. In the case of a successful tumor treatment, skin changes regress.",
"affiliations": "Prof. Hana Jedlickova, MD, PhD, St. Anna University Hospital, Masaryk University, Brno, Czech Republic; [email protected].",
"authors": "Jedlickova|Hana|H|;Durčanská|Veronika|V|;Vašků|Vladimír|V|",
"chemical_list": null,
"country": "Croatia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1330-027X",
"issue": "24(1)",
"journal": "Acta dermatovenerologica Croatica : ADC",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Croat",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010257:Paraneoplastic Syndromes; D012594:Scleroderma, Localized",
"nlm_unique_id": "9433781",
"other_id": null,
"pages": "78-80",
"pmc": null,
"pmid": "27149136",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paraneoplastic Scleroderma: Are There Any Clues?",
"title_normalized": "paraneoplastic scleroderma are there any clues"
}
|
[
{
"companynumb": "CZ-SUN PHARMACEUTICAL INDUSTRIES LTD-2017R1-139465",
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"patient": {
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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": "JEDLICKOVA H, DURCANSKA V, VASKU V. PARANEOPLASTIC SCLERODERMA: ARE THERE ANY CLUES?. ACTA DERMATOVENEROL CROAT. 2016;APR;24(1):78-80",
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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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},
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}
] |
{
"abstract": "Olanzapine is a second-generation antipsychotic. Incidence of olanzapine-induced seizures (OIS) is low with monotherapy. Combination therapy with another antipsychotic, drug metabolism and old age are risk factors for OIS. Our patient was a 71-year-old man, admitted to the psychiatry unit. He was managed on the lines of bipolar affective disorder current episode depression and dementia. He was started on olanzapine 1.25 mg two times/day. The patient developed generalised tonic-clonic seizure that lasted for around two and a half minutes within 24 hours of olanzapine treatment. His electroencephalogram showed findings that were suggestive of mild slowing. Our case discusses the incidence of OIS on the subtherapeutic dose. This presentation involves multiple risk factors for OIS: a history of stroke, poststroke seizure, old age and cognitive impairment. Due to scarcity of evidence of OIS; mostly with recommended therapeutic dose range physicians may underestimate seizure risk at subtherapeutic doses.",
"affiliations": "Psychiatry, Aga Khan University, Karachi, Pakistan [email protected].;Psychiatry, Aga Khan University, Karachi, Pakistan.;Psychiatry, Aga Khan University, Karachi, Pakistan.",
"authors": "Mansoor|Marium|M|;Mesiya|Mohammad Hanif|MH|;Chachar|Aisha Sanober|AS|",
"chemical_list": "D000927:Anticonvulsants; D014150:Antipsychotic Agents; D014635:Valproic Acid; D000077152:Olanzapine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-230018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(12)",
"journal": "BMJ case reports",
"keywords": "epilepsy and seizures; psychiatry (drugs and medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000927:Anticonvulsants; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D016903:Drug Monitoring; D004569:Electroencephalography; D006801:Humans; D008297:Male; D000077152:Olanzapine; D012307:Risk Factors; D012640:Seizures; D016896:Treatment Outcome; D014635:Valproic Acid",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31888915",
"pubdate": "2019-12-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Generalised tonic-clonic seizures on the subtherapeutic dose of olanzapine.",
"title_normalized": "generalised tonic clonic seizures on the subtherapeutic dose of olanzapine"
}
|
[
{
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"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
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"drugdosagetext": "10 MILLIGRAM, QD",
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"drugindication": "PSYCHOTIC DISORDER",
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"medicinalproduct": "OLANZAPINE 10 MG"
},
{
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"activesubstancename": "VALPROIC ACID"
},
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"drugindication": "SEIZURE",
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"medicinalproduct": "VALPROATE"
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Humerus fracture",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Generalised tonic-clonic seizure",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Convulsive threshold lowered",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MANSOOR M, MESIYA MH, CHACHAR AS.. GENERALISED TONIC-CLONIC SEIZURES ON THE SUBTHERAPEUTIC DOSE OF OLANZAPINE.. BMJ CASE REP.. 2019?12(12):E230018",
"literaturereference_normalized": "generalised tonic clonic seizures on the subtherapeutic dose of olanzapine",
"qualification": "3",
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},
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"receivedate": "20200120",
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},
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},
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"transmissiondate": "20200409"
}
] |
{
"abstract": "To evaluate the efficacy and safety of pegylated interferon-lambda-1a (Lambda)/ribavirin (RBV)/daclatasvir (DCV) for treatment of patients coinfected with chronic hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Treatment-naive patients were assigned to cohort A [HCV genotype (GT)-2 or -3] or cohort B [HCV GT-1(a or b) or -4]. All patients received Lambda/RBV/DCV for the first 12 weeks; cohort A received Lambda/RBV for an additional 12 weeks, followed by 24 weeks of follow-up, and cohort B received response-guided therapy. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post-treatment week 12 (SVR12). In cohort A (n = 104), 84.6% achieved SVR12 (95.0% in GT-2; 83.1% in GT-3). In cohort B (n = 196), 76.0% achieved SVR12 (71.7% in GT-1a; 86.0% in GT-1b; 70.7% in GT-4). Rates of discontinuation due to adverse events (AEs) (3.8% and 6.1%) and serious AEs (5.8% and 6.1%) were low in cohorts A and B, respectively. In addition, treatment with Lambda/RBV/DCV had little impact on CD4 counts. SVR12 rates with Lambda/RBV/DCV in an HCV/HIV-coinfected population ranged from 71.7% to 95.0%. Treatment was generally well tolerated, with a low proportion of patients discontinuing due to AEs. Clinical trial registration NCT01866930.",
"affiliations": "1 Chelsea and Westminster Hospital , London, United Kingdom .;2 Hospital Universitario 12 Octubre , Centro de Actividades Ambulatorias, Madrid, Spain .;3 Scientific Institute Ospedale , San Raffaele, Milan, Italy .;4 State Research Center-Institute of Biophysics , Russian Ministry of Health, Moscow, Russia .;5 Zuckerberg San Francisco General, University of California , San Francisco, San Francisco, California.;6 Vancouver Infectious Diseases Centre , Vancouver, Canada .;7 Department of Infectious Diseases, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, University of Paris Diderot , Paris, France .;8 Bristol-Myers Squibb , Wallingford, Connecticut.;8 Bristol-Myers Squibb , Wallingford, Connecticut.;9 Shionogi Inc. , Florham Park, New Jersey.",
"authors": "Nelson|Mark|M|;Rubio|Rafael|R|;Lazzarin|Adriano|A|;Romanova|Svetlana|S|;Luetkemeyer|Annie|A|;Conway|Brian|B|;Molina|Jean-Michel|JM|;Xu|Dong|D|;Srinivasan|Subasree|S|;Portsmouth|Simon|S|",
"chemical_list": "D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; C000624353:interferon-lambda, human; D012254:Ribavirin; D007372:Interferons; D014633:Valine; C549273:daclatasvir",
"country": "United States",
"delete": false,
"doi": "10.1089/jir.2016.0082",
"fulltext": null,
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"issn_linking": "1079-9907",
"issue": "37(3)",
"journal": "Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research",
"keywords": "IFN receptors; IFNs and cytokines; antiviral actions; infectious disease",
"medline_ta": "J Interferon Cytokine Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D018791:CD4 Lymphocyte Count; D002219:Carbamates; D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D007093:Imidazoles; D007372:Interferons; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D012254:Ribavirin; D016896:Treatment Outcome; D014633:Valine; D019562:Viral Load",
"nlm_unique_id": "9507088",
"other_id": null,
"pages": "103-111",
"pmc": null,
"pmid": "28282271",
"pubdate": "2017-03",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Safety and Efficacy of Pegylated Interferon Lambda, Ribavirin, and Daclatasvir in HCV and HIV-Coinfected Patients.",
"title_normalized": "safety and efficacy of pegylated interferon lambda ribavirin and daclatasvir in hcv and hiv coinfected patients"
}
|
[
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{
"abstract": "We reported the case of a patient with stage IV Hodgkin's disease (involving the nodes and Liver) presenting with paraneoplastic fever and who subsequently developed hypothermia during chemotherapy administration. We also reviewed the 12 other cases of hypothermia in Hodgkin's disease reported in the literature and discussed the most probable physiopathologic aetiologies.",
"affiliations": "Department of Intensive Care and Thoracic Oncology, Institut Jules Bordet, Brussels, Belgium. [email protected]",
"authors": "Meert|A P|AP|;Berghmans|T|T|;Sculier|J P|JP|",
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"mesh_terms": "D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D006689:Hodgkin Disease; D006801:Humans; D007035:Hypothermia; D008297:Male; D008875:Middle Aged; D014750:Vincristine",
"nlm_unique_id": "0370306",
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"pages": "252-4",
"pmc": null,
"pmid": "17240740",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypothermia and Hodgkin's disease: case report and review of the literature.",
"title_normalized": "hypothermia and hodgkin s disease case report and review of the literature"
}
|
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],
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] |
{
"abstract": "Paclitaxel and platinum combination is the standard chemotherapy regimen for patients with advanced epithelial ovarian cancer. The dose-limiting toxicity effects of this combination are myelosuppression and neuropathy. Herein, we report a case of a 71-year-old female with advanced epithelial ovarian cancer who developed bilateral total loss of hearing and acute renal failure related with paclitaxel- and carboplatin-based chemotherapy. Acute renal failure accompanied by complete loss of hearing in patients treated with carboplatin and paclitaxel combination has not been previously reported. This uncommon adverse effect of carboplatin and paclitaxel combination was discussed, and all the literature in English related with the toxicity of paclitaxel and carboplatin were reviewed.",
"affiliations": "Section of Medical Oncology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey. [email protected]",
"authors": "Ozguroglu|M|M|;Sari|O|O|;Turna|H|H|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1111/j.1525-1438.2006.00214.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1048-891X",
"issue": "16 Suppl 1()",
"journal": "International journal of gynecological cancer : official journal of the International Gynecological Cancer Society",
"keywords": null,
"medline_ta": "Int J Gynecol Cancer",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002277:Carcinoma; D003638:Deafness; D017809:Fatal Outcome; D005260:Female; D013509:Gynecologic Surgical Procedures; D006801:Humans; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D012086:Reoperation",
"nlm_unique_id": "9111626",
"other_id": null,
"pages": "394-6",
"pmc": null,
"pmid": "16515631",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Devastating effects of chemotherapy: deafness and acute renal failure in a patient with epithelial ovarian cancer.",
"title_normalized": "devastating effects of chemotherapy deafness and acute renal failure in a patient with epithelial ovarian cancer"
}
|
[
{
"companynumb": "TR-CIPLA LTD.-2014TR02873",
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"occurcountry": "TR",
"patient": {
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{
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"activesubstancename": "PACLITAXEL"
},
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"drugdosagetext": "175 MG/M2 3 HOUR",
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"drugindication": "OVARIAN CANCER",
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"medicinalproduct": "PACLITAXEL."
},
{
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"activesubstancename": "CARBOPLATIN"
},
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"drugdosageform": "INJECTION",
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"medicinalproduct": "CARBOPLATIN."
}
],
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"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Renal failure",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pancytopenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Sepsis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Deafness",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "OZGUROGLU M, SARI O, TURNA H.. DEVASTATING EFFECTS OF CHEMOTHERAPY: DEAFNESS AND ACUTE RENAL FAILURE IN A PATIENT WITH EPITHELIAL OVARIAN CANCER.. INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER. 2006;394-6",
"literaturereference_normalized": "devastating effects of chemotherapy deafness and acute renal failure in a patient with epithelial ovarian cancer",
"qualification": "3",
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},
"primarysourcecountry": "TR",
"receiptdate": "20141226",
"receivedate": "20141226",
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},
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"safetyreportversion": 2,
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},
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}
] |
{
"abstract": "BACKGROUND\nThis is the 26th Annual Report of the American Association of Poison Control Centers (AAPCC; http://www. aapcc.org ) National Poison Data System (NPDS). During 2008, 60 of the nation's 61 US poison centers uploaded case data automatically. The median upload time was 24 [7.2, 112] (median [25%, 75%]) minutes creating a real-time national exposure and information database and surveillance system.\n\n\nMETHODS\nWe analyzed the case data tabulating specific indices from NPDS. The methodology was similar to that of previous years. Where changes were introduced, the differences are identified. Poison center cases with medical outcomes of death were evaluated by a team of 28 medical and clinical toxicologist reviewers using an ordinal scale of 1-6 to determine Relative Contribution to Fatality (RCF) from the exposure to the death.\n\n\nRESULTS\nIn 2008, 4,333,012 calls were captured by NPDS: 2,491,049 closed human exposure cases, 130,495 animal exposures, 1,703,762 information calls, 7,336 human confirmed nonexposures, and 370 animal confirmed nonexposures. The top five substances most frequently involved in all human exposures were analgesics (13.3%), cosmetics/personal care products (9.0%), household cleaning substances (8.6%), sedatives/hypnotics/antipsychotics (6.6%), and foreign bodies/toys/miscellaneous (5.2%). The top five most common exposures in children age 5 or less were cosmetics/personal care products (13.5%), analgesics (9.7%), household cleaning substances (9.7%), foreign bodies/toys/miscellaneous (7.5%), and topical preparations (6.9%). Drug identification requests comprised 66.8% of all information calls. NPDS documented 1,756 human exposures resulting in death with 1,315 human fatalities deemed related with an RCF of at least contributory (1, 2, or 3).\n\n\nCONCLUSIONS\nPoisoning continues to be a significant cause of morbidity and mortality in the US. The near real-time, always current status of NPDS represents a national resource to collect and monitor US poisoning exposure cases and information calls. NPDS continues its mission as one of the few real-time national surveillance systems in existence, providing a model public health surveillance system for all types of exposures, public health event identification, resilience response and situational awareness tracking.",
"affiliations": "American Association of Poison Control Centers, 515 King Street, Suite 510, Alexandria, VA 22314, USA. [email protected]",
"authors": "Bronstein|Alvin C|AC|;Spyker|Daniel A|DA|;Cantilena|Louis R|LR|;Green|Jody L|JL|;Rumack|Barry H|BH|;Giffin|Sandra L|SL|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3109/15563650903438566",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "47(10)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D016208:Databases, Factual; D004781:Environmental Exposure; D006801:Humans; D011039:Poison Control Centers; D011041:Poisoning; D011159:Population Surveillance; D012952:Societies; D014481:United States",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "911-1084",
"pmc": null,
"pmid": "20028214",
"pubdate": "2009-12",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report.",
"title_normalized": "2008 annual report of the american association of poison control centers national poison data system npds 26th annual report"
}
|
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"activesubstancename": "ACETAMINOPHEN\\DIPHENHYDRAMINE"
},
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"drugdosageform": "FILM-COATED TABLET",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "PARACETAMOL + DIPHENHYDRAMINE"
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},
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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}
],
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},
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"literaturereference_normalized": "2008 annual report of the american association of poison control centers national poison data system npds 26th annual report",
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},
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},
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},
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"seriousnesscongenitalanomali": null,
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"transmissiondate": "20150529"
},
{
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},
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"medicinalproduct": "PARACETAMOL + DIPHENHYDRAMINE"
},
{
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},
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"medicinalproduct": "OXYCODONE W/PARACETAMOL"
},
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},
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"transmissiondate": "20150529"
},
{
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},
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{
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},
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"medicinalproduct": "PARACETAMOL + DIPHENHYDRAMINE"
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"abstract": "Transradial artery approach as primary access for transcatheter diagnosis and intervention is associated with lower risk of bleeding and major vascular complications, improved patient comfort and shorter time to hemostasis and ambulation than femoral one. Patient's adequate hand collateral perfusion, assessed by the Barbeau test, must be depicted prior to transradial artery approach in order to assess any absolute contraindication (D waveform). We describe the distal transradial artery approach, recently proposed for coronary interventions, used in emergency to embolize an intestinal bleeding in an 84-year-old woman and a left pectoralis major muscle bleeding in an 83-year-old woman, both with high risk of bleeding for femoral approach and contraindication for transradial artery approach (Barbeau D waveform).",
"affiliations": "Department of Medical Surgical Sciences and Advanced Technologies - Radiology I Unit, University Hospital \"Policlinico-Vittorio Emanuele\", Catania, Italy.;Department of Diagnostic and Interventional Radiology, Garibaldi Centro Hospital, Catania, Italy.;Department of Medical Surgical Sciences and Advanced Technologies - Radiology I Unit, University Hospital \"Policlinico-Vittorio Emanuele\", Catania, Italy.;Department of Medical Surgical Sciences and Advanced Technologies - Radiology I Unit, University Hospital \"Policlinico-Vittorio Emanuele\", Catania, Italy.;Department of Diagnostic and Interventional Radiology, Azienda Ospedaliera per L'Emergenza \"Cannizzaro\", Catania, Italy.;Department of Medical Surgical Sciences and Advanced Technologies - Radiology I Unit, University Hospital \"Policlinico-Vittorio Emanuele\", Catania, Italy.;Department of Medical Surgical Sciences and Advanced Technologies - Radiology I Unit, University Hospital \"Policlinico-Vittorio Emanuele\", Catania, Italy.",
"authors": "Boncoraglio|Andrea|A|https://orcid.org/0000-0002-0251-1133;Caltabiano|Giuseppe|G|;Foti|Pietro Valerio|PV|;Mammino|Luca|L|;Failla|Giovanni|G|;Palmucci|Stefano|S|;Basile|Antonio|A|",
"chemical_list": null,
"country": "England",
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"doi": "10.1177/2050313X18823918",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1882391810.1177_2050313X18823918Case ReportDistal radial artery: The last extreme rescue arterial access for interventional radiologists? https://orcid.org/0000-0002-0251-1133Boncoraglio Andrea 1Caltabiano Giuseppe 2Foti Pietro Valerio 1Mammino Luca 1Failla Giovanni 3Palmucci Stefano 1Basile Antonio 11 Department of Medical Surgical Sciences and Advanced Technologies - Radiology I Unit, University Hospital “Policlinico-Vittorio Emanuele”, Catania, Italy2 Department of Diagnostic and Interventional Radiology, Garibaldi Centro Hospital, Catania, Italy3 Department of Diagnostic and Interventional Radiology, Azienda Ospedaliera per L’Emergenza “Cannizzaro”, Catania, ItalyAndrea Boncoraglio, Department of Medical Surgical Sciences and Advanced Technologies - Radiology I Unit, University Hospital “Policlinico-Vittorio Emanuele”, Via Santa Sofia 78, Catania 95123, Italy. Email: [email protected] 1 2019 2019 7 2050313X188239183 5 2018 12 12 2018 © The Author(s) 20192019SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Transradial artery approach as primary access for transcatheter diagnosis and intervention is associated with lower risk of bleeding and major vascular complications, improved patient comfort and shorter time to hemostasis and ambulation than femoral one. Patient’s adequate hand collateral perfusion, assessed by the Barbeau test, must be depicted prior to transradial artery approach in order to assess any absolute contraindication (D waveform). We describe the distal transradial artery approach, recently proposed for coronary interventions, used in emergency to embolize an intestinal bleeding in an 84-year-old woman and a left pectoralis major muscle bleeding in an 83-year-old woman, both with high risk of bleeding for femoral approach and contraindication for transradial artery approach (Barbeau D waveform).\n\nRadial arteryfemoral approachdistal radial arteryBarbeau testtransradial arterial accessembolizationcover-dateJanuary-December 2019\n==== Body\nIntroduction\nThe use of radial artery (RA) as the primary access for transcatheter diagnosis and intervention is associated with considerable reduction in the risk of vascular and bleeding complications, including easier accomplishment of postprocedural hemostasis, than femoral approach (FA).1,2 Other advantages of transradial arterial access (TRA), over transfemoral one, are shorter patient resumption leading to instant ambulation, with reduction-related costs and increased patient gratification. Furthermore, TRA may be advantageous in obese patients.2 Some studies in literature have demonstrated the feasibility and safety of TRA also for non-coronary vascular interventions, such as uterine artery embolization, arterial renal disease and transarterial chemoembolization.3\n\nBefore attempting TRA, it is fundamental to evaluate collateral perfusion to the hand through Barbeau test, in order to avoid ischemic hand complications.3 A pulse oximetry is put on the patient’s thumb and the procedure starts with contemporary radial and ulnar artery occlusion. For 2 min following the release of the compression on the ulnar artery, the pulse should be measured and the wave must be recorded through the pulse oximetry. Depending on the type of waveform, registered ulnopalmar patency includes the following four types: (1) no damping of the pulse tracing immediately after compression, (2) damping of pulse tracing, (3) loss of pulse tracing followed by recovery within 2 min and (4) loss of pulse tracing without recovery within 2 min.2–4 Barbeau D waveform is the only true contraindication of TRA.2,3 It relieves high risk of hand ischemia in case of radial obstructive complication secondary to poor ulnar compensation.\n\nAlthough TRA has many advantages, sometimes it can be difficult or impossible to reach not only in case of Barbeau D waveform but also for a small RA (⩽2 mm), anatomical variations (RA loops, tortuosity, hypoplasia) and in patients with a dialysis fistula.2,5 For these reasons, it would be desirable to find another arterial access having the advantages of radial access when the latter is not feasible.\n\nVery recently, the distal transradial artery approach, from the anatomical snuffbox (AS), on the dorsal side of the hand has been proposed.6 The puncture is distal from the branch supplying the superficial palmar arch. An occlusion at this site potentially maintains antegrade flow through the superficial palmar arch, preventing ischemia and hand disability.6\n\nCase report\nCase 1\nAn 84-year-old woman with a history of arterial hypertension, type II diabetes mellitus, atrial fibrillation and chronic heart failure recently underwent to percutaneous transluminal coronary angioplasty (PTCA) and valvuloplasty for which she was taking anticoagulation (Sintrom 4 mg) and double antiplatelet therapy (clopidrogrel 75 mg + ASA 100 mg). Some days later, she presented melena and shock requiring blood transfusion and resuscitation maneuvers (hemoglobin (Hbg): 6.6 g/dL; platelet (PLT): 112 × 10³ µL). Once she was hemodynamically stabilized, a gastroscopy was performed which showed normal findings and a colonoscopy which showed digested blood in the colon with many clots within ascending colon; hence, an urgent angiography and eventually embolization were requested.\n\nBecause of high value of coagulation test (international normalized ratio (INR): 2.8; prothrombin time (PT): 33.6 s), the patient had a high risk of bleeding and vascular complications related to the FA, so we performed a TRA. The right RA was inaccessible because it was occluded by the previous PTCA. We performed the Barbeau test showing a type D waveform (Figure 1), which is a contraindication to TRA. Both high risk of bleeding to FA and the contraindication to the TRA forced us to find another possible arterial access with less risk of complications. We decide to evaluate with ultrasound (US) examination the left distal radial artery (DRA), in the AS, that was of sufficient diameter (2 mm). Patient gave her informed consent before the interventional procedures.\n\nFigure 1. Barbeau test shows a D waveform recorded through the pulse oximeter. It demonstrates a loss of pulse tracing without recovery within 2 min (yellow line at the bottom).\n\nA subcutaneous local anesthesia consisting of an injection of a solution of 1 mL of lidocaine 2% and 100 μg of nitroglycerin was injected in order to prevent arterial spasms. The DRA access was obtained under US guidance and Seldinger technique with a 21-gauge micropuncture needle and a 0.018-in. wire. After a 4-French sheath was inserted (Figure 2), another bolus of nitroglycerin (200 μg) and heparin (2000 IU) were administered intra-arterially on the basis of our institutional protocol. The superior mesenteric artery angiography showed ectatic vessels and early venous opacification indicating an ileal angiodysplasia. Then, a microcatheter was introduced for a superselective angiography of the ileo-colic artery. In order to stop the active bleeding, we performed an ileo-colic artery embolization using Spongostan and coil. A final diagnostic angiogram demonstrated the success of the procedure. Hemostasis was obtained with the TR band injecting 7 cm3 of air, deflating 1 cm3 every 5 min on the basis of our protocol for RA (Figure 3).\n\nFigure 2. The 4 F sheath placed in the distal radial artery at the site of the anatomical snuffbox.\n\nFigure 3. (a) TR band placement at the site of the vascular access, (b) insufflation of air, (c) removal of the sheath and (d) final result in the absence of bleeding.\n\nThe procedure of embolization was safely and successfully performed without any complications or discomfort for the operator and the patient. No RA occlusions occurred.\n\nA color Doppler examination of the left RA that showed the patency of the vessel was performed the following day. Evaluation of the access site and a color Doppler examination of the left RA were repeated before discharge and during the follow-up at 1, 3 and 6 months.\n\nCase 2\nAn 83-year-old woman with a history of autoimmune thrombocytopenia, arterial hypertension and type II diabetes mellitus was admitted to the hospital with extensive hematoma of the left hemithorax following trauma. Blood tests revealed anemia (Hbg: 10 g/dL) and thrombocytopenia (PLT: 24 × 10³ µL). A computed tomographic (CT) scan of the thorax proved contrast blush in the region of left pectoralis major muscle; hence, an urgent angiography and embolization were requested.\n\nBecause of thrombocytopenia, the patient had a high risk of bleeding and vascular complications related to the FA, so we decided to perform a TRA, but the Barbeau test showed a type D waveform. DRA diameter (2 mm) was suitable for puncture at US examination. The patient gave her informed consent before the interventional procedures.\n\nThe DRA access was obtained with the same technique already described. A diagnostic angiography of left axillary and subclavian arteries was performed using a 100-cm 4-French Berenstein catheter. It showed contrast extravasation of left lateral thoracic artery (LLTA). A microcatheter was introduced for a superselective angiography of the LLTA and we used Spongostan to embolize the LLTA. A final diagnostic angiogram demonstrated the success of the procedure. An occlusive pressure of the DRA was obtained in the same way as described. The evaluation of the RA patency, using a color Doppler examination, was performed in the same way as in case 1, which gave similar results.\n\nDiscussion\nAn accurate and profound knowledge of vascular anatomy of the hand related to possible variations is mandatory for selecting patients suitable for such vascular access in order to obviate disappointing unexpected complications.5\n\nRA and ulnar artery are widely interconnected at the level of the hand through the superficial and deep palmar arches, commonly with good hemodynamic compensation.5,7 This compensation is evaluated by Barbeau test.\n\nWe can find the DRA in AS that is a depression located in the radial part of the wrist; it is laterally limited by the tendons of abductor pollicis longus and extensor pollicis brevis muscles and medially limited by the tendon of extensor pollicis longus muscle.8\n\nThe site of puncture of DRA, in AS, is distal from the origin of the palmar carpal branch, the superficial palmar branch and the dorsal carpal branch.5–7 So this access is distal from the origin of some branches that determine the main perfusion of the hand; this means that in case of occlusion, theoretically, the RA feeding flow to the hand is not totally compromised.\n\nThe most frequent complication described in the literature, even if rare, is the occlusion of the RA in the snuffbox, which can be prevented through administration of nitroglycerin; however, for the reasons described above, antegrade flow is maintained via the superficial palmar arch, preventing ischemia and hand disability.6 Other complications described, very rare, are hematoma of wrist, edema, numbness, dissection, arteriovenous fistula and aneurysm.6\n\nIn these two cases described, we used the distal transradial artery approach in patients with a high risk of bleeding and vascular complications related to the FA and contraindication to the TRA, but for its advantages and the low complication rate, more studies should be carried out to use this new technique in all patients with sufficient diameter of DRA.\n\nConclusion\nIn case of indication for TRA and type D waveform at Barbeau test, especially in emergency, the DRA represents a potential safe option for arterial access.\n\nIt is a feasible and safe technique that combines the benefits of radial access in cases of contraindications to it; indeed, DRA is distal to the origin of the branches that determine the main perfusion of the hand.\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. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\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 patients for their anonymized information to be published in this article. Informed consent was obtained from all individual participants included in the study.\n\nORCID iD: Andrea Boncoraglio \nhttps://orcid.org/0000-0002-0251-1133\n==== Refs\nReferences\n1 \nJolly SS Amlani S Hamon M et al \nRadial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: a systematic review and meta-analysis of randomized trials . Am Heart J \n2009 ; 157 (1 ): 132 –140 .19081409 \n2 \nFischman AM Swinburne NC Patel RS. \nA technical guide describing the use of transradial access technique for endovascular interventions . Tech Vasc Interv Radiol \n2015 ; 18 (2 ): 58 –65 .26070616 \n3 \nPosham R Biederman DM Patel RS. \nTransradial approach for noncoronary interventions: a single-center review of safety and feasibility in the first 1,500 cases . J Vasc Interv Radiol \n2016 ; 27 (2 ): 159 –166 .26706186 \n4 \nBarbeau GR Arsenault F Dugas L et al \nEvaluation of the ulnopalmar arterial arches with pulse oximetry and plethysmography: comparison with the Allen’s test in 1010 patients . Am Heart J \n2004 ; 147 (3 ): 489 –493 .14999199 \n5 \nYoo BS Yoon J Ko JY et al \nAnatomical consideration of the radial artery for transradial coronary procedures: arterial diameter, branching anomaly and vessel tortuosity . Int J Cardiol \n2005 ; 101 (3 ): 421 –427 .15907410 \n6 \nKiemeneij F. \nLeft distal transradial access in the anatomical snuffbox for coronary angiography (ldTRA) and interventions (ldTRI) . Eurointervention \n2017 ; 13 (7 ): 851 –857 .28506941 \n7 \nBrzezinski M Luisetti T London M. \nRadial artery cannulation: a comprehensive review of recent anatomic and physiologic investigations . Anesth Analg \n2009 ; 109 (6 ): 1763 –1781 .19923502 \n8 \nCerda A Del Sol M. \nAnatomical snuffbox and it clinical significance. A literature review . Int J Morphol \n2015 ; 3 : 1355 –1360 .\n\n",
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"issn_linking": "2050-313X",
"issue": "7()",
"journal": "SAGE open medical case reports",
"keywords": "Barbeau test; Radial artery; distal radial artery; embolization; femoral approach; transradial arterial access",
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"mesh_terms": null,
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"title": "Distal radial artery: The last extreme rescue arterial access for interventional radiologists?",
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{
"abstract": "In metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide).\n\n\n\nThis randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR.\n\n\n\nOverall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline.\n\n\n\nTechnetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.",
"affiliations": "Department of Urology, Yale School of Medicine, New Haven, USA. Electronic address: [email protected].;Division of Solid Tumor Oncology, Karmanos Cancer Institute, Detroit, USA.;Arizona Institute of Urology, Tucson, USA.;University of Washington, Seattle, USA.;Indiana University Health Melvin and Bren Simon Cancer Center, Indianapolis, USA.;Georgetown Lombardi Comprehensive Cancer Center, Washington, USA.;Oregon Urology Institute, Springfield, USA.;Department of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, USA.;Department of Medical Oncology, Genitourinary Research Network, Omaha, USA.;Bayer Consumer Care AG, Basel, Switzerland.;Oncology Clinical Statistics, Bayer HealthCare Pharmaceuticals Inc., Whippany, USA.;Bayer Consumer Care AG, Basel, Switzerland.;Tulane Cancer Center, Tulane University School of Medicine, New Orleans, USA.",
"authors": "Petrylak|D P|DP|;Vaishampayan|U N|UN|;Patel|K R|KR|;Higano|C S|CS|;Albany|C|C|;Dawson|N A|NA|;Mehlhaff|B A|BA|;Quinn|D I|DI|;Nordquist|L T|LT|;Wagner|V J|VJ|;Siegel|J|J|;Trandafir|L|L|;Sartor|O|O|",
"chemical_list": "D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C000615150:Radium-223; C540278:enzalutamide; D000069501:Abiraterone Acetate; D011241:Prednisone; D011883:Radium",
"country": "England",
"delete": false,
"doi": "10.1016/j.esmoop.2021.100082",
"fulltext": "\n==== Front\nESMO Open\nESMO Open\nESMO Open\n2059-7029\nElsevier\n\nS2059-7029(21)00038-7\n10.1016/j.esmoop.2021.100082\n100082\nOriginal Research\nA randomized phase IIa study of quantified bone scan response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride alone or in combination with abiraterone acetate/prednisone or enzalutamide\nPetrylak D.P. [email protected]\n1∗\nVaishampayan U.N. 2\nPatel K.R. 3\nHigano C.S. 4\nAlbany C. 5\nDawson N.A. 6\nMehlhaff B.A. 7\nQuinn D.I. 8\nNordquist L.T. 9\nWagner V.J. 10\nSiegel J. 11\nTrandafir L. 10\nSartor O. 12\n1 Department of Urology, Yale School of Medicine, New Haven, USA\n2 Division of Solid Tumor Oncology, Karmanos Cancer Institute, Detroit, USA\n3 Arizona Institute of Urology, Tucson, USA\n4 University of Washington, Seattle, USA\n5 Indiana University Health Melvin and Bren Simon Cancer Center, Indianapolis, USA\n6 Georgetown Lombardi Comprehensive Cancer Center, Washington, USA\n7 Oregon Urology Institute, Springfield, USA\n8 Department of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, USA\n9 Department of Medical Oncology, Genitourinary Research Network, Omaha, USA\n10 Bayer Consumer Care AG, Basel, Switzerland\n11 Oncology Clinical Statistics, Bayer HealthCare Pharmaceuticals Inc., Whippany, USA\n12 Tulane Cancer Center, Tulane University School of Medicine, New Orleans, USA\n∗ Correspondence to: Prof. Daniel P. Petrylak, Department of Urology, Yale School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06510, USA. Tel: +1 (203) 785 2815 [email protected]\n19 3 2021\n4 2021\n19 3 2021\n6 2 100082© 2021 Published by Elsevier Ltd on behalf of European Society for Medical Oncology.\n2021\n\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nIn metastatic castration-resistant prostate cancer (mCRPC), assessing treatment response and bone lesions with technetium-99m is limited by image resolution and subjectivity. We evaluated bone scan lesion area (BSLA), a quantitative imaging assessment of response in patients with mCRPC receiving radium-223 alone or in combination with androgen receptor pathway inhibitors (abiraterone/prednisone or enzalutamide).\n\nPatients and methods\n\nThis randomized, non-comparative phase IIa three-arm trial (NCT02034552) evaluated technetium-99m-based BSLA response rate (RR), safety, radiologic progression-free survival (rPFS), and time to first symptomatic skeletal event (SSE) in men with mCRPC and bone metastases receiving radium-223 with/without abiraterone/prednisone or enzalutamide. The primary endpoint was week 24 BSLA RR.\n\nResults\n\nOverall, 63 patients received treatment (abiraterone/prednisone combination, n = 22; enzalutamide combination, n = 22; radium-223 monotherapy, n = 19). Median treatment duration (first to last dose of any study treatment) was 12 months (abiraterone/prednisone combination), 10 months (enzalutamide combination), and 3 months (radium-223 monotherapy). Week 24 BSLA RR was 58% [80% confidence interval (CI) 41% to 74%; one-sided P < 0.0001; 11/19 patients] with abiraterone/prednisone combination, 50% (32% to 68%; one-sided P < 0.0001; 8/16 patients) with enzalutamide combination, and 22% (10% to 40%; one-sided P = 0.0109; 4/18 patients) with radium-223 monotherapy. Median rPFS was not evaluable for combination arms and 4 months (80% CI 4 to 12) for monotherapy. SSEs were reported in 32% of patients; median time to first SSE was not estimable. Fatigue and back pain were the most commonly reported treatment-emergent adverse events (TEAEs); more patients receiving combination therapy than monotherapy had TEAEs. Fractures were reported in 18% receiving abiraterone/prednisone, 32% receiving enzalutamide, and 11% receiving radium-223 monotherapy. Fracture rates were lower in patients taking bone health agents versus not taking bone health agents at baseline.\n\nConclusions\n\nTechnetium-99m imaging BSLA may offer objective, quantifiable assessment of isotope uptake changes, and potentially treatment response, in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide. In this largely treatment-naive population, BSLA RR was numerically lower with radium-223 monotherapy versus combination therapy, indicating a limited role as first-line treatment. Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.\n\nHighlights\n\n• Radium-223 is a targeted alpha therapy for bone-dominant metastatic castration-resistant prostate cancer.\n\n• Assessing bone lesions and treatment response with technetium-99m is limited by image resolution and subjectivity.\n\n• We used computer-aided detection (CAD) of bone scan lesion area (BSLA) to assess radium-223 ± abiraterone/enzalutamide.\n\n• On preliminary assessment, CAD-based BSLA demonstrated positive response to radium-223 ± abiraterone/enzalutamide therapy.\n\n• Use of radium-223 should follow evidence-based treatment guidelines and the licensed indication.\n\nKey words\n\nmetastatic castration-resistant prostate cancer\nradium-223\nabiraterone\nenzalutamide\nbone scan lesion area\ntechnetium-99m\n==== Body\nIntroduction\n\nMultiple life-prolonging therapies are approved for metastatic castration-resistant prostate cancer (mCRPC), including androgen receptor pathway inhibitors (ARPIs; abiraterone/prednisone and enzalutamide), chemotherapy (docetaxel, cabazitaxel), immunotherapy (sipuleucel-T), and targeted alpha therapy (radium-223 dichloride). Abiraterone (a CYP17 inhibitor), enzalutamide (a second-generation androgen receptor inhibitor1), and radium-223 (a targeted alpha therapy that selectively binds to areas of increased bone turnover in bone metastases2) have all demonstrated overall survival (OS) benefit in patients with mCRPC in phase III clinical trials.3, 4, 5, 6, 7, 8, 9, 10 The different mechanisms of action of these agents and limited overlapping toxicity provided a rationale for their use in combination.1 However, additional clarity about such combination therapies is now required in light of recent negative findings for abiraterone/prednisone plus radium-223 combination therapy compared with abiraterone/prednisone alone in the ERA 223 trial in men with chemotherapy-naive, asymptomatic, or mildly symptomatic mCRPC.11\n\nBone metastases occur in approximately 90% of men with mCRPC,3,10 but there are challenges with staging and determining treatment response.12 The conventional approach with technetium-99m uses visual assessment of images to monitor metastases based on the number of bone lesions over time. However, limited image resolution and the subjectivity of visual assessment precludes reliable quantitative assessment of lesion size. These issues of specificity and sensitivity mean that conventional bone scan imaging is too ‘blurry’ for clear visual discernment and resolution of distinct lesions.12,13 Consequently, currently there is no reliable means to evaluate changes in bone lesion burden in mCRPC. Accordingly, Response Evaluation Criteria in Solid Tumors (RECIST) 1.114 and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria15 recommend limited use of imaging endpoints in evaluating bone lesions compared with soft-tissue lesions. Both RECIST 1.1 and PCWG3 use bone lesions as non-target lesions (assessed qualitatively); thus, both criteria permit assessment of complete response (CR) and progressive disease (PD), but cannot distinguish partial response (PR) from stable disease (SD). This severely limits the use of bone lesion response as an efficacy endpoint. Therefore, when determining treatment efficacy in patients with mCRPC and bone metastases, quantifiable time-to-event-based efficacy outcomes, including radiologic progression-free survival (rPFS) or time to symptomatic skeletal events (SSEs), may be more reliable than qualitative response categories (CR, PD, or neither). Accordingly, the PCWG3 suggests using alternative endpoints to response, even in early-phase clinical trials of new agents for the treatment of mCRPC.15\n\nRecently, bone scan lesion area (BSLA), determined using an automated computer-aided detection (CAD) system, has been used to quantify whole-body bone scintigraphic images and act as a biomarker for bone tumor burden.16 This automated system was reported to have a sensitivity of 94% and specificity of 89% for tumor pixels on bone scans, compared with ∼77% sensitivity and 84% to 96% specificity of manual interpretation.16 In a subsequent validation study in men with mCRPC and bone metastases receiving either abiraterone/prednisone or placebo, BSLA <200 cm2 at baseline was prognostic for delayed progression and predictive of prolonged OS in treated patients. Furthermore, patients with PD, defined as a 30% increase in BSLA from baseline to week 12 of treatment, had a significantly shorter OS than patients without progression.13\n\nThis phase IIa three-arm study evaluated bone scan response rate (RR) using the above-mentioned CAD system to measure technetium-99m bone scan BSLA, safety, and other outcomes in patients with mCRPC following treatment with radium-223 alone or in combination with either abiraterone/prednisone or enzalutamide. The study also explored the clinical value of different imaging modalities [diffusion-weighted magnetic resonance imaging (DW-MRI) and sodium fluoride positron emission tomography/computed tomography (Na18F PET/CT)] for evaluating treatment response in bone lesions. Detailed rationales for investigating BSLA, DW-MRI, and Na18F PET/CT in this setting are provided in the Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100082. This study was initiated and patients completed radium-223 treatments before the results of the ERA 223 trial of abiraterone/prednisone plus radium-223 were available and before publication of the CAD BSLA validation study.\n\nPatients and methods\n\nStudy design and conduct\n\nThe study was a randomized, non-comparative, open-label, multicenter, phase IIa trial (NCT02034552). The study protocol and all subsequent amendments were approved by an independent ethics committee or institutional review board at each participating site (19 sites in 15 states and the District of Columbia within the United States). The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Conference on Harmonization. All patients provided written informed consent before participating in the study.\n\nPatients\n\nPatients aged ≥18 years were eligible for inclusion if they had histologically or cytologically confirmed progressive CRPC and two or more bone metastases detected by whole-body bone imaging, but no known visceral metastases. Key exclusion criteria included history of or known visceral metastases, treatment with >1 chemotherapy agent for prostate cancer, or previous abiraterone/prednisone, enzalutamide, radium-223, or systemic radiotherapy. The definition of castration-resistant disease and a full list of inclusion/exclusion criteria are provided in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2021.100082.\n\nStudy design and treatment regimens\n\nFollowing screening, eligible patients were randomized in a 1 : 1 : 1 ratio to one of three treatment arms: radium-223 plus abiraterone acetate and prednisone, radium-223 plus enzalutamide, or radium-223 monotherapy. Radium-223 55 kBq/kg was administered intravenously once every 4 weeks for six cycles. Patients in the combination arms also received either oral abiraterone acetate (1000 mg once daily) and oral prednisone/prednisolone (5 mg twice daily) or oral enzalutamide (160 mg once daily). Abiraterone/prednisone or enzalutamide were administered concurrently with radium-223. Patients could continue abiraterone/prednisone or enzalutamide for up to 2 years after the last radium-223 dose if investigators determined that patients would receive clinical benefit.\n\nDuring treatment, all concomitant medications, including those for prostate cancer, but excluding medication for procedures and imaging, were to be recorded. Hormonal therapy (e.g. luteinizing hormone-releasing hormone agonists or antagonists, anti-androgens) was permitted in any treatment arm. In the radium-223 arm only, other prostate cancer therapies (e.g. diethylstilbestrol, estradiol, ketoconazole, dexamethasone, hydrocortisone, prednisone) could be used according to routine clinical practice, at the discretion of the investigator, with the exception of concomitant abiraterone/prednisone or enzalutamide. Differential permissibility was considered ethically necessary, given the lack of expected efficacy of radium-223 in soft tissue disease, notwithstanding its potential for bias.\n\nThe primary endpoint for each treatment arm was BSLA RR at week 24 calculated from each patient's digitized technetium-99m bone scan and based on a series of intermediate calculations. Bone scans were evaluated by central review using CAD software (MedQIA, LLC, Los Angeles, CA) to evaluate each patient's digitized whole-body technetium-99m bone scan at each time point (see Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100082 for details). The reviewer identified bone pixels and determined the BSLA (in cm2), defined as the sum of the pixel areas identified as bone lesions from the set of whole-body technetium-99m bone imaging pixels, and disease status (bone lesion or not bone lesion) for each pixel. For each treatment arm, response was classified as a decrease in BSLA of ≥30% from baseline at week 24.\n\nSecondary endpoints included rPFS (non-bone or bone progression, whichever occurred first), time to radiologic non-bone (soft-tissue) progression (modified RECIST 1.1), time to radiologic bone progression (adapted PCWG2 guidelines),17 SSE-free survival (SSE-FS), time to first SSE, OS, and safety. An SSE was defined as any of the following: use of external-beam radiotherapy (EBRT) to relieve skeletal pain, new symptomatic pathologic bone fractures (vertebral or nonvertebral), spinal cord compression, or tumor-related orthopedic surgical intervention. Bone fractures and bone-associated events were assessed both as SSEs and as adverse events (AEs). Use of bone health agents (BHAs) was assessed at baseline and during treatment and follow-up. Follow-up safety assessments occurred every 12 weeks from the end of treatment and for up to 2 years from the last radium-223 dose.\n\nThe study treatment period was from treatment initiation up to 30 days after the last dose of study treatment. Patients entered an active follow-up period of up to 2 years after the last radium-223 dose for efficacy, imaging, and select safety information. After the active follow-up period, patients entered a long-term follow-up period for up to 7 years from the last radium-223 dose. Following a protocol amendment, patients were transitioned into a separate long-term safety follow-up study for the remainder of their long-term follow-up.\n\nAll AEs (severity, seriousness, and duration) and laboratory values were reported during the study treatment period. Any AEs arising during this period were classified as treatment-emergent AEs (TEAEs). All AEs related to study medication and all serious AEs (SAEs) were also reported during active follow-up. Select safety data were collected throughout the study, including long-term follow-up data, regardless of the investigator's causality assessment. These data included bone fractures and bone-associated events, e.g. osteoporosis (reported as AEs or SAEs); all occurrences of leukemia, myelodysplastic syndrome, aplastic anemia, and primary bone cancer, or any other new primary malignancy (reported as SAEs); and survival.\n\nAll AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) v.21.0, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0, and assessed by the investigator for their relationship to treatment.\n\nClinical and imaging-related exploratory endpoints are described in the Supplementary Materials, available at https://doi.org/10.1016/j.esmoop.2021.100082.\n\nPatients were assessed at screening and at weeks 8, 16, and 24 using a whole-body technetium-99m bone scan and MRI/CT imaging of the chest, abdomen, and pelvis. Assessment continued every 12 weeks or until confirmed radiologic progression (bone and/or soft tissue). Patients were also assessed for SSEs at each clinic visit. Exploratory imaging with DW-MRI and Na18F PET/CT was conducted at screening, at weeks 8, 16, and 24, and then every 12 weeks at selected sites. Results from each imaging method underwent separate central review.\n\nStatistical analysis\n\nPatient baseline characteristics for the intention-to-treat (ITT) population (all randomized patients) were reported by treatment arm using descriptive statistics. The efficacy population comprised a modified ITT population (mITT; patients who received at least one dose of study drug). The primary imaging analysis population included all patients in the mITT population with evaluable baseline technetium-99m bone scans. The safety population comprised all patients who received at least one radium-223 dose.\n\nThe primary endpoint analysis in each treatment arm was based on formal non-comparative hypothesis tests for BSLA RR at week 24, without adjustment for multiplicity. The hypothesis tested in each arm was H0: BSLA RR ≤5% versus HA: BSLA RR >5%, using an exact single-arm binomial test with a one-sided alpha of 0.10. Twenty evaluable participants were required to obtain 90% power to detect a bone scan RR of >5% at week 24 when the true RR was 30%. Bone scan RR at week 24 was estimated with exact binomial confidence intervals (CIs). There were no statistical comparisons between treatment arms.\n\nEfficacy endpoints and AEs were reported using summary statistics. Time-to-event variables (rPFS, SSE-FS, OS, time to first SSE, time to radiologic bone progression) were summarized by treatment arm using the Kaplan–Meier method, with median values and Brookmeyer–Crowley CIs. Week 24 rates for time-to-event efficacy variables were based on a Kaplan–Meier analysis. Frequencies and percentages were tabulated for categorical variables.\n\nResults\n\nPatients and study regimen\n\nFrom March 2014 to May 2018, 68 patients were entered into the randomized study and 63 received treatment. Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2021.100082, shows the efficacy, imaging, and safety populations in each treatment arm. At baseline, overall, the median time since diagnosis of bone metastasis was 16 months, and 44% of patients had 6 to 20 metastases (Table 1). Patients received a median of six radium-223 injections in each combination arm and four in the radium-223 monotherapy arm. Median duration of treatment (from first to last dose of any study treatment) was 12 months with the abiraterone/prednisone combination, 10 months with the enzalutamide combination, and 3 months with radium-223 monotherapy. The median duration of the active follow-up period (up to 2 years after the last radium-223 dose) was 7 months for both combination regimens and 19 months for radium-223 monotherapy. This was expected, as patients in the radium-223 arm received a maximum of six doses of radium-223, whereas patients in the combination arms could receive abiraterone/prednisone or enzalutamide for up to 2 years after the last radium-223 dose until progression.Table 1 Baseline patient characteristics (ITT population)\n\n\tRadium-223 monotherapy (n = 22)\tRadium-223 + abiraterone/prednisone (n = 24)\tRadium-223 + enzalutamide (n = 22)\tTotal (N = 68)\t\nMedian age, years\t72\t68\t73\t71\t\nECOG PS, n (%)\t\t\t\t\t\n 0\t10 (45)\t13 (54)\t11 (50)\t34 (50)\t\n 1\t9 (41)\t9 (38)\t11 (50)\t29 (43)\t\nMedian total ALP, U/l\t96\t101\t98\t99\t\nMedian PSA, μg/l\t31\t17\t19\t19\t\nMedian time since PC diagnosis, months\t25\t52\t48\t46\t\nMedian time since first cancer progression, months\t15\t32\t20\t21\t\nMedian time since bone metastasis initial diagnosis, months\t10\t15\t22\t16\t\nExtent of disease, n (%)\t\t\t\t\t\n <6 metastases\t9 (41)\t6 (25)\t6 (27)\t21 (31)\t\n 6-20 metastases\t7 (32)\t11 (46)\t12 (55)\t30 (44)\t\n >20 lesions\t3 (14)\t5 (21)\t4 (18)\t12 (18)\t\n Superscan\t1 (5)\t0\t0\t1 (1)\t\nMedian baseline BSLA, mm2\t4315\t7479\t7516\t7266\t\nPrior systemic anticancer therapies, n (%)a\t\t\t\t\t\n Sipuleucel-T\t5 (23)\t6 (25)\t3 (14)\t14 (21)\t\n Docetaxel\t4 (18)\t3 (13)\t5 (23)\t12 (18)\t\nPrior BHA use, n (%)\t8 (42)b\t7 (32)c\t8 (36)\t23 (37)d\t\n Denosumab\t7 (37)b\t6 (27)c\t7 (32)\t20 (32)d\t\n Zoledronic acid\t1 (5)b\t1 (5)c\t1 (5)\t3 (5)d\t\nALP, alkaline phosphatase; BHA, bone health agent; BSLA, bone scan lesion area; ECOG PS, Eastern Cooperative Oncology Group performance status; ITT, intention-to-treat; PC, prostate cancer; PSA, prostate-specific antigen.\n\na >15% of patients overall.\n\nb n = 19.\n\nc n = 22.\n\nd n = 63.\n\nMost patients (85%) received ≥1 concomitant systemic anticancer therapy during the treatment period (abiraterone/prednisone arm: 83%, enzalutamide arm: 95%, and radium-223 arm: 77%), and 81% received ≥1 concomitant hormonal therapy (83%, 86%, and 73%, respectively). The majority of patients received androgen-deprivation therapies such as leuprorelin/leuprorelin acetate (75% of patients), degarelix/degarelix acetate (4%), and goserelin (4%). Few patients received first-generation androgen receptor inhibitors, such as bicalutamide (3%), and other prostate cancer therapies were reported in <3% of patients each. During follow-up, 88% of patients received ≥1 systemic anticancer therapy (83%, 96%, and 86%, respectively), and 87% received ≥1 hormonal therapy (83%, 91%, and 86%, respectively).\n\nEfficacy\n\nPrimary endpoint\n\nThe BSLA RR at week 24 based on technetium-99m bone scans in the imaging analysis population was 58% (80% CI 41% to 74%; one-sided P < 0.0001; 11/19 patients) for radium-223 plus abiraterone/prednisone, 50% (80% CI 32% to 68%; one-sided P < 0.0001; 8/16 patients) for radium-223 plus enzalutamide, and 22% (80% CI 10% to 40%; one-sided P = 0.0109; 4/18 patients) for radium-223 monotherapy (Table 2).Table 2 Primary and secondary efficacy endpoints (mITT population)\n\n\tRadium-223 monotherapy (n = 19)\tRadium-223 + abiraterone/prednisone (n = 22)\tRadium-223 + enzalutamide (n = 22)\t\nBSLA RR at week 24, % (80% CI),a\nP value\t22 (10-40); P = 0.0109b\t58 (41-74); P < 0.0001b\t50 (32-68); P < 0.0001b\t\nMedian rPFS, months (80% CI)c\t4 (4-12)\tNE (19-NE)\tNE (10-NE)\t\nMedian time to radiologic disease (non-bone) progression, months (80% CI)c\t5 (4-NE)\tNE (NE-NE)\tNE (NE-NE)\t\nMedian time to radiologic bone progression, months (80% CI)c\t12 (4-12)\tNE (NE-NE)\tNE (NE-NE)\t\nPatients with an SSE, n (%)\t6 (32)\t7 (32)\t7 (32)\t\nMedian SSE-FS, months (80% CI)\t12 (10-25)\tNE (17-NE)\t20 (12-28)\t\nMedian time to first SSE, months (80% CI)\tNE (13-NE)\tNE (17-NE)\tNE (20-NE)\t\nMedian OS, months (80% CI)\t36 (21-41)\t38 (36-NE)\t30 (27-NE)\t\nBSLA, bone scan lesion area; CI, confidence interval; mITT, modified intention-to-treat; NE, not estimable; OS, overall survival; rPFS, radiologic progression-free survival; RR, response rate; SSE, symptomatic skeletal event; SSE-FS, SSE-free survival.\n\na Imaging population: radium-223 + abiraterone/prednisone, n = 19; radium-223 + enzalutamide, n = 16; radium-223 monotherapy, n = 18.\n\nb Test of the null hypothesis of BSLA RR ≤5% at week 24 using an exact single-arm binomial test in each treatment group with one-sided alpha = 0.10.\n\nc Central review.\n\nSecondary endpoints\n\nMedian rPFS, time to radiologic non-bone progression, time to radiologic bone progression, and time to first SSE are shown in Table 2 and Figure 1A. In each arm, 32% of patients had an SSE. Median SSE-FS was also not estimable for the radium-223 plus abiraterone/prednisone arm (Table 2). The 24-month SSE-FS rates were 66% (80% CI 50% to 79%), 47% (80% CI 33% to 61%), and 35% (80% CI 20% to 50%) for radium-223 plus abiraterone/prednisone, radium-223 plus enzalutamide, and radium-223 monotherapy, respectively.Figure 1 Kaplan–Meier curves of (A) radiologic progression-free survival by central review and (B) overall survival (mITT population). Abi, abiraterone/prednisone; Enza, enzalutamide; mITT, modified intention-to-treat; Ra-223, radium-223.\n\nMedian OS was 38 months (80% CI 36 to not estimable) for radium-223 plus abiraterone/prednisone, 30 months (80% CI 27 to not estimable) for radium-223 plus enzalutamide, and 36 months (80% CI 21 to 41) for radium-223 monotherapy (Table 2); 24-month OS rates were ≥75% for each combination treatment and 64% for radium-223 monotherapy (Figure 1B).\n\nExploratory endpoints\n\nClinical exploratory endpoints\n\nThe alkaline phosphatase (ALP) RR at the end of radium-223 treatment was 36% (80% CI 26% to 59%) for radium-223 plus abiraterone/prednisone, 50% (80% CI 41% to 74%) for radium-223 plus enzalutamide, and 42% (80% CI 30% to 65%) for radium-223 monotherapy. Median percentage change in ALP from baseline to the end of radium-223 treatment was −25% for radium-223 plus abiraterone/prednisone, −31% for radium-223 plus enzalutamide, and −21% for radium-223 monotherapy. Median time to confirmed ALP progression on study was 10 months (80% CI 8 to 13) for radium-223 plus abiraterone/prednisone, 9 months (80% CI 8 to 16) for radium-223 plus enzalutamide, and not estimable for radium-223 monotherapy.\n\nThe prostate-specific antigen (PSA) RR at the end of radium-223 treatment was 64% (80% CI 60% to 90%) for each combination arm and 21% (80% CI 11% to 4%) for radium-223 monotherapy. Median percentage change in PSA from baseline was −84% for radium-223 plus abiraterone/prednisone, −93% for radium-223 plus enzalutamide, and 50% for radium-223 monotherapy. Median time to confirmed PSA progression was 26 months (80% CI 19 to not estimable) for radium-223 plus abiraterone/prednisone, 10 months (80% CI 9 to 25) for radium-223 plus enzalutamide, and 4 months (80% CI 3 to not estimable) for radium-223 monotherapy.\n\nTechnetium-99-based imaging exploratory endpoints\n\nMean BSLA at week 24 was numerically lower than at baseline for the combination treatments and higher than baseline for radium-223 monotherapy; CIs were overlapping (Figure 2). Based on BSLA best overall response rate (BORR) during the study using technetium-99m bone imaging, 13/19 patients (68%) had a response with radium-223 plus abiraterone/prednisone, 14/16 patients (88%) with radium-223 plus enzalutamide, and 5/18 patients (28%) with radium-223 monotherapy. These values are higher than the BSLA RR at week 24 because responses in some patients occurred later than week 24.Figure 2 Bone scan lesion area over time based on technetium-99m imaging (imaging analysis population). Abi, abiraterone/prednisone; Enza, enzalutamide; Ra-223, radium-223.\n\nAt week 24, >30% of patients across the three treatment arms had quantitative involvement in all four axial regions (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2021.100082).\n\nAdditional exploratory radiologic methods for imaging bone metastases (DW-MRI and Na18F PET/CT) are reported in the Supplementary Information, available at https://doi.org/10.1016/j.esmoop.2021.100082.\n\nSafety\n\nAdverse events\n\nAll patients, except one in the radium-223 monotherapy arm, experienced at least one TEAE during the study (Table 3). Generally, the percentage of patients with TEAEs was higher with combination treatment than with radium-223 monotherapy. Overall, a greater percentage of patients receiving combination treatment [12 patients (55%) with abiraterone/prednisone and 15 patients (68%) with enzalutamide] experienced Grade 3-4 TEAEs compared with those receiving radium-223 monotherapy [seven patients (37%)]. One patient in the enzalutamide arm died from Grade 5 general physical deterioration considered unrelated to study treatment. Treatment-related TEAEs were reported in 43 patients (68%) overall: 17 (77%), 18 (82%), and 8 (42%) in the radium-223 plus abiraterone/prednisone, radium-223 plus enzalutamide, and radium-223 monotherapy arms, respectively. The most commonly reported any-grade treatment-related TEAEs overall were fatigue (n = 17; 27%), diarrhea (n = 14, 22%), and nausea (n = 8, 13%). The only treatment-related serious TEAE was nausea in one patient receiving radium-223 plus abiraterone/prednisone.Table 3 Treatment-emergent adverse events (any grade) occurring in ≥20% of patients in any treatment arm (safety population)\n\nAdverse event (MedDRA preferred term), n (%)\tRadium-223 monotherapy (n = 19)\tRadium-223 + abiraterone/prednisone (n = 22)\tRadium-223 + enzalutamide (n = 22)\tTotal (N = 63)\t\nAny TEAE\t18 (95)\t22 (100)\t22 (100)\t62 (98)\t\nFatigue\t6 (32)\t8 (36)\t9 (41)\t23 (37)\t\nBack pain\t5 (26)\t8 (36)\t9 (41)\t22 (35)\t\nDiarrhea\t4 (21)\t8 (36)\t9 (41)\t21 (33)\t\nNausea\t2 (11)\t9 (41)\t6 (27)\t17 (27)\t\nArthralgia\t3 (16)\t5 (23)\t6 (27)\t14 (22)\t\nDecreased appetite\t3 (16)\t3 (14)\t5 (23)\t11 (17)\t\nHypertension\t3 (16)\t2 (9)\t6 (27)\t11 (17)\t\nConstipation\t1 (5)\t6 (27)\t3 (14)\t10 (16)\t\nDizziness\t1 (5)\t3 (14)\t6 (27)\t10 (16)\t\nHot flush\t1 (5)\t3 (14)\t5 (23)\t9 (14)\t\nVomiting\t2 (11)\t6 (27)\t1 (5)\t9 (14)\t\nHeadache\t1 (5)\t5 (23)\t1 (5)\t7 (11)\t\nUpper respiratory tract infection\t0\t5 (23)\t2 (9)\t7 (11)\t\nMedDRA, Medical Dictionary for Regulatory Activities (v.21.0); TEAE, treatment-emergent adverse event.\n\nDrug-related AEs during active follow-up were reported in six patients (10%) overall: one patient receiving radium-223 plus abiraterone/prednisone (pathological fracture), three patients receiving radium-223 plus enzalutamide (pathological fracture, arthralgia, and acute promyelocytic leukemia), and two patients receiving radium-223 monotherapy (constipation and atypical femur fracture). Post-treatment drug-related SAEs occurred in one patient receiving radium-223 plus enzalutamide (acute promyelocytic leukemia) and one patient receiving radium-223 monotherapy (atypical femur fracture). In addition to the one patient in the enzalutamide combination arm who died during the study treatment period, 20 patients died during active 2-year follow-up, and 8 died during long-term follow-up. Most deaths during follow-up were related to prostate cancer (n = 26); none was considered to be study drug related.\n\nFractures/time to first fracture\n\nThe incidence of fractures during study treatment or active follow-up and median time to first fracture (censoring for death or loss to follow-up) are shown in Table 4. Fracture rates were generally lower in patients taking BHAs at baseline than in patients not taking BHAs at baseline (Table 4).Table 4 Number of fractures and time to first fracture during and after treatment (safety population)\n\nAll patients in the safety population\tRadium-223 monotherapy (n = 19)\tRadium-223 + abiraterone/prednisone (n = 22)\tRadium-223 + enzalutamide (n = 22)\t\nNumber of patients with ≥1 fracture, n (%)\t2 (11)\t4 (18)\t7 (32)\t\nMedian time to first fracture, months (80% CI)\t18 (6-18)\tNE (17-NE)\t35 (24-35)\t\nEvent-free rate at 2 years, % (95% CI)\t0\t72 (39-89)\t67 (38-85)\t\nPatients without baseline BHA use, n\t11\t15\t14\t\n Patients with ≥1 fracture, n (%)\t1 (9)\t4 (27)\t5 (36)\t\n Median time to first fracture, months (80% CI)\t18 (NE-NE)\tNE (8-NE)\t35 (8-35)\t\n Event-free rate at 2 years, % (95% CI)\t0\t60 (23-84)\t58 (17-85)\t\nPatients with baseline BHA use, n\t8\t7\t8\t\n Patients with ≥1 fracture, n (%)\t1 (13)\t0\t2 (25)\t\n Median time to first fracture, months (80% CI)\tNE (6-NE)\tNE (NE-NE)\tNE (2-NE)\t\n Event-free rate at 2 years, % (95% CI)\tNE (NE)\t100 (100-100)\t75 (31-93)\t\nBHA, bone health agent; CI, confidence interval; NE, not estimable.\n\nDiscussion\n\nThis non-comparative trial was conducted to evaluate BSLA RR using technetium-99m bone scans in patients with mCRPC and bone metastases treated with radium-223 as monotherapy or in combination with either abiraterone/prednisone or enzalutamide. Patients in the combination arms generally had a longer median duration of treatment and a greater median number of radium-223 injections than patients in the monotherapy arm. The primary endpoint of a BSLA RR >5% at week 24 was met in each treatment arm and BSLA RRs were numerically greater in each combination arm than in the radium-223 monotherapy arm. The BSLA BORR during the study was consistent with the BSLA RR at week 24. Median rPFS and median times to radiologic non-bone and bone progression were not estimable in either combination arm (due to insufficient follow-up time) but were reached in the monotherapy arm. As patients generally stopped follow-up for radiologic progression at the first progression event, estimates of the components of radiologic progression (bone and non-bone) may be biased. A similar proportion of patients in each treatment arm experienced SSEs, but median SSE-FS was not estimable or longer with the combinations than with radium-223 monotherapy, suggesting that SSEs occurred later with combination therapy than with monotherapy.\n\nThe toxicity profile of each drug was consistent with previously reported clinical experience.3, 4, 5, 6, 7 Furthermore, although this study was non-comparative and low patient numbers preclude between-arm conclusions regarding survival and disease progression, the study had rigorous follow-up for drug-related and SSE-related events and no new safety signals for the combination regimens were reported for up to 2 years following the last study treatment.\n\nProportionally more patients had fractures with combination treatment than with radium-223 monotherapy. However, for all three treatment arms combined, the proportion of patients who experienced fractures was lower in patients receiving BHAs at baseline than in patients not receiving BHAs at baseline, although sample sizes and numbers of events were small. Time to first fracture results by treatment arm were inconclusive. Although current treatment guidelines recommend a BHA, such as denosumab or zoledronic acid, for all patients with mCRPC for the prevention of skeletal-related events,18,19 at the time the study was conducted (2014-2018), only 37% of patients were receiving BHAs at baseline, and BHA use during the study was not mandatory. Recent findings from the PEACE III trial of enzalutamide alone or in combination with radium-223 in patients with mCRPC showed that the increased risk of fracture with this combination is almost eliminated with mandatory use of BHAs,20 suggesting that mandatory BHA use in the current study may have reduced fracture rates for combination regimens. In the ERA 223 trial, which was not completed at the time of initiation of the current study, an increased fracture rate was reported with abiraterone/prednisone plus radium-223 (compared with abiraterone/prednisone plus placebo), yet only 39% of patients in the abiraterone/prednisone plus radium-233 group received concomitant BHAs. Moreover, in the ERA 223 combination therapy group, the fracture rate was lower in patients taking BHAs rather than not taking BHAs (15% versus 37%, respectively).11\n\nNevertheless, our results should be interpreted with caution as patients were followed for different durations in each treatment arm. The combination arms, which allowed abiraterone/prednisone or enzalutamide therapy for up to 2 years, had substantially longer treatment periods than the monotherapy arm, where treatment was generally limited to 24 weeks. In addition, discrepancies were evident in the proportions of patients who had received prior docetaxel therapy: 18% of patients in the radium-223 monotherapy group; 13% in the abiraterone/prednisone group; and 23% in the enzalutamide group. These differences may have contributed to intergroup differences in the primary outcome. However, such subgroup differences are normal and consistent with chance in a small randomized study. Consequently, the effect of these differences cannot be evaluated, given the small sample size. Future real-world evidence studies of sequential ARPI-radium-223 therapy in clinical practice would be useful to determine the impact of prior taxane therapy on BSLA measurements and rPFS in men with progressive CRPC and bone metastases. In addition, it is possible that the differential permissibility of concomitant therapy in the radium-223 monotherapy group compared with the other treatment groups may have resulted in bias.\n\nThis study also explored the feasibility of CAD-derived BSLA based on technetium-99m bone imaging to assess treatment response.16 A whole-body bone scan is the standard imaging assessment for patients with prostate cancer.12 However, visual assessment of lesion numbers based on technetium-99 imaging is not a reliable method to quantify changes in total bone lesion burden, as lack of image resolution and subjectivity in visual evaluation yield variability in scan interpretation.16 Consequently, standard bone scans are inadequate for measuring bone lesions and existing technology limitations require RECIST to classify bone metastases as non-measurable disease.14 Similarly, PCWG3 guidelines focused on new lesion detection rather than changes to existing lesions.17 In the current study, BSLA measurements derived using an automated CAD system provided a feasible, quantitative, and objective method to measure changes in isotope uptake in patients with mCRPC. Although additional evaluation of its reliability is required, this method may be able to differentiate between PR and SD, thereby permitting a response assessment. A meaningful comparison between technetium-99m and DW-MRI and Na18F PET/CT was not possible because the number of patient scans was too low.\n\nRecently, the prognostic value of an automated bone scan index (aBSI) derived using artificial intelligence has been increasingly reported,21, 22, 23, 24 although for patients treated with radium-223, the aBSI requires validation in prospective studies.22 The aBSI primarily has been evaluated as a prognostic biomarker, whereas the BSLA is a quantitative imaging biomarker being evaluated primarily for treatment response assessment in prostate cancer.13 There has been clinical interest in the use of baseline aBSI and changes in aBSI during treatment as possible predictors of OS and time to symptom progression.21, 22, 23, 24 A recent analysis of 721 evaluable men with mCRPC enrolled in a phase III trial of tasquinimod reported that baseline aBSI was an independent prognostic imaging marker of survival in mCRPC,25 and a recent meta-analysis of aBSI in 567 patients with mCRPC from nine studies suggested that high baseline aBSI and a high change in aBSI during treatment were associated with poor survival.26 However, this technique had not been validated at the time our study was designed, and prospective studies of systemic therapies are needed to clearly define the utility of changes in aBSI over time as a primary endpoint in clinical trials and as a prognostic biomarker in routine clinical practice.22,24\n\nLimitations of our study include its small sample size, lack of correlative studies with survival, the open-label design, differential concomitant therapy, and the small number of patients evaluable to explore the utility of an automated CAD system to measure BSLA and the use of DW-MRI and Na18F PET/CT to assess treatment response. The primary endpoint of BSLA RR was based on an experimental method, which could be considered a limitation, although conventional endpoints were also measured. Differences in median durations of treatment between arms make it difficult to draw conclusions on AE frequency between arms. Therefore, interpretation of the results of this phase IIa trial should consider the limited sample size and the use of BSLA as an exploratory method that was not confirmed by larger randomized studies at the time our study was conducted. Subsequent to the conduct of this study, a clinical validation was published of baseline BSLA and 12-week disease control calculated by the CAD BSLA method as a surrogate biomarker for OS in 198 men with mCRPC.13 However, a limitation of this validation study is that the two BSLA-based endpoints validated are different from the primary endpoint in our study, 24-week BSLA response.\n\nIn conclusion, in our study in patients with mCRPC and bone metastases treated with radium-223 alone or in combination with abiraterone/prednisone or enzalutamide, the primary endpoint of BSLA RR >5% was met in each treatment arm. In the combination arms, rPFS and time to radiologic progression were not estimable, and a lower bone fracture incidence was observed in patients who were receiving BHAs at baseline than in patients who were not receiving BHAs at baseline. Although patients receiving combination treatment experienced more drug-related TEAEs than patients receiving radium-223 monotherapy, the safety profile of each drug was consistent with previous experience and there were no new safety signals. However, no preferred treatment combination or sequencing can be recommended based on the results of this trial. The use of radium-223 should follow current evidence-based treatment guidelines.18,19 Our findings suggest that technetium-99m imaging BSLA, using a CAD system, may be an objective and quantifiable means of assessing isotope uptake changes in this patient population, and represents a potential method for assessing treatment response, improving assessment of technetium-99m bone scans, complementing other imaging modalities, and improving scan results in countries where more expensive imaging is unavailable. Although this study was too small to reliably correlate CAD-based technetium-99m imaging BSLA with clinical outcomes, a validation of this approach was subsequently conducted, although not with the 24-week BSLA response endpoint, which was the primary endpoint in our study. Future studies should examine its utility further in this setting.\n\nSupplementary data\n\nSupplementary Material\n\nSupplementary Figure S1\n\nSupplementary Figure S2\n\nAcknowledgements\n\nWriting support for the preparation of this article was provided by Yvonne E. Yarker, PhD, of OPEN Health Communications (London, UK) with financial support from Bayer HealthCare.\n\nFunding\n\nThis work was supported by 10.13039/501100000801 Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ, USA (no grant number).\n\nDisclosure\n\nDPP has received honoraria from Advanced Accelerator Applications, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche, Seattle Genetics, and UroGen; and has received research grants/funding from Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche, Sanofi Aventis, and Seattle Genetics. UNV has received honoraria, has acted as an advisor/consultant, and has received research grants/funding from Bayer, Sanofi Inc., Exelixis, Bristol-Myers Squibb, Pfizer, and EMD Serono Inc. CSH has acted as an advisor/consultant for Aptevo, Asana, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Churchill Pharma, Clovis Oncology, Dendreon, Endocyte, Ferring, Hinova Pharma, Janssen, Myriad Genetics, Orion Corporation, and Pfizer; has received research grants/funding from Aptevo, Bayer, Aragon Pharma, Astellas, AstraZeneca, Dendreon, Genentech, Hoffman-La Roche, Medivation, Sanofi, and Pfizer; and has received travel, accommodation, and expenses from Bayer, Blue Earth Diagnostics, Clovis Oncology, Ferring, Genentech, Hinova, Janssen, Myriad Genetics, Orion Corporation, and Pfizer. CA has acted as a speaker bureau/expert testimony for Sanofi. NAD has acted as a speaker bureau/expert testimony for Astellas/Pfizer and Janssen. BAM has received honoraria, travel, and accommodation expenses, and acted as an advisor/consultant for Astellas, Amgen, Bayer, Janssen, and Pfizer; and has received grants/funding from Astellas, Bayer, Janssen, and Pfizer. DIQ has received research grants/funding from Seattle Genetics, MSD, and Novartis; has acted as an advisor/consultant for Astellas, AstraZeneca, Bayer, BMS, Dendreon, Exelixis, Roche, Janssen, MSD, Novartis, Pfizer, and Sanofi; and has received travel, accommodation, and expenses from Pfizer, MSD, AstraZeneca, BMS, and Roche. OS reports grand and/or fees from Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Bellicum, Blue Earth Diagnostics, Inc., Bristol-Myers Squibb, Celgene, Constellation, Dendreon, EMD Serono, Innocrin, Invitae, Johnson & Johnson, Merck, Myovant, Pfizer, Sanofi, and SOTIO. VJW, JS, and LT are employees of Bayer HealthCare Pharmaceuticals. All other authors have declared no conflicts of interest.\n==== Refs\nReferences\n\n1 Lorente D. Fizazi K. Sweeney C. de Bono J.S. Optimal treatment sequence for metastatic castration-resistant prostate cancer Eur Urol Focus 2 2016 488 498 28723514\n2 Bruland O.S. Nilsson S. Fisher D.R. Larsen R.H. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res 12 2006 6250s 6257s 17062709\n3 de Bono J.S. Logothetis C.J. Molina A. Abiraterone and increased survival in metastatic prostate cancer N Engl J Med 364 2011 1995 2005 21612468\n4 Scher H.I. Fizazi K. Saad F. Increased survival with enzalutamide in prostate cancer after chemotherapy N Engl J Med 367 2012 1187 1197 22894553\n5 Ryan C.J. Smith M.R. de Bono J.S. Abiraterone in metastatic prostate cancer without previous chemotherapy N Engl J Med 368 2013 138 148 23228172\n6 Beer T.M. Armstrong A.J. Rathkopf D.E. Enzalutamide in metastatic prostate cancer before chemotherapy N Engl J Med 371 2014 424 433 24881730\n7 Parker C. Nilsson S. Heinrich D. Alpha emitter radium-223 and survival in metastatic prostate cancer N Engl J Med 369 2013 213 223 23863050\n8 Kantoff P.W. Higano C.S. Shore N.D. Sipuleucel-T immunotherapy for castration-resistant prostate cancer N Engl J Med 363 2010 411 422 20818862\n9 de Bono J.S. Oudard S. Ozguroglu M. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial Lancet 376 2010 1147 1154 20888992\n10 Tannock I.F. de Wit R. Berry W.R. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer N Engl J Med 351 2004 1502 1512 15470213\n11 Smith M. Parker C. Saad F. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial Lancet Oncol 20 2019 408 419 30738780\n12 Cook G.J. Azad G. Padhani A.R. Bone imaging in prostate cancer: the evolving roles of nuclear medicine and radiology Clin Transl Imaging 4 2016 439 447 27933280\n13 Brown M.S. Kim G.H.J. Chu G.H. Quantitative bone scan lesion area as an early surrogate outcome measure indicative of overall survival in metastatic prostate cancer J Med Imaging (Bellingham) 5 2018 011017 29340285\n14 Eisenhauer E.A. Therasse P. Bogaerts J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 45 2009 228 247 19097774\n15 Scher H.I. Morris M.J. Stadler W.M. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3 J Clin Oncol 34 2016 1402 1418 26903579\n16 Brown M.S. Chu G.H. Kim H.J. Computer-aided quantitative bone scan assessment of prostate cancer treatment response Nucl Med Commun 33 2012 384 394 22367858\n17 Scher H.I. Halabi S. Tannock I. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group J Clin Oncol 26 2008 1148 1159 18309951\n18 National Comprehensive Cancer Network® Prostate cancer version 2.2021 – February 17, 2021 Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf Accessed March 11, 2021\n19 Mottet N, Cornford P, van den Bergh RCN, et al. EAU - EANM - ESTRO - ESUR - SIOG Guidelines on Prostate Cancer 2020. Available at: https://uroweb.org/wp-content/uploads/EAU-EANM-ESTRO-ESUR-SIOG-Guidelines-on-Prostate-Cancer-2020v4.pdf. Accessed March 11, 2021.\n20 Tombal B.F. Loriot Y. Saad F. Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis J Clin Oncol 37 suppl 15 2019 5007\n21 Ali A. Hoyle A.P. Parker C.C. The automated bone scan index as a predictor of response to prostate radiotherapy in men with newly diagnosed metastatic prostate cancer: an exploratory analysis of STAMPEDE's “M1|RT Comparison” Eur Urol Oncol 3 2020 412 419 32591246\n22 Anand A. Tragardh E. Edenbrandt L. Assessing radiographic response to (223)Ra with an automated bone scan index in metastatic castration-resistant prostate cancer patients J Nucl Med 61 2020 671 675 31586004\n23 Reza M. Wirth M. Tammela T. Automated bone scan index as an imaging biomarker to predict overall survival in the Zometa European Study/SPCG11 Eur Urol Oncol 4 2019 49 55 31186177\n24 Mota J.M. Armstrong A.J. Larson S.M. Measuring the unmeasurable: automated bone scan index as a quantitative endpoint in prostate cancer clinical trials Prostate Cancer Prostatic Dis 22 2019 522 530 31036925\n25 Armstrong A.J. Anand A. Edenbrandt L. Phase 3 assessment of the automated bone scan index as a prognostic imaging biomarker of overall survival in men with metastatic castration-resistant prostate cancer: a secondary analysis of a randomized clinical trial JAMA Oncol 4 2018 944 951 29799999\n26 Song H. Jin S. Xiang P. Prognostic value of the bone scan index in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis BMC Cancer 20 2020 238 32197590\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2059-7029",
"issue": "6(2)",
"journal": "ESMO open",
"keywords": "abiraterone; bone scan lesion area; enzalutamide; metastatic castration-resistant prostate cancer; radium-223; technetium-99m",
"medline_ta": "ESMO Open",
"mesh_terms": "D000069501:Abiraterone Acetate; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D006801:Humans; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin; D011241:Prednisone; D064129:Prostatic Neoplasms, Castration-Resistant; D011883:Radium; D014057:Tomography, X-Ray Computed",
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"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
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"title": "A randomized phase IIa study of quantified bone scan response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 dichloride alone or in combination with abiraterone acetate/prednisone or enzalutamide.",
"title_normalized": "a randomized phase iia study of quantified bone scan response in patients with metastatic castration resistant prostate cancer mcrpc treated with radium 223 dichloride alone or in combination with abiraterone acetate prednisone or enzalutamide"
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"medicinalproduct": "ENZALUTAMIDE"
}
],
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Acute promyelocytic leukaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PETRYLAK DP, VAISHAMPAYAN UN, PATEL KR, HIGANO CS, ALBANY C, DAWSON NA, ET AL. A RANDOMIZED PHASE IIA STUDY OF QUANTIFIED BONE SCAN RESPONSE IN PATIENTS WITH METASTATIC CASTRATION?RESISTANT PROSTATE CANCER (MCRPC) TREATED WITH RADIUM?223 DICHLORIDE ALONE OR IN COMBINATION WITH ABIRATERONE ACETATE/PREDNISONE OR ENZALUTAMIDE. ESMO OPEN. 2021?6 (2):1?10",
"literaturereference_normalized": "a randomized phase iia study of quantified bone scan response in patients with metastatic castration resistant prostate cancer mcrpc treated with radium 223 dichloride alone or in combination with abiraterone acetate prednisone or enzalutamide",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210330",
"receivedate": "20210330",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 19073558,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210420"
}
] |
{
"abstract": "Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported.\n\n\n\nWe enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls.\n\n\n\nAmong 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013).\n\n\n\nHLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.",
"affiliations": "Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan. Electronic address: [email protected].;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.;Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan.;Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.",
"authors": "Yano|Seiichi|S|;Ashida|Kenji|K|;Sakamoto|Ryuichi|R|;Sakaguchi|Chihiro|C|;Ogata|Masatoshi|M|;Maruyama|Kengo|K|;Sakamoto|Shohei|S|;Ikeda|Munehiko|M|;Ohe|Kenji|K|;Akasu|Shoko|S|;Iwata|Shimpei|S|;Wada|Nobuhiko|N|;Matsuda|Yayoi|Y|;Nakanishi|Yoichi|Y|;Nomura|Masatoshi|M|;Ogawa|Yoshihiro|Y|",
"chemical_list": "D000911:Antibodies, Monoclonal; D015415:Biomarkers; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; D061026:Programmed Cell Death 1 Receptor",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2020.02.049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "130()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "ACTH deficiency; Adrenal insufficiency; Autoimmunity; CTLA4; HLA; Hypophysitis; IL-17; Immune checkpoint inhibitors; PD-1",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000309:Adrenal Insufficiency; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D005260:Female; D059810:HLA-DR Serological Subtypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "198-203",
"pmc": null,
"pmid": "32229416",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Human leucocyte antigen DR15, a possible predictive marker for immune checkpoint inhibitor-induced secondary adrenal insufficiency.",
"title_normalized": "human leucocyte antigen dr15 a possible predictive marker for immune checkpoint inhibitor induced secondary adrenal insufficiency"
}
|
[
{
"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-116927",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugadditional": "3",
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"drugdosageform": "SOLUTION FOR INJECTION",
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"drugindication": "MALIGNANT MELANOMA",
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"medicinalproduct": "OPDIVO"
},
{
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},
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"drugdosageform": "INJECTION",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "PEMBROLIZUMAB."
}
],
"patientagegroup": null,
"patientonsetage": "68",
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"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Adrenocorticotropic hormone deficiency",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Secondary adrenocortical insufficiency",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fulminant type 1 diabetes mellitus",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YANO S ET AL. HUMAN LEUCOCYTE ANTIGEN DR15, A POSSIBLE PREDICTIVE MARKER FOR IMMUNE CHECKPOINT INHIBITOR-INDUCED SECONDARY ADRENAL INSUFFICIENCY. EUROPEAN JOURNAL OF CANCER. 2020?130:198-203",
"literaturereference_normalized": "human leucocyte antigen dr15 a possible predictive marker for immune checkpoint inhibitor induced secondary adrenal insufficiency",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200612",
"receivedate": "20191209",
"receiver": {
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},
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"sender": {
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200713"
}
] |
{
"abstract": "Autologous peripheral blood stem cell transplantation(auto-PBSCT)combined with high-dose chemotherapy has been considered as the standard therapy for relapsed or induction therapy-refractory aggressive lymphomas sensitive to chemotherapy. While various regimens have been applied as the conditioning,none has yet been established as the standard. We have begun to employ high-dose ranimustine,cytarabine,etoposide and cyclophosphamide(MCVAC)regimen. The present study was undertaken to review the efficacy and safety of MCVAC. Regimen: We carried out a retrospective analysis of 20 patients diagnosed as diffuse large B-cell lymphoma. The median follow-up duration of 20 patients was 13.05 months(range, 0.57-49.5 months). The 4-year OS and PFS were 57.8% and 30.2%,respectively. Relapse was the most frequent cause of treatment failure(n=7). The major toxicities were anorexia/nausea(95%),diarrhea (75%),hypokalemia (70%). One patient died of hepatic veno-occlusive disease(VOD). The serious adverse events included hypokalemia,arrhythmia,cerebral hemorrhage,and heart failure(1 case[5%]each). There was 1 case of a late-onset adverse event: therapy-related myelo- dysplastic syndrome/acute myeloblastic leukemia(MDS/AML). MCVAC regimen was concluded as effective and well-toler- ated. However,we should carefully monitored for the possible development of VOD and MDS/AML. Further follow-up is needed to evaluate the long-term efficacy and safety.",
"affiliations": "Dept. of Hematology, Juntendo University Urayasu Hospital.",
"authors": "Sekiguchi|Yasunobu|Y|;Wakabayashi|Mutsumi|M|;Takizawa|Haruko|H|;Iizuka|Hiroko|H|;Sakajiri|Sakura|S|;Sugimoto|Keiji|K|;Inano|Tadaaki|T|;Fukuda|Yasutaka|Y|;Hamano|Yasuharu|Y|;Hirano|Takao|T|;Sato|Eriko|E|;Aritaka|Nanae|N|;Yahata|Yuriko|Y|;Morita|Kimio|K|;Okamura|Takamitsu|T|;Tomita|Shigeki|S|;Izumi|Hiroshi|H|;Okubo|Mitsuo|M|;Nakamura|Noriko|N|;Sawada|Tomohiro|T|;Noguchi|Masaaki|M|",
"chemical_list": "D005047:Etoposide; D003520:Cyclophosphamide",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(8)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D005047:Etoposide; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1265-1273",
"pmc": null,
"pmid": "31501368",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Retrospective Analysis of 20 Patients with DLBCL Who Received MCVAC Followed by Autologous Peripheral Blood Stem Cell Transplantation.",
"title_normalized": "retrospective analysis of 20 patients with dlbcl who received mcvac followed by autologous peripheral blood stem cell transplantation"
}
|
[
{
"companynumb": "NVSC2019JP002692",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
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"drugindication": "B-CELL LYMPHOMA STAGE IV",
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"medicinalproduct": "RITUXIMAB."
},
{
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},
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"drugindication": "DIFFUSE LARGE B-CELL LYMPHOMA STAGE IV",
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"medicinalproduct": "PREDNISOLONE."
},
{
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},
{
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{
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},
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},
{
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},
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"medicinalproduct": "GEMCITABINE."
}
],
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"patientonsetage": "68",
"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Diffuse large B-cell lymphoma recurrent",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Therapeutic response decreased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SEKIGUCHI Y, WAKABAYASHI M, TAKIZAWA H, IIZUKA H, SAKAJIRI S, SUGIMOTO K ET AL.. RETROSPECTIVE ANALYSIS OF 20 PATIENTS WITH DLBCL WHO RECEIVED MCVAC FOLLOWED BY AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION. JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY. 2019?46 (8):1265-73",
"literaturereference_normalized": "retrospective analysis of 20 patients with dlbcl who received mcvac followed by autologous peripheral blood stem cell transplantation",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20191016",
"receivedate": "20191016",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20200122"
},
{
"companynumb": "JP-TEVA-2019-JP-1121873",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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},
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"drugindication": "BONE MARROW CONDITIONING REGIMEN",
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},
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},
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"medicinalproduct": "CYTARABINE."
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{
"abstract": "To evaluate the safety and efficacy of induced hypertension in patients with acute ischemic stroke.\n\n\n\nIn this multicenter randomized clinical trial, patients with acute noncardioembolic ischemic stroke within 24 hours of onset who were ineligible for revascularization therapy and those with progressive stroke during hospitalization were randomly assigned (1:1) to the control and intervention groups. In the intervention group, phenylephrine was administered intravenously to increase systolic blood pressure (SBP) up to 200 mm Hg. The primary efficacy endpoint was early neurologic improvement (reduction in NIH Stroke Scale [NIHSS] score of ≥2 points during the first 7 days). The secondary efficacy endpoint was a modified Rankin Scale score of 0 to 2 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage/edema, myocardial infarction, and death.\n\n\n\nIn the modified intention-to-treat analyses, 76 and 77 patients were included in the intervention and control groups, respectively. After adjustment for age and initial stroke severity, induced hypertension increased the occurrence of the primary (odds ratio 2.49, 95% confidence interval [CI] 1.25-4.96, p = 0.010) and secondary (odds ratio 2.97, 95% CI 1.32-6.68, p = 0.009) efficacy endpoints. Sixty-seven (88.2%) patients of the intervention group exhibited improvements in NIHSS scores of ≥2 points during induced hypertension (mean SBP 179·7 ± 19.1 mm Hg). Safety outcomes did not significantly differ between groups.\n\n\n\nAmong patients with noncardioembolic stroke who were ineligible for revascularization therapy and those with progressive stroke, phenylephrine-induced hypertension was safe and resulted in early neurologic improvement and long-term functional independence.\n\n\n\nNCT01600235.\n\n\n\nThis study provides Class III evidence that for patients with acute ischemic stroke, therapeutic-induced hypertension increases the probability of early neurologic improvement.",
"affiliations": "From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea. [email protected].;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea. [email protected].;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.;From the Department of Neurology (O.Y.B., J.-W.C., M.J.L., W.-K.S.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; Department of Neurology and Institute of Health Science (S.-K.K.), Gyeongsang National University College of Medicine, Jinju; Department of Neurology (S.J.K.), Hana General Hospital, Cheongju; Department of Neurology (J.H.), Kyungpook National University Chilgok Hospital, Daegu; Department of Neurology (Y.S.H.), Wonkwang University, School of Medicine, Iksan; Department of Neurology (S.M.S.), Pusan National University Hospital; Department of Neurology (E.-G.K.), Busan Paik Hospital, Inje University; Department of Neurology (S.-I.S.), Keimyung University School of Medicine, Daegu; and Department of Neurology (M.-K.H.), Seoul National University Bundang Hospital, Seongnam, Korea.",
"authors": "Bang|Oh Young|OY|;Chung|Jong-Won|JW|;Kim|Soo-Kyoung|SK|;Kim|Suk Jae|SJ|;Lee|Mi Ji|MJ|0000-0003-1364-1969;Hwang|Jaechun|J|;Seo|Woo-Keun|WK|;Ha|Yeon Soo|YS|;Sung|Sang Min|SM|;Kim|Eung-Gyu|EG|;Sohn|Sung-Il|SI|0000-0002-6900-1242;Han|Moon-Ku|MK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000008520",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "93(21)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure; D001921:Brain; D001929:Brain Edema; D003097:Collateral Circulation; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D006801:Humans; D006973:Hypertension; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009203:Myocardial Infarction; D010347:Patient Care Planning; D020521:Stroke; D016896:Treatment Outcome",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e1955-e1963",
"pmc": null,
"pmid": "31645472",
"pubdate": "2019-11-19",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "25353321;19834012;15079024;28477676;16675735;9368553;21705025;12677087;23370205;2887477;12865611;21939900;23652626;28636854;16174926;24473178;24076337;17515473;28460496;29367334;23566412;11342689;15800252;25465108;26451027;20829514;16498187;26598796;28820296;11935051",
"title": "Therapeutic-induced hypertension in patients with noncardioembolic acute stroke.",
"title_normalized": "therapeutic induced hypertension in patients with noncardioembolic acute stroke"
}
|
[
{
"companynumb": "KR-MEITHEAL PHARMACEUTICALS-2019MHL00013",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYLEPHRINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "210334",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1.2 MG PER HOUR UNTIL A 20% INCREASE IN SBP WAS ACHIEVED",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ISCHAEMIC STROKE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosagenumb": "1.2",
"drugstructuredosageunit": "003",
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"medicinalproduct": "PHENYLEPHRINE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cerebral haemorrhage",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BANG OY, CHUNG JW, KIM SK, ET AL.. THERAPEUTIC-INDUCED HYPERTENSION IN PATIENTS WITH NONCARDIOEMBOLIC ACUTE STROKE.. NEUROLOGY.. 2019?93:1-9",
"literaturereference_normalized": "therapeutic induced hypertension in patients with noncardioembolic acute stroke",
"qualification": "1",
"reportercountry": "KR"
},
"primarysourcecountry": "KR",
"receiptdate": "20191115",
"receivedate": "20191115",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17037857,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200122"
},
{
"companynumb": "KR-AVADEL LEGACY PHARMACEUTICALS, LLC-2019AVA00095",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PHENYLEPHRINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "204300",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1.2 MG PER HOUR, UNTIL 20% INCREASE IN SBP ACHIEVED",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ISCHAEMIC STROKE",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosagenumb": "1.2",
"drugstructuredosageunit": "003",
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"medicinalproduct": "PHENYLEPHRINE"
}
],
"patientagegroup": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cerebral haemorrhage",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BANG OY, CHUNG JW, KIM SK, ET AL.. THERAPEUTIC-INDUCED HYPERTENSION IN PATIENTS WITH NONCARDIOEMBOLIC ACUTE STROKE.. NEUROLOGY.. 2019?93:1-9",
"literaturereference_normalized": "therapeutic induced hypertension in patients with noncardioembolic acute stroke",
"qualification": "3",
"reportercountry": "KR"
},
"primarysourcecountry": "KR",
"receiptdate": "20191119",
"receivedate": "20191119",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17049110,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200122"
}
] |
{
"abstract": "Triamcinolone acetonide is a synthetic glucocorticoid used to treat numerous acute and chronic inflammatory conditions. The various side effects of this drug from parenteral administration are well documented in the literature. In this study, three patients present with a rare side effect of violaceous dermal pigmentation. To the best of the authors' knowledge, this finding is rarely presented in the current literature. The purpose of this study is to provide awareness of a less-documented, delayed side effect from triamcinolone acetonide administration. Although all patients presenting in this study had a known history of autoimmune disease (eg, lupus, psoriatic arthritis) further research is needed to suggest a possible association between dermal violaceous change and the use of triamcinolone.",
"affiliations": null,
"authors": "Wright|James A|JA|;Wenz|Jessica A|JA|;Madrigal|Gabrielle Jackson|GJ|",
"chemical_list": "D005938:Glucocorticoids; D014222:Triamcinolone Acetonide",
"country": "United States",
"delete": false,
"doi": "10.7547/20-210",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1930-8264",
"issue": "111(4)",
"journal": "Journal of the American Podiatric Medical Association",
"keywords": null,
"medline_ta": "J Am Podiatr Med Assoc",
"mesh_terms": "D001327:Autoimmune Diseases; D005938:Glucocorticoids; D006801:Humans; D014222:Triamcinolone Acetonide",
"nlm_unique_id": "8501423",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34478539",
"pubdate": "2021-07-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dermal Discoloration Secondary to Triamcinolone Acetonide Injection Observed in Patients with Autoimmune Disorders.",
"title_normalized": "dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders"
}
|
[
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-108670",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional": "3",
"drugadministrationroute": "014",
"drugauthorizationnumb": "012041",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Injection",
"drugdosagetext": "40 MG/DL",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Psoriatic arthropathy",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TRIAMCINOLONE ACETONIDE"
}
],
"patientagegroup": null,
"patientonsetage": "40",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Skin discolouration",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional product use issue",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Wright JA, Wenz JA, Madrigal GJ. Dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders. Journal of the American Podiatric Medical Association. 2021;111(4):1-4",
"literaturereference_normalized": "dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211020",
"receivedate": "20211020",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19970434,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
},
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-26856",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "208763",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "APPROXIMATELY 0.5 CC OF TRIAMCINOLONE ACETONIDE 40 MG/DL WAS DELIVERED INTO THE RIGHT FIRST METATARS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Pain in extremity",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "032",
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"medicinalproduct": "TRIAMCINOLONE ACETONIDE"
}
],
"patientagegroup": null,
"patientonsetage": "57",
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"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Skin discolouration",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Wright JA, Wenz JA, Madrigal GJ. Dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders. Journal of the American Podiatric Medical Association. 2021;111(4):1-4",
"literaturereference_normalized": "dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20220114",
"receivedate": "20220114",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20334367,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220423"
},
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-26855",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional": "3",
"drugadministrationroute": "051",
"drugauthorizationnumb": "208763",
"drugbatchnumb": "unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 DOSAGE FORM (0.5 CC OF TRIAMCINOLONE ACETONIDE 40 MG/DL WAS ADMINISTERED INTO THE RIGHT FIRST META",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Pain in extremity",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "032",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TRIAMCINOLONE ACETONIDE"
}
],
"patientagegroup": null,
"patientonsetage": "40",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Skin discolouration",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Wright JA, Wenz JA, Madrigal GJ. Dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders. Journal of the American Podiatric Medical Association. 2021;111 (4):1-4",
"literaturereference_normalized": "dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20220113",
"receivedate": "20220113",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 2,
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"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220423"
},
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-108669",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional": "3",
"drugadministrationroute": "014",
"drugauthorizationnumb": "012041",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Injection",
"drugdosagetext": "40 MG/DL",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Psoriatic arthropathy",
"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": "TRIAMCINOLONE ACETONIDE"
}
],
"patientagegroup": null,
"patientonsetage": "52",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Skin discolouration",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional product use issue",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Wright JA, Wenz JA, Madrigal GJ. Dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders. Journal of the American Podiatric Medical Association. 2021;111(4):1-4",
"literaturereference_normalized": "dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211020",
"receivedate": "20211020",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19970435,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
},
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-103616",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
"drugadditional": "3",
"drugadministrationroute": "014",
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
"drugdosageform": "Injection",
"drugdosagetext": "40 MG/DL",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Systemic lupus erythematosus",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TRIAMCINOLONE ACETONIDE"
}
],
"patientagegroup": null,
"patientonsetage": "57",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Skin discolouration",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional product use issue",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Wright JA, Wenz JA, Madrigal GJ. Dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders. Journal of the American Podiatric Medical Association. 2021;111(4):1-4",
"literaturereference_normalized": "dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211020",
"receivedate": "20211020",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19970441,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220303"
},
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2021-26854",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "208763",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 DOSAGE FORM",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Pain in extremity",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "032",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TRIAMCINOLONE"
}
],
"patientagegroup": null,
"patientonsetage": "52",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Skin discolouration",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Wright JA, Wenz JA, Madrigal GJ. Dermal Discoloration Secondary to Triamcinolone Acetonide Injection Observed in Patients with Autoimmune Disorders. Journal of the American Podiatric Medical Association. 2021;111(4):1-4",
"literaturereference_normalized": "dermal discoloration secondary to triamcinolone acetonide injection observed in patients with autoimmune disorders",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20220112",
"receivedate": "20220112",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20327883,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220423"
}
] |
{
"abstract": "Lenalidomide (Len) and dexamethasone (dex) therapy is a standard therapy in patients with multiple myeloma. Elderly or unfit patients may reduce Len or dex doses to prevent toxicities that lead to treatment discontinuation. However, there have been few studies evaluating the efficacy and safety of lower doses of Len and dex. We conducted a phase II study of 1.5-year low-dose Len and dex therapy following melphalan and prednisolone (MP), the number of which cycles was determined by a response within 9 cycles. The Len dose was 10 mg daily and the dex dose was 20 mg weekly, which were continued for 1.5 years. Twenty-one patients were enrolled. The median number of cycles of MP was 3 (range, 2-9). The overall response rate was 81% and a very good partial response or better was achieved in 33.3% of patients. The median follow-up time for survivors was 70.5 months (range, 42-83 months), the median progression-free survival (PFS) was 27 months (95% CI, 21-33 months), and the median overall survival was not reached. Grade 3 or 4 adverse events were observed in 28.6% of patients. In conclusion, the low-dose Len and dex therapy safely achieved comparable efficacies to the standard-dose regimen in elderly patients with newly diagnosed multiple myeloma. UMIN000007889.",
"affiliations": "Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-857, Japan. [email protected].;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-857, Japan.;Department of Hematology, Sendai Medical Center, National Hospital Organization, Sendai, Miyagi, Japan.;Department of Hematology, Sendai Medical Center, National Hospital Organization, Sendai, Miyagi, Japan.;Department of Hematology, Suihu Hospital, Ibaraki, Japan.;Department of Hematology, Sendai City Hospital, Sendai, Miyagi, Japan.;Department of Hematology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Miyagi, Japan.;Department of Hematology, Miyagi Cancer Center, Natori, Miyagi, Japan.;Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Department of Hematology, Japanese Red Cross Sendai Hospital, Sendai, Miyagi, Japan.;Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Department of Hematology, Fukushima Medical University, Fukushima, Japan.;Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Hokkaido, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-857, Japan.",
"authors": "Onishi|Yasushi|Y|http://orcid.org/0000-0003-0032-6994;Yokoyama|Hisayuki|H|;Katsuoka|Yuna|Y|;Ito|Toshihiro|T|;Kimura|Tomohumi|T|;Yamamoto|Joji|J|;Nakajima|Shinji|S|;Sasaki|Osamu|O|;Ara|Takahide|T|;Minauchi|Koichiro|K|;Fukuhara|Osamu|O|;Kobayashi|Naoki|N|;Noji|Hideyoshi|H|;Ota|Shuichi|S|;Harigae|Hideo|H|",
"chemical_list": "D003907:Dexamethasone; D011239:Prednisolone; D000077269:Lenalidomide; D008558:Melphalan",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-04240-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(10)",
"journal": "Annals of hematology",
"keywords": "Elderly; Low-dose lenalidomide; Melphalan; Multiple myeloma; Transplant-ineligible",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064147:Febrile Neutropenia; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009101:Multiple Myeloma; D011239:Prednisolone; D000077982:Progression-Free Survival; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "2351-2356",
"pmc": null,
"pmid": "32865607",
"pubdate": "2020-10",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": "25184863;29150421;21841166;21410373;25628469;15057291;20088798;11418482;12660941;15638853;21747400;24525202;27864218;16855634;22571200;28197996;18032762;18032763;28728162",
"title": "Low-dose lenalidomide and dexamethasone therapy after melphalan-prednisolone induction in elderly patients with newly diagnosed multiple myeloma.",
"title_normalized": "low dose lenalidomide and dexamethasone therapy after melphalan prednisolone induction in elderly patients with newly diagnosed multiple myeloma"
}
|
[
{
"companynumb": "JP-CELGENEUS-JPN-20200902764",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "021880",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "CAPSULES",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PLASMA CELL MYELOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "REVLIMID"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLETS",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PLASMA CELL MYELOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "20",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DEXAMETHASONE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": "81 TO 100 MG",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "THROMBOSIS PROPHYLAXIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ASPIRIN."
}
],
"patientagegroup": "6",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Colon cancer",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ONISHI Y, YOKOYAMA H, KATSUOKA Y, ITO T, KIMURA M, YAMAMOTO J. LOW-DOSE LENALIDOMIDE AND DEXAMETHASONE THERAPY AFTER MELPHALAN-PREDNISOLONE INDUCTION IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA. ANNALS OF HEMATOLOGY. 2020?99:2351-2356.",
"literaturereference_normalized": "low dose lenalidomide and dexamethasone therapy after melphalan prednisolone induction in elderly patients with newly diagnosed multiple myeloma",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20201112",
"receivedate": "20200911",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18258793,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210113"
}
] |
{
"abstract": "A 40-year-old woman was admitted to the hospital for an acute outbreak of multiple pustular lesions with an underlying erythematous base affecting cheeks and chin. These lesions were referred to as \"aching\". The patient had been taking amoxicillin-clavulanic acid (3 g a day) over the past three days for oral prophylaxis for dental treatment. Given the possible allergic reaction to the drug administered and the extension of the pustular lesions over all face and neck during the following four days, we replaced the amoxicillin-clavulanic acid with another antibiotic with wide range (ciprofloxacin). Resolution of the pustular lesions occurred within ten days and was accompanied by light scarring and pigmentation. On the basis of the close relationship between the administration of amoxicillin-clavulanic acid and the development of the disease, in combination with a rapid, acute resolution as soon as this treatment was interrupted, and all the histologic findings, we consider this to be an unusual type of acute generalized pustular eruption (AGEP) recently defined as acute localized pustular eruption (ALEP) due to amoxicillin-clavulanic acid.",
"affiliations": "Dermatology Unit and Pathologic Anatomy Service, San Bortolo Hospital, Vicenza, Italy. [email protected]",
"authors": "Betto|Paola|P|;Germi|Lerica|L|;Bonoldi|Emanuela|E|;Bertazzoni|Marina|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019980:Amoxicillin-Potassium Clavulanate Combination",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-4632.2008.03477.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-9059",
"issue": "47(3)",
"journal": "International journal of dermatology",
"keywords": null,
"medline_ta": "Int J Dermatol",
"mesh_terms": "D000328:Adult; D019980:Amoxicillin-Potassium Clavulanate Combination; D000900:Anti-Bacterial Agents; D003875:Drug Eruptions; D005076:Exanthema; D005148:Facial Dermatoses; D005260:Female; D006801:Humans; D012867:Skin",
"nlm_unique_id": "0243704",
"other_id": null,
"pages": "295-6",
"pmc": null,
"pmid": "18289337",
"pubdate": "2008-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute localized exanthematous pustulosis (ALEP) caused by amoxicillin-clavulanic acid.",
"title_normalized": "acute localized exanthematous pustulosis alep caused by amoxicillin clavulanic acid"
}
|
[
{
"companynumb": "IT-AUROBINDO-AUR-APL-2018-033043",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "201090",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "3 MILLIGRAM, ONCE A DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DENTAL DISORDER PROPHYLAXIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "3",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "AMOXICILLIN+CLAVULANIC ACID"
}
],
"patientagegroup": null,
"patientonsetage": "40",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute generalised exanthematous pustulosis",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BETTO P, ET AL.. ACUTE LOCALIZED EXANTHEMATOUS PUSTULOSIS (ALEP) CAUSED BY AMOXICILLIN-CLAVULANIC ACID.. INT J DERMATOL.. 2008",
"literaturereference_normalized": "acute localized exanthematous pustulosis alep caused by amoxicillin clavulanic acid",
"qualification": "5",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20180630",
"receivedate": "20180630",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15094348,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "OBJECTIVE\nAdding taxanes to anthracycline-based adjuvant therapy improves survival outcomes of patients with node-positive breast cancer (BC). Currently, however, most patients with BC are node negative at diagnosis. The only pure node-negative study (Spanish Breast Cancer Research Group 9805) reported so far showed a docetaxel benefit but significant toxicity. Here we tested the efficacy and safety of weekly paclitaxel (wP) in node-negative patients, which is yet to be established.\n\n\nMETHODS\nPatients with BC having T1-T3/N0 tumors and at least one high-risk factor for recurrence (according to St. Gallen 1998 criteria) were eligible. After primary surgery, 1,925 patients were randomly assigned to receive fluorouracil, doxorubicin, and cyclophosphamide (FAC) × 6 or FAC × 4 followed by wP × 8 (FAC-wP). The primary end point was disease-free survival (DFS) after a median follow-up of 5 years. Secondary end points included toxicity and overall survival.\n\n\nRESULTS\nAfter a median follow-up of 63.3 months, 93% and 90.3% of patients receiving FAC-wP or FAC regimens, respectively, remained disease free (hazard ratio [HR], 0.73; 95% CI, 0.54 to 0.99; log-rank P = .04). Thirty-one patients receiving FAC-wP versus 40 patients receiving FAC died (one and seven from cardiovascular diseases, respectively; HR, 0.79; 95% CI, 0.49 to 1.26; log-rank P = .31). The most relevant grade 3 and 4 adverse events in the FAC-wP versus the FAC arm were febrile neutropenia (2.7% v 3.6%), fatigue (7.9% v 3.4%), and sensory neuropathy (5.5% v 0%).\n\n\nCONCLUSIONS\nFor patients with high-risk node-negative BC, the adjuvant FAC-wP regimen was associated with a small but significant improvement in DFS compared with FAC therapy, in addition to manageable toxicity, especially regarding long-term cardiac effects.",
"affiliations": "Instituto de Investigación Sanitaria Gregorio Marañon, Universidad Complutense, Dr. Esquerdo 46, Madrid 28009, Spain. [email protected]",
"authors": "Martín|Miguel|M|;Ruiz|Amparo|A|;Ruiz Borrego|Manuel|M|;Barnadas|Agustí|A|;González|Sonia|S|;Calvo|Lourdes|L|;Margelí Vila|Mireia|M|;Antón|Antonio|A|;Rodríguez-Lescure|Alvaro|A|;Seguí-Palmer|Miguel Angel|MA|;Muñoz-Mateu|Montserrat|M|;Dorca Ribugent|Joan|J|;López-Vega|José Manuel|JM|;Jara|Carlos|C|;Espinosa|Enrique|E|;Mendiola Fernández|César|C|;Andrés|Raquel|R|;Ribelles|Nuria|N|;Plazaola|Arrate|A|;Sánchez-Rovira|Pedro|P|;Salvador Bofill|Javier|J|;Crespo|Carmen|C|;Carabantes|Francisco J|FJ|;Servitja|Sonia|S|;Chacón|José Ignacio|JI|;Rodríguez|César A|CA|;Hernando|Blanca|B|;Álvarez|Isabel|I|;Carrasco|Eva|E|;Lluch|Ana|A|",
"chemical_list": "D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2012.46.9841",
"fulltext": null,
"fulltext_license": null,
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"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D016001:Confidence Intervals; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes; D008408:Mastectomy; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D017239:Paclitaxel; D016016:Proportional Hazards Models; D018570:Risk Assessment; D016019:Survival Analysis; D016896:Treatment Outcome",
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"pages": "2593-9",
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"pubdate": "2013-07-10",
"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",
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"title": "Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study.",
"title_normalized": "fluorouracil doxorubicin and cyclophosphamide fac versus fac followed by weekly paclitaxel as adjuvant therapy for high risk node negative breast cancer results from the geicam 2003 02 study"
}
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{
"abstract": "Disseminated intravascular coagulation is a complex and potentially lethal complication of malignancy, in which the fundamental abnormality is excessive activation of the coagulation system. It is a rare complication of melanoma which can be difficult to diagnose in some circumstances, leading to delay in treatment. Herein, we describe the first case of disseminated intravascular coagulation occurring in BRAF and NRAS-mutant metastatic melanoma, and systematically review the literature regarding disseminated intravascular coagulation in melanoma. This review summarizes the reported cases of disseminated intravascular coagulation in melanoma and those secondary to the novel treatment of melanoma, and explores the pathophysiology of disseminated intravascular coagulation in melanoma, highlighting the key role of expression of markers of coagulation and fibrinolysis in disseminated intravascular coagulation, as well as more widely in melanoma. Current limitations in the literature are also identified and discussed, particularly with respect to improving the management of this lethal complication. Disseminated intravascular coagulation is a rare complication of melanoma that typically portends poor prognosis.",
"affiliations": "The Wollongong Hospital, Wollongong, New South Wales, Australia.",
"authors": "Haggstrom|Lucy|L|;Duong|Tuan Anh|TA|;Thomas|Benjamin|B|;Brungs|Daniel|D|;Aghmesheh|Morteza|M|;Parmar|Gurdeep|G|",
"chemical_list": "D007093:Imidazoles; D008565:Membrane Proteins; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C561627:dabrafenib",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000622",
"fulltext": null,
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"issn_linking": "0960-8931",
"issue": "29(5)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001777:Blood Coagulation; D004211:Disseminated Intravascular Coagulation; D005260:Female; D005342:Fibrinolysis; D020558:GTP Phosphohydrolases; D006801:Humans; D007093:Imidazoles; D008545:Melanoma; D008565:Membrane Proteins; D009154:Mutation; D009362:Neoplasm Metastasis; D010091:Oximes; D048493:Proto-Oncogene Proteins B-raf; D011728:Pyridones; D011744:Pyrimidinones; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "533-538",
"pmc": null,
"pmid": "31095038",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Disseminated intravascular coagulation and melanoma: a novel case occurring in metastatic melanoma with BRAF and NRAS mutations and systematic review.",
"title_normalized": "disseminated intravascular coagulation and melanoma a novel case occurring in metastatic melanoma with braf and nras mutations and systematic review"
}
|
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{
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{
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{
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{
"abstract": "Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and life-threatening delayed drug hypersensitivity reaction characterized by skin eruption, fever, lymphadenopathies, and visceral involvement. Here, we are presenting a 12 year old boy, who developed rare but life threatening DRESS syndrome due to Lamotrigine. Early detection and treatment led to his rapid recovery. This case is presented to highlight the importance of early detection of rare fatal syndrome.",
"affiliations": "Department of Dermatology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital (SDMCMS and H), Sattur, Dharwad, Karnataka, India.",
"authors": "Naveen|Kikkeri Narayanasetty|KN|;Ravindra|Mysore Satyanarayana|MS|;Pai|Varadraj V|VV|;Rai|Vijetha|V|;Athanikar|Sharatchandra B|SB|;Girish|Meravanige|M|",
"chemical_list": "D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine",
"country": "India",
"delete": false,
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"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-44-79810.4103/0253-7613.103305Drug WatchLamotrigine induced DRESS syndrome Naveen Kikkeri Narayanasetty Ravindra Mysore Satyanarayana 1Pai Varadraj V. Rai Vijetha Athanikar Sharatchandra B. Girish Meravanige 2Department of Dermatology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital (SDMCMS and H), Sattur, Dharwad, Karnataka, India1 Department of Paediatrics, Sri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital (SDMCMS and H), Sattur, Dharwad, Karnataka, India2 Department of Pharmacology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences and Hospital (SDMCMS and H), Sattur, Dharwad, Karnataka, IndiaCorrespondence to: Dr. Kikkeri Narayanasetty Naveen, E-mail: [email protected] 2012 44 6 798 800 14 6 2012 19 7 2012 31 8 2012 Copyright: © Indian Journal of Pharmacology2012This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and life-threatening delayed drug hypersensitivity reaction characterized by skin eruption, fever, lymphadenopathies, and visceral involvement. Here, we are presenting a 12 year old boy, who developed rare but life threatening DRESS syndrome due to Lamotrigine. Early detection and treatment led to his rapid recovery. This case is presented to highlight the importance of early detection of rare fatal syndrome.\n\nKEY WORDS\nDRESSearly detectionlamotrigine\n==== Body\nIntroduction\nDrug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and life-threatening delayed drug hypersensitivity reaction characterized by skin eruption, fever, lymphadenopathies, and visceral involvement.[1]\n\nLamotrigine [6-(2,3-dichlorophenyl)-1,2,4-triazine- 3,5-diamine] is an antiepileptic drug, effective for a broad range of seizures in adults and children, which is structurally and pharmacologically unrelated to other antiepileptic medications.[2] Several reports of lamotrigine-induced DRESS syndrome have been reported in the literature.[3–5]\n\nHere we report a case of DRESS syndrome induced by lamotrigine, which was detected early and completely responded to the treatment/thereby reducing the morbidity in the patient.\n\nCase Report\nA 12 year old boy, with a known case of seizure disorder presented to the casualty with generalized maculopapular rash, fever and facial puffiness. The patient had been operated for gastric perforation when he was 3 days old following which the seizure episodes started. He was treated with phenobarbitone till the age of five. The drug was gradually withdrawn on the advice of a physician. Six months ago he suffered an episode of convulsion. He was started on sodium valproate and levetiracetam. One month back levetiracetam was stopped and lamotrigine was initiated. The patient was taking 1 tablet of 25mg daily for the first 15 days; later the dose was doubled. On the 18th day, patient presented with generalized maculopapular rash, itching and fever and on 20th day he developed colicky abdominal pain and vomiting followed by facial puffiness.\n\nOn examination, he was alert and oriented, with a temperature of 100°F and pulse was 114/ minutes. There was significant angioedema of his face with edematous lips and swollen ears, and an extensive maculo-papular rash on his entire trunk [Figure 1], buttocks, extremities and face. The whole body had a red tinge. Examination showed yellow sclera, conjunctival congestion and crusting over his lips. He experienced no joint pain or neurological symptoms, and no abdominal or respiratory complaints. There was no history of any allergies. The birth history and immunization were uneventful. He had 3 siblings: one of them also had history of epileptic disorders for which she was on treatment.\n\nFigure 1 Maculo-papular rashes on the trunk\n\nInvestigations revealed leukocytosis (15,960cells/cmm) with eosinophilia (19%) AEC=2600/cmm. Hemoglobin was 10.8gm%, platelet count 2.53lakhs/cmm; ESR and PCV were normal. Liver enzymes were raised with SGOT=905U/l, SGPT=495U/l, ALP=855U/l and GGT= 155U/l. Total bilirubin was 1.5mg% (direct 0.51mg% and indirect 0.99mg%). Blood urea and creatinine were normal. Routine examination of the urine was normal. Provisional diagnosis of DRESS was made based on the above findings.\n\nParental cortisteroids and systemic antihistamines were initiated. Lamotrigine was stopped. Within 5 days the rash subsided. Patient's general condition improved. On discharge patient was given oral steroids and antihistaminic's.\n\nDiscussion\nDrug hypersensitivity syndrome (DHS), recently being also referred to as DRESS (drug reaction with eosinophilia and systemic symptoms) or DIDMOHS (drug-induced delayed multi-organ hypersensitivity syndrome), is a distinct type of adverse drug reaction. It was first associated with the aromatic antiepileptic drugs (AEDs). DHS is characterized by a constellation of symptoms involving various organs and organ systems. The skin, liver and hematologic system are most commonly involved, with cutaneous changes being the most apparent.[6] The presence of the 2 criteria, as given by Bocquet et al., has high sensitivity (>95%) but weak specificity (<80%).[7] [Table 1]. In the present case, there was eosinophilia, lymphadenopathy and liver enzymes were raised, which satisfied the criteria, and established a diagnosis of DRESS. Prompt resolution of the symptoms after the withdrawal of the lamotrigine, further supported the diagnosis. Lamotrigine was the probable cause of DRESS syndrome in the present case, as assessed by the Naranjo causality criteria.[8]\n\nTable 1 Diagnostic criteria for drug hypersensitivity syndrome[7]\n\nThe liver is the most commonly involved organ in DRESS. The degree of hepatitis is related to the interval between the onset of the syndrome and the discontinuation of the anticonvulsant. This emphasizes the importance of early recognition of the syndrome.[9]\n\nThe mechanism of the hypersensitivity syndrome is unknown. Several theories have been proposed. The reaction is either secondary to circulating antibodies or involves toxic metabolites. Associated infection by human herpes virus 6 may also play a role in its development. Hypersensitivity reactions to aromatic antiepileptic drugs appear to have an immune etiology, much like the lamotrigine-induced reaction: bio activation, detoxification, covalent adduct formation, processing and presentation of antigen to the immune system, and consequent formation of antibody and T-cell immune effectors. Another theory involves toxic metabolites. The aromatic antiepileptic agents are metabolized by cytochrome P-450 to an arene oxide metabolite.[10] These are usually detoxified by the enzyme epoxide hydrolase, which may be lacking or mutated in persons that develop the syndrome. Lamotrigine exhibits first-order linear elimination. It is chiefly metabolized by hepatic glucuronidation; the resulting metabolite has no pharmacologic activity and is excreted in urine. The average elimination half-life in adults is 20 to 35 hours.[3]\n\nOur patient was comfortable when he was receiving single dose of lamotrigine, but he developed DRESS, 3 days after the dose was doubled. This may be explained by the fact that, there may be a threshold concentration of lamotrigine above which the body's ability to metabolize the drug may be overwhelmed, leading to a hypersensitivity reaction.[5] In pediatric age group who are on sodium valproate sudden increase in dosage of lamotrigine increases the risk of lamotrigine induced rash.\n\nThe incidence of DHS (approximately 1 in 1,000 to 1 in 10,000 exposures)[11] is probably underestimated. Though no standard treatment has been proposed, intravenous corticosteroids may be effective. In severe cases, pulse therapy with high dose of intravenous methyl prednisolone, plasmapharesis and human intravenous immunoglobin may be tried.[6]\n\nLamotrigine treatment has been associated with multiorgan failure, DRESS syndrome, acute hepatic failure, and disseminated intravascular coagulation.[1213] We suggest that these potentially fatal side effects should be considered in any patient when clinical deterioration follows treatment with this drug. Early recognition and withdrawal of the suspected agent may avoid irreversible damage to the liver and will be life saving.\n\nThis case reiterates the necessity of early recognition of this syndrome, especially when lamotrigine is given concurrently with sodium valproate. It helps in the rapid resolution of DRESS, thereby mitigating the morbidity and mortality in the patient.\n\nSource of Support: Nil.\n\nConflict of Interest: No.\n==== Refs\n1 Bocquet H Bagot M Roujeau JC Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS) Semin Cutan Med Surg 1996 15 250 7 9069593 \n2 Jawad S Yuen WC Peck AW Hamilton MJ Oxley JR Richens A Lamotrigine: Single-dose pharmacokinetics and initial 1 week experience in refractory epilepsy Epilepsy Res 1987 1 194 201 3504397 \n3 Shawcross D Auzinger G Lamotrigine and the risk of fulminant hepatic failure Lancet 2008 371 649 50 18295021 \n4 Roquin G Peres M Lerolle N Dib N Mercat A Croue A First report of lamotrigine-induced drug rash with eosinophilia and systemic symptoms syndrome with pancreatitis Ann Pharmacother 2010 44 1998 2000 21098750 \n5 Amante MF Filippini AV Cejas N Lendoire J Imventarza O Parisi C Dress syndrome and fulminant hepatic failure induced by lamotrigine Ann Hepatol 2009 8 75 7 19221540 \n6 Kumari R Timshina DK Thappa DM Drug hypersensitivity syndrome Indian J Dermatol Venereol Leprol 2011 77 7 15 21220873 \n7 Valliant L Drug hypersensitivity syndrome: Drug rash with eosinophilia and systemic symptoms J Dermatolog Treat 1999 10 267 72 \n8 Vittorio CC Muglia JJ Anticonvulsant hypersensitivity syndrome Arch Intern Med 1995 155 2285 90 7487252 \n9 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n10 Veyrac G Marcade G Chiffoleau A Bourin M Jolliet P Characteristics of hypersensitivity syndrome to lamotrigine: Review of one case reported in the Regional Center of Pharmacovigilance of Nantes Therapie 2002 57 289 96 12422544 \n11 Knowles SR Shapiro L Shear NH Anticonvulsant hypersensitivity syndrome: Incidence prevention and management Drug Saf 1999 21 489 501 10612272 \n12 Schaub JE Williamson PJ Barnes EW Trewby PN Multisystem adverse reaction to lamotrigine Lancet 1994 344 481 7914595 \n13 Makin AJ Fitt S Williams R Duncan JS Fulminant hepatic failure induced by lamotrigine BMJ 1995 311 292 7633236\n\n",
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"issue": "44(6)",
"journal": "Indian journal of pharmacology",
"keywords": "DRESS; early detection; lamotrigine",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000927:Anticonvulsants; D002648:Child; D004342:Drug Hypersensitivity; D004802:Eosinophilia; D006801:Humans; D006968:Hypersensitivity, Delayed; D000077213:Lamotrigine; D008297:Male; D013577:Syndrome; D014227:Triazines",
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"title": "Lamotrigine induced DRESS syndrome.",
"title_normalized": "lamotrigine induced dress syndrome"
}
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{
"abstract": "FOLFIRINOX is a standard chemotherapeutic regimen for patients with advanced pancreatic cancer who have a good performance status. In this study, we present the case of a 64-year-old male who developed dysarthria following FOLFIRINOX treatment, and review all four cases of dysarthria encountered among the nine patients who received this treatment in our hospital. In all cases, dysarthria occurred during the infusion of irinotecan in the first course of treatment, persisted for several hours, and then resolved rapidly without any sequelae. Physical and neurological examinations at the onset of dysarthria revealed no other abnormalities. Imaging studies revealed no abnormal findings. Atropine was prophylactically administered in the second and subsequent courses of treatment and effectively prevented or alleviated dysarthria. This acute neurological symptom is surprising and uncommon in traditional cancer chemotherapy, and medical oncologists may initially suspect the onset of stroke or cerebrovascular disease. However, consistent with our experience, all reported cases resolved completely, with no need for dose reduction or treatment interruption.",
"affiliations": "Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan ; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Endoscopy, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Endoscopy, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.;Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan ; Department of Endoscopy, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.;Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi 466-8550, Japan.",
"authors": "Matsuoka|Ayumu|A|;Maeda|Osamu|O|;Inada-Inoue|Megumi|M|;Ohno|Eizaburo|E|;Hirooka|Yoshiki|Y|;Yokoyama|Yukihiro|Y|;Fujii|Tsutomu|T|;Nagino|Masato|M|;Goto|Hidemi|H|;Ando|Yuichi|Y|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2015.3591",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "10(4)",
"journal": "Oncology letters",
"keywords": "FOLFIRINOX; dysarthria; irinotecan; oxaliplatin; pancreatic cancer",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "2662-2664",
"pmc": null,
"pmid": "26622908",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": "22379477;16449682;19745023;21561347;25117729;6483188;19259288;20702138;23271209;17470860;12481397;15772291;6391208;11562394;16508637;21829085;15205214;10203287;23784161;17924208",
"title": "FOLFIRINOX-induced reversible dysarthria: A case report and review of previous cases.",
"title_normalized": "folfirinox induced reversible dysarthria a case report and review of previous cases"
}
|
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{
"abstract": "Pregnant women with inflammatory bowel disease (IBD) may require biologic or thiopurine therapy to control disease activity. Lack of safety data has led to therapy discontinuation during pregnancy, with health repercussions to mother and child.\n\n\n\nBetween 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States. The primary analysis was a comparison of 5 outcomes (congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infant infections) among pregnancies exposed vs unexposed in utero to biologics, thiopurines, or a combination. Bivariate analyses followed by logistic regression models adjusted for relevant confounders were used to determine the independent effects of specific drug classes on outcomes of interest.\n\n\n\nAmong 1490 completed pregnancies, there were 1431 live births. One-year infant outcomes were available in 1010. Exposure was to thiopurines (n = 242), biologics (n = 642), or both (n = 227) vs unexposed (n = 379). Drug exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, low birth weight, and infections during the first year of life. Higher disease activity was associated with risk of spontaneous abortion (hazard ratio, 3.41; 95% confidence interval, 1.51-7.69) and preterm birth with increased infant infection (odds ratio, 1.73; 95% confidence interval, 1.19-2.51).\n\n\n\nBiologic, thiopurine, or combination therapy exposure during pregnancy was not associated with increased adverse maternal or fetal outcomes at birth or in the first year of life. Therapy with these agents can be continued throughout pregnancy in women with IBD to maintain disease control and reduce pregnancy-related adverse events. ClinicalTrials.gov, Number: NCT00904878.",
"affiliations": "Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, California. Electronic address: [email protected].;Division of Gastroenterology and Hepatology, Data Management Center, University of North Carolina, Chapel Hill, North Carolina.;Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.;Division of Gastroenterology, Kaiser Permanente, San Leandro, California.;Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.;Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.;Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois.;Department of Pediatrics, University of California San Diego, La Jolla, California.;Division of Gastroenterology and Hepatology, University of California San Diego, La Jolla, California.",
"authors": "Mahadevan|Uma|U|;Long|Millie D|MD|;Kane|Sunanda V|SV|;Roy|Abhik|A|;Dubinsky|Marla C|MC|;Sands|Bruce E|BE|;Cohen|Russell D|RD|;Chambers|Christina D|CD|;Sandborn|William J|WJ|;|||",
"chemical_list": "D000893:Anti-Inflammatory Agents; D001688:Biological Products; D015122:Mercaptopurine; D001379:Azathioprine",
"country": "United States",
"delete": false,
"doi": "10.1053/j.gastro.2020.11.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5085",
"issue": "160(4)",
"journal": "Gastroenterology",
"keywords": "Crohn’s Disease; Pregnancy; Ulcerative Colitis",
"medline_ta": "Gastroenterology",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D001379:Azathioprine; D001688:Biological Products; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007413:Intestinal Mucosa; D015122:Mercaptopurine; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies; D014481:United States",
"nlm_unique_id": "0374630",
"other_id": null,
"pages": "1131-1139",
"pmc": null,
"pmid": "33227283",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "22687963;28346274;9771402;30658060;29961771;6102236;23200982;27063728;26375613;22613901;26688268;11967923;17847119;23855425;17573787;22691619;17764676;32007542;21830263;23674866;23902720;25602023;23318480",
"title": "Pregnancy and Neonatal Outcomes After Fetal Exposure to Biologics and Thiopurines Among Women With Inflammatory Bowel Disease.",
"title_normalized": "pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease"
}
|
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{
"abstract": "OBJECTIVE\nTo identify factors predicting primary resistance to new-generation hormonal agents (NHAs), abiraterone acetate and enzalutamide in patients with castration-resistant prostate cancer (CRPC).\n\n\nMETHODS\nOur hospital has conducted two successive named patient NHA programs. A total of 57 patients with progressive CRPC previously treated with first-line docetaxel-based chemotherapy received standard NHA doses: abiraterone acetate 1000 mg once-daily combined with prednisone (5 mg twice daily) or enzalutamide 160 mg once-daily. Patients, who were assessed monthly to check their hematological parameters and prostate-specific antigen (PSA) levels, also underwent imaging investigations every 3-4 months. In total, 24 variables were assessed as potential predictors of primary NHA resistance.\n\n\nRESULTS\nUnivariate analysis indicated that baseline pain and lactate dehydrogenase levels, and PSA levels after 1 month's treatment were predictive of primary NHA resistance. Only the predictive value of PSA levels after 1 month of treatment was confirmed at multivariate analysis. This factor strongly predicted progression-free and overall survival.\n\n\nCONCLUSIONS\nRESULTS suggest the use of a simple and rapid method of identifying patients with primary resistance to NHAs: patients not achieving a ≥ 50% reduction in PSA levels within the first treatment month should undergo intensive investigations to verify whether they have primary resistance to NHAs.",
"affiliations": "Medical Oncology Department, Santa Chiara Hospital, Trento, Italy.",
"authors": "Caffo|Orazio|O|;Veccia|Antonello|A|;Maines|Francesca|F|;Bonetta|Alberto|A|;Spizzo|Gilbert|G|;Galligioni|Enzo|E|",
"chemical_list": "D000730:Androstadienes; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; D017430:Prostate-Specific Antigen; D000069501:Abiraterone Acetate",
"country": "England",
"delete": false,
"doi": "10.2217/fon.14.24",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "10(6)",
"journal": "Future oncology (London, England)",
"keywords": "abiraterone acetate; castration-resistant prostate cancer; enzalutamide; predictive factors",
"medline_ta": "Future Oncol",
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"pmc": null,
"pmid": "24941984",
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"title": "Potential value of rapid prostate-specific antigen decline in identifying primary resistance to abiraterone acetate and enzalutamide.",
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}
|
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"abstract": "A multicentre phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with refractory or relapsed indolent non-Hodgkin's lymphoma. Thirty-six patients were enrolled onto the study, including 11 cases of mantle cell lymphoma (MCL), 10 cases of chronic lymphocytic leukaemia (CLL)/lymphocytic lymphoma, nine cases of follicular lymphoma, four cases of lymphoplasmacytic lymphoma and two cases of T-cell lymphoma. Gemcitabine 1 g/m(2) was administered as a 30-min infusion on d 1, 8 and 15 of a 28-d schedule, up to a maximum of six cycles. Complete responses were observed in two patients with MCL, and partial responses were observed in seven patients, including three patients with CLL/lymphocytic lymphoma, two patients with T-cell lymphoma, one patient with MCL and one patient with follicular lymphoma. Minor responses were observed in three patients, including two patients with MCL and one patient with CLL. The median duration of response was 150 d and the overall progression-free survival was 342 d. Haematological toxicity was observed as grade 3-4 leucopenia in 12 patients (33%) and grade 3-4 thrombocytopenia in 18 patients (50%). Severe non-haematological toxicity included one case of fatal veno-occlusive disease, one case of thrombotic microangiopathy leading to terminal renal failure, one case of capillary leak syndrome, one case of myocardial infarction and drug-induced fever in two patients. These data suggest that gemcitabine displays activity in patients with MCL and CLL/lymphocytic lymphoma. Haematological toxicity was frequent in these heavily treated patients. Severe non-haematological toxicity was significant and should be taken into account in the design of future trials.",
"affiliations": "Services d'Hématologie Pierre Bénite, Lille, France. [email protected]",
"authors": "Dumontet|C|C|;Morschhauser|F|F|;Solal-Celigny|P|P|;Bouafia|F|F|;Bourgeois|E|E|;Thieblemont|C|C|;Leleu|X|X|;Hequet|O|O|;Salles|G|G|;Coiffier|B|B|",
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"delete": false,
"doi": "10.1046/j.1365-2141.2001.02795.x",
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"issue": "113(3)",
"journal": "British journal of haematology",
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"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000963:Antimetabolites; D019559:Capillary Leak Syndrome; D003841:Deoxycytidine; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D007970:Leukopenia; D008224:Lymphoma, Follicular; D020522:Lymphoma, Mantle-Cell; D008228:Lymphoma, Non-Hodgkin; D016399:Lymphoma, T-Cell; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011668:Pulmonary Veno-Occlusive Disease; D012008:Recurrence; D051437:Renal Insufficiency; D015996:Survival Rate; D013921:Thrombocytopenia; D013997:Time Factors",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "772-8",
"pmc": null,
"pmid": "11380469",
"pubdate": "2001-06",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
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"title": "Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin's lymphoma.",
"title_normalized": "gemcitabine as a single agent in the treatment of relapsed or refractory low grade non hodgkin s lymphoma"
}
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"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DUMONTET, C.. GEMCITABINE AS A SINGLE AGENT IN THE TREATMENT OF RELAPSED OR REFRACTORY LOW-GRADE NON-HODGKIN^S LYMPHOMA. BRITISH JOURNAL OF HAEMATOLOGY. 2001;113 (3):772-778",
"literaturereference_normalized": "gemcitabine as a single agent in the treatment of relapsed or refractory low grade non hodgkin s lymphoma",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20171101",
"receivedate": "20171101",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 14149783,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180321"
}
] |
{
"abstract": "To investigate the effects of prior treatment and determine the predictors of a 12-month treatment response of romosozumab (ROMO) in 148 patients with postmenopausal osteoporosis.\n\n\n\nIn this prospective, observational, and multicenter study, treatment naïve patients (Naïve; n=50) or patients previously treated with bisphosphonates (BP; n=37) or denosumab (DMAb; n=45) or teriparatide (TPTD; n=16) (mean age, 75.0 years; T-scores of the lumbar spine [LS] -3.2 and total hip [TH] -2.6) were switched to ROMO due to insufficient effects of prior treatment. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 12 months.\n\n\n\nAt 12 months, changes in LS BMD were Naïve (18.2%), BP (10.2%), DMAb (6.4%), and TPTD (11.2%) (P<0.001 between groups) and changes in TH BMD were Naïve (5.6%), BP (3.3%), DMAb (0.6%), and TPTD (4.4%) (P<0.01 between groups), respectively. In all groups, the LS BMD significantly increased from baseline at 6 and 12 months, although only the DMAb group failed to obtain a significant increase in TH BMD during 12-month treatment. Mean values of N-terminal type I procollagen propeptide (PINP; μg/L) from baseline → 1 month → 12 months were Naïve (67.9 → 134.1 → 51.0), BP (32. 2 → 81.7 → 40.9), DMAb (30.4 → 56.2 → 75.3), and TPTD (97.4 → 105.1 → 37.1), and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b; mU/dL) were Naïve (500.4 → 283.8 → 267.1), BP (273.4 → 203.1 → 242.0), DMAb (220.3 → 246.1 → 304.8), and TPTD (446.6 → 305.1 → 235.7), respectively. Multiple regression analysis revealed that the significant predictors of BMD change at 12 months were difference of prior treatment (r=-2.8, P<0.001) and value of PINP at 1 month (r=0.04, P<0.01) for LS, and difference of prior treatment (r=-1.3, P<0.05) and percentage change of TRACP-5b at 1 month (r=-0.06, P<0.05) for TH.\n\n\n\nThe early effects of ROMO on LS and TH BMD increase at 12 months were significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers.",
"affiliations": "Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, Suita 565-0871, Japan; Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Suita 565-0871, Japan. Electronic address: [email protected].;Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Sakai, Kita-ku 591-8025, Japan.;Nagayama Rheumatology and Orthopaedic Clinic, 4-3-25 Hiokisounishi-machi, Sakai, Higashi-ku 599-8114, Japan.;Department of Orthopaedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Osaka, Toyonaka 560-8565, Japan.;Department of Orthopaedic Surgery, Osaka Toneyama Medical Center, 5-1-1 Toneyama, Osaka, Toyonaka 560-8552, Japan.;Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Suita 565-0871, Japan.;Department of Orthopaedic Surgery, Japan Community Health care Organization, Osaka Hospital, 4-2-78 Fukushima, Fukushima Ward, Osaka 553-0003, Japan.;Department of Orthopaedic Surgery, Japan Community Health care Organization, Hoshigaoka Medical Center, 4-8-1 Hoshigaoka, 573-8511, Hirakata, Osaka, Japan.;Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Suita 565-0871, Japan.;Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-cho, Sakai, Kita-ku 591-8025, Japan.;Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Suita 565-0871, Japan.;Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Suita 565-0871, Japan.;Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Suita 565-0871, Japan.;Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Suita 565-0871, Japan.;Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Osaka, Suita 565-0871, Japan.;Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Suita 565-0871, Japan.",
"authors": "Ebina|Kosuke|K|;Tsuboi|Hideki|H|;Nagayama|Yoshio|Y|;Kashii|Masafumi|M|;Kaneshiro|Shoichi|S|;Miyama|Akira|A|;Nakaya|Hiroyuki|H|;Kunugiza|Yasuo|Y|;Hirao|Makoto|M|;Okamura|Gensuke|G|;Etani|Yuki|Y|;Takami|Kenji|K|;Goshima|Atsushi|A|;Miura|Taihei|T|;Nakata|Ken|K|;Okada|Seiji|S|",
"chemical_list": "D000911:Antibodies, Monoclonal; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D019379:Teriparatide; C557282:romosozumab; D000069448:Denosumab",
"country": "France",
"delete": false,
"doi": "10.1016/j.jbspin.2021.105219",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "88(5)",
"journal": "Joint bone spine",
"keywords": "Bone turnover marker; Postmenopausal osteoporosis; Predictor; Prior treatment; Romosozumab",
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D015519:Bone Density; D050071:Bone Density Conservation Agents; D000069448:Denosumab; D005260:Female; D006801:Humans; D010024:Osteoporosis; D015663:Osteoporosis, Postmenopausal; D011446:Prospective Studies; D019379:Teriparatide",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "105219",
"pmc": null,
"pmid": "34020048",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis.",
"title_normalized": "effects of prior osteoporosis treatment on 12 month treatment response of romosozumab in patients with postmenopausal osteoporosis"
}
|
[
{
"companynumb": "JP-AMGEN-JPNSP2021082139",
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"occurcountry": "JP",
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{
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},
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},
{
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},
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},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROMOSOZUMAB-AQQG"
},
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"drugdosagetext": "210 MILLIGRAM",
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"drugindication": "Osteoporosis postmenopausal",
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"medicinalproduct": "EVENITY"
},
{
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"activesubstancename": "ALFACALCIDOL"
},
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"medicinalproduct": "ALFACALCIDOL"
},
{
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},
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"medicinalproduct": "ELDECALCITOL"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ERGOCALCIFEROL"
},
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"medicinalproduct": "ERGOCALCIFEROL"
},
{
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"activesubstancename": "CALCIUM"
},
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"medicinalproduct": "CALCIUM"
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Spinal fracture",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Subarachnoid haemorrhage",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aneurysm ruptured",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pathological fracture",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Humerus fracture",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Radius fracture",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tibia fracture",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Patella fracture",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fracture",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rib fracture",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Heart valve operation",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Injection site pain",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood pressure increased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood pressure decreased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Flushing",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dizziness",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Herpes zoster",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Therapeutic product effect incomplete",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oral lichen planus",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tartrate-resistant acid phosphatase increased",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Kosuke E.; Hideki T.; Yoshio N. et al.. Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis. Joint Bone Spine. 2021;1-23",
"literaturereference_normalized": "effects of prior osteoporosis treatment on 12 month treatment response of romosozumab in patients with postmenopausal osteoporosis",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20220307",
"receivedate": "20210601",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19358525,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220423"
}
] |
{
"abstract": "BACKGROUND\nDespite advances in the treatment of Hodgkin lymphoma with the introduction of PET-adapted regimens, practical challenges prevent more widespread use of these approaches. The ECHELON-1 study assessed the safety and efficacy of front-line A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) in patients with stage III or IV classical Hodgkin lymphoma. The primary analysis showed improved modified progression-free survival with A+AVD. We present an updated analysis of ECHELON-1 at 5 years, an important landmark for this patient population.\n\n\nMETHODS\nECHELON-1 was an international, open-label, randomised, phase 3 trial done at 218 clinical sites, including hospitals, cancer centres, and community clinics, in 21 countries. Previously untreated patients (≥18 years with an Eastern Cooperative Oncology Group performance status of ≤2) with stage III or IV classical Hodgkin lymphoma were randomly assigned (1:1) to receive A+AVD (brentuximab vedotin, 1·2 mg/kg of bodyweight, doxorubicin 25 mg/m2 of body surface area, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) intravenously on days 1 and 15 of each 28-day cycle for up to six cycles. Stratification factors included region (Americas vs Europe vs Asia) and International Prognostic Score risk group (low, intermediate, or high risk). The primary endpoint was modified progression-free survival; this 5-year update includes analysis of progression-free survival as per investigator assessment in the intention-to-treat population, which was an exploratory endpoint, although the 5-year analysis was not prespecified in the protocol. This trial is registered with ClinicalTrials.gov (NCT01712490) and EudraCT (2011-005450-60), and is ongoing.\n\n\nRESULTS\nBetween Nov 19, 2012, and Jan 13, 2016, 1334 patients were randomly assigned to receive A+AVD (n=664) or ABVD (n=670). At a median follow-up of 60·9 months (IQR 52·2-67·3), 5-year progression-free survival was 82·2% (95% CI 79·0-85·0) with A+AVD and 75·3% (71·7-78·5) with ABVD (hazard ratio [HR] 0·68 [95% CI 0·53-0·87]; p=0·0017). Among PET-2-negative patients, 5-year progression-free survival was higher with A+AVD than with ABVD (84·9% [95% CI 81·7-87·6] vs 78·9% [75·2-82·1]; HR 0·66 [95% CI 0·50-0·88]; p=0·0035). 5-year progression-free survival for PET-2-positive patients was 60·6% (95% CI 45·0-73·1) with A+AVD versus 45·9% (32·7-58·2) with ABVD (HR 0·70 [95% CI 0·39-1·26]; p=0·23). Peripheral neuropathy continued to improve or resolve over time with both A+AVD (375 [85%] of 443 patients) and ABVD (245 [86%] of 286 patients); more patients had ongoing peripheral neuropathy in the A+AVD group (127 [19%] of 662) than in the ABVD group (59 [9%] of 659). Fewer secondary malignancies were reported with A+AVD (19 [3%] of 662) than with ABVD (29 [4%] of 659). More livebirths were reported in the A+AVD group (n=75) than in the ABVD group (n=50).\n\n\nCONCLUSIONS\nWith 5 years of follow-up, A+AVD showed robust and durable improvement in progression-free survival versus ABVD, regardless of PET-2 status, and a consistent safety profile. On the basis of these findings, A+AVD should be preferred over ABVD for patients with previously untreated stage III or IV classical Hodgkin lymphoma.\n\n\nBACKGROUND\nMillennium Pharmaceuticals (a wholly owned subsidiary of Takeda Pharmaceutical Company), and Seagen.",
"affiliations": "Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected].;Department of Clinical Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Kraków, Poland.;Centre for Lymphoid Cancer and Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada.;Petrov Research Institute of Oncology, St Petersburg, Russia.;University of Debrecen, Debrecen, Hungary.;Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.;Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.;John Theurer Cancer Center, Hackensack Meridian Health School of Medicine, Hackensack, NJ, USA.;Medical University of Lodz, Poland.;Centre for Lymphoid Cancer and Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada.;Washington University School of Medicine Siteman Cancer Center, St Louis, MO, USA.;Maria Sklodowska-Curie National Research Institute of Oncology, European Reference Network, Warszawa, Poland.;The University of Tennessee Graduate School of Medicine, Knoxville, TN, USA.;IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia Seràgnoli, Bologna, Italy; Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università degli Studi, Bologna, Italy.;Department of Haematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.;Banner MD Anderson Cancer Center, Gilbert, AZ, USA.;University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.;Department of Medicine, Division of Oncology, Stanford University, Stanford, CA, USA.;Division of Hematology, Mayo Clinic, Rochester, MN, USA.;Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; AstraZeneca Pharmaceuticals, LP Wilmington, DE, USA.;Research Innovation and Statistics, Antoine-Lacassagne Cancer Centre, Nice, France.;Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceuticals, Cambridge, MA, USA.;Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceuticals, Cambridge, MA, USA.;Seagen, Bothell, WA, USA.;Seagen, Bothell, WA, USA.;University of Manchester and the Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.",
"authors": "Straus|David J|DJ|;Długosz-Danecka|Monika|M|;Connors|Joseph M|JM|;Alekseev|Sergey|S|;Illés|Árpád|Á|;Picardi|Marco|M|;Lech-Maranda|Ewa|E|;Feldman|Tatyana|T|;Smolewski|Piotr|P|;Savage|Kerry J|KJ|;Bartlett|Nancy L|NL|;Walewski|Jan|J|;Ramchandren|Radhakrishnan|R|;Zinzani|Pier Luigi|PL|;Hutchings|Martin|M|;Munoz|Javier|J|;Lee|Hun Ju|HJ|;Kim|Won Seog|WS|;Advani|Ranjana|R|;Ansell|Stephen M|SM|;Younes|Anas|A|;Gallamini|Andrea|A|;Liu|Rachael|R|;Little|Meredith|M|;Fenton|Keenan|K|;Fanale|Michelle|M|;Radford|John|J|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D000079963:Brentuximab Vedotin; D004317:Doxorubicin",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(21)00102-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3026",
"issue": "8(6)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D000079963:Brentuximab Vedotin; D004317:Doxorubicin; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D000077982:Progression-Free Survival; D014747:Vinblastine",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e410-e421",
"pmc": null,
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{
"abstract": "BACKGROUND\nPrimary focal segmental glomerular sclerosis (FSGS) recurs in 20 - 40% of patients after kidney transplantation. Rituximab has been used to treat several glomerular diseases.\n\n\nRESULTS\nWe treated two renal-transplant patients with recurrence of FSGS with rituximab. Despite a prophylactic perioperative therapy of plasmapheresis (PE) and i.v. cyclosporine A, Patient 1 developed significant proteinuria, at 1 day after his first kidney transplantation. After two infusions of rituximab (375 mg/m2) he had complete remission. A second relapse, which occurred on Day 40, was also successfully treated by PE and one additional infusion of rituximab. 10 months after transplantation, he still has complete remission from recurrent nephrotic syndrome. Patient 2 also developed significant proteinuria, but 1 day after a second kidney transplantation. Nephrotic syndrome persisted despite 27 sessions of PE and cyclophosphamide therapy. At 13 months after transplantation, he received four infusions of rituximab (375 mg/m(2)), but this was ineffective.\n\n\nCONCLUSIONS\nThere is a need to demonstrate whether or not rituximab therapy is of interest to prevent and to treat nephritic syndrome in renal-transplant patients who suffer from FSGS.",
"affiliations": "Department of Nephrology, Dialysis and Multi-Organ Transplantation, Toulouse University Hospital, Toulouse, France. [email protected]",
"authors": "Kamar|N|N|;Faguer|S|S|;Esposito|L|L|;Guitard|J|J|;Nogier|M B|MB|;Durand|D|D|;Rostaing|L|L|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.5414/cnp67250",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-0430",
"issue": "67(4)",
"journal": "Clinical nephrology",
"keywords": null,
"medline_ta": "Clin Nephrol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007155:Immunologic Factors; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D000069283:Rituximab",
"nlm_unique_id": "0364441",
"other_id": null,
"pages": "250-4",
"pmc": null,
"pmid": "17474562",
"pubdate": "2007-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of focal segmental glomerular sclerosis with rituximab: 2 case reports.",
"title_normalized": "treatment of focal segmental glomerular sclerosis with rituximab 2 case reports"
}
|
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"abstract": "Atrial masses are an uncommon but serious clinical problem. The authors report a case of an atrial mass associated with a tunnelled vascular access catheter in an immunosuppressed haemodialysis patient. In the setting of immunosuppression with fevers, a broad differential for the atrial mass was considered. Multidisciplinary team review was pursued to guide management decisions. Ultimately, surgical excision of the mass was pursued with an excellent result. The causes and management of this complex clinical scenario are discussed.",
"affiliations": "Department of Cardiology, Liverpool Hospital, NSW, 2170 Sydney, Australia.;Department of Cardiothoracic Surgery, Liverpool Hospital, NSW, 2170 Sydney, Australia.;Department of Cardiology, Liverpool Hospital, NSW, 2170 Sydney, Australia.;Department of Cardiology, Liverpool Hospital, NSW, 2170 Sydney, Australia.;Department of Cardiothoracic Surgery, Liverpool Hospital, NSW, 2170 Sydney, Australia.;Department of Medicine, University of New South Wales, NSW, 2052 Sydney, Australia.;Department of Cardiology, Liverpool Hospital, NSW, 2170 Sydney, Australia.",
"authors": "Ferreira|David|D|https://orcid.org/0000-0003-3142-4503;Le|Anthony|A|;Khoo|John|J|;Nguyen|Paul|P|;Jain|Manish|M|;Spicer|Timothy|T|;Juergens|Craig|C|",
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"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404 2090-6412 Hindawi \n\n10.1155/2020/4590147\nCase Report\nSurgical Management of Right Atrial Mass Associated with a Vascular Access Catheter\nhttps://orcid.org/0000-0003-3142-4503Ferreira David [email protected]\n1\n\n2\n Le Anthony \n3\n Khoo John \n1\n Nguyen Paul \n1\n Jain Manish \n3\n Spicer Timothy \n2\n\n4\n Juergens Craig \n1\n\n2\n \n1Department of Cardiology, Liverpool Hospital, NSW, 2170 Sydney, Australia\n\n2Department of Medicine, University of New South Wales, NSW, 2052 Sydney, Australia\n\n3Department of Cardiothoracic Surgery, Liverpool Hospital, NSW, 2170 Sydney, Australia\n\n4Department of Nephrology, Liverpool Hospital, NSW, 2170 Sydney, Australia\nAcademic Editor: Assad Movahed\n\n\n2020 \n10 6 2020 \n2020 459014717 1 2020 10 5 2020 25 5 2020 Copyright © 2020 David Ferreira et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Atrial masses are an uncommon but serious clinical problem. The authors report a case of an atrial mass associated with a tunnelled vascular access catheter in an immunosuppressed haemodialysis patient. In the setting of immunosuppression with fevers, a broad differential for the atrial mass was considered. Multidisciplinary team review was pursued to guide management decisions. Ultimately, surgical excision of the mass was pursued with an excellent result. The causes and management of this complex clinical scenario are discussed.\n==== Body\n1. Introduction\nAtrial masses pose an infrequent diagnostic and management dilemma. The differential diagnoses are broad and include primary and secondary malignancy, benign neoplasms, thrombi, and infective foci [1, 2]. Assessment and management require integration of clinical, laboratory, and imaging investigations and may necessitate involvement from multiple specialty teams. In this report, the authors describe a case of a right atrial mass complicating immunosuppression for lupus nephritis and haemodialysis via a tunnelled vascular access catheter. Ultimately, a diagnosis of atrial thrombus was confirmed on histology. The considered differential diagnoses and management strategy will be described. The management of atrial thrombus associated with vascular access catheters will then be discussed.\n\n2. Case Presentation\nAn 18-year-old female with lupus nephritis, treated with tacrolimus and rituximab, was referred for admission to hospital. She had, until recently, required haemodialysis via a tunnelled permanent vascular access catheter which was still in situ. Complicating her immunosuppression, Cryptococcus neoformans meningitis was diagnosed through lumbar puncture seven months earlier. She was initially treated with intravenous amphotericin and flucytosine and was subsequently placed on therapeutic oral fluconazole.\n\nOutpatient transthoracic echocardiography demonstrated a large echogenic mass in the right atrium at the tip of the vascular access catheter. Transoesophageal echocardiography confirmed an echogenic mass in the right atrium measuring 23 mm × 26 mm (see Figure 1) and a patent foramen ovale (PFO) with left to right shunt (see Clip 1). The differential diagnoses considered were that of atrial thrombus complicating vascular access, as well as an infective focus. A primary tumour was unlikely given a normal transthoracic echocardiogram four months before.\n\nInflammatory markers and septic screening with blood cultures were performed. C-reactive protein was 0.9 mg/L, and the neutrophil count was 9.5 × 109. Three blood cultures were negative for bloodstream infection. Ventilation perfusion scanning revealed segmental pulmonary emboli. After multidisciplinary discussion, standard percutaneous catheter removal was deemed high risk due to potential embolisation. Anticoagulation with Apixaban was initiated for suspected atrial thrombus, and serial cardiac imaging was organised. Removal of the vascular access catheter was to be planned after thrombus resolution, and the patient was discharged [3].\n\nFour weeks later, she represented with lethargy and fevers to 39.4 degrees Celsius. Inflammatory markers were elevated with a C-reactive protein of 157 mg/L and neutrophils of 10.2 × 109. A repeat infective panel was performed, and empiric therapy with intravenous gentamicin and vancomycin was provided due to skin colonisation with methicillin-resistant Staphylococcus aureus. Blood cultures, including vascular catheter cultures, were positive for Stenotrophomonas maltophilia, and a diagnosis of line-associated bacteraemia was made. Infectious diseases input was sought, and broad-spectrum antimicrobials with intravenous trimethoprim-sulfamethoxazole and cefepime were administered. Regular therapeutic oral fluconazole was continued. Rapid clinical response to antimicrobial therapy was seen with defervescence within 24 hours.\n\nRepeat transthoracic echocardiogram showed no interval change in the right atrial mass despite anticoagulation. This placed the diagnosis of thrombus in doubt, and in the setting of bacteraemia, complicating infection could not be excluded. After multidisciplinary review by infectious diseases, cardiology, cardiothoracic surgery, nephrology, and interventional radiology, definitive management of the atrial mass was deemed appropriate. This decision was made considering the diagnosis of thrombus was in doubt after anticoagulation failed to reduce its size, and in the setting of bacteraemia, complicating infection could not be excluded. Endovascular removal and thrombolysis were deemed high risk due to potential for embolisation. The decision was made to pursue open surgical thrombectomy, PFO closure, and vascular catheter removal. Brain magnetic resonance imaging (MRI) was negative for ischaemic stroke prior to on-pump cardiothoracic surgery.\n\nSurgery was performed (see Figure 2) with no postoperative complications, and she was discharged seven days later. Histology demonstrated organised thrombus with no evidence of abscess, granuloma, endocarditis, or myxoma (see Figure 3).\n\n3. Discussion\nThough infrequent, atrial masses can pose a significant diagnostic and management challenge. The differential diagnosis is broad and includes primary and secondary cardiac tumours, infective processes, and thrombi. Primary tumours are rare and have an incidence of 0.02% based on large autopsy series [4]. Secondary cardiac metastases occur 20 times more often, the most common primaries being mesothelioma, lung cancer, and melanoma [4]. Primary atrial mural endocarditis is rare with reported organisms including staphylococcus species, streptococci species, aspergillus, and candida [2, 5–7]. Secondary infection complicating myxoma has also been reported with similar bacterial pathogens [8].\n\nIn this case, the atrial mass was histologically confirmed as organised thrombus without an infective component. While atrial thrombi are rare, they can complicate 5-18% of vascular access catheters for haemodialysis patients [9, 10]. This is related to factors including the intra-atrial prothrombotic foreign body, frequent complicating infections in the immunosuppressed, and thrombotic predisposition in the chronic kidney disease population [11]. Atrial thrombi complicating vascular catheters are associated with mortality rates of 18.3-20.6%, most often due to pulmonary embolism, cardiac failure, and overwhelming sepsis [3, 12]. Mortality rates appear high (44%) in those managed without thrombus specific intervention [3].\n\nDue to the infrequent nature of atrial thrombi complicating vascular catheters, there are no prospective data informing management. Prevention is better than cure, and in the haemodialysis population, fistula formation should be considered over vascular access catheters if feasible [12]. When a thrombus is present, removal of the vascular catheter is ideal [3]. Percutaneous removal may not be possible due to risk of thrombus dislodgement and life-threatening pulmonary embolism. Current retrospective reviews have shown that in 50% of cases, therapeutic anticoagulation was the initial treatment of choice. Primary surgical thrombectomy is pursued in 25% of patients while first line thrombolysis occurs in 7-17%. The choice of initial therapy is influenced by patient comorbidities, thrombus characteristics, and access to local surgical expertise. In those with contraindications to anticoagulation, thrombus size of greater than 6 cm or those with another indication for cardiothoracic surgery (e.g., infective endocarditis), a primary surgical strategy may be preferred [3, 12].\n\nIn patients chosen for anticoagulation, six months of therapy appears reasonable with serial imaging, close follow-up, and careful monitoring for infective, embolic, and cardiac sequelae [9]. A longer course of anticoagulation may be required if thrombus resolution is not achieved. Anticoagulation failure occurs in 30% of treated patients, and second-line options are thrombectomy or thrombolysis, though the latter is associated with failure rates of 30-75% [12].\n\nWhen failing anticoagulation, particularly with the potential for life-threatening complications, surgical intervention for vascular access catheter associated atrial thrombus is a potential management option in complex patients [13, 14].\n\nConsent\nInformed written consent has been provided by the patient.\n\nConflicts of Interest\nThe authors have no conflicts of interest to declare.\n\nSupplementary Materials\nSupplementary Materials Clip 1: small patent foramen ovale with left to right shunt.\n\nClick here for additional data file.\n\n Figure 1 Transoesophageal echocardiography demonstrating vascular catheter tip abutting a right atrial mass.\n\nFigure 2 Intraoperative image of open right atrium with right atrial mass.\n\nFigure 3 Histology of the atrial mass demonstrating organised thrombus with fibrin scaffold.\n==== Refs\n1 Mankad R. Herrmann J. Cardiac tumors: echo assessment Echo Research and Practice 2017 3 4 R65 R77 10.1530/erp-16-0035 2-s2.0-85023750142 27600455 \n2 Soman S. O. Vijayaraghavan G. Padmaja N. P. Warrier A. R. Unni M. Aspergilloma of the heart Indian Heart Journal 2014 66 2 238 240 10.1016/j.ihj.2013.12.006 2-s2.0-84900416071 24814126 \n3 Stavroulopoulos A. Aresti V. Zounis C. Right atrial thrombi complicating haemodialysis catheters. A meta-analysis of reported cases and a proposal of a management algorithm Nephrology, Dialysis, Transplantation 2012 27 7 2936 2944 10.1093/ndt/gfr739 2-s2.0-84864418065 \n4 Silvestri F. Bussani R. Pavletic N. Mannone T. Metastases of the heart and pericardium Giornale Italiano di Cardiologia 1997 27 12 1252 1255 9470058 \n5 Hosokawa S. Okayama H. Hiasa G. Isolated left atrial infective mural endocarditis Internal Medicine 2018 57 7 957 960 10.2169/internalmedicine.9559-17 2-s2.0-85044720307 29225261 \n6 Agrawal Y. Dada R. Dada J. Degregorio M. Primary mural infective endocarditis with associated central line infection BMJ Case Reports 2018 11 1 10.1136/bcr-2018-227504 2-s2.0-85058796172 \n7 Chowdhury W. Lodhi M. U. Syed I. A. Rahim U. Miller M. Rahim M. Catheter-related Candida endocarditis on the right atrial septum - a case report Cureus 2018 10 2, article e2158 10.7759/cureus.2158 29637039 \n8 Yuan S.-M. Infected cardiac myxoma: an updated review Brazilian Journal of Cardiovascular Surgery 2015 30 5 571 578 10.5935/1678-9741.20140112 2-s2.0-84954442414 26735605 \n9 Shah A. Murray M. Nzerue C. Right atrial thrombi complicating use of central venous catheters in hemodialysis The Journal of Vascular Access 2018 6 1 18 24 10.1177/112972980500600105 \n10 Dilek M. Kaya C. Karatas A. Ozer I. Arik N. Gulel O. Catheter-related atrial thrombus: tip of the iceberg? Renal Failure 2015 37 4 567 571 10.3109/0886022x.2015.1007461 2-s2.0-84930337866 25694191 \n11 Wattanakit K. Cushman M. Chronic kidney disease and venous thromboembolism: epidemiology and mechanisms Current Opinion in Pulmonary Medicine 2009 15 5 408 412 10.1097/MCP.0b013e32832ee371 2-s2.0-68949190810 19561505 \n12 Tran M.-H. Wilcox T. Tran P. N. Cather-related right atrial thrombosis The Journal of Vascular Access 2020 21 3, article 1129729819873851 10.1177/1129729819873851 \n13 Hussain N. Shattuck P. E. Senussi M. H. Large right atrial thrombus associated with central venous catheter requiring open heart surgery Case Reports in Medicine 2012 2012 4 501303 10.1155/2012/501303 2-s2.0-84891815021 23251176 \n14 Akçay M. Deşer S. B. Gedikli Ö. Yüksel S. Gülel O. Successful management of complications after inappropriate positioning of a hemodialysis catheter Anatolian Journal of Cardiology 2017 18 4 E7 E8 10.14744/AnatolJCardiol.2017.8001 2-s2.0-85032743090\n\n",
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"abstract": "While the developed nations are discussing giving a third dose of the COVID-19 vaccine to immunocompromised individuals, there are still challenges that are of global concern, especially in developing countries. The Delta variant which is predominantly responsible for the disease burden has now been reported in over 148 countries. The catastrophe caused in the Indian subcontinent has highlighted some associations, most notable being the unprecedented rise in the cases of mucormycosis in COVID-19 patients referred to as CAM (COVID-19 associated mucormycosis). This life-threatening opportunistic fungal infection which was historically associated with immunosuppression has reached a new peak as its incidence has increased many folds with the advent of COVID-19. Here we present one of the very first Case reports on how to post COVID immunosuppression state, uncontrolled blood sugar levels in the background of diabetic ketoacidosis led to the development of pulmonary mucormycosis with superimposed pulmonary tuberculosis and later Sino-nasal mucormycosis eventually leading to life-threatening massive hemoptysis, causing mortality of a post-COVID-19 infected middle-aged diabetic Asian male patient who presented twenty days after COVID-19 infection. However, our patient did not have risk factors such as severe COVID-19 infection requiring hospitalization, use of steroids or other immunomodulatory drugs like remdesivir or tocilizumab. Our case report aims to bring forth this post COVID pulmonary mucormycosis with pulmonary tuberculosis association as well as highlight the fact that tuberculosis is still a major public health burden that should not be forgotten in the fight to combat the pandemic.",
"affiliations": "Department of Internal Medicine, Maulana Azad Medical College, New Delhi, 11002, India.;Department of Internal Medicine, Maulana Azad Medical College, New Delhi, 11002, India.;Department of Internal Medicine, Maulana Azad Medical College, New Delhi, 11002, India.;Department of Internal Medicine, Maulana Azad Medical College, New Delhi, 11002, India.;Department of Pulmonary Medicine, Maulana Azad Medical College, New Delhi, 11002, India.;Department of Internal Medicine, Maulana Azad Medical College, New Delhi, 11002, India.",
"authors": "Rana|Gunjan|G|;Gautam|Sachin|S|;Mawari|Govind|G|;Daga|Mradul Kumar|MK|;Kumar|Naresh|N|;Raghu|R V|RV|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2021.101511",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00173-8\n10.1016/j.rmcr.2021.101511\n101511\nCase Report\nMassive hemoptysis causing mortality in a post COVID-19 infected Asian male patient: Presenting as pulmonary mucormycosis, pulmonary tuberculosis and later sino-nasal mucormycosis\nRana Gunjan a\nGautam Sachin [email protected]\na∗\nMawari Govind a\nDaga Mradul Kumar a\nKumar Naresh b\nRaghu RV a\na Department of Internal Medicine, Maulana Azad Medical College, New Delhi, 11002, India\nb Department of Pulmonary Medicine, Maulana Azad Medical College, New Delhi, 11002, India\n∗ Corresponding author. Department of Internal Medicine, Maulana Azad Medical College, New Delhi, 110 002, India. [email protected]\n04 9 2021\n2021\n04 9 2021\n34 10151125 8 2021\n1 9 2021\n© 2021 Published by Elsevier Ltd.\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/).\nWhile the developed nations are discussing giving a third dose of the COVID-19 vaccine to immunocompromised individuals, there are still challenges that are of global concern, especially in developing countries. The Delta variant which is predominantly responsible for the disease burden has now been reported in over 148 countries. The catastrophe caused in the Indian subcontinent has highlighted some associations, most notable being the unprecedented rise in the cases of mucormycosis in COVID-19 patients referred to as CAM (COVID-19 associated mucormycosis). This life-threatening opportunistic fungal infection which was historically associated with immunosuppression has reached a new peak as its incidence has increased many folds with the advent of COVID-19. Here we present one of the very first Case reports on how to post COVID immunosuppression state, uncontrolled blood sugar levels in the background of diabetic ketoacidosis led to the development of pulmonary mucormycosis with superimposed pulmonary tuberculosis and later Sino-nasal mucormycosis eventually leading to life-threatening massive hemoptysis, causing mortality of a post-COVID-19 infected middle-aged diabetic Asian male patient who presented twenty days after COVID-19 infection. However, our patient did not have risk factors such as severe COVID-19 infection requiring hospitalization, use of steroids or other immunomodulatory drugs like remdesivir or tocilizumab. Our case report aims to bring forth this post COVID pulmonary mucormycosis with pulmonary tuberculosis association as well as highlight the fact that tuberculosis is still a major public health burden that should not be forgotten in the fight to combat the pandemic.\n\nKeywords\n\nPost COVID-19\nPulmonary mucormycosis\nPulmonary tuberculosis\nMassive\nHaemoptysis\nBronchospopy\nCo-infection\n==== Body\npmc1 Introduction\n\nAmid the global rampage caused by the Delta variant, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has set a new record. The cumulative number has crossed over 206 million cases with more than 4.4 million deaths [1]. A noteworthy finding is an unprecedented rise in the number of cases of the morbid fungal disease mucormycosis, which is now increasingly being associated with COVID-19. Mucormycosis has a global incidence varying from 0.005 to 1.7 per million population. In India, however, the prevalence is estimated to be 140 per million, which is 80 times higher than the developed countries [2]. Data indicates, since the advent of COVID-19 until the beginning of April 2021, India has contributed to almost 71% of global cases of mucormycosis in patients with COVID-19 [3]. Another significant finding amidst the pandemic is the rise of the worldwide burden of tuberculosis, which remains the leading cause of death amongst infectious diseases [4]. Both the conditions are airborne, have considerable overlap in their symptoms, have similar social determinants, target the lungs, and impair host immune responses [5]. We hereby, present a first Case report of pulmonary and rhino-sinusoidal mucormycosis and pulmonary tuberculosis in a post-COVID-19 infected patient. It is crucial to learn from the disease trends in the South-East Asian and European regions during the past few months and be vigilant as the cases begin to rise predominantly in the Western Pacific region and region of Americas.\n\n2 Case report\n\nA 48 years old Asian male diagnosed with type 2 diabetes mellitus two years back presented to our emergency with complaints of left-sided chest pain, radiating to back and dry cough for 25 days along with a low-grade fever of 99.8 °F without any diurnal variation, relieved on medications for 20 days. There was no complaint of shortness of breath, orthopnea, abdominal discomfort, headache, or contact with a tuberculosis patient; however, he had a history of insignificant weight loss and loss of appetite for two months. He was on injectable human insulin (30/70) as 12 units subcutaneously before breakfast and eight units before dinner, and his blood dextrose level was uncontrolled since he reported positive for COVID-19 20 days back. However, he did not need hospitalization, steroids, or oxygen therapy and was managed conservatively in a COVID care center. The characteristic clinical, laboratory, and treatment profile of the patient have been tabulated in Table 1. On presentation, he had a blood pressure of 144/90 mmHg in the right radial artery, a random blood glucose level of 478 mg/dL with positive urinary ketones, a pulse rate of 89/min regular, and oxygen saturation of oxygen 98% under room air. General physical examination was unremarkable, and on chest auscultation, bilateral coarse crepitations were heard more over left interscapular and inframammary areas. An electrocardiograph was done, which showed normal sinus rhythm, and a portable bedside chest radiograph showed bilateral hilar prominence with a possibility of consolidation or a mass lesion (left > right), as shown in Fig. 1. A nasal and oropharyngeal swab for SARS-CoV-2 was taken, which was reported negative. The patient's arterial blood gas showed metabolic acidosis with a pH of 7.32, bicarbonate as 16.8 mEq/L, and normal partial pressure of oxygen and carbon dioxide. On presentation, a provisional diagnosis of newly diagnosed hypertensive with type 2 diabetes mellitus complicated by diabetic ketoacidosis and a lower respiratory tract infection with a query of perihilar mass was made. The patient's blood samples for routine blood parameters were withdrawn along with blood and urine cultures before starting intravenous antibiotics. On admission, blood parameters revealed a hemoglobin of 10.1g/dL, TLC of 13,400 cells/mm3, DLC of 91% neutrophils, 8% lymphocytes, platelets of 4.1 lakhs/mm3, ALT of 50 U/L, AST of 41U/L, LDH of 352 U/L, D-dimer of 497 ng/ml, INR of 1.14, IL-6 of 34 (<7pg/ml) and highly sensitive CRP of 212 mg/L. The patient had a normal renal function test, serum electrolytes, calcium, phosphate, total proteins, and serum albumin levels. As a result, treatment was started with empirical antibiotics as a piperacillin-tazobactam combination with levofloxacin along with strict blood glucose control with an insulin infusion and intravenous fluids. Subsequently, a Contrast-Enhanced Computed Tomography Angiography (CECT- Angio) of the chest was performed, which depicted findings consistent with Pulmonary Mucormycosis and bilateral ground-glass opacities in lower lobes without any evidence of pulmonary artery thrombosis, as shown in Fig. 2, and a normal transthoracic 2D-echo study. On the second day, as the patient recovered from diabetic ketoacidosis, injection liposomal amphotericin B (5–10mg/kg/day) at a dose of 300mg intravenously daily was added to the treatment with the aim of a total dose of 4 g along with strict monitoring of kidney function and serum electrolytes. Later, as the patient continued to have a low-grade fever and dry cough, a bronchoscope-guided bronchial biopsy of the left lower lobe mass was performed. Serial sections of processed tissue demonstrated large areas of necrosis and inflammatory granulation tissue along with aseptate branched fungal hyphae visualized as consistent with mucormycosis. However, an Acid-Fast Bacilli (AFB) stain was negative. As the patient continued to experience low-grade fever, injection vancomycin was added to the treatment because of an elevated serum procalcitonin level, i.e., 1.8 (>2ng/ml for high risk of infection), although his urine microscopy, blood and urine cultures were sterile after 48 hours of incubation. Peripheral smear for malaria antigen, serologies for HIV, hepatitis A, B, C, D, E, dengue, rickettsia, scrub typhus, Leptospira, beta 2 glucans, aspergillosis, galactomannan, and repeated urine routine microscopy, blood and urine cultures reported negative. The patient's blood glucose was taken care of by human (plain) intravenous insulin injections and intravenous fluids, and potassium supplementations. On the seventh day, he developed cough with expectoration, hence sputum for AFB, CBNAAT (Cartridge Based Nucleic Acid Amplification), gram stain, culture sensitivity, and fungal cultures were sent for analysis. On the ninth day, his sputum for AFB was reported positive. CBNAAT showed no rifampicin resistance; hence weight-based anti-tubercular therapy (ATT) (isoniazid 300mg, rifampicin 450 mg, pyrazinamide 1200mg and ethambutol 800mg) along with tablet pyridoxine 20mg were added further to the treatment. The patient started experiencing vomiting and abdominal pain on the eleventh day with deranged liver function tests (AST -127U/L, ALT-98, Total Bilirubin −1.7), hepatic modified ATT (injection streptomycin 0.75g daily, tablet ethambutol 800mg, and tablet levofloxacin 750 mg alternate day) was initiated. However, his abdominal ultrasonography was normal. On the thirteenth day, tab Posaconazole 300mg was also added to treatment. On the sixteenth day, he experienced right nasal congestion with blackish crusting of the nasal septum, a nasal swab for 20% KOH mount was sent, which showed aseptate branched fungal hyphae consisting of mucormycosis, as shown in Fig. 3. A CECT of paranasal sinuses and orbit was done, which showed findings of Sino-nasal mucormycosis, as shown in Fig. 2. Hence, a FESS (Functional Endoscopic Sinus Surgery) guided biopsy and local debridement were done, as shown in Fig- 3. However, on the twentieth day, the patient developed massive hemoptysis and went into hypovolemic shock. Hence, Ryle's tube was inserted, two packed cell volumes of blood were transfused along with inotropes, and the patient was planned for an emergency therapeutic bronchoscopy, however as the patient's GCS (Glasgow Coma Scale) deteriorated patient was electively intubated. Unfortunately, the patient succumbed to his illness on the very next day. Written consent was taken from the patient's relative to reproduce the clinical data.Table 1 Timeline showing characterstic clinico- laboratory and treatment profile of the patient during hospital stay.\n\nTable 1\tDay 1\tDay 5\tDay 25\tDay 26/27\tDay 32–34\tDay 36\tDay 41\tDay 45\t\nClincal Profile\tType 2 diabetes mellitus on injectable insulin therapy Chest pain (dull aching) Dry cough\tLow grade fever, chest pain, dry cough\tPresented to hospital With DKA\tPerihilar mass evaluated\tDeveloped productive cough\tDeveloped vomiting, abdominal pain, deranged LFT\tRight nasal congestion and crusting of nasal septum\tMassive hemoptysis, hypovolemic shock\t\nInvestigations\t\tTested COVID +\tCOVID - status CXR s/o B/L LRTI perihilar lung mass\tCECT chest, angiography, Suspected pulmonary mucormycosis, Confirmed after bronchoscopic biopsy\tSputum for AFB + CBNAAT for Rifampicin resistance negative\tDaignosed with ATT induced hepatotoxicity\tKOH mount and MRI parental sinuses confirmed sino-nasal mucormycosis\tRyle's tube inserted, 2 PCV transfused, Inotropes started, Elective intubation in view of declining GCS\t\nTreatment\t\t\tAdmitted to hospital, piperacillin/tazobactam, levofloxacin, insulin\tStarted on Amphotericin B, antibiotics continued\tStarted on ATT\tStarted on Heaptic modified ATT\tFESS guided biopsy and local debridement performed\tPatient died on Day 46\t\n\nFig. 1 Chest radiograph: Showing bilateral middle zone (left > right) perihilar opacities with possibility of consolidation or left perihilar mass along with prominent bronchovascular marking.\n\nFig. 1\n\nFig. 2 [A], [B] and [E] CECT Chest showing a well-defined area in the superior and anteromedial segments of left lower lobe comprising of peripheral consolidation, central ground glass opacities and areas of cavitation suggestive of pulmonary mucormycosis along with bilateral ground glass opacities in peripheral and basal segments of bilateral lower lobes. [C] and [D]: CECT paranasal sinuses with orbit shows soft tissue thickening of right and left maxillary sinuses, and destruction of right maxillary sinus medial wall along with blocked right osteomeatal complex without orbital involvement suggestive of Sino-Nasal mucormycosis.\n\nFig. 2\n\nFig. 3 [A]: Fungal KOH showing aseptate broad fungal hyphae consistent with mucormycosis. [B] Showing magnified view of silver methenamine stain in which 1–6 fungal hyphae seen.\n\nFig. 3\n\n3 Discussion\n\nMucormycosis is a rare but angio-invasive disease caused by a group of fungi called Mucoromycetes. This ubiquitous mold is found anywhere from the soil, plant surfaces, decaying vegetables to fallen leaves, compost, and animal manure [6]. Individuals who have decreased immunity are specifically at high risk of being affected by this life-threatening opportunistic infection. The susceptible groups are post-COVID recovered, immunosuppressed, those on long-term corticosteroids, chemotherapy, and iron chelation therapy. Individuals with uncontrolled hyperglycemia irrespective of the diagnosis of diabetes mellitus, unchecked iron overload states, transplant, malignancy, burns, neutropenia, monocytopenia, tuberculosis, HIV, and chronic kidney disease are highly vulnerable [7]. Our patient had risk factors like a history of COVID-19 infection 20 days before presenting to our hospital, uncontrolled blood sugar levels, and diabetic ketoacidosis. Although our Case had been COVID-19 positive 20 days before, he didn't require hospitalization, steroids, or oxygen therapy. COVID-19 associated mucormycosis (CAM) refers to individuals infected with mucormycosis while on treatment or after recovering from COVID-19 [8]. The most common form of this condition is rhino-orbital-cerebral mucormycosis (ROCM), which includes Sino-nasal (involvement of nose and paranasal sinuses), limited rhino-orbital disease, and rhino-orbital-cerebral disease (extension to CNS) [9]. ROCM is followed by cutaneous, pulmonary, gastrointestinal, and disseminated disease [7,10]. Pulmonary mucormycosis accounts for 10% of the cases [8]. COVID-19 can worsen or even precipitate diabetes mellitus by causing glycemic abnormalities that can persist even up to two months after recovery [11]. The mechanisms altering the glucose metabolic control in these patients include infection followed by proliferation in the islet cells causing direct pancreatic injury and the storm of cytokines (predominantly IL-6) released, causing insulin resistance. Superimposed treatment with agents such as corticosteroids and remdesivir further contributes to hyperglycemia [8]. Severe COVID-19 and diabetic ketoacidosis are implicated in causing elevated ferritin and serum iron levels causing free radical damage [12,13]. Acidosis has also been involved in impairing phagocyte function [8]. Although our case never had a severe COVID-19 infection and was not prescribed drugs like corticosteroids or remdesivir, his blood glucose levels started to worsen after he got infected with SARS-COV2 twenty days back, as he presented with uncontrolled hyperglycemia and diabetic ketoacidosis. Post COVID-19 immunosuppression has also been mentioned in the literature, which again is a risk factor in the pathogenesis of mucormycosis [7]. Hence, these interactions explain pulmonary mucormycosis, which further spread to cause sino-nasal involvement, as evident by the CECT chest and CECT paranasal sinuses (demonstrating orbital involvement). A bronchoscopic biopsy later confirmed the diagnosis.\n\nInterestingly, various studies have explored the association between COVID-19 and tuberculosis; most of them have attributed the findings to either post TB development of COVID or a co-infection [14,15]. A Case report highlights the development of tuberculosis post recovery from COVID-19 in a young patient without any risk factors [16]. Moreover, in a case report by “Gautam S and colleagues,” tubercular empyema thoracic presented acutely with COVID-19 co-infection in a diabetic Asian male patient [17]. Superimposed to pulmonary mucormycosis, our patient also developed pulmonary tuberculosis as detected on sputum for AFB and without rifampicin resistance in CBNAAT. As a result, anti-tubercular therapy (ATT) was started. However, our patient later developed complications like hepatitis, as evident from deranged LFTs after ATT initiation; hence hepatic modification of doses was done. Intensified case-finding initiatives to detect tuberculosis in post-COVID patients taken by the Government of Kerala is a step forward in the fight against eradicating tuberculosis [18]. Our goal is to highlight the need for post-COVID diabetic patients to be screened timely for detection of tuberculosis and invasive fungal infections such as mucormycosis and diagnosed with a high index of suspicion at the earliest.\n\n4 Conclusion\n\nWith our very first case report on pulmonary mucormycosis along with pulmonary tuberculosis in a post COVID-19 infected patient, we would like to urge clinicians to focus more on these uncontrolled diabetic post COVID-19 infected patients, even without classical risk factors like severe COVID-19 infection requiring hospitalization, steroid intake or intake of any other immunomodulator drugs like remdesivir or tocilizumab, who are high risk of deveoping mucormycosis and tuberculosis. Hence, strict monitoring of blood sugar in diabetic patients is of utmost improtance especially in COVID-19 infected and post covid-19 patients to combat this yet another growing epidemic of mucormycosis especially in Indian subcontinent.\n\nFunding\n\nNo organized funding source was used in study conduction.\n\nDeclaration of competing interest\n\nThe all authors declare that they have no conflict of interest.\n\nAcknowledgements\n\nNone.\n==== Refs\nReferences\n\n1 WHO, Weekly operational update on COVID-19 - 23 August 2021, Issue No. 69; Emergency Situational Updates, Accessed August 24, 2021.\n2 WHO, Emergencies/home/coronavirus disease(COVID-19)/mucormycosis, Accessed August 24, 2021.\n3 John T.M. Jacob C.N. Kontoyiannis D.P. When uncontrolled diabetes mellitus and severe COVID-19 converge: the perfect storm for mucormycosis J Fungi (Basel) 7 4 2021 298 10.3390/jof7040298 33920755\n4 Alagna R. Besozzi G. Codecasa L.R. Celebrating world tuberculosis day at the time of COVID-19 Eur. Respir. J. 55 4 2020 2000650 10.1183/13993003.00650-2020\n5 Tassi Mousquer Gabriel Peres Alessandra Fiegenbaum Marilu Pathology of TB/COVID-19 Co-Infection: the phantom menace Tuberculosis 126 2021 Jan 102020 10.1016/j.tube.2020.102020\n6 Ashley Hagen, American Society of Microbiology COVID-19-Associated mucormycosis: triple threat of the pandemic https://asm.org/Articles/2021/July/COVID-19-Associated-Mucormycosis-Triple-Threat-of July 15, 2021\n7 National Centre for Disease Control Directorate general of health services, government of India; CD alert June, 2021 2230179 2232021 O/O IDSP-NCDC https://www.ncdc.gov.in/WriteReadData/l892s/22911839231625743853.pdf\n8 Pal R. Singh B. Bhadada S.K. COVID-19-associated mucormycosis: an updated systematic review of literature Mycoses 2021 10.1111/myc.13338 10.1111/myc.13338\n9 Peterson K.L. Wang M. Canalis R.F. Abemayor E. Rhinocerebral mucormycosis: evolution of the disease and treatment options Laryngoscope 107 7 1997 855 862 10.1097/00005537-199707000-00004 9217119\n10 Singh A.K. Singh R. Joshi S.R. Misra A. Mucormycosis in COVID-19: a systematic review of cases reported worldwide and in India Diabetes Metab Syndr 15 4 2021 102146 10.1016/j.dsx.2021.05.019\n11 Montefusco L. Ben Nasr M. D'Addio F. Acute and long-term disruption of glycometabolic control after SARS-CoV-2 infection Nat Metab 3 2021 774 785 10.1038/s42255-021-00407-6 34035524\n12 Ibrahim A.S. Spellberg B. Edwards J. Jr. Iron acquisition: a novel perspective on mucormycosis pathogenesis and treatment Curr. Opin. Infect. Dis. 21 6 2008 620 625 10.1097/QCO.0b013e3283165fd1 18978530\n13 Perricone C Bartoloni E Bursi R COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy Immunol 68 4 2020 213 224 10.1007/s12026-020-09145-5\n14 Tadolini M. Codecasa L.R. García-García J.M. Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases Eur. Respir. J. 56 1 July 9, 2020 2001398 10.1183/13993003.01398-2020\n15 Gupta N. Ish P. Gupta A. Malhotra N. A profile of a retrospective cohort of 22 patients with COVID-19 and active/treated tuberculosis Eur. Respir. J. 56 5 Nov 2020 2003408 10.1183/13993003.03408-2020\n16 Zahid A. Iqbal N. Moeen S. Irfan M. Post COVID-19 tuberculosis: an emerging threat of pandemic Monaldi Arch. Chest Dis. 2021 10.4081/monaldi.2021.1749 10.4081/monaldi.2021.1749,31],3,2021\n17 Gautam S. Pandit S. Bhadoria Tubercular empyema thoracic: an acute presentation with COVID-19 co-infection J. Clin. Diagn. Res. 15 6 2021 6 9 Article in English | EMBASE | ID: covidwho-1302770\n18 Government of Kerala, Health and Family Welfare Department COVID-19 outbreak control and prevention state cell, intensified case finding for TB among post COVID patients No 34/31/F2/2020/Health June 14, 2021 Accessed August 24, 2021\n\n",
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"title": "Massive hemoptysis causing mortality in a post COVID-19 infected Asian male patient: Presenting as pulmonary mucormycosis, pulmonary tuberculosis and later sino-nasal mucormycosis.",
"title_normalized": "massive hemoptysis causing mortality in a post covid 19 infected asian male patient presenting as pulmonary mucormycosis pulmonary tuberculosis and later sino nasal mucormycosis"
}
|
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"literaturereference": "Rana G, Gautam S, Mawari G, Daga MK, Kumar N, Raghu RV. Massive hemoptysis causing mortality in a post COVID-19 infected Asian male patient: Presenting as pulmonary mucormycosis, pulmonary tuberculosis and later sino-nasal mucormycosis. Respiratory Medicine Case Reports. 2021;34:341-345",
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{
"abstract": "OBJECTIVE\nA case is presented to illustrate a potential effect of Chinese herbal medicine (CHM) formulas in treating chemotherapy-induced cardiotoxicity.\n\n\nMETHODS\nAn 18-year-old adolescent male with refractory acute lymphoblastic leukemia (ALL) had experienced anthracycline-induced congestive heart failure (CHF) for 3 weeks. Under intensive care with conventional therapy, the patient still had exercise intolerance and depended on supplemental oxygen all day. Therefore, he consented to treatment with traditional Chinese medicine (TCM) for alternative therapy.\n\n\nRESULTS\nThis patient was treated with modified Zhi Gan Cao Tang (ZGCT), three times a day for 2 months. After 6 days of CHM treatment, the patient could tolerate daily activity without supplemental oxygen. After 2 months of CHM treatment, the follow-up chest X-ray showed great improvements in pulmonary edema and cardiomegaly.\n\n\nCONCLUSIONS\nIn this case, anthracycline-induced cardiotoxicity resolved slowly following the administration of modified ZGCT. It is suggested that the CHM formula has a protective effect on the progression of CHF secondary to the use of anthracyclines in pediatric cancer. Further studies to determine the mechanism and clinical trials are warranted.",
"affiliations": "Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.;Department of Pediatrics, E-DA Hospital and I-Shou University, Kaohsiung, Taiwan.;Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan. Electronic address: [email protected].",
"authors": "Wu|Bei-Yu|BY|;Liu|Chun-Ting|CT|;Chen|Shih-Yu|SY|;Tsai|Ming-Yen|MY|",
"chemical_list": "D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D004365:Drugs, Chinese Herbal",
"country": "Scotland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0965-2299",
"issue": "23(2)",
"journal": "Complementary therapies in medicine",
"keywords": "Chemotherapy; Heart failure; Traditional Chinese medicine; Zhi Gan Cao Tang",
"medline_ta": "Complement Ther Med",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D004365:Drugs, Chinese Herbal; D006333:Heart Failure; D006801:Humans; D008297:Male; D008516:Medicine, Chinese Traditional; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "9308777",
"other_id": null,
"pages": "251-6",
"pmc": null,
"pmid": "25847563",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of chemotherapy-induced congestive heart failure successfully treated with Chinese herbal medicine.",
"title_normalized": "a case of chemotherapy induced congestive heart failure successfully treated with chinese herbal medicine"
}
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{
"abstract": "An 84-year-old African American woman was admitted to the hospital secondary to severe abdominal pain accompanied by septic shock. She underwent exploratory laparotomy, which revealed extensive small bowel necrosis likely due to small bowel torsion. A small bowel resection was performed with primary anastomoses and the patient was subsequently transferred to the intensive care unit (ICU). She recovered from shock but had a persistent gastroparesis interfering with enteral feeding, for which metoclopramide was prescribed. She was then transferred to a general medical-surgical unit in a stable condition where she received a total of four 10-mg oral doses of metoclopramide administered every 8 hours. Approximately 32 hours after receiving the first dose of metoclopramide, the patient was subsequently transferred back to the ICU because of fever and inability to maintain respirations. Neuroleptic malignant syndrome was suspected, and the patient was intubated and received supportive care. After a week in the ICU, she was discharged back to the medical-surgical unit in a stable condition and recovered completely. The patient was later discharged home.",
"affiliations": "Richard Breeden, PharmD, BCPS, BCNSP, is Assistant Professor, South College School of Pharmacy, Critical Care Pharmacist, Methodist Medical Center of Oak Ridge, Knoxville, Tennessee. Heath Ford, PharmD, PhD, CGP, is Assistant Professor, South College School of Pharmacy, Knoxville, Tennessee. Carey Chrisman, PharmD, is Affiliate Assistant Professor, University of Tennessee College of Pharmacy, and Critical Care Pharmacist, Methodist Medical Center of Oak Ridge, Oak Ridge, Tennessee. Charles Mascioli, MD, MBA, FCCP, is Critical Care Physician, Methodist Medical Center of Oak Ridge, Oak Ridge, Tennessee.",
"authors": "Breeden|Richard|R|;Ford|Heath|H|;Chrisman|Carey|C|;Mascioli|Charles|C|",
"chemical_list": "D008787:Metoclopramide",
"country": "United States",
"delete": false,
"doi": "10.1097/SGA.0000000000000173",
"fulltext": null,
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"issn_linking": "1042-895X",
"issue": "40(2)",
"journal": "Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates",
"keywords": null,
"medline_ta": "Gastroenterol Nurs",
"mesh_terms": "D000369:Aged, 80 and over; D013505:Digestive System Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D018589:Gastroparesis; D006801:Humans; D007362:Intensive Care Units; D007415:Intestinal Obstruction; D007813:Laparotomy; D008787:Metoclopramide; D009336:Necrosis; D009459:Neuroleptic Malignant Syndrome; D011183:Postoperative Complications; D020127:Recovery of Function; D018570:Risk Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "8915377",
"other_id": null,
"pages": "93-100",
"pmc": null,
"pmid": "28362659",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Neuroleptic Malignant Syndrome Secondary to Metoclopramide Use in an Elderly Gastroenterologic Surgery Patient.",
"title_normalized": "neuroleptic malignant syndrome secondary to metoclopramide use in an elderly gastroenterologic surgery patient"
}
|
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] |
{
"abstract": "Giant cell tumour of bone (GCTOB) is a relatively uncommon, benign, but locally aggressive neoplasm. Denosumab is a fully human monoclonal antibody with inhibitory effects on receptor activator of nuclear factor kappa-B ligand that has shown early promise as a possible treatment adjuvant for GCTB. However, much is still unknown about its current indications, long-term effects, the potential risk for rapid relapse and its involvement in sarcomatous transformation.\n\n\n\nWe analysed the outcomes of 154 patients with GCTOB. We assessed clinical outcomes via local recurrence free-survival, metastatic free-survival and sarcomatous transformation between those treated without Denosumab and those with neo-adjuvant Denosumab. Our radiological and pathological outcomes were assessed through independent specialist reviews.\n\n\n\nFour (19.0%) patients of the neo-adjuvant group had local recurrence of disease versus 16 (12.0%) patients in the surgery alone group; this results in a 3.62 times increased likelihood of developing local recurrence (P = 0.030). The median time to local recurrence was shorter for the neo-adjuvant group (421.5 days versus 788.5 days) (P = 0.01). There was no difference between Denosumab and the surgery groups in terms of metastatic disease (P = 0.45). Two patients in our cohort with GCTOB developed sarcomatous transformation, both were treated with Denosumab.\n\n\n\nOur use of Denosumab tended to be for those patients who had surgically difficult tumours to halt the progression and allow easier resections. Of concern we noted a trend towards increasing recurrence rates with the potential risk for rapid relapse. Furthermore, two cases experienced sarcomatous transformation, which is a growing area of concern within the literature.",
"affiliations": "Department of Orthopaedics and The University of Melbourne Department of Surgery, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.;Department of Orthopaedics and The University of Melbourne Department of Surgery, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.;Department of Orthopaedics and The University of Melbourne Department of Surgery, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.;Department of Anatomical Pathology, St Vincent's Hospital, Melbourne, Victoria, Australia.;Department of Anatomical Pathology, St Vincent's Hospital, Melbourne, Victoria, Australia.;Department of Orthopaedics and The University of Melbourne Department of Surgery, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.;Department of Orthopaedics and The University of Melbourne Department of Surgery, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.;Department of Orthopaedics and The University of Melbourne Department of Surgery, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.",
"authors": "Murphy|Benjamin|B|0000-0002-6008-6526;Vodanovich|Domagoj|D|0000-0001-7618-1280;Spelman|Tim|T|;Gullifer|James|J|;Slavin|John|J|;Powell|Gerard|G|;Pang|Grant|G|;Choong|Peter|P|",
"chemical_list": "D050071:Bone Density Conservation Agents; D000069448:Denosumab",
"country": "Australia",
"delete": false,
"doi": "10.1111/ans.16157",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1445-1433",
"issue": "90(12)",
"journal": "ANZ journal of surgery",
"keywords": "Denosumab; giant cell tumour",
"medline_ta": "ANZ J Surg",
"mesh_terms": "D050071:Bone Density Conservation Agents; D001859:Bone Neoplasms; D000069448:Denosumab; D018212:Giant Cell Tumor of Bone; D006801:Humans; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "101086634",
"other_id": null,
"pages": "2553-2558",
"pmc": null,
"pmid": "32767541",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical, radiological and pathological outcomes following treatment of primary giant cell tumour of bone with Denosumab.",
"title_normalized": "clinical radiological and pathological outcomes following treatment of primary giant cell tumour of bone with denosumab"
}
|
[
{
"companynumb": "AU-AMGEN-AUSSP2020129470",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
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"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": "120 MILLIGRAM, ON DAYS 1, 8, AND 15 OF THE FIRST MONTH",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BONE GIANT CELL TUMOUR",
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},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
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"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": "120 MILLIGRAM, QMO",
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"medicinalproduct": "XGEVA"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Bone giant cell tumour",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pain in extremity",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sarcoma",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MURPHY B.? VODANOVICH D.? SPELMAN T. ET AL.. CLINICAL, RADIOLOGICAL AND PATHOLOGICAL OUTCOMES FOLLOWING TREATMENT OF PRIMARY GIANT CELL TUMOUR OF BONE WITH DENOSUMAB. ANZ JOURNAL OF SURGERY. 2020?1?6",
"literaturereference_normalized": "clinical radiological and pathological outcomes following treatment of primary giant cell tumour of bone with denosumab",
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},
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}
] |
{
"abstract": "Pediatric primary lung carcinomas are extremely rare. Apart from known associations with congenital adenomatoid malformations, cases of primary lung adenocarcinomas after prolonged treatments of pediatric malignancy have been reported. We describe the morphological and molecular features of three cases of lung adenocarcinoma developed in adolescents aged 8 to 17 years during progression of their bone osteosarcoma or Ewing sarcomas. The morphological features overlapped those of adult lung adenocarcinoma including in situ, minimally invasive, and invasive forms. EGFR gene mutations were found in all three cases by targeted next-generation sequencing. The two patients with Ewing sarcoma had no progression of their lung cancer and no further progression of the metastatic bone tumor after additional chemo- and radio-therapy. Conversely, the osteosarcoma patient refused further treatments after thoracic surgery for metastatic osteosarcoma and locally advanced adenocarcinoma and died 2 years later of widespread distant metastases. Our results indicate that primary lung cancer might originate in pediatric patients during prolonged adjuvant therapies for primary bone neoplasm, and this possibility should be considered in the presence of suspected lung disease progression to correctly monitor the primary tumor evolution and define the appropriate therapeutic strategy at each time point. If appropriately treated, second primary lung cancer may not affect the patients' prognosis. The pathogenetic mechanisms of these rare lung adenocarcinomas are not clear, but the presence of EGFR mutations in all three cases indicates an oncogene addiction of the lung tumor, rather than a direct cancerogenic effect of the sarcoma-related treatment.",
"affiliations": "Department of Oncology, University of Turin, Turin, Italy.;Division of Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.;Department of Oncology, University of Turin, Turin, Italy.;Department of Oncology, University of Turin, Turin, Italy.;Department of Oncology, University of Turin, Turin, Italy.;Department of Oncology, University of Turin, Turin, Italy.;Department of Orthopaedic Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.;Department of Orthopaedic Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.;Divisions of Pathology, Policlinico Hospital and University of Perugia, Perugia, Italy.;Divisions of Pathology, Policlinico Hospital and University of Perugia, Perugia, Italy.;Department of Oncology, University of Turin, Turin, Italy.;Department of Medicine, University of Padua School of Medicine, Padua, Italy.;Department of Oncology, University of Turin, Turin, Italy. [email protected].;Department of Oncology, University of Turin, Turin, Italy.",
"authors": "Righi|Luisella|L|;Righi|Alberto|A|;Vatrano|Simona|S|;Rapa|Ida|I|;Listì|Angela|A|;Metovic|Jasna|J|;Rocca|Michele|M|;Salone|Mariacristina|M|;Giovenali|Paolo|P|;Sidoni|Angelo|A|;Tabbò|Fabrizio|F|;Dei Tos|Angelo Paolo|AP|;Volante|Marco|M|;Papotti|Mauro|M|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00428-020-02990-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0945-6317",
"issue": "478(6)",
"journal": "Virchows Archiv : an international journal of pathology",
"keywords": "EGFR mutation; Ewing sarcoma; Lung adenocarcinoma; Osteosarcoma; Pediatric tumors",
"medline_ta": "Virchows Arch",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000293:Adolescent; D001859:Bone Neoplasms; D002648:Child; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009154:Mutation; D016609:Neoplasms, Second Primary; D012516:Osteosarcoma",
"nlm_unique_id": "9423843",
"other_id": null,
"pages": "1125-1134",
"pmc": null,
"pmid": "33420836",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "2853363",
"title": "Primary lung adenocarcinoma in three adolescent patients affected by bone sarcomas.",
"title_normalized": "primary lung adenocarcinoma in three adolescent patients affected by bone sarcomas"
}
|
[
{
"companynumb": "IT-TEVA-2021-IT-1944475",
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},
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"drugindication": "EWING^S SARCOMA",
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},
{
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}
],
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"reaction": [
{
"reactionmeddrapt": "Lung adenocarcinoma stage I",
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"reactionoutcome": "1"
}
],
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},
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"literaturereference": "RIGHI L, RIGHI A, VATRANO S, RAPA I, LISTI A, METOVIC J, ET AL. PRIMARY LUNG ADENOCARCINOMA IN THREE ADOLESCENT PATIENTS AFFECTED BY BONE SARCOMAS. VIRCHOWS?ARCH 2021?478(6):1125?1134.",
"literaturereference_normalized": "primary lung adenocarcinoma in three adolescent patients affected by bone sarcomas",
"qualification": "3",
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},
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{
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"medicinalproduct": "ETOPOSIDE."
},
{
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"medicinalproduct": "IPHOSPHAMIDE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Lung adenocarcinoma",
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}
],
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},
"primarysource": {
"literaturereference": "RIGHI L, RIGHI A, VATRANO S, RAPA I, LISTI A, METOVIC J, ET AL. PRIMARY LUNG ADENOCARCINOMA IN THREE ADOLESCENT PATIENTS AFFECTED BY BONE SARCOMAS. VIRCHOWS?ARCH 2021?478(6):1125?1134.",
"literaturereference_normalized": "primary lung adenocarcinoma in three adolescent patients affected by bone sarcomas",
"qualification": "3",
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},
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}
] |
{
"abstract": "BACKGROUND\nHemolytic-uremic syndrome (HUS) presents with hemolytic anemia, thrombocytopenia, and thrombotic microangiopathy of the kidney and usually results from Shiga-toxin induced activation of the alternative complement pathway. Gastroenteritis is a common feature of the Shiga-toxin producing Escherichia coli HUS, referred to as STEC-HUS. An inherited or acquired complement dysregulation may lead to HUS referred to as non-STEC or atypical (a)HUS. Although gastroenteritis is not a common presentation of aHUS, some patients develop ischemic colitis and may be misdiagnosed as acute appendicitis or acute ulcerative colitis (UC).\nWe present a patient with low circulating complement (C) 3 levels who developed aHUS in the course of chronic active UC. Resolution of renal and gastrointestinal manifestations in response to treatment with eculizumab, a humanized monoclonal antibody against terminal C5 protein suggests the role of alternative complement in the pathogenesis of both, aHUS and UC.\n\n\nCONCLUSIONS\nThis case illustrates that dysregulation of the alternative complement pathway may manifest in other organs besides the kidney and that the circulating C3 levels do not correlate with the disease activity or the clinical response to eculizumab.",
"affiliations": "Department of Pediatric Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.;Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.;Department of Pediatric Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.;Department of Gastroenterology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.;Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.;Department of Pediatric Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.;Department of Pediatrics, Innsbruck Medical University, Austria.;Department of Pediatric Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.; Department of Clinical Biology and Physiology, University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, Pennsylvania, USA.",
"authors": "Webb|Tennille N|TN|;Griffiths|Heidi|H|;Miyashita|Yosuke|Y|;Bhatt|Riha|R|;Jaffe|Ronald|R|;Moritz|Michael|M|;Hofer|Johannes|J|;Swiatecka-Urban|Agnieszka|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.9734/IJMPCR/2015/18771",
"fulltext": "\n==== Front\n10164803343324Int J Med Pharm Case ReportsInt J Med Pharm Case ReportsInternational journal of medical and pharmaceutical case reports2394-109X10.9734/IJMPCR/2015/18771nihpa767126ArticleAtypical Hemolytic Uremic Syndrome and Chronic Ulcerative Colitis Treated with Eculizumab Webb Tennille N. 1Griffiths Heidi 2Miyashita Yosuke 1Bhatt Riha 3Jaffe Ronald 4Moritz Michael 1Hofer Johannes 5Swiatecka-Urban Agnieszka 16*1 Department of Pediatric Nephrology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.2 Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA.3 Department of Gastroenterology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania4 Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.5 Department of Pediatrics, Innsbruck Medical University, Austria.6 Department of Clinical Biology and Physiology, University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, Pennsylvania, USA.* Corresponding author: [email protected], [email protected] 3 2016 19 6 2015 2015 28 4 2016 4 5 105 112 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nHemolytic-uremic syndrome (HUS) presents with hemolytic anemia, thrombocytopenia, and thrombotic microangiopathy of the kidney and usually results from Shiga-toxin induced activation of the alternative complement pathway. Gastroenteritis is a common feature of the Shiga-toxin producing Escherichia coli HUS, referred to as STEC-HUS. An inherited or acquired complement dysregulation may lead to HUS referred to as non-STEC or atypical (a)HUS. Although gastroenteritis is not a common presentation of aHUS, some patients develop ischemic colitis and may be misdiagnosed as acute appendicitis or acute ulcerative colitis (UC).\n\nCase Diagnosis –Treatment\nWe present a patient with low circulating complement (C) 3 levels who developed aHUS in the course of chronic active UC. Resolution of renal and gastrointestinal manifestations in response to treatment with eculizumab, a humanized monoclonal antibody against terminal C5 protein suggests the role of alternative complement in the pathogenesis of both, aHUS and UC.\n\nConclusion\nThis case illustrates that dysregulation of the alternative complement pathway may manifest in other organs besides the kidney and that the circulating C3 levels do not correlate with the disease activity or the clinical response to eculizumab.\n\nHemolytic–uremic syndrome (HUS)thrombotic microangiopathy (TMA)ulcerative colitis (UC)inflammatory bowel disease (IBD)acute kidney injury (AKI)membrane attack complex (MAC)\n==== Body\n1. INTRODUCTION\nA 16-year-old Caucasian male with a 4-year history of chronic active ulcerative colitis presented with severe symptomatic anemia, thrombocytopenia, intravascular hemolysis, acute kidney injury, nephritis, and decreased C3 levels. Three months earlier he was hospitalized for UC flare (Fig. 1a) and worsening microcytic anemia (Hb 8.2 mg/dL) and his symptoms responded to treatment with intravenous (IV) methyprednisolone and packed red blood cells (RBC) transfusion. After hospital discharge he was continued on a prednisone taper and started on 6-mercaptopurine (6MP; 1.7 mg/kg/day). One month later he developed a flu-like illness with high fever and was treated with cephalexin for possible bacterial sinusitis. Routine monitoring laboratories, including complete blood cell count and serum chemistries were normal. Over the course of the following two weeks he developed increased stool output, bloody stools, decreased appetite, fatigue, shortness of breath, and pallor. He had no urinary symptoms and no dark discoloration of urine. On arrival to the hospital he had increased blood pressure and tachycardia. Laboratory studies were remarkable for severe anemia (Hb 4.4 mg/dL), neutropenia (absolute neutrophil count 0.615 × 109/L), decrease in baseline platelet count to 143 × 105/mL, doubling of serum creatinine from baseline (1.4 mg/dL), increased LDH (428 IU/L), hypoalbuminemia (2.7 mg/dL), and elevated inflammatory markers (CRP 3.7 mg/dl, ESR 113 mm/h). Urinalysis revealed microscopic hematuria, 300 mg/dL protein and no pyuria. He was transfused with packed RBCs, started on IV fluids and methyprednisolone, and 6MP was discontinued. His clinical symptoms improved; however, he continued to have frequent Hemoccult positive stools. Evaluation of the peripheral blood smear, worsening thrombocytopenia (the lowest count was 38 × 105/ml), rising LDH, decreased haptoglobin, and elevated free plasma hemoglobin were consistent with intravascular hemolysis (Table 1). Serum creatinine remained elevated despite hydration, and two 24-hour urine collections confirmed nephrotic range proteinuria. Serial review of urine microscopy showed interval development of RBC casts. Circulating complement (C) 3 was decreased and C4 was normal (Table 1). Stool studies were negative for E. coli O157:H7 by sorbitol-MacConkey agar and Shiga toxin I and II by PCR. Other workup was unremarkable except for transiently elevated homocysteine levels (Table 1).\n\nNative kidney biopsy showed widespread and acute thrombotic microangiopathy (TMA) without chronic changes (Fig. 1b & c). Immunostaining for Membrane Attack Complex (MAC; C5b-9 complement) showed heavy granular deposition along the glomerular basement membranes of most glomeruli, with some mesangial and afferent arteriolar staining and staining of the tubular basement membrane (Fig. 1d). A working diagnosis of atypical HUS was made. After confirmation of immunization with the pneumococcal and meningococcal series, the patient received the first dose of eculizumab (900 mg). Penicillin was started for prophylaxis against Neisseria meningitidis serotype B. Laboratory studies did not reveal the underlying cause of aHUS (Table 1). Soluble MAC and anti-CFH antibodies were not detected before starting eculizumab, genetic studies on Complement Factor (CF)H, CFI, CFB, CFHR1-3, MCP, C3 and thrombomodulin did not reveal disease causing mutations.\n\nHe was discharged home on prednisone, metronidazole, balsalazide, penicillin, iron, and multivitamin. He received three additional weekly doses of eculizumab (900 mg) followed by every other week maintenance (1,200 mg). Clinical symptoms continued to improve. All blood counts and markers of inflammation and hemolysis normalized. C3 normalized briefly but subsequently remained low (Fig. 2).\n\nProteinuria resolved and serum creatinine returned to baseline. RBC casts were no longer present and microscopic hematuria resolved. Six weeks after initiation of eculizumab the patient experienced one brief UC flare demonstrated by increased stool output, bloody stools and elevated calprotectin (1,661.9 mcg/g) without evidence of hemolysis or AKI. The gastrointestinal symptoms resolved and calprotectin decreased to normal (<160 mcg/g) within a week with no additional therapy. Subsequently, the patient has been asymptomatic and normotensive despite having persistently low C3 levels while remaining on eculizumab. He was able to resume full activity including school attendance and participation in sports.\n\n2. DISCUSSION\naHUS represents 5-10% of HUS in children but the majority of HUS in adults [1]. While the alternative complement gene mutations predispose to aHUS additional triggers are necessary for the devastating disease manifestations including platelet activation, endothelial damage, and microthrombi formation known as TMA [1]. The triggers that account for the episodic nature of aHUS are poorly understood [2,3]. Activation of the alternative complement can be caused by infectious agents, malignancy, bone marrow or solid organ transplantation and chemotherapeutic or immunosuppressive agents [4,5], systemic illness (systemic lupus erythematous, membranoproliferative glomerulonephritis, antiphospholipid antibody syndrome, scleroderma) [6,7], severe pre-ecclampsia [8], hyperhomocystinemia [9,10], mutations in the thrombomodulin (THMB) [11] or diacylglycerol kinase ε (DGKE) gene [12]. In some of these disorders TMA may result from factors outside of the complement system such as thrombophilia [9-12]. The preceding flu-like illness in the presented patient may have precipitated aHUS. By contrast, 6MP has no reported association with aHUS. Hyperhomocystinemia is an independent risk factor for intravascular thrombosis [13] and for mucosal microvascular activation in inflammatory bowel disease (IBD), including UC [14]. Many patients with IBD have elevated homocystine levels due to nutritional deficiencies or genetic polymorphisms of enzymes linked to homocysteine metabolisms [2,3]. Thus, elevated homocysteine may have been a trigger or a modifier of aHUS. Alternatively, it may have been the result of aHUS because homocysteine levels are increased in patients with renal failure [15]. The presented patient is heterozygous for the thermolabile variant 677C>T of methylenetetrahydrofolate reductase (MTHFR) necessary for re-methylation of homocysteine to methionine. However, only a homozygous or compound heterozygous mutation in the MTHFR gene was shown to increase homocysteine level. Further genetic testing was not performed due to normalization of the homocysteine level (7.4 μmol/L). Overall, the genetic factors leading to pathologic activation of the alternative complement cascade remain unknown in almost 50% of aHUS patients [16,17]. The specific complement gene mutation was not identified in the patient.\n\nHistorically, the clinical outcomes of aHUS have been unfavorable with up to 25% of patients dying during the acute phase and up to 50% of survivors progressing to end-stage renal disease (ESRD) [1]. The outcomes are likely to improve thanks to humanized monoclonal antibody eculizumab that blocks C5 cleavage and the formation of the pro-thrombotic, pro-inflammatory, lytic and cytotoxic terminal complement products C5a and MAC [18,19]. The patient experienced complete resolution of clinical signs and symptoms associated with TMA of the kidney and had no evidence of chronic kidney disease during 24 months of eculizumab therapy.\n\nAt least 20% of patients with primary aHUS experience extra-renal manifestations and approximately 5% of patients develop life-threatening multivisceral failure [5,20]. HUS may present with ischemic colitis and may be misdiagnosed as acute appendicitis or acute UC [21,22]. The present case is unique in that the patient developed aHUS in the course of chronic active UC. Hyperactivity of the alternative complement cascade plays a role in the pathogenesis of IBD, including UC [23-26]. It is still unclear whether deposition of C3a, C5a or MAC is responsible for inflammation in the intestinal mucosa in all IBD patients or only in a selected group. We were unable to demonstrate deposition of MAC using paraffin-embedded rectal tissue obtained during the UC flare 3 months before the diagnosis of aHUS. This procedure is less sensitive than immunostaining on frozen tissue and the negative findings in the colon may represent false negatives due to the low sensitivity for small amounts of deposit. Improvement of gastrointestinal manifestations after starting eculizumab in the patient who previously suffered severe gastrointestinal symptoms suggests the role of alternative complement pathway in the intestinal inflammation.\n\nSimilar to genetically mediated C5 deficiency, functional C5 deficiency created by eculizumab increases the risk of Neisseria meningitidis infection [18]. At the time of presentation, available vaccines did not cover all Neisseria meningitidis strains, including the most prevalent in the US serotype B. The two cases of meningococcal sepsis reported during eculizumab exposure occurred in immunized patients who were not receiving antibiotic prophylaxis [27]. The patient has continued antibiotic prophylaxis for Neisseria meningitidis without experiencing infectious complications 24 months after the initiation of therapy.\n\nDeposition of C3 and MAC in the endothelium can predict complement activation in aHUS [28]. While circulating C3 levels are decreased in 30-50% of aHUS patients [1,29], the levels do not correlate with the disease activity or the clinical response to eculizumab [28]. This is illustrated by the fluctuating C3 levels in the patient (Fig. 2). Specific and sensitive markers of complement activation in aHUS are lacking and such markers are needed for the diagnostic and prognostic evaluation and for monitoring the C5 blockade in response to eculizumab.\n\n3. CONCLUSION\nDysregulation of the alternative complement pathway may not only manifest in the kidney but other organs may be involved as well. As illustrated by this case, there is no correlation between C3 levels and disease activity in aHUS, but resolution of clinical symptoms is important to establish effectiveness of therapy. Biomarkers of complement activation in aHUS are needed for the diagnostic and prognostic evaluation and for monitoring the C5 blockade in response to eculizumab. \n\n\nAuthors’ contributions\n\nThis work was carried out in collaboration between all authors. Authors TNW and HG wrote the draft of the manuscript. Author ASU managed the literature searches. Authors ASU, TNW and RJ designed the figures, managed literature searches and contributed to the correction of the draft. Author ASU provided the case, the figures and supervised the work. All authors read and approved the final manuscript.\n\nCONSENT\n\nAll authors declare that written informed consent was obtained from the patient (or other approved parties) for publication of this case report and accompanying images.\n\nETHICAL APPROVAL\n\nIt is not applicable.\n\nCOMPETING INTERESTS\n\nAuthors have declared that no competing interests exist.\n\nABBREVIATIONS\nLDHlactate dehydrohenase\n\nESRerythrocyte sedimentation rate\n\nCRPC-reactive protein\n\nCcomplement protein\n\nPNHparoxysmal nocturnal hemoglobinuria\n\nADAMTSa disintegrin and metalloproteinase with a thrombospondin type 1 motif\n\nAPCactivated Protein C\n\nMTHFRmethylenetetrahydrofolate reductase\n\nANAanti-nuclear antibody\n\nANCAantineutrophil cytoplasmic antibody\n\nASOanti-streptolysin O; methylenetetrahydrofolate reductase\n\nLAClupus anticoagulant\n\nvWDvonWillebrand factor\n\nCFcomplement factor\n\ndsDNAdouble stranded DNA\n\nMPLAmultiplex ligation-dependent probe amplification testing\n\nMCPmembrane cofactor protein\n\nTCCterminal complement complex; Normal values are in parenthesis\n\nFig. 1. (a) Light microscopy of colon biopsy specimen demonstrating chronic active colitis. Thickened muscularis mucosae, lamina propria fibrosis, crypt distortion, and heavy lymphoid and plasma cell component as well as stromal neutrophils and crypt abscess formation (arrow). (Hematoxylin and eosin; original magnification × 100). Specimen was obtained 3 months before presentation with aHUS\n\nFig. 1. (b) Light microscopy of kidney biopsy specimen demonstrating acute thrombotic microangiopathy without chronic findings of glomerulosclerosis or interstitial fibrosis. There is glomerular capillary dilatation, increased mesangial matrix, as well as platelet and fibrin thrombi in glomerular loops with focal and segmental necrosis. There is extension to afferent arterioles with fibrinoid change. RBC fragments are present in the glomerulus. Tubules have large resorption droplets, are often dilated with RBC casts. The interstitium has focal RBC (Hematoxylin and eosin; original magnification × 400)\n\nFig. 1. (c) Electron microscopy of the glomerular capillary loop. Fibrin is present in a capillary lumen (asterisk) and there is fibrillar material that separates the endothelial cell from the capillary basement membrane (arrow) (Original magnification × 22,800)\n\nFig. 1. (d) Immunostaining (antibody DAKO #M0777, clone aE11) for membrane attack complex (MAC; C5b-9 complement) of kidney biopsy specimen demonstrating heavy granular deposition along the glomerular basement membranes with some mesangial and afferent arteriolar staining. (Original magnification × 400)\n\nFig. 2 Fluctuating levels of circulating complement (C) 3. The horizontal lines delineate the normal C3 levels. Glucocorticosteroids were started on 2/23/13 and were tapered off by 5/7/13. Eculizumab was started on 3/5/13. Additional medications were metronidazole, balsalazide, penicillin, iron, and multivitamin. The patient started to improve within days after starting eculizumab but experienced a short UC flare on 5/20/13. He became asymptomatic within a week without additional therapy. The patient has been asymptomatic, normotensive and has had normal kidney function during the 24 month follow-up while remaining on eculizumab\n\nTable 1 The laboratory test results\n\nDirect coombs\tNegative\t\nIndirect coombs\tNegative\t\nHaptoglobin\t<15 mg/dL (30-200)\t\nLDH\t428-735 IU/L (115-257)\t\nFree plasma hemoglobin\t11.7 (<6)\t\nESR\t113 mm/h (< 20)\t\nCRP\t3.7 mg/dL (0.04-0.79)\t\nC3\t49 mg/dL (82-163)\t\nC4\t18 mg/dL (14-41)\t\nPNH flow cytometry\tNegative\t\nADAMTS13 activity\t85% (>68)\t\nADAMTS13 inhibitor\t15% (<30)\t\nRistocetin cofactor\t1.77 U/mL(0.5-1.5)\t\nRussel viper venom time\tNormal\t\nAPC resistance\t3.4 (2.1-3)\t\nPT/PTT/INR\tNormal\t\nThrombin\tNormal\t\nProtein C\tNormal\t\nProtein S\t170% (58-128)\t\nFactor X\tNormal\t\nAntithrombin III\tNormal\t\nHomocysteine\t19.8 umol/L (5.5-13.8)\t\nMTHFR gene\t677C>T variant, heterozygous\t\nProthrombin gene\tNo 20210G>A mutation\t\nANA\tNegative\t\nANCA\tNegative\t\nLAC/vWD\tNegative\t\nASO titer\tNegative\t\nanti-dNAse B antibody\tNegative\t\nAnti-dsDNA antibody\tNegative\t\nCFH level\t256 mcg/ml (160-412)\t\nAnti-CFH antibody\tNegative\t\nCFH coding region\tNo disease causing mutations\t\nMLPA for CFHR3-1 deletion\tNegative\t\nCFB level\t205.6 mcg/ml (127.6-278.5)\t\nCFB coding region\tNo disease causing mutations\t\nCFI level\t44.0 mcg/ml (29.3-58.5)\t\nCFI coding region\tNo disease causing mutations\t\nMCP\tNormal\t\nMCP coding region\tNo disease causing mutations\t\nELISA for TCC\tNegative (no TCC consumption)\t\nC3 coding region\tNo disease causing mutations\t\nThrombomodulin gene\tNo disease causing mutations\n==== Refs\nREFERENCES\n1 Loirat C Fremeaux-Bacchi V Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 2011 6 60 21902819 \n2 Romagnuolo J Fedorak RN Dias VC Bamforth F Teltscher M Hyperhomocysteinemia and inflammatory bowel disease: Prevalence and predictors in a cross-sectional study. Am J Gastroenterol 2001 96 7 2143 2149 11467646 \n3 Jiang Y Xia X Wang W Hyperhomocysteinemia and related genetic polymorphisms correlate with ulcerative colitis in Chinese Han population in Central China [corrected]. Cell Biochem Biophys 2012 62 1 203 210 21947961 \n4 Loomis LJ Aronson AJ Rudinsky R Spargo BH Hemolytic uremic syndrome following bone marrow transplantation: a case report and review of the literature. Am J Kidney Dis 1989 14 4 324 328 2679060 \n5 Komeno Y Ogawa S Ishida T Ischemic colitis as a manifestation of thrombotic microangiopathy following bone marrow transplantation. Intern Med 2003 42 12 1228 1232 14714965 \n6 Lansigan F Isufi I Tagoe CE Microangiopathic haemolytic anaemia resembling thrombotic thrombocytopenic purpura in systemic lupus erythematosus: the role of ADAMTS13. Rheumatology (Oxford) 2011 50 5 824 829 21149242 \n7 Skerka C Licht C Mengel M Autoimmune forms of thrombotic microangiopathy and membrano-proliferative glomerulonephritis: Indications for a disease spectrum and common pathogenic principles. Mol Immunol 2009 46 14 2801 2807 19640589 \n8 Ganesan C Maynard SE Acute kidney injury in pregnancy: The thrombotic microangiopathies. J Nephrol 2011 24 5 554 563 21240869 \n9 Geraghty MT Perlman EJ Martin LS Cobalamin C defect associated with hemolytic-uremic syndrome. J Pediatr 1992 120 6 934 937 1593355 \n10 Van Hove JL Van Damme-Lombaerts R Grunewald S Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy. Am J Med Genet 2002 111 2 195 201 12210350 \n11 Delvaeye M Noris M De Vriese A Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009 361 4 345 357 19625716 \n12 Lemaire M Fremeaux-Bacchi V Schaefer F Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 2013 45 5 531 536 23542698 \n13 Kemp EJ Strain L Diaz-Torres ML Goodship JA Goodship TH The development of atypical hemolytic uremic syndrome is not influenced by thrombophilia susceptibility factors. J Thromb Haemost 2005 3 9 2128 2130 16102133 \n14 Danese S Sgambato A Papa A Homocysteine triggers mucosal microvascular activation in inflammatory bowel disease. Am J Gastroenterol 2005 100 4 886 895 15784037 \n15 van Guldener C Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrol Dial Transplant 2006 21 5 1161 1166 16490741 \n16 Noris M Remuzzi G Atypical hemolytic-uremic syndrome. N Engl J Med 2009 361 17 1676 1687 19846853 \n17 Noris M Mescia F Remuzzi G STECHUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 2012 8 11 622 633 22986360 \n18 Zuber J Fakhouri F Roumenina LT Loirat C Fremeaux-Bacchi V French Study Group for a HCG Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol 2012 8 11 643 657 23026949 \n19 Legendre CM Licht C Muus P Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013 368 23 2169 2181 23738544 \n20 Fremeaux-Bacchi V Fakhouri F Roumenina L Dragon-Durey MA Loirat C [Atypical hemolytic-uremic syndrome related to abnormalities within the complement system]. Rev Med Interne 2011 32 4 232 240 21376430 \n21 Craner GE Burdick GE Acute colitis resembling ulcerative colitis in the hemolytic-uremic syndrome. Am J Dig Dis 1976 21 1 74 76 1258852 \n22 Dillard RP Hemolytic-uremic syndrome mimicking ulcerative colitis. Lack of early diagnostic laboratory findings. Clin Pediatr (Phila) 1983 22 1 66 67 6600218 \n23 Johswich K Martin M Bleich A Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease. Inflamm Bowel Dis 2009 15 12 1812 1823 19714742 \n24 Sugihara T Kobori A Imaeda H The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease. Clin Exp Immunol 2010 160 3 386 393 20089077 \n25 Lu F Fernandes SM Davis AE The role of the complement and contact systems in the dextran sulfate sodium-induced colitis model: the effect of C1 inhibitor in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 2010 298 6 G878 883 20338925 \n26 Jain U Woodruff TM Stadnyk AW The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10. Br J Pharmacol 2013 168 2 488 501 22924972 \n27 Hillmen P Muus P Roth A Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013 162 1 62 73 23617322 \n28 Noris M Galbusera M Gastoldi S Dynamics of complement activation in atypical HUS and how to monitor eculizumab therapy. Blood 2014 \n29 Noris M Caprioli J Bresin E Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010 5 10 1844 1859 20595690\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2394-109X",
"issue": "4(5)",
"journal": "International journal of medical and pharmaceutical case reports",
"keywords": "Hemolytic–uremic syndrome (HUS); acute kidney injury (AKI); inflammatory bowel disease (IBD); membrane attack complex (MAC); thrombotic microangiopathy (TMA); ulcerative colitis (UC)",
"medline_ta": "Int J Med Pharm Case Reports",
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"nlm_unique_id": "101648033",
"other_id": null,
"pages": "105-112",
"pmc": null,
"pmid": "27135055",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "22986360;19714742;19640589;21947961;19846853;23617322;20089077;21149242;1593355;23738544;16102133;20595690;25037630;12210350;2679060;21240869;23542698;23026949;21902819;20338925;16490741;14714965;15784037;1258852;11467646;19625716;6600218;22924972;21376430",
"title": "Atypical Hemolytic Uremic Syndrome and Chronic Ulcerative Colitis Treated with Eculizumab.",
"title_normalized": "atypical hemolytic uremic syndrome and chronic ulcerative colitis treated with eculizumab"
}
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{
"reactionmeddrapt": "Faecal volume increased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Complement factor C3 decreased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haematochezia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Colitis ulcerative",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20130320"
}
},
"primarysource": {
"literaturereference": "WEBB, T., GRIFFITHS, H., MIYASHITA, Y., BHATT, R., JAFFE, R., MORITZ, M., HOFER, J., SWIATECKA-URBAN, A.. ATYPICAL HEMOLYTIC UREMIC SYNDROME AND CHRONIC ULCERATIVE COLITIS TREATED WITH ECULIZUMAB. INTERNATIONAL JOURNAL OF MEDICAL AND PHARMACEUTICAL CASE REPORTS. 2015?4(5):105-112",
"literaturereference_normalized": "atypical hemolytic uremic syndrome and chronic ulcerative colitis treated with eculizumab",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180416",
"receivedate": "20180404",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14715347,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "OBJECTIVE\nTo determine the incidence of major complications in patients undergoing regional anesthesia (RA) in China.\n\n\nMETHODS\nMulticenter prospective survey.\n\n\nMETHODS\nEleven teaching hospitals in China.\n\n\nMETHODS\nA total of 106,569 patients undergoing RA from April 1, 2009, to April 30, 2011, were involved.\n\n\nMETHODS\nInformation on patients, types of surgery, and RA techniques was collected with a standardized chart. After RA, the patients were followed up by an investigator in each center for 1 to 3 weeks according to the patient's condition. Data were integrated and analyzed with a structured query language server system.\n\n\nRESULTS\nAmong the patients undergoing RA, 37 developed major complications, including Horner syndrome (n = 9; 0.84/10,000), recurrent laryngeal nerve blockade (n = 6; 0.56/10,000), cardiac arrest (n = 1; 0.09/10,000), hematoma (n = 2; 0.19/10,000), seizures (n = 5; 0.46/10,000), catheter break (n = 1; 0.09/10,000), paraplegia (n = 1; 0.09/10,000), cauda equina syndrome (n = 2; 0.19/10,000), and extensive neuraxial block (n = 10; 0.94/10,000). The incidence of major RA complications varied from 0.8/10,000 to 18.8/10,000 among centers and was highest in cervical plexum block. Plastic surgery had the highest incidence of complications (19.0/10,000), most of which were recurrent extensive neuraxial block. The total incidence of major RA complications was 3.47/10,000.\n\n\nCONCLUSIONS\nThis large, multicenter, prospective survey revealed the incidence of major complications after RA in China's hospitals. Although severe complication like cardiac arrest is rare, it is distressing and challenging. Hence, there is still a room to improve on daily basis to further reduce complications related to RA.",
"affiliations": "Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China.;Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China.;Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, PR China.;Department of Anesthesiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, PR China.;Department of Anesthesiology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, PR China.;Department of Anesthesiology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200081, PR China.;Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, PR China.;Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China.;Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China.;Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, PR China. Electronic address: [email protected].",
"authors": "Huo|Tingting|T|;Sun|Li|L|;Min|Su|S|;Li|Wenzhi|W|;Heng|Xinhua|X|;Tang|Lijun|L|;Zhu|Shengmei|S|;Dong|Hailong|H|;Wang|Qiang|Q|;Xiong|Lize|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "31()",
"journal": "Journal of clinical anesthesia",
"keywords": "Cardiac arrest; Complications; Horner syndrome; Incidence; Neuraxial block; Regional anesthesia",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000765:Anesthesia, Conduction; D002681:China; D005260:Female; D006323:Heart Arrest; D006406:Hematoma; D006784:Hospitals, Teaching; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D011446:Prospective Studies; D055815:Young Adult",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "154-61",
"pmc": null,
"pmid": "27185700",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Major complications of regional anesthesia in 11 teaching hospitals of China: a prospective survey of 106,569 cases.",
"title_normalized": "major complications of regional anesthesia in 11 teaching hospitals of china a prospective survey of 106 569 cases"
}
|
[
{
"companynumb": "CN-FRESENIUS KABI-FK201704407",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ROPIVACAINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "020533",
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"drugcharacterization": "1",
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"drugindication": "ANAESTHESIA",
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"drugrecurreadministration": "3",
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"medicinalproduct": "ROPIVACAINE (OTHER MANUFACTURER)"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
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"medicinalproduct": "LIDOCAINE."
}
],
"patientagegroup": null,
"patientonsetage": "74",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": "51",
"reaction": [
{
"reactionmeddrapt": "Incorrect route of drug administration",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HUO T,SUN L,MIN S,LI W,HENG X,TANG L. MAJOR COMPLICATIONS OF REGIONAL ANESTHESIA IN 11 TEACHING HOSPITALS OF CHINA: A PROSPECTIVE SURVEY OF 106,569 CASES. J-CLIN-ANESTH 2016;31154-61:154-161.",
"literaturereference_normalized": "major complications of regional anesthesia in 11 teaching hospitals of china a prospective survey of 106 569 cases",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20170524",
"receivedate": "20170524",
"receiver": {
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},
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"sender": {
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170830"
}
] |
{
"abstract": "To help curb the opioid overdose epidemic, many states are implementing overdose education and naloxone distribution (OEND) programs. Few evaluations of these programs exist. Maryland's OEND program incorporated the services of the poison center. It asked bystanders to call the poison center within 2 hours of administration of naloxone. Bystanders included law enforcement (LE).\n\n\n\nDescription of the initial experience with this unique OEND program component.\n\n\n\nRetrospective case series of all cases of bystander-administered naloxone reported to the Maryland Poison Center over 16 months. Cases were followed to final outcome, for example, hospital discharge or death. Indications for naloxone included suspected opioid exposure and unresponsiveness, respiratory depression, or cyanosis. Naloxone response was defined as person's ability to breathe, talk, or walk within minutes of administration.\n\n\n\nSeventy-eight cases of bystander-administered naloxone were reported. Positive response to naloxone was observed in 75.6% of overall cases. Response rates were 86.1% and 70.9% for suspected exposures to heroin and prescription opioids, respectively. Two individuals failed to respond to naloxone and died.\n\n\n\nNaloxone response rates were higher and admission to the intensive care unit rates were lower in heroin overdoses than prescription opioid overdoses.\n\n\n\nThis retrospective case series of 78 cases of bystander-administered naloxone reports a 75.6% overall rate of reversal.\n\n\n\nThe findings of this study may be more generalizable. Incorporation of poison center services facilitated the capture of more timely data not usually available to OEND programs. (Am J Addict 2016;25:301-306).",
"affiliations": "Department of Emergency Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.;University of Maryland School of Medicine, Baltimore, Maryland.;University of Maryland School of Pharmacy, Baltimore, Maryland.;Department of Health and Mental Hygiene, Behavioral Health Administration, Baltimore, Maryland.;Department of Health and Mental Hygiene, Behavioral Health Administration, Baltimore, Maryland.;Department of Health and Mental Hygiene, Behavioral Health Administration, Baltimore, Maryland.;Maryland Department of Juvenile Services, Baltimore, Maryland.;Department of Health and Mental Hygiene, Behavioral Health Administration, Baltimore, Maryland.;Institutes for Behavioral Resources, Baltimore, Maryland.;Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland.",
"authors": "Doyon|Suzanne|S|;Benton|Carleigh|C|;Anderson|Bruce A|BA|;Baier|Michael|M|;Haas|Erin|E|;Hadley|Lisa|L|;Maehr|Jennifer|J|;Rebbert-Franklin|Kathleen|K|;Olsen|Yngvild|Y|;Welsh|Christopher|C|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone",
"country": "England",
"delete": false,
"doi": "10.1111/ajad.12384",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1055-0496",
"issue": "25(4)",
"journal": "The American journal on addictions",
"keywords": null,
"medline_ta": "Am J Addict",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D008396:Maryland; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D011039:Poison Control Centers; D011314:Preventive Health Services; D015397:Program Evaluation; D012189:Retrospective Studies; D016320:Substance Abuse Treatment Centers; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9208821",
"other_id": null,
"pages": "301-6",
"pmc": null,
"pmid": "27219823",
"pubdate": "2016-06",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Incorporation of poison center services in a state-wide overdose education and naloxone distribution program.",
"title_normalized": "incorporation of poison center services in a state wide overdose education and naloxone distribution program"
}
|
[
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"medicinalproduct": "METHADONE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drugadditional": null,
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"drugauthorizationnumb": "018276",
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"medicinalproduct": "ALPRAZOLAM."
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
}
],
"summary": null
},
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"literaturereference": "DOYON, S.. INCORPORATION OF POISON CENTER SERVICES IN A STATE-WIDE OVERDOSE EDUCATION AND NALOXONE DISTRIBUTION PROGRAM. AMERICAN JOURNAL ON ADDICTIONS. 2016;25 (4):301-306",
"literaturereference_normalized": "incorporation of poison center services in a state wide overdose education and naloxone distribution program",
"qualification": "1",
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},
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},
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},
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},
{
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{
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"activesubstancename": "MORPHINE SULFATE"
},
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"medicinalproduct": "MORPHINE SULFATE."
}
],
"patientagegroup": null,
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"reaction": [
{
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"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
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"literaturereference_normalized": "incorporation of poison center services in a state wide overdose education and naloxone distribution program",
"qualification": "1",
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},
"primarysourcecountry": "US",
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"receivedate": "20160614",
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},
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"sendertype": "2"
},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160815"
},
{
"companynumb": "US-PFIZER INC-2016289149",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAZOSIN HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "017442",
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"medicinalproduct": "PRAZOSIN HCL"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "QUETIAPINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"medicinalproduct": "CLONAZEPAM."
},
{
"actiondrug": "5",
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"activesubstancename": "LITHIUM"
},
"drugadditional": null,
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"medicinalproduct": "LITHIUM."
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DOYON, S.. INCORPORATION OF POISON CENTER SERVICES IN A STATE-WIDE OVERDOSE EDUCATION AND NALOXONE DISTRIBUTION PROGRAM. AMERICAN JOURNAL ON ADDICTIONS. 2016;25 (4):301-306",
"literaturereference_normalized": "incorporation of poison center services in a state wide overdose education and naloxone distribution program",
"qualification": "1",
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},
"primarysourcecountry": "US",
"receiptdate": "20160622",
"receivedate": "20160622",
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnessother": 1,
"transmissiondate": "20160815"
},
{
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"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "DIACETYLMORPHINE"
},
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{
"abstract": "Pseudotumor cerebri is a syndrome characterized by an elevated intracranial pressure greater than 20 cmH2O with ventricles and cerebrospinal fluid of normal characteristics. Consumption of minocycline have been described among the causes associated with this syndrome. We present a 13-year old female patient with a history of acne treated with minocycline who began with severe headache, diplopia and blurred vision. The diagnosis of pseudotumor cerebri was made, indicating the immediate antibiotic suspension and the beginning of the treatment with acetazolamide. Although the pathogenesis of pseudotumor cerebri is not fully known, an association with minocycline has been observed. This antibiotic is often used by health professionals for the management of acne, so it is important to consider its complications before being prescribed.",
"affiliations": "Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina. [email protected].;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.;Hospital Municipal de Agudos \"Dr. Leónidas Lucero\", Bahía Blanca, Buenos Aires, 8000, Argentina.",
"authors": "González Gili|Lucas O|LO|;Buffone|Ignacio R|IR|;Carrara|Laura E|LE|;Coto|María B|MB|;Fortunatti|Eliana A|EA|;Dejtera|Mabel|M|;García Elliot|María F|MF|;Giacone|Alejandra|A|;Luncio|Anabella C|AC|;Masnicoff|Sebastián D|SD|;Oviedo Crosta|María B|MB|;Parroua|Marianela|M|;Romano|Mariana|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
"country": "Argentina",
"delete": false,
"doi": "10.5546/aap.2016.e78",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0325-0075",
"issue": "114(2)",
"journal": "Archivos argentinos de pediatria",
"keywords": "Children; Minocycline; Pseudotumor cerebri",
"medline_ta": "Arch Argent Pediatr",
"mesh_terms": "D000152:Acne Vulgaris; D000293:Adolescent; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D008911:Minocycline; D011559:Pseudotumor Cerebri",
"nlm_unique_id": "0372460",
"other_id": null,
"pages": "e78-83",
"pmc": null,
"pmid": "27079408",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pseudotumor cerebri secondary to consumption of minocycline in a pediatric patient.",
"title_normalized": "pseudotumor cerebri secondary to consumption of minocycline in a pediatric patient"
}
|
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "CAPSULE",
"drugdosagetext": "100 MG, DAILY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "100",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MINOCYCLINE HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": "17",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Benign intracranial hypertension",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GONZALEZ GILI LO, BUFFONE IR, CARRARA LE, COTO MB, FORTUNATTI EA, DEJTERA M ET AL.. PSEUDOTUMOR CEREBRI SECONDARY TO CONSUMPTION OF MINOCYCLINE IN A PEDIATRIC PATIENT. ARCHIVOS ARGENTINOS DE PEDIATRIA. 2016;114 (2):E78-83",
"literaturereference_normalized": "pseudotumor cerebri secondary to consumption of minocycline in a pediatric patient",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "IL",
"receiptdate": "20161123",
"receivedate": "20161123",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12970613,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170207"
}
] |
{
"abstract": "BACKGROUND\nIdiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults. Although various studies have demonstrated the efficacy of tacrolimus combined with corticosteroids for treating IMN, both tacrolimus and corticosteroids have been shown to be diabetogenic, particularly following organ transplantation. Furthermore, the frequency and risk factors for new-onset diabetes mellitus (NODM) in IMN patients treated with tacrolimus plus low-dose corticosteroids remain unclear.\n\n\nOBJECTIVE\nTo evaluate the incidence of NODM in IMN patients undergoing tacrolimus plus low-dose corticosteroid therapy and to confirm the risk factors for NODM development.\n\n\nMETHODS\nThis retrospective study recruited 72 eligible patients with biopsy-proven IMN from our center, between September 2013 and June 2018. All subjects were treated with tacrolimus plus low-dose corticosteroids for a minimum of 3 months. The primary outcome was NODM development during the follow-up period. The secondary outcome was complete or partial remission. Patients were divided into 2 groups: patients with NODM (NODM group) and those without NODM (No-NODM group). Demographic and clinical data at baseline and follow-up were assessed.\n\n\nRESULTS\nDuring follow-up, 31 of the 72 patients developed NODM (43.0%). The median time to occurrence was 3 months after treatment initiation. NODM patients were significantly older (median age 59 vs. 40 years) than No-NODM patients. Baseline fasting blood glucose levels were slightly higher in the NODM group; however, the difference was not significant (p = 0.07). Older age was an independent risk factor for NODM (OR 1.73 and 95% CI 1.20-2.47, p = 0.003). Overall kidney remission rates were 80.6%. There was no significant difference in remission rate between groups. There was a significant difference in development of pulmonary infection, which occurred in 7 NODM patients and only in 1 No-NODM patient (p = 0.018). IMN reoccurred in 5 NODM patients but only 1 No-NODM patient.\n\n\nCONCLUSIONS\nTacrolimus plus low-dose corticosteroid therapy was an efficient treatment for IMN; however, it was accompanied by increased NODM morbidity, which should be considered serious, due to the increased risk of life-threatening complications. Increasing age was a major risk factor for NODM in IMN patients treated with tacrolimus plus low-dose corticosteroid therapy.",
"affiliations": "Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, China.;Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, China.;Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, China.;Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, China.;Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, China.;Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, China.;Nephrology National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.;Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, China.;Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, China, [email protected].",
"authors": "Shao|Lina|L|;Jin|Juan|J|;Ye|Binxian|B|;Xu|Baihui|B|;Li|Yiwen|Y|;Gong|Jianguang|J|;Zhang|Jiong|J|;Chen|Maosheng|M|;He|Qiang|Q|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D016559:Tacrolimus",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000502693",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1420-4096",
"issue": "44(6)",
"journal": "Kidney & blood pressure research",
"keywords": "Age; Corticosteroid; Idiopathic membranous nephropathy; New-onset diabetes mellitus; Tacrolimus",
"medline_ta": "Kidney Blood Press Res",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000367:Age Factors; D003920:Diabetes Mellitus; D004359:Drug Therapy, Combination; D005260:Female; D015433:Glomerulonephritis, Membranous; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus",
"nlm_unique_id": "9610505",
"other_id": null,
"pages": "1352-1362",
"pmc": null,
"pmid": "31645044",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "New-Onset Diabetes Mellitus in Patients with Idiopathic Membranous Nephropathy Undergoing Tacrolimus and Low-Dose Corticosteroid Therapy.",
"title_normalized": "new onset diabetes mellitus in patients with idiopathic membranous nephropathy undergoing tacrolimus and low dose corticosteroid therapy"
}
|
[
{
"companynumb": "CN-ACCORD-159900",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "091195",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "TARGET CONCENTRATION TO BETWEEN 5 AND?8 NG/ML",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "GLOMERULONEPHRITIS MEMBRANOUS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosagenumb": ".05",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
},
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "5 MG EVERY 4 WEEKS TO 10 MG/DAY FOR 6 MONTHS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "GLOMERULONEPHRITIS MEMBRANOUS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
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"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Respiratory tract infection",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHAO L, JIN J, YE B, XU B, LI Y, GONG J ET. AL. NEW-ONSET DIABETES MELLITUS IN PATIENTS WITH IDIOPATHIC MEMBRANOUS NEPHROPATHY UNDERGOING TACROLIMUS AND LOW-DOSE CORTICOSTEROID THERAPY. KIDNEY BLOOD PRESS RES. 2019 OCT 23:1-11.",
"literaturereference_normalized": "new onset diabetes mellitus in patients with idiopathic membranous nephropathy undergoing tacrolimus and low dose corticosteroid therapy",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20191106",
"receivedate": "20191106",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"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": "We present our experience in the hematopoietic stem cell transplantation (HSCT) in two children diagnosed with Mendelian susceptibility to mycobacterial diseases. The first child underwent a haploidentical HSCT with posttransplant cyclophosphamide using a reduced intensity conditioning following which he had primary graft failure. He was subsequently found to have interferon-γ1 receptor deficiency. He had immune reconstitution and is on antitubercular therapy. The second child diagnosed with IL12RB1 gene mutation underwent matched sibling donor HSCT with myeloablative conditioning following pretransplant immunosuppression with fludarabine and dexamethasone. He is 13 months post-HSCT with complete and remains disease free.",
"affiliations": "Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Anna Salai, Teynampet, Chennai, Tamil Nadu, India.;Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Anna Salai, Teynampet, Chennai, Tamil Nadu, India.;Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Anna Salai, Teynampet, Chennai, Tamil Nadu, India.;Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Anna Salai, Teynampet, Chennai, Tamil Nadu, India.;Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Anna Salai, Teynampet, Chennai, Tamil Nadu, India.;Department of Pediatric Hematology, Oncology, Blood and Marrow Transplantation, Apollo Hospitals, Anna Salai, Teynampet, Chennai, Tamil Nadu, India.",
"authors": "Patel|Shivani|S|;Uppuluri|Ramya|R|0000-0001-5771-8214;Vellaichamy Swaminathan|Venkateswaran|V|;Ravichandran|Nikila|N|0000-0002-6456-8506;Melarcode Ramanan|Kesavan|K|;Raj|Revathi|R|",
"chemical_list": "C508438:IL12RB1 protein, human; D053707:Receptors, Interleukin-12; D003907:Dexamethasone; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(5)",
"journal": "Pediatric blood & cancer",
"keywords": "Mendelian susceptibility to mycobacterial diseases; children; cure; hematopoietic stem cell transplantation",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D064591:Allografts; D002675:Child, Preschool; D003907:Dexamethasone; D020022:Genetic Predisposition to Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007223:Infant; D008297:Male; D009154:Mutation; D009161:Mycobacterium; D009164:Mycobacterium Infections; D053707:Receptors, Interleukin-12; D019172:Transplantation Conditioning; D014740:Vidarabine",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28187",
"pmc": null,
"pmid": "31965686",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mendelian susceptibility to mycobacterial disease-Challenges in hematopoietic stem cell transplantation.",
"title_normalized": "mendelian susceptibility to mycobacterial disease challenges in hematopoietic stem cell transplantation"
}
|
[
{
"companynumb": "IN-ADIENNEP-2020AD000221",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
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"drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "TACROLIMUS."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THIOTEPA"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "8 MG/KG",
"drugenddate": null,
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"drugindication": "ALLOGENIC STEM CELL TRANSPLANTATION",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "THIOTEPA."
},
{
"actiondrug": "6",
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"activesubstancename": "TREOSULFAN"
},
"drugadditional": null,
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},
{
"actiondrug": "6",
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"activesubstancename": "METHOTREXATE"
},
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"drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE",
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"medicinalproduct": "METHOTREXATE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "40 MG/M2",
"drugenddate": null,
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"drugindication": "ALLOGENIC STEM CELL TRANSPLANTATION",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUDARABINE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10 MG/M2",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS AGAINST GRAFT VERSUS HOST DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHOTREXATE."
}
],
"patientagegroup": "3",
"patientonsetage": "5",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute graft versus host disease in skin",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PATEL S, UPPULURI R, VELLAICHAMY SWAMINATHAN V, RAVICHANDRAN N, MELARCODE RAMANAN K, RAJ R. MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASE-CHALLENGES IN HEMATOPOIETIC STEM CELL TRANSPLANTATION. PEDIATR BLOOD CANCER. 2020 67:5 DOI: 10.1002/PBC.28187",
"literaturereference_normalized": "mendelian susceptibility to mycobacterial disease challenges in hematopoietic stem cell transplantation",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20200512",
"receivedate": "20200512",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17770597,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
}
] |
{
"abstract": "BACKGROUND\nChoriocarcinoma is a subtype of gestational trophoblastic disease, gestational trophoblastic neoplasia. Patients with brain metastasis are rare and information on the optimal treatment and patient outcome is limited. In order to improve the prognosis of this disease, accurate and timely treatments are very important for the patient of brain metastasis by choriocarcinoma.\n\n\nMETHODS\nA 17-year-old unmarried girl was misdiagnosed with a cerebral hemangioma with intracranial hemorrhage in a local hospital after presentation with severe head pain. She underwent craniotomy three times for treatment. The pathological results of posterior intracranial hematoma showed choriocarcinoma, and the patient was diagnosed as choriocarcinoma (21 points in stage IV). After uterine artery embolization, etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy for 7 cycles, and whole brain radiotherapy, the patient achieved remission. She has been followed for 2 years with no signs of tumor recurrence.\n\n\nCONCLUSIONS\nFor female patients of childbearing age with an intracranial hematoma, the possibility of brain metastasis by choriocarcinoma should be considered. It is necessary to obtain a detailed history, including menstruation, beginning age of first sex, contraception, etc. The level of β-human chorionic gonadotropin should be tested at the beginning, and a stratified treatment should be administered according to the International Federation of Gynecology and Obstetrics staging and World Health Organization prognostic scoring systems.",
"affiliations": "Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.;Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.;Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China. [email protected].;Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.",
"authors": "Huang|Hui-Qiong|HQ|;Gong|Feng-Ming|FM|;Yin|Ru-Tie|RT|;Lin|Xiao-Juan|XJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i30.9174",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i30.pg9174\n10.12998/wjcc.v9.i30.9174\nCase Report\nChoriocarcinoma misdiagnosed as cerebral hemangioma: A case report\nHuang HQ et al. Choriocarcinoma misdiagnosed as cerebral hemangioma\nHuang Hui-Qiong Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China\n\nGong Feng-Ming Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China\n\nYin Ru-Tie Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China. [email protected]\n\nLin Xiao-Juan Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China\n\nAuthor contributions: Huang HQ analyzed the data and wrote the manuscript; Lin XJ and Gong FM analyzed the data; Yin RT designed the research study; All authors have read and approve the final manuscript.\n\nCorresponding author: Ru-Tie Yin, MD, Doctor, Professor, Gynecological Oncology of Biotherapy Laboratory, Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, No. 20 Section 3 South People’s Road, Chengdu 610041, Sichuan Province, China. [email protected]\n\n26 10 2021\n26 10 2021\n9 30 91749181\n13 4 2021\n9 7 2021\n10 9 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nChoriocarcinoma is a subtype of gestational trophoblastic disease, gestational trophoblastic neoplasia. Patients with brain metastasis are rare and information on the optimal treatment and patient outcome is limited. In order to improve the prognosis of this disease, accurate and timely treatments are very important for the patient of brain metastasis by choriocarcinoma.\n\nCASE SUMMARY\n\nA 17-year-old unmarried girl was misdiagnosed with a cerebral hemangioma with intracranial hemorrhage in a local hospital after presentation with severe head pain. She underwent craniotomy three times for treatment. The pathological results of posterior intracranial hematoma showed choriocarcinoma, and the patient was diagnosed as choriocarcinoma (21 points in stage IV). After uterine artery embolization, etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine chemotherapy for 7 cycles, and whole brain radiotherapy, the patient achieved remission. She has been followed for 2 years with no signs of tumor recurrence.\n\nCONCLUSION\n\nFor female patients of childbearing age with an intracranial hematoma, the possibility of brain metastasis by choriocarcinoma should be considered. It is necessary to obtain a detailed history, including menstruation, beginning age of first sex, contraception, etc. The level of β-human chorionic gonadotropin should be tested at the beginning, and a stratified treatment should be administered according to the International Federation of Gynecology and Obstetrics staging and World Health Organization prognostic scoring systems.\n\nBrain metastasis\nChoriocarcinoma\nUterine artery embolization\nChemotherapy\nWhole brain radiotherapy\nCraniotomy\nCase report\n==== Body\npmc Core Tip: A 17-year-old unmarried girl was misdiagnosed with a cerebral hemangioma with intracranial hemorrhage in a local hospital after presentation with severe head pain. The patient was treated with craniotomy three times. The pathological results of posterior intracranial hematoma showed choriocarcinoma, and the patient was diagnosed as choriocarcinoma (21 points in stage IV). For female patients of childbearing age with an intracranial hematoma, the possibility of brain metastasis by choriocarcinoma should be considered. It is necessary to obtain a detailed sexual history, include menstruation, beginning age of first sex, contraception, etc. The level of β-human chorionic gonadotropin should be tested at the beginning, and a stratified treatment should be administered according to the International Federation of Gynecology and Obstetrics staging and World Health Organization prognostic scoring systems.\n\nINTRODUCTION\n\nGestational trophoblastic neoplasia (GTN) is a group of malignant tumors characterized by abnormal growth of trophoblastic tissue, which can occur after a molar or non-molar pregnancy. Choriocarcinoma, a subtype of gestational trophoblastic disease first described in 400 BC by Hippocrates, is a rare and aggressive neoplasm[1] that can easily metastasize via the hematogenous pathway to multiple organs, such as uterus, vagina, lung, kidney, brain, liver, etc.[2]. GTN patients with brain metastasis are rare and information on the optimal treatment and patient outcome is limited[3]. However, since this type of tumor shows a high cure rate, early diagnosis and subsequent treatment are important. In this report, we present a rare case of choriocarcinoma with brain metastasis in a 17-year-old girl with intracerebral hemorrhage at initial presentation, which may provide a clinical references for aiding in diagnosing and treating brain metastases of choriocarcinoma, especially in adolescent women.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 17-year-old girl with no disease history initially presented to a local community hospital for the acute onset of intense cephalagia, emesis, and left hemiplegia with normal mental state with bilateral pupils equal and reacting.\n\nHistory of present illness\n\nComputed tomography (CT) scan of the brain showed the right frontal parietal lobe intracerebral hemorrhage of the patient at the local hospital, and the patient underwent evacuation of hematoma by emergency craniotomy. Nine days after the first surgery, the patient complaint of severe headache, accompanied by jet vomiting, and the vomit was gastric contents. The patient underwent another evacuation of hematoma by craniotomy. Five days after the second operation, a third attack of headache and vomiting began, and the patient underwent the third evacuation of hematoma by craniotomy to control the hemorrhage. Postoperative pathological examination showed foam-like histiocyte proliferation, and tumor cells were found in the hemorrhagic and necrotic tissues (Figure 1). Immunohistochemical results: pan-cytokeratin (+), epithelial membrane antigen (+), human chorionic gonadotropin (HCG) (+), granulocyte chemotactic protein-3 (+, focal area), Sal-like protein 4 (+), octamer binding transcription factor 3/4 (-), and placental alkaline phosphatase (-), supporting metastatic choriocarcinoma. After confrontation, the patient admitted to having a sexual history and having had an abortion 2 years ago. She hid her medical history for fear that her parents would find out. Laboratory findings revealed that serum β-HCG level was more than 200000 U/mL. Based on all these findings, choriocarcinoma was strongly indicated. She received mannitol dehydration and brain protective treatment, and was then transferred to a general hospital for further treatment, at which time she was transferred to our center.\n\nFigure 1 Pathological pictures of the patient showed infiltrating large and pleomorphic tumor cells into the brain parenchyma with extensive hemorrhage and necrosis. Hematoxylin and eosin stain, intermediate power.\n\nHistory of past illness\n\nThe patient’s menstrual cycle was regular and she declared no history of sexual intercourse or abortion. No history of hypertension could be identified.\n\nPersonal and family history\n\nNo personal and family history available.\n\nPhysical examination\n\nOn presentation in our hospital, the patient was in a normal mental state with bilateral pupils equal and reacting. The muscle strength of left limb was grade III, the right limb grade V. The physical examination showed there was a bluish violet nodule with a diameter of about 6 cm at the cervix.\n\nLaboratory examinations\n\nThe blood level of β-HCG was 766510.0 mIU/mL (normal value, < 2.0 mIU/mL).\n\nImaging examinations\n\nBrain CT with contrast enhancement showed the right parietal lobe in the area of the previous operations had obvious edema, and local softening foci were formed. The adjacent meninges and brain were swollen, indicating residual tumor at the surgical area. Chest CT showed multiple round nodules and masses of variable sizes in both lungs, with scanty amounts of right pleural effusion, compatible with lung metastasis. Abdomen CT showed an abnormal, high and low mixed density in the spleen and kidneys, and the cervical was enlarged with uneven and enhancement CT value.\n\nFINAL DIAGNOSIS\n\nOn the basis of clinical and laboratory investigations, the patient was diagnosed with choriocarcinoma, International Federation of Gynecology and Obstetrics (FIGO) stage IV and score of the Prognostic Scoring Index modified by the FIGO score was 21 (extreme high risk).\n\nTREATMENT\n\nThe patient underwent a multidisciplinary approach to treatment which consisted of a modified multi-agent chemotherapy regimen of etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) with higher doses of methotrexate. The regimen was as follows: methotrexate 100 mg/m2, followed by methotrexate 200 mg/m2 over 12 h day 1, etoposide 100 mg/m2 and dactinomycin 0.5 mg days 1 and 2, calcium folate 15 mg intramuscular injection every 12 h days 2 and 3, alternating with cyclophosphamide 600 mg/m2 and vincristine 2 mg day 8, every 14 days. During the first chemotherapy regimen, the patient suddenly had vaginal bleeding. Physical examination found a large amount of blood in the vagina and the bluish violet nodule on the cervix had ruptured. After vaginal gauze packing, there was still active bleeding. Uterine artery embolization was performed to selectively embolize the bleeding vessel and successfully control uterine hemorrhage (Figure 2). The patient underwent a blood transfusion to compensate for blood loss. Because of the brain metastasis and indications of residual tumor at the brain operation area, the patient underwent whole-brain radiotherapy with 50 Gy in 25 fractions. Usually patients with lung metastasis or disease in the pulmonary vasculature might have a combination of hemoptysis, shortness of breath, or pleuritic chest pain; however, the patient fortunately had no sign of those symptoms, and after the treatments, the lung CT showed favorable therapeutic response.\n\nFigure 2 The pictures of uterine artery angiograms for the patient. A, B: Selective uterine artery angiograms proved active bleeding of the branches of uterine arteries before operation (arrows); C-E: Hemorrhage of blood vessels was ceased immediately after selective embolization (arrows).\n\nOUTCOME AND FOLLOW-UP\n\nSerumβ-HCG decreased logarithmically to normal levels after the 7th chemotherapy regimen (Figure 3). The patient then completed 4 consolidation courses of chemotherapy. The results of lung CT, brain magnetic resonance imaging (MRI), and chest radiograph after treatments all showed favorable therapeutic response (Figures 4, 5 and 6). However, the patient still experienced alopecia, I° liver dysfunction, I-II° canker sore, I-II° nausea and vomiting, and II° granulocytopenia.\n\nFigure 3 Diagram of curves of β-human chorionic gonadotropin level decreased with the course of chemotherapy. β-HCG: β-human chorionic gonadotropin.\n\nFigure 4 Brain images of the patient before and after therapy. A: Brain computed tomography image of the patient before therapy indicated residual tumor at the brain operation area; B: Brain magnetic resonance image of the patient after treatment was significantly decreased compared with that before treatment and there was no sign of residual tumor.\n\nFigure 5 Lung computed tomography images of the patient at different stages of treatment. A-C: Multiple nodules of bilateral pulmonary were shown on computed tomography (CT) image before chemotherapy (orange arrows, metastatic nodules); D-F: CT images revealed an almost normal lung field after treatment.\n\nFigure 6 Abdominal computed tomography images of the patient at different stages of treatment. A: Multiple nodules of spleen were shown on computed tomography (CT) image before chemotherapy (orange arrows, metastatic nodules); B: CT images revealed an almost normal spleen after treatment; C: Large cystic occupying lesion of left renal was shown on CT image before chemotherapy (orange arrows, metastatic cystic occupying lesion); D: CT images revealed an almost normal but smaller left kidney after treatment; E: Large solid occupying lesion of cervix was shown on CT image before chemotherapy (orange arrows, metastatic solid occupying lesion); F: CT images revealed an almost normal cervix after treatment.\n\nLong-term follow-up with evaluation of serum β-HCG levels every 3 mo and CT of her chest and MRI of her brain every 6 mo showed no evidence of disease. The patient has been followed up for 14 mo at the outpatient clinic. She complained of no self-conscious discomfort and the β-HCG value has been maintained in the normal range. The muscle strength of her limbs was almost normal. The patient consented to publication of the case.\n\nDISCUSSION\n\nMetastatic brain tumors are not frequently the cause of the intracerebral hemorrhage in the young, which is usually caused by arteriovenous malformations and aneurysms. About 10%-20% of brain metastases cases are found in choriocarcinoma, which most often manifests as an intracerebral or subdural hematoma because of the innate capacity of trophoblastic cells to invade vessel walls[4].\n\nThe pathological mechanism of choriocarcinoma metastasis to the brain is still controversial, and the formation mechanism may have the following points: (1) Vascular injury mechanism: microthrombotic injury of blood vessels, vascular endothelial scar formation, resulting in changes in vascular hydrodynamics, and hematoma formation[5]; (2) After the destruction of arterial blood vessels, tumor cells invade cerebral blood vessels through vascular nutrient tubes. However, vascular trophoblast tubes in experimental animals and humans are rare[6]; and (3) Tumor crossing mechanism: tumor cells have the ability to bind closely with endothelial cells at the terminal deposition site, and even destroy endothelial cells. With the growth of endothelial cells, they eventually cross and destroy arterial blood vessels[7]. No matter which of the three mechanisms mentioned above, microthrombosis is the earliest. More scholars now agree with the theory of tumor traversing mechanism because histopathologists have found that tumor cells proliferate in hemangioma cells and invaded the inner elastic membrane in various tumors. In conclusion, the biological characteristics of brain metastatic tumor cells play a very important role in the formation of brain metastatic hemangioma.\n\nThe strategy to treat patients who have GTN and brain metastases is with intravenous multidrug chemotherapy; however, the 2013 Cochrane review could not come to a conclusion on what the most effective multidrug chemotherapy regime was to treat high-risk GTN. The EMA-CO combination is most commonly used with an increased dose of Methotrexate from 300 to 1000 mg/m2 in the case of brain metastases (EMA-CO CNS), as recommended by the FTDRC[8]. According to our center's data on previous cases of GTN with brain metastasis, increasing the methotrexate (MTX) dose to 1.0 g/m2 results in unbearable side effects in patients. Patients who are administered low-dose 5-FU and actinomycin D chemotherapy with intermittent intrathecal MTX (15 mg) injection (2–3 times per cycle) until β-HCG is absent in the cerebrospinal fluid, with or without radiotherapy based on the efficacy of chemotherapy, have a remission rate of 75%[9,10]. These patients experience fewer side effects and can tolerate chemotherapy. The patient in this report received EMA-CO combination with usual dose of Methotrexate chemotherapy and showed a good prognosis. Reported by Soper et al[11], treating brain metastases from choriocarcinoma by using systemic intravenous chemotherapy (although alternative regimens to EMA-CO) with surgery or stereotactic brain radiation without the need for whole brain radiation and intrathecal chemotherapy is successful. HCG is key to effective management of gestational trophoblastic disease as the choriocarcinomas are malignant HCG-producing epithelial tumors. HCG is comprised of an α subunit and a β subunit that confers specificity. β-HCG is a good predictive indicator of prognosis and recurrence[12]. However, apart from clinical and radiological signs, the key diagnostic feature of choriocarcinoma is an elevated serum β-HCG. Elevation of β-HCG in the serum of a patient with a history of normal or abnormal pregnancy suggests the diagnosis of choriocarcinoma[12].\n\nBecause of the characteristics of trophoblast cell growth, it is easy for choriocarcinoma lesions to hemorrhage throughout the therapy. In this case, the patient presented with hemorrhages at both the cervix and the brain. Conservative treatment for choriocarcinoma hemorrhagic lesions should first be considered due to chemosensitivity. Arterial embolization has also proven to be an effective nonsurgical way to treat acute and massive genital bleeding in gestational trophoblastic disease, providing specific occlusion of the uterine vessels. Transcatheter angiographic embolization is an accepted treatment modality to control recurrent massive genital bleeding and can avoiding of hysterectomy and preserve fertility[13].\n\nCONCLUSION\n\nThe literature advises that early diagnosis and treatment can significantly improve the prognosis of this disease[14]. In this case brain metastases were already present at time of diagnosis, which worsened the long-term prognosis of the choriocarcinoma. This highlights the importance of increasing awareness of the disease on the part of general practitioners, midwives, and emergency medicine staff, as they are most likely to receive the first presentations of patients with choriocarcinoma, and this will to ensure timely diagnosis and will improve prognosis and reduce morbidity[15]. Because of the Chinese traditional dichotomy, Chinese parents do not allow their daughters to have premarital sex, and therefore, adolescent girls often hide their sexual life history, and doctors in China always ignore their intercourse history. Therefore, there are no reliable data on the age of sexual debut in Chinese women, and the proportion of young women aged 15-19 years who had experienced sexual activity with a partner ranged from 4.5% among rural respondents to 10.8% among urban respondents[16]. In women at childbearing age, metastatic choriocarcinoma must be considered in the differential diagnosis of intracerebral hemorrhage because of its multiple clinical and radiological presentations. It is difficult to differentiate the imaging appearances from those due to cerebrovascular disease[17].\n\nInformed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.\n\nConflict-of-interest statement: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: April 13, 2021\n\nFirst decision: June 24, 2021\n\nArticle in press: September 10, 2021\n\nSpecialty type: Oncology\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Jeong KY, Schulten HJ S-Editor: Wang JL L-Editor: Filipodia P-Editor: Li X\n==== Refs\n1 Seckl MJ Fisher RA Salerno G Rees H Paradinas FJ Foskett M Newlands ES Choriocarcinoma and partial hydatidiform moles Lancet 2000 356 36 39 10892763\n2 Bonnet L Raposo N Blot-Souletie N Faruch Bilfeld M Chollet F Mazière J Olivot JM Albucher JF Stroke Caused by a Pulmonary Vein Thrombosis Revealing a Metastatic Choriocarcinoma Circulation 2015 131 2093 2094 26056347\n3 Piura E Piura B Brain metastases from gestational trophoblastic neoplasia: review of pertinent literature Eur J Gynaecol Oncol 2014 35 359 367 25118474\n4 Savage P Kelpanides I Tuthill M Short D Seckl MJ Brain metastases in gestational trophoblast neoplasia: an update on incidence, management and outcome Gynecol Oncol 2015 137 73 76 25598530\n5 Ashalatha R Moosa A Gupta AK Krishna Manohar SR Sandhyamani S Cerebral aneurysms in atrial myxoma: a delayed, rare manifestation Neurol India 2005 53 216 218 16010063\n6 Sedat J Chau Y Dunac A Gomez N Suissa L Mahagne MH Multiple cerebral aneurysms caused by cardiac myxoma. A case report and present state of knowledge Interv Neuroradiol 2007 13 179 184 20566147\n7 Radoi MP Stefanescu F Arsene D Brain metastases and multiple cerebral aneurysms from cardiac myxoma: case report and review of the literature Br J Neurosurg 2012 26 893 895 22686128\n8 Deng L Zhang J Wu T Lawrie TA Combination chemotherapy for primary treatment of high-risk gestational trophoblastic tumour Cochrane Database Syst Rev 2013 CD005196 23440800\n9 Song L Li Q Yin R Wang D Choriocarcinoma with brain metastasis after term pregnancy: A case report Medicine (Baltimore) 2018 97 e12904 30335019\n10 Hiramatsu Y Masuyama H Ishida M Murakami K Sakurai M Term delivery choriocarcinoma patient with brain and lung metastases successfully treated by etoposide, methotrexate, actomycin D, cyclophosphamide and vincristine (EMA-CO) chemotherapy Acta Med Okayama 2005 59 235 238 16286962\n11 Soper JT Spillman M Sampson JH Kirkpatrick JP Wolf JK Clarke-Pearson DL High-risk gestational trophoblastic neoplasia with brain metastases: individualized multidisciplinary therapy in the management of four patients Gynecol Oncol 2007 104 691 694 17137617\n12 Ngan HYS Seckl MJ Berkowitz RS Xiang Y Golfier F Sekharan PK Lurain JR Massuger L Update on the diagnosis and management of gestational trophoblastic disease Int J Gynaecol Obstet 2018 143 Suppl 2 79 85 30306586\n13 Frati A Ducarme G Wernet A Chuttur A Vilgrain V Luton D Uterine artery embolization as treatment for life-threatening haemorrhage from a cervical choriocarcinoma: a case report Eur J Obstet Gynecol Reprod Biol 2008 141 87 88 18649986\n14 Wreczycka-Cegielny P Cegielny T Oplawski M Sawicki W Kojs Z Current treatment options for advanced choriocarcinoma on the basis of own case and review of the literature Ginekol Pol 2018 89 711 715 30618041\n15 Ma Y Xiang Y Wan XR Chen Y Feng FZ Lei CZ Yang XY The prognostic analysis of 123 postpartum choriocarcinoma cases Int J Gynecol Cancer 2008 18 1097 1101 18021220\n16 Zhao FH Tiggelaar SM Hu SY Xu LN Hong Y Niyazi M Gao XH Ju LR Zhang LQ Feng XX Duan XZ Song XL Wang J Yang Y Li CQ Liu JH Lu YB Li L Zhou Q Liu JF Zhao N Schmidt JE Qiao YL A multi-center survey of age of sexual debut and sexual behavior in Chinese women: suggestions for optimal age of human papillomavirus vaccination in China Cancer Epidemiol 2012 36 384 390 22377277\n17 Lappin JM Darke S Duflou J Kaye S Farrell M Fatal Stroke in Pregnancy and the Puerperium Stroke 2018 49 3050 3053 30571397\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "9(30)",
"journal": "World journal of clinical cases",
"keywords": "Brain metastasis; Case report; Chemotherapy; Choriocarcinoma; Craniotomy; Uterine artery embolization; Whole brain radiotherapy",
"medline_ta": "World J Clin Cases",
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"pages": "9174-9181",
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"pmid": "34786402",
"pubdate": "2021-10-26",
"publication_types": "D002363:Case Reports",
"references": "30618041;25598530;23440800;30306586;18649986;22686128;22377277;17137617;30571397;16286962;25118474;18021220;16010063;30335019;26056347;10892763;20566147",
"title": "Choriocarcinoma misdiagnosed as cerebral hemangioma: A case report.",
"title_normalized": "choriocarcinoma misdiagnosed as cerebral hemangioma a case report"
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{
"abstract": "There are few case reports of concomitant chronic inflammatory demyelinating polyneuropathy (CIDP) and focal segmental glomerulosclerosis. A rare autoantibody to a neuronal and podocyte structural component, neurofascin, may be contributory. A Black man in his 40s presented with worsening polyneuropathy requiring mechanical ventilation and initially acute inflammatory demyelinating polyneuropathy was diagnosed. After a poor response to intravenous immunoglobulin, plasmapheresis was initiated. The patient also had concomitant new-onset nephrotic-range proteinuria. A limited kidney biopsy was interpreted as minimal change disease and was treated with prednisone. After some improvement, the patient was extubated; however, he later re-presented with worsening symptoms requiring mechanical ventilation and was re-treated with plasmapheresis. Due to the protracted course and poor response to intravenous immunoglobulin, acute-onset CIDP was diagnosed and a neuromuscular antibody workup returned positive for neurofascin, supporting the diagnosis of seropositive acute-onset CIDP. A repeat kidney biopsy demonstrated focal segmental glomerulosclerosis and acute tubular damage. The patient was treated with steroids and tacrolimus and later transitioned to rituximab. Neurofascin enzyme-linked immunosorbent assay then tested negative with concomitant resolution of both neuropathy and proteinuria. Further studies will help validate these findings and the treatment strategy.",
"affiliations": "SUNY Upstate Medical University, Syracuse, NY.;Duke University, Durham, NC.;University of Virginia, Charlottesville, VA.;Virginia Commonwealth University, Richmond, VA.;University of Virginia, Charlottesville, VA.;University of Virginia, Charlottesville, VA.",
"authors": "Bukhari|Syed|S|;Bettin|Margaret|M|;Cathro|Helen P|HP|;Gwathmey|Kelly|K|;Gautam|Jitendra|J|;Bowman|Brendan|B|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.xkme.2020.06.016",
"fulltext": "\n==== Front\nKidney Med\nKidney Med\nKidney Medicine\n2590-0595 Elsevier \n\nS2590-0595(20)30214-4\n10.1016/j.xkme.2020.06.016\nCase Report\nAnti-Neurofascin–Associated Nephrotic-Range Proteinuria in Chronic Inflammatory Demyelinating Polyneuropathy\nBukhari Syed 1 Bettin Margaret 2 Cathro Helen P. 3 Gwathmey Kelly 4 Gautam Jitendra 3 Bowman Brendan [email protected]∗ 1 SUNY Upstate Medical University, Syracuse, NY\n2 Duke University, Durham, NC\n3 University of Virginia, Charlottesville, VA\n4 Virginia Commonwealth University, Richmond, VA\n∗ Address for Correspondence: Brendan Bowman, MD, Division of Nephrology, PO Box 800133, 1300 Jefferson Park Ave, Charlottesville, VA 22908. [email protected]\n23 10 2020 \nNov-Dec 2020 \n23 10 2020 \n2 6 797 800\n© 2020 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).There are few case reports of concomitant chronic inflammatory demyelinating polyneuropathy (CIDP) and focal segmental glomerulosclerosis. A rare autoantibody to a neuronal and podocyte structural component, neurofascin, may be contributory. A Black man in his 40s presented with worsening polyneuropathy requiring mechanical ventilation and initially acute inflammatory demyelinating polyneuropathy was diagnosed. After a poor response to intravenous immunoglobulin, plasmapheresis was initiated. The patient also had concomitant new-onset nephrotic-range proteinuria. A limited kidney biopsy was interpreted as minimal change disease and was treated with prednisone. After some improvement, the patient was extubated; however, he later re-presented with worsening symptoms requiring mechanical ventilation and was re-treated with plasmapheresis. Due to the protracted course and poor response to intravenous immunoglobulin, acute-onset CIDP was diagnosed and a neuromuscular antibody workup returned positive for neurofascin, supporting the diagnosis of seropositive acute-onset CIDP. A repeat kidney biopsy demonstrated focal segmental glomerulosclerosis and acute tubular damage. The patient was treated with steroids and tacrolimus and later transitioned to rituximab. Neurofascin enzyme-linked immunosorbent assay then tested negative with concomitant resolution of both neuropathy and proteinuria. Further studies will help validate these findings and the treatment strategy.\n\nIndex Words\nFSGSanti-neurofascinnephrotic syndromeproteinuriaCIDPdemyelinating polyneuropathy\n==== Body\nIntroduction\nThere is limited knowledge regarding the pathogenesis of focal segmental glomerulosclerosis (FSGS) in the setting of chronic inflammatory demyelinating polyneuropathy (CIDP). Previous studies have listed complex immune dysregulation as a cause of neuron and podocyte injury; however, a definite cause remains elusive. We believe that a rare autoantibody to an intrinsic part of both neurons and podocytes may be contributing to both pathologic states. We present the first case of anti-neurofascin–seropositive CIDP with concurrent FSGS and provide evidence of the pathogenicity of this autoantibody for both pathologic states. Our case also illustrates a potential treatment strategy. As more cases are described and the pathophysiology is further elucidated, optimal treatment strategies can be instituted earlier in hopes of improving outcomes.\n\nCase Report\nA Black man in his 40s presented to the hospital with 2 weeks of lower extremity paresthesias and progressive weakness. Neurologic examination was notable for an inability to lift his arms against gravity, inability to walk unassisted, distal predominant decrease in vibration sensation, and diffuse areflexia. A lumbar puncture was performed, which noted an albuminocytologic gradient with white blood cell count of 11,000 μL and protein level of 127 mg/dL. An electromyogram and nerve conduction study demonstrated sural nerve-sparing sensorimotor neuropathy with prolonged and absent F waves, findings associated with a diagnosis of acute inflammatory demyelinating polyneuropathy. Also, conduction block and markedly reduced recruitment of normal-appearing motor unit potentials was noted, consistent with a diagnosis of acute inflammatory demyelinating polyneuropathy (Fig S1). The patient was treated with 2 g/kg of intravenous immunoglobulin (IVIG) over 5 days.\n\nConcomitantly, the patient was noted to have worsening bilateral lower extremity edema and new-onset proteinuria with protein excretion of 10 g on spot urinary albumin-creatinine ratio. A limited kidney biopsy with 3 glomeruli showed no glomerular abnormalities and tubulointerstitial damage on light microscopy and severe podocyte foot-process effacement on electron microscopy and was interpreted as minimal change disease. The patient was subsequently started on treatment with 1.0 mg/kg of prednisone daily.\n\nThe neuromuscular symptoms progressed and the patient subsequently developed respiratory failure requiring mechanical ventilation. It was then decided to treat with plasmapheresis for acute inflammatory demyelinating polyneuropathy progression. The patient underwent 7 sessions of plasmapheresis, after which he was able to be extubated with minimal motor improvement and was discharged to a skilled nursing facility. The patient re-presented within 1 week of discharge with worsening neurologic symptoms including quadriplegia, a complete lack of sensation throughout trunk and limbs, new-onset bulbar weakness, and autonomic dysfunction, including urinary retention and constipation. The patient was retreated with IVIG; however, the symptoms progressed, requiring reintubation and mechanical ventilation. After another 5 sessions of plasmapheresis, the patient was able to be extubated.\n\nGiven the acuity of onset, persistence of symptoms, and refractory course, there was concern for an atypical acute-onset seropositive CIDP, and blood testing for neuromuscular antibodies including neurofascin 155 (NF155), NF140, and contactin-1 antibodies was sent.\n\nConcurrently, proteinuria had also worsened to protein excretion of 24 g on spot urinary albumin-creatinine ratio despite continued prednisone therapy. A repeat kidney biopsy showed 1 of 12 glomeruli with segmental sclerosis, and acute tubular damage on light microscopy, no deposits on immunofluorescence, and severe podocyte foot-process effacement on electron microscopy (Fig 1). Given these findings, FSGS was diagnosed and tacrolimus therapy was initiated. In addition, the patient was started on weekly treatment with pulse methylprednisolone, 1,000 mg, intravenously. One week after the first treatment, the patient was able to move his distal extremities in the plane of the bed. Given this rapid improvement, the patient was discharged to a rehabilitation facility and, on follow-up in the neuromuscular clinic 5 weeks after discharge, walked into the clinic unassisted with only minimal weakness at hip flexors bilaterally (4/5). The demyelinating antibody workup returned positive for autoantibodies against NF140 and NF155, which have been reported with IVIG-refractory acute-onset seropositive CIDP.Figure 1 (A) Light microscopy: glomerulus with segmental sclerosis. (B) Electron microscopy: severe visceral podocyte effacement.\n\n\n\nHigh-dose steroid and tacrolimus treatments were continued for 6 months and on follow-up, complete remission of proteinuria had been achieved in association with resolution of the neuropathy. The patient was then transitioned to rituximab therapy and was tested again for the neurofascin antibody after a single dose of 1 g. An enzyme-linked immunosorbent assay was negative for the neurofascin antibody and the patient has no neurologic or kidney disease recurrence at the 1-year follow-up.\n\nDiscussion\nThis case makes 3 important points that may affect future care. First, this case provides a rare phenotype of acute-onset anti-neurofascin CIDP in association with FSGS. Second, this case supports the role of anti-neurofascin antibodies in seropositive CIDP. Finally, this case demonstrates the importance of clarifying disease phenotypes and antibodies for early optimal treatment.\n\nNeurofascin is a cell adhesion molecule located in the paranodal region of the node of Ranvier and axonal initial segment, which is responsible for the initial formation of the action potential.1 It is critical to saltatory conduction, axonal subcellular targeting, and synapse formation during neural development. It is also integral for cell-to-cell contact between axon and myelin loops from Schwann cells. There are 3 recognized isoforms of neurofascin termed NF140, NF155, and NF186.2 NF140 and NF186 are produced by neuronal cells and are located at nodal and axonal initial segments. NF155 is produced by glial cells and is located within the paranodal junction.1, 2, 3, 4\n\nThe most common autoantibodies to neurofascin belong to the immunoglobulin G4 (IgG4) subclass.2 Autoantibodies against neurofascin have been found in 2% to 7% of patients with CIDP. This subset of CIDP has been increasingly recognized as acute-onset seropositive CIDP.5 Moreover, the pathology caused by these antibodies is referred to as a nodopathy/paranodopathy. Paranodopathies are characterized by dissection of myelin loops from the axon at the paranode and subsequent axonal degeneration.6 Notably, neurofascin is also a component of the podocyte cytoskeleton and has been reportedly involved in glomerulogenesis and podocyte maturation. Studies have shown that neurofascin is closely associated with vimentin, an integral part of podocyte major processes that are made of bundles of microtubules and intermediate filaments. This close association suggests their role in cell-cell contact and microtubule cytoskeletal support. Further studies are needed to better elucidate the physiologic role of neurofascin in podocytes.7\n\nCIDP is traditionally seronegative with an incidence reported between 0.8 and 0.9 per 100,000 patients. Seronegative CIDP is characterized by symmetric proximal and distal weakness with paresthesias that typically progress over 8 weeks. Treatment consists of IVIG, corticosteroids, and plasma exchange, and overall, 80% to 90% of patients improve with one of these therapies.8 Acute-onset seropositive CIDP generally manifests in a younger patient demographic with a subacute and more severe presentation, distal dominant weakness, sensory ataxia, tremor, and, importantly, refractory to IVIG.5,6\n\nThere have been a few case reports of seronegative CIDP associated with proteinuria. However, most of these cases have been reported with membranous nephropathy.9 The pathogenesis of concomitant CIDP and FSGS has been poorly understood to date. To our knowledge, there have been only a few known cases of CIDP and concomitant FSGS.10, 11, 12 Previous cases have proposed a common antigenic target on neuronal and renal cells, host immunologic factors affected by dysregulated T- and B-cell responses,10 and immunologic mechanisms13,14 as potential underlying pathologies. One of the case reports suggested inverted formin 2 expression on Schwann cells and podocytes to be the target of antibodies.15 Two case reports discussed dysregulation of cellular and humoral responses resulting in the formation of antibodies to monosialoganglioside GM1 of the IgG1 subclass, along with deposition of a circulating immune complex in the setting of increased interleukin 2 and vascular endothelial growth factor levels and increased capillary permeability.10,11 A decreased erythropoietin level in the setting of nephropathy and its role as a neurotrophic factor, vital to neuronal growth and myelin integrity, was also deemed responsible for neuropathy in another report.9\n\nThe previous cases of seropositive CIDP have reported a poor or suboptimal response to the use of IVIG. In a study of 533 patients with CIDP, neurofascin antibodies were identified in 38 patients and 80% of these patients had a poor response to IVIG.5 After a transient improvement with steroids and plasma exchange, a rebound was noted after 2 to 3 weeks. A benefit has been reported with steroids and other immunotherapies including cyclophosphamide and rituximab.16,17 Rituximab has been used successfully in other IgG4-mediated diseases and is known to reduce IgG4 titers.18\n\nThere are only a few case reports in which anti-neurofascin antibodies have been isolated in concomitant seropositive CIDP and FSGS. The pathogenesis of anti-neurofascin antibodies and their production and prognosis remain undefined. In our patient, neurofascin antibody was initially isolated and then was negative on enzyme-linked immunosorbent assay testing after treatment (Fig 2). These results support the need to further study the role of neurofascin autoantibody in patients with concomitant CIDP and FSGS.Figure 2 Neurofascin sandwich enzyme-linked immunosorbent assay (ELISA) results demonstrate the lack of neurofascin-specific binding in patient serum. This inference is based on comparison of values between patient serum versus control serum and positive control values. Abbreviation: AB, antibody.\n\n\n\nBecause there are no guidelines for an optimal treatment regimen for such patients, we propose that in patients suspected of seropositive CIDP with or without proteinuria, anti-neurofascin antibodies should be checked. Furthermore, these patients should initially be offered plasma exchange and/or steroid therapy along with immunomodulation with either calcineurin inhibitors or rituximab. Further studies are needed to validate these findings.\n\nSupplementary Material\nSupplementary File (PDF)\nFigure S1.\n\n \n\nArticle Information\nAuthors’ Full Names and Academic Degrees\nSyed Bukhari, MD, Margaret Bettin, MD, Helen P. Cathro, MBChB, MPH, Kelly Gwathmey, MD, Jitendra Gautam, PhD, and Brendan Bowman, MD.\n\nSupport\nNone.\n\nFinancial Disclosure\nThe authors declare that they have no relevant financial interests.\n\nAcknowledgements\nWe thank Mark Okusa, MD, and Kambiz Kalantari, MD, of the University of Virginia for providing valuable input and support for this project.\n\nPrior Presentation\nAbstract accepted as a poster at The ISN World Congress of Nephrology on April 12-15, 2019 at Melbourne, Australia.\n\nPatient Consent\nThe authors declare that they have obtained consent from the patient discussed in the report.\n\nPeer Review\nReceived March 23, 2020. Evaluated by 1 external peer reviewer, with direct editorial input from an Associate Editor and the Editor-in-Chief. Accepted in revised form June 28, 2020.\n\nComplete author and article information provided before references.\n\nSupplementary File (PDF)\n\nFigure S1: Nerve conduction study (NCS): the image on the left demonstrates conduction block in the right peroneal nerve. The image on the right demonstrates the presence of an F wave in the right tibial nerve.\n==== Refs\nReferences\n1 Zonta B. Desmazieres A. Brophy P.-J. A critical role for neurofascin in regulating action potential initiation through maintenance of the axon initial segment Neuron 69 5 2011 945 956 21382554 \n2 Delmont E. Manso C. Devaux J.-J. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy Brain 140 7 2017 1851 1858 28575198 \n3 Vallat J.-M. Yuki N. Devaux J.J. Paranodal lesions in chronic inflammatory demyelinating polyneuropathy associated with anti-neurofascin 155 antibodies Neuromusc Disord 27 3 2017 290 293 27986399 \n4 Zhang A. Desmazieres A. Brophy P.-J. Neurofascin 140 is an embryonic neuronal neurofascin isoform that promotes the assembly of the node of Ranvier J Neurosci 35 5 2015 2246 2254 25653379 \n5 Devaux J.J. Miura Y. Yuki N. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy Neurology 86 9 2016 800 807 26843559 \n6 Vural A. Doppler K. Meinl E. Autoantibodies against the node of Ranvier in seropositive chronic inflammatory demyelinating polyneuropathy: diagnostic, pathogenic, and therapeutic relevance Front Immunol 9 2018 1029 29867996 \n7 Sistani L. Rodriguez P.-Q. Patrakka J. Neuronal proteins are novel components of podocyte major processes and their expression in glomerular crescents supports their role in crescent formation Kidney Int 83 1 2013 63 71 22913984 \n8 Cocito D. Paolasso I. Nobile-Orazio E. A nationwide retrospective analysis on the effect of immune therapies in patients with chronic inflammatory demyelinating polyradiculoneuropathy Eur J Neurol 17 2 2010 289 294 19863650 \n9 Smyth S. Menkes D.L. Coincident membranous glomerulonephritis and chronic inflammatory demyelinating polyradiculoneuropathy: questioning the autoimmunity hypothesis Muscle Nerve 37 1 2008 130 135 17614320 \n10 Girolami F. Galassi G. Cappelli G. Coincident chronic inflammatory demyelinating polyneuropathy and focal segmental glomerulosclerosis: a common autoimmunity? Clin Exp Nephrol 14 3 2010 294 295 20049621 \n11 Olbricht C.J. Stark E. Koch K.-M. Glomerulonephritis associated with inflammatory demyelinating polyradiculoneuropathy: a case report and review of the literature Nephron 64 1 1993 139 141 8502319 \n12 Souayah N. Cros D. Chong P.S.T. Relapsing Guillain Barré syndrome and nephrotic syndrome secondary to focal segmental glomerulosclerosis J Neurol Sci 270 1-2 2008 184 188 18325535 \n13 Kohli A. Tandon P. Kher V. Chronic inflammatory demyelinating polyradiculoneuropathy with membranous glomerulonephritis: report of one case Clin Neurol Neurosurg 94 1 1992 31 33 1321695 \n14 Wu A.D. Russell J.A. Bouthout B.A. Chronic inflammatory demyelinating polyneuropathy and membranous glomerulonephropathy: report of two cases J Clin Neuromusc Dis 3 2 2001 70 74 \n15 Quek A.M.L. Soon D. Yuki N. Acute-onset chronic inflammatory demyelinating polyneuropathy with focal segmental glomerulosclerosis J Neurol Sci 41 1-2 2014 139 143 \n16 Chen K.-H. Chang C.-T. Hung C.-C. Glomerulonephritis associated with chronic inflammatory demyelinating polyneuropathy Ren Fail 28 3 2006 255 259 16703799 \n17 Querol L. Rojas-García R. Illa I. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins Neurol Neuroimmunol Neuroinflamm 2 5 2015 e149 26401517 \n18 Quattrocchio G. Barreca A. Roccatello D. IgG4-related kidney disease: the effects of a rituximab-based immunosuppressive therapy Oncotarget 9 2018 21337 21347 29765543\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2590-0595",
"issue": "2(6)",
"journal": "Kidney medicine",
"keywords": "CIDP; FSGS; anti-neurofascin; demyelinating polyneuropathy; nephrotic syndrome; proteinuria",
"medline_ta": "Kidney Med",
"mesh_terms": null,
"nlm_unique_id": "101756300",
"other_id": null,
"pages": "797-800",
"pmc": null,
"pmid": "33319203",
"pubdate": "2020",
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"title": "Anti-Neurofascin-Associated Nephrotic-Range Proteinuria in Chronic Inflammatory Demyelinating Polyneuropathy.",
"title_normalized": "anti neurofascin associated nephrotic range proteinuria in chronic inflammatory demyelinating polyneuropathy"
}
|
[
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{
"abstract": "Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical manifestations are diverse and can vary from mild respiratory symptoms to severe hypoxic respiratory failure. In severe cases, infection can cause gastrointestinal, renal, cardiac, neurological and haematological complications and result in multi-organ failure. There are very few reports of parapneumonic effusion in patients with COVID-19. We describe two patients with COVID-19 who had loculated empyema and discuss the clinical course and therapeutic options.\nThe clinical manifestations of COVID-19 vary from mild to severe disease and can result in multi-organ failure.Pleural empyema is usually treated with a combination of antibiotics and surgical drainage of the pleural cavity.",
"affiliations": "Internal Medicine, Rutgers-New Jersey Medical School/Trinitas Regional Medical Center, Elizabeth, New Jersey, USA.;Internal Medicine, McLaren Health Care, Flint, Michigan, USA.;Internal Medicine, Rutgers-New Jersey Medical School/Trinitas Regional Medical Center, Elizabeth, New Jersey, USA.;St. George's University, Grenada, West Indies.;Internal Medicine, McLaren Health Care, Flint, Michigan, USA.;Internal Medicine, Rutgers-New Jersey Medical School/Trinitas Regional Medical Center, Elizabeth, New Jersey, USA.;Department of Pulmonology, Trinitas Regional Medical Center, Elizabeth, New Jersey, USA.",
"authors": "Ayad|Sarah|S|;Gergis|Kirolos|K|;Elkattawy|Sherif|S|;Mirza|Noreen|N|;Abdelazeem|Basel|B|;Patel|Latika|L|;Remolina|Carlos|C|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2021_002706",
"fulltext": null,
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"issn_linking": "2284-2594",
"issue": "8(7)",
"journal": "European journal of case reports in internal medicine",
"keywords": "COVID-19; Empyema; SARS-CoV-2; loculated pleural effusion",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "002706",
"pmc": null,
"pmid": "34377699",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "32436847;32983308;17990232;17548905;32226823;17258562;33831700;22276145;32425337;33221888;4699956",
"title": "Loculated Empyema and SARS-CoV-2 Infection: A Report of Two Cases and Review of the Literature.",
"title_normalized": "loculated empyema and sars cov 2 infection a report of two cases and review of the literature"
}
|
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},
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"drugindication": "Infectious pleural effusion",
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"activesubstancename": "DEXTROSE"
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"activesubstancename": "GLUCAGON"
},
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"drugdosagetext": "1 MILLIGRAM, UNK",
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"drugindication": "Product used for unknown indication",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "GLUCAGON"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
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"drugdosageform": null,
"drugdosagetext": "3 LITER, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Product used for unknown indication",
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"medicinalproduct": "OXYGEN"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
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"drugadministrationroute": "065",
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Antibiotic therapy",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MEROPENEM"
}
],
"patientagegroup": null,
"patientonsetage": "73",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Ayad S, Gergis K, Elkattawy S, Mirza N, Abdelazeem B, Patel L, et al. Loculated empyema and SARS-CoV-2 infection: A report of two cases and review of the literature. European Journal of Case Reports in Internal Medicine.. 2021;8(7)",
"literaturereference_normalized": "loculated empyema and sars cov 2 infection a report of two cases and review of the literature",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20220526",
"receivedate": "20220526",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20876710,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220720"
}
] |
{
"abstract": "Antibiotic prophylaxis is a routine procedure in management of burns. As such it is a safe practice, yet unusual complications can occur with the use of even safest antibiotics and their emergency management may be life saving. Here we present a case of 35% second and third degree burns who was taken for a second sitting of stamp grafting for remnant raw areas, who was administered intraoperative prophylactic antibiotic, developed a series of unusual complications sequentially, which were life threatening. Prompt recognition of signs and symptoms of adverse reactions of the drug used and timely management resulted in the successful outcome. A good team effort by surgeon, anaesthetist and the physician was mandatory.",
"affiliations": "B/h Civil Hospital, Ahmedabad, India.",
"authors": "Pillai|T A|TA|;Jalewa|A K|AK|;Chadha|I A|IA|",
"chemical_list": "D002511:Cephalosporins; D002439:Cefotaxime",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/s0305-4179(98)00106-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-4179",
"issue": "24(8)",
"journal": "Burns : journal of the International Society for Burn Injuries",
"keywords": null,
"medline_ta": "Burns",
"mesh_terms": "D000328:Adult; D000707:Anaphylaxis; D019072:Antibiotic Prophylaxis; D002056:Burns; D002439:Cefotaxime; D002511:Cephalosporins; D004211:Disseminated Intravascular Coagulation; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D019106:Postoperative Hemorrhage; D016038:Skin Transplantation",
"nlm_unique_id": "8913178",
"other_id": null,
"pages": "760-2",
"pmc": null,
"pmid": "9915680",
"pubdate": "1998-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antibiotic prophylaxis--Hobson's choice in burns management.",
"title_normalized": "antibiotic prophylaxis hobson s choice in burns management"
}
|
[
{
"companynumb": "IN-VALIDUS PHARMACEUTICALS LLC-IN-2021VAL000971",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "DIAZEPAM."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DICLOFENAC SODIUM"
},
"drugadditional": null,
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"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DICLOFENAC SODIUM."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE BITARTRATE\\LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": null,
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"medicinalproduct": "LIGNOCAINE WITH ADRENALINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "050547",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 G (INJECTION)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstructuredosageunit": "002",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CEFOTAXIME SODIUM"
}
],
"patientagegroup": null,
"patientonsetage": "26",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Ecchymosis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Irritability",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Anaphylactic reaction",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Disseminated intravascular coagulation",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Aggression",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hyperhidrosis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cyanosis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Skin haemorrhage",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PILLAI TA, JALEWA AK,CHADHA IA. ANTIBIOTIC PROPHYLAXIS HOBSON^S CHOICE IN BURNS MANAGEMENT. BURNS. 1998?24:760?2",
"literaturereference_normalized": "antibiotic prophylaxis hobson s choice in burns management",
"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20210405",
"receivedate": "20210405",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19094730,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20210717"
},
{
"companynumb": "IN-SA-2018SA300957",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPINEPHRINE BITARTRATE\\LIDOCAINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1% LIGNOCAINE AND ADRENALINE IN THE CONCENTRATION OF 1:1000 AMOUNTING TO 30 CC",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LIGNOCAINE WITH ADRENALINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "INJECTION",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DIAZEPAM."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "062659",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 G (INJECTION)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "002",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CEFOTAXIME SODIUM"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC SODIUM"
},
"drugadditional": "3",
"drugadministrationroute": "030",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "ONE AMPOULE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DICLOFENAC SODIUM."
}
],
"patientagegroup": "5",
"patientonsetage": "26",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Disseminated intravascular coagulation",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cyanosis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Skin haemorrhage",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Aggression",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Irritability",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Ecchymosis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hyperhidrosis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Anaphylactic reaction",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PILLAI TA, JALEWA AK,CHADHA IA.. ANTIBIOTIC PROPHYLAXIS HOBSON^S CHOICE IN BURNS MANAGEMENT. BURNS. 1998?24:760-2",
"literaturereference_normalized": "antibiotic prophylaxis hobson s choice in burns management",
"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20181105",
"receivedate": "20181105",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15587511,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20190205"
}
] |
{
"abstract": "OBJECTIVE\nTo clarify whether anti-epileptic drug exposure during pregnancy is associated with an increased risk of intrauterine foetal death.\n\n\nMETHODS\nAnalysis of data from 2064 pregnancies with known outcomes included in the Australian Register of Antiepileptic Drugs in Pregnancy, 170 of the pregnancies being unexposed to the drugs in at least the first half of pregnancy.\n\n\nRESULTS\nThe relative risk (6.46; 95% C.I. 0.90, 46.22) of intrauterine death appeared higher, though not statistically significantly higher, in drug-exposed pregnancies compared with unexposed ones (3.44% vs 0.59%). There was no statistically significantly increased hazard associated with AED polytherapy as compared with monotherapy. Logistic regression analysis showed a statistically significantly increased and dose-related hazard of intrauterine death in relation to carbamazepine exposure.\n\n\nCONCLUSIONS\nIntrauterine exposure to anti-epileptic drugs, particularly carbamazepine, may be associated with an increased risk of foetal death during pregnancy.",
"affiliations": "Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.;Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.;Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.;Department of Medicine and Neurosciences, Royal Melbourne Hospital and University of Melbourne, Parkville, VIC, Australia.;Royal Brisbane and Women's Hospital and School of Medicine and Biomedical Science, University of Queensland, Brisbane, QLD, Australia.;Royal Brisbane and Women's Hospital and School of Medicine and Biomedical Science, University of Queensland, Brisbane, QLD, Australia.",
"authors": "Vajda|F J E|FJE|http://orcid.org/0000-0001-5570-7538;O'Brien|T J|TJ|;Graham|J|J|;Hitchcock|A A|AA|;Lander|C M|CM|;Eadie|M J|MJ|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ane.12816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6314",
"issue": "137(1)",
"journal": "Acta neurologica Scandinavica",
"keywords": "anti-epileptic drugs; carbamazepine; foetal death; spontaneous abortion; stillbirth",
"medline_ta": "Acta Neurol Scand",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D001315:Australia; D002220:Carbamazepine; D004827:Epilepsy; D005260:Female; D005313:Fetal Death; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D012042:Registries; D012306:Risk",
"nlm_unique_id": "0370336",
"other_id": null,
"pages": "20-23",
"pmc": null,
"pmid": "28857118",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anti-epileptic drug exposure and risk of foetal death in utero.",
"title_normalized": "anti epileptic drug exposure and risk of foetal death in utero"
}
|
[
{
"companynumb": "AU-UNICHEM PHARMACEUTICALS (USA) INC-UCM201806-000146",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "090162",
"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": "TOPIRAMATE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal death",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VAJDA F, O BRIEN T, GRAHAM J, HITCHCOCK A, LANDER C, EADIE M. ANTI?EPILEPTIC DRUG EXPOSURE AND RISK OF FOETAL DEATH IN UTERO. ACTA NEUROLOGICA SCANDINAVICA (2018). 2018 JAN 01?137 (1):20?23.",
"literaturereference_normalized": "anti epileptic drug exposure and risk of foetal death in utero",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": null,
"receiptdate": "20180703",
"receivedate": "20180703",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 15099858,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20181010"
}
] |
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