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{
"abstract": "Two dialysis-dependent patients with end-stage renal disease underwent brain and spine MR imaging a few days after having undergone gadolinium-enhanced imaging studies. Increased signal intensity in the subarachnoid space on T1-weighted and fluid-attenuated inversion recovery images was noted. Excretion of gadolinium into the CSF was proven in one case by mass spectrometry. Dialysis-dependent patients with end-stage renal disease and neurologic abnormalities often undergo contrast-enhanced MR imaging. Recognition that these patients may show increased signal intensity in the subarachnoid space because of gadolinium excretion into CSF may prevent diagnostic errors.",
"affiliations": "Department of Radiology, West Virginia University, 2278 HSCS, Morgantown, WV 26506-9235, USA.",
"authors": "Rai|A T|AT|;Hogg|J P|JP|",
"chemical_list": "D003287:Contrast Media; D005682:Gadolinium",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-6108",
"issue": "22(7)",
"journal": "AJNR. American journal of neuroradiology",
"keywords": null,
"medline_ta": "AJNR Am J Neuroradiol",
"mesh_terms": "D000368:Aged; D001812:Blood-Brain Barrier; D001921:Brain; D002552:Cerebral Ventricles; D003287:Contrast Media; D003937:Diagnosis, Differential; D005260:Female; D005682:Gadolinium; D006801:Humans; D007676:Kidney Failure, Chronic; D007677:Kidney Function Tests; D008159:Lumbar Vertebrae; D008279:Magnetic Resonance Imaging; D008657:Metabolic Clearance Rate; D010531:Peritoneal Dialysis, Continuous Ambulatory; D006435:Renal Dialysis; D013346:Subarachnoid Space",
"nlm_unique_id": "8003708",
"other_id": null,
"pages": "1357-61",
"pmc": null,
"pmid": "11498427",
"pubdate": "2001-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10227646;10639034;4630265;10541135;10063891;10189481;10997567;10077031;9456974;9653466;4418317;1885275;10669233;7549213;1743921;9275912;9866990;7960618",
"title": "Persistence of gadolinium in CSF: a diagnostic pitfall in patients with end-stage renal disease.",
"title_normalized": "persistence of gadolinium in csf a diagnostic pitfall in patients with end stage renal disease"
} | [
{
"companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OSCN-PR-1506L-0118",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOLINIUM"
},
"drugadditional": null,
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"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": null,
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"drugindication": "PERITONITIS",
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"medicinalproduct": "GADOLINIUM (UNSPECIFIED)"
},
{
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"activesubstancename": "GADOLINIUM"
},
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"medicinalproduct": "GADOLINIUM (UNSPECIFIED)"
},
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"medicinalproduct": "GADOLINIUM (UNSPECIFIED)"
}
],
"patientagegroup": null,
"patientonsetage": "70",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "False positive investigation result",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nuclear magnetic resonance imaging abnormal",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RAI A,HOGG J. PERSISTENCE OF GADOLINIUM IN CSF: A DIAGNOSTIC PITFALL IN PATIENTS WITH END-STAGE RENAL DISEASE. AMERICAN JOURNAL OF NEURORADIOLOGY. 2001 AUG 01;22:1357-1361.",
"literaturereference_normalized": "persistence of gadolinium in csf a diagnostic pitfall in patients with end stage renal disease",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150616",
"receivedate": "20150616",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11194018,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
},
{
"companynumb": "US-GE HEALTHCARE MEDICAL DIAGNOSTICS-OSCN-PR-1506L-0119",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
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"activesubstance": {
"activesubstancename": "GADOLINIUM"
},
"drugadditional": null,
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"drugindication": "MUSCULAR WEAKNESS",
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"medicinalproduct": "GADOLINIUM (UNSPECIFIED)"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOLINIUM"
},
"drugadditional": null,
"drugadministrationroute": "065",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "BACK PAIN",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "GADOLINIUM (UNSPECIFIED)"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOLINIUM"
},
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"drugindication": "DIAGNOSTIC PROCEDURE",
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"medicinalproduct": "GADOLINIUM (UNSPECIFIED)"
}
],
"patientagegroup": null,
"patientonsetage": "74",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "False positive investigation result",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Nuclear magnetic resonance imaging abnormal",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "RAI A,HOGG J. PERSISTENCE OF GADOLINIUM IN CSF: A DIAGNOSTIC PITFALL IN PATIENTS WITH END-STAGE RENAL DISEASE. AMERICAN JOURNAL OF NEURORADIOLOGY. 2001 AUG 01;22:1357-1361.",
"literaturereference_normalized": "persistence of gadolinium in csf a diagnostic pitfall in patients with end stage renal disease",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150616",
"receivedate": "20150616",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11194032,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "BACKGROUND\nFingolimod is a widely used treatment for highly active relapsing-remitting multiple sclerosis.\n\n\nOBJECTIVE\nTo describe the case of a 27-year-old patient treated for more than 2 years by Fingolimod, who presented hemiplegia and speech disturbances associated with extensive white matter lesions on brain magnetic resonance imaging (MRI).\n\n\nMETHODS\nCase study.\n\n\nRESULTS\nAlthough initial presentation questioned the possibility of progressive multifocal leukoencephalopathy, final diagnosis was multiple sclerosis (MS) relapse. Appropriate treatment resulted in clinical and radiological improvement.\n\n\nCONCLUSIONS\nSevere MS relapses under Fingolimod have been reported, but late onset after treatment initiation and extensive subcortical topography is unusual and represents a diagnostic challenge.",
"affiliations": "Neurology Department, Pitié-Salpêtrière Hospital, APHP, Paris, France.;Neurology Department, Pitié-Salpêtrière Hospital, APHP, Paris, France.;Diagnostic and Functional Neuroradiology Department, Pitié-Salpêtrière Hospital, APHP, Paris, France/Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Inria Paris-Rocquencourt, Paris, France.;Neurology Department, Pitié-Salpêtrière Hospital, APHP, Paris, France.;Neurology Department, Pitié-Salpêtrière Hospital, APHP, Paris, France.;Neurology Department, Pitié-Salpêtrière Hospital, APHP, Paris, France.;Neurology Department, Pitié-Salpêtrière Hospital, APHP, Paris, France.",
"authors": "Boudot de la Motte|Marine|M|;Louapre|Céline|C|;Bertrand|Anne|A|;Reach|Pauline|P|;Lubetzki|Catherine|C|;Papeix|Caroline|C|;Maillart|Elisabeth|E|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069442:Natalizumab; D000068876:Fingolimod Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1177/1352458516682858",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "23(4)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "MRI; Multiple sclerosis; fingolimod; progressive multifocal leukoencephalopathy",
"medline_ta": "Mult Scler",
"mesh_terms": "D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D007968:Leukoencephalopathy, Progressive Multifocal; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D016896:Treatment Outcome; D066127:White Matter",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "614-616",
"pmc": null,
"pmid": "28273764",
"pubdate": "2017-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Extensive white matter lesions after 2 years of fingolimod: Progressive multifocal leukoencephalopathy or MS relapse?",
"title_normalized": "extensive white matter lesions after 2 years of fingolimod progressive multifocal leukoencephalopathy or ms relapse"
} | [
{
"companynumb": "FR-Zentiva-2021-ZT-010561",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FINGOLIMOD"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "208005",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Multiple sclerosis",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "FINGOLIMOD"
}
],
"patientagegroup": null,
"patientonsetage": "27",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Speech disorder",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hemiplegia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Multiple sclerosis relapse",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "De La Motte M, Louapre C, Bertrand A, Reach P, Lubetzki C, Papeix C, et al.. Extensive white matter lesions after 2 years of fingolimod: Progressive multifocal leukoencephalopathy or MS relapse. Multiple sclerosis journal. 2017;23:4:614-616",
"literaturereference_normalized": "extensive white matter lesions after 2 years of fingolimod progressive multifocal leukoencephalopathy or ms relapse",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20211116",
"receivedate": "20211116",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20074834,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 1,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
},
{
"companynumb": "PHHY2017FR068394",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD HYDROCHLORIDE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "022527",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "CAPSULE",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RELAPSING-REMITTING MULTIPLE SCLEROSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "201306",
"drugstartdateformat": "610",
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "GILENYA"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GLATIRAMER ACETATE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": "201110",
"drugenddateformat": "610",
"drugindication": "MULTIPLE SCLEROSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "GLATIRAMER ACETATE."
}
],
"patientagegroup": null,
"patientonsetage": "27",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Multiple sclerosis relapse",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hypoaesthesia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hemiplegia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Speech disorder",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "White matter lesion",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Multiple sclerosis relapse",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cerebellar ataxia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2013"
}
},
"primarysource": {
"literaturereference": "MOTTE MBDL, LOUAPRE C, BERTRAND A, REACH P, LUBETZKI C, PAPEIX C ET AL.. EXTENSIVE WHITE MATTER LESIONS AFTER 2 YEARS OF FINGOLIMOD: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY OR MS RELAPSE?. MULTIPLE SCLEROSIS JOURNAL. 2017;23 (4):614-6",
"literaturereference_normalized": "extensive white matter lesions after 2 years of fingolimod progressive multifocal leukoencephalopathy or ms relapse",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20170512",
"receivedate": "20170512",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13541782,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
}
] |
{
"abstract": "Trastuzumab and pertuzumab are monoclonal antibodies used for the treatment of breast cancer. Until now, there have been no reports on the use of pertuzumab during pregnancy and on its potential effects on the fetus. Herein, we present a breast cancer patient who received trastuzumab and pertuzumab treatment during the first 20 weeks of pregnancy. This 22-year-old patient initially diagnosed with invasive ductal carcinoma of the breast was found to be negative for estrogen receptor and progesterone receptor and positive for human epidermal growth factor receptor in the immunohistochemical examination. At the time of diagnosis, she had metastatic lesions and a protocol of docetaxel, trastuzumab, pertuzumab, q21, and zolendronic acid 4 mg every month was started. Following six courses of therapy, she had near-complete response, and, after administration of the same course of treatment for two additional cycles, treatment with pertuzumab plus trastuzumab was continued. While she was being followed-up with remission, a 20-week pregnancy was detected. A fetal ultrasound examination showed oligohydramnios and right renal agenesis. Treatment was stopped, and the fetus was monitored. After 7 weeks of follow-up, fetal growth retardation and anhydramnios were detected. The pregnancy was terminated. Fetal autopsy showed no urinary system pathology, but macroscopic and microscopic hyperplasia of the right adrenal gland was identified. Concomitant use of pertuzumab and trastuzumab during pregnancy may be associated with an unresolved oligohydramnios and/or anhydramnios risk. Extreme caution should be used when these monoclonal antibodies are administered during pregnancy.",
"affiliations": "Department of Medical Oncology, Dr Ersin Arslan Training and Research Hospital, Gaziantep, Turkey.",
"authors": "Yildirim|Nilgun|N|;Bahceci|Aykut|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; C485206:pertuzumab; D000068878:Trastuzumab",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000658",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "29(8)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000077143:Docetaxel; D005260:Female; D005333:Fetus; D006801:Humans; D016104:Oligohydramnios; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D000068878:Trastuzumab; D055815:Young Adult",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "810-813",
"pmc": null,
"pmid": "30110018",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of pertuzumab and trastuzumab during pregnancy.",
"title_normalized": "use of pertuzumab and trastuzumab during pregnancy"
} | [
{
"companynumb": "TR-SA-2018SA287192",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PERTUZUMAB"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "3",
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"drugdosagetext": "840 MG, LOADING DOSE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BREAST CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugseparatedosagenumb": null,
"drugstartdate": "201609",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "840",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PERTUZUMAB."
},
{
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"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
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"drugdosagetext": "6 MG/KG, MAINTENANCE DOSE",
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"medicinalproduct": "TRASTUZUMAB."
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{
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"drugstructuredosageunit": "009",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DOCETAXEL."
},
{
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"activesubstancename": "TRASTUZUMAB"
},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TRASTUZUMAB."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PERTUZUMAB"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "3",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "420 MG, MAINTENANCE DOSE, IN EVERY 21 DAYS",
"drugenddate": null,
"drugenddateformat": null,
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"drugstructuredosagenumb": "420",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PERTUZUMAB."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "4 MG, QM",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BREAST CANCER",
"drugintervaldosagedefinition": "802",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "201609",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "4",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ZOLEDRONIC ACID."
}
],
"patientagegroup": "5",
"patientonsetage": "22",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Abortion induced",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal movement disorder",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abdominal distension",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oligohydramnios",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YILDIRIM N., BAHCECI A.. USE OF PERTUZUMAB AND TRASTUZUMAB DURING PREGNANCY.. ANTI-CANCER DRUGS. 2018?29:8:810-813",
"literaturereference_normalized": "use of pertuzumab and trastuzumab during pregnancy",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20181120",
"receivedate": "20181017",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15516819,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
},
{
"companynumb": "TR-MYLANLABS-2018M1068505",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PERTUZUMAB"
},
"drugadditional": "1",
"drugadministrationroute": "064",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "THE MOTHER RECEIVED PERTUZUMAB 840 MG LOADING AND 420 MG MAINTENANCE EVERY 21 DAYS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INVASIVE DUCTAL BREAST CARCINOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PERTUZUMAB."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "1",
"drugadministrationroute": "064",
"drugauthorizationnumb": "761074",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "THE MOTHER RECEIVED 8 MG/KG LOADING AND 6 MG/KG MAINTENANCE DOSES",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INVASIVE DUCTAL BREAST CARCINOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TRASTUZUMAB."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Renal aplasia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Foetal growth restriction",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Adrenogenital syndrome",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YILDIRIM N, BAHCECI A. USE OF PERTUZUMAB AND TRASTUZUMAB DURING PREGNANCY. ANTICANCER?DRUGS 2018?29(8):810?813.",
"literaturereference_normalized": "use of pertuzumab and trastuzumab during pregnancy",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20180924",
"receivedate": "20180924",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15417983,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 1,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20181010"
}
] |
{
"abstract": "Vitamin B6 is a rate-limiting coenzyme that plays an important role in the biosynthesis of heme and the incorporation of iron into protoporphyrin. Its deficiency is often seen in chronic kidney disease (CKD), particularly those requiring dialysis and following administration of erythropoietin-stimulating agent (ESA).\n\n\n\nA 16-year-old African-American male with stage 5 CKD on chronic hemodialysis experienced a decrease in hemoglobin over a 3-month period from 11 to 6.5 g/dl while receiving ESA, resulting in multiple blood transfusions. His transferrin saturation was 41%, ferritin level 706 [80-388] ng/mL, mean corpuscular volume (MCV) 87 [78-98] μm3, corrected reticulocytes count 2.3% [0.2-1.8%], and vitamin B6 1.2 [5.3-46.7] μg/L. Bone marrow biopsy was normocellular (65%) with erythroid hyperplasia and rare dyserythropoiesis. Prussian blue staining showed increased iron storage. Supplemental vitamin B6 (100 mg daily) was initiated at hemoglobin 7.3 g/dL with correction of anemia. Eighteen months later, his hemoglobin is 11.7 g/dL, transferrin saturation 45%, with no additional blood transfusions.\n\n\n\nVitamin B6 deficiency anemia should be considered in any pediatric patient on hemodialysis who does not respond to standard ESA and iron therapy.",
"affiliations": "LSU Health Sciences Center Shreveport, Shreveport, LA, USA. ksearc@lsuhsc.edu.;LSU Health Sciences Center Shreveport, Shreveport, LA, USA.;LSU Health Sciences Center Shreveport, Shreveport, LA, USA.;LSU Health Sciences Center Shreveport, Shreveport, LA, USA.",
"authors": "Searcy|Kristie|K|https://orcid.org/0000-0002-3978-3060;Rainwater|Sarah|S|;Jeroudi|Majed|M|;Baliga|Radhakrishna|R|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-020-04810-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "36(2)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Anemia; Chronic kidney disease; Erythropoietin stimulating agent (ESA); High flux/high efficiency (HF/HE) hemodialysis; Kidney failure; Vitamin B6",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "473-476",
"pmc": null,
"pmid": "33156411",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "21609363;7554526",
"title": "Erythropoietin-stimulating agent-resistant vitamin B6 deficiency anemia in a pediatric patient on hemodialysis.",
"title_normalized": "erythropoietin stimulating agent resistant vitamin b6 deficiency anemia in a pediatric patient on hemodialysis"
} | [
{
"companynumb": "US-AMGEN-USASP2020048394",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "103951",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": "0.5 MICROGRAM/KILOGRAM, QWK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HAEMOGLOBIN DECREASED",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"drugstartdateformat": null,
"drugstructuredosagenumb": ".5",
"drugstructuredosageunit": "008",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DARBEPOETIN ALFA"
},
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "103951",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INJECTION",
"drugdosagetext": "1.0 MICROGRAM/KILOGRAM, QWK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "008",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DARBEPOETIN ALFA"
}
],
"patientagegroup": "4",
"patientonsetage": "16",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Serum ferritin increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Anaemia vitamin B6 deficiency",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Ceruloplasmin increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood parathyroid hormone increased",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash pruritic",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SEARCY K.? RAINWATER S.? JEROUDI M. ET AL.. ERYTHROPOIETIN?STIMULATING AGENT?RESISTANT VITAMIN B6 DEFICIENCY ANEMIA IN A PEDIATRIC PATIENT ON HEMODIALYSIS. PEDIATRIC NEPHROLOGY. 2021?36:473?476",
"literaturereference_normalized": "erythropoietin stimulating agent resistant vitamin b6 deficiency anemia in a pediatric patient on hemodialysis",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210205",
"receivedate": "20200402",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17616464,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210419"
}
] |
{
"abstract": "The underlying mechanism involved in dapsone-induced mania remains unknown.\n\n\n\nWe report the case of a 54-year-old man with a dapsone-induced mania.\n\n\n\nThe maximum of manic symptoms was correlated with the maximum of methemoglobinemia and mania decreased concomitantly with the methemoglobinemia level.\n\n\n\nThis is a single case.\n\n\n\nThis case shows that dapsone-induced mania severity is correlated with methemoglobinemia level, leading for the first time to the hypothesis of a physiopathological mechanism by which dapsone could induce mania.",
"affiliations": "Service Hospitalo-Universitaire de Psychiatrie de Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France; INSERM UMR-1178, CESP, \"Depression and Antidepressants\" team, Faculté de Médecine Paris-Sud, Université Paris Sud, France. Electronic address: romain.colle@aphp.fr.;Service Hospitalo-Universitaire de Psychiatrie de Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France; INSERM UMR-1178, CESP, \"Depression and Antidepressants\" team, Faculté de Médecine Paris-Sud, Université Paris Sud, France.;INSERM UMR-1178, CESP, \"Depression and Antidepressants\" team, Faculté de Médecine Paris-Sud, Université Paris Sud, France.;Service de Médecine Interne et Immunologie Clinique, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France.;INSERM UMR-1178, CESP, \"Depression and Antidepressants\" team, Faculté de Médecine Paris-Sud, Université Paris Sud, France; Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France.;INSERM UMR-1178, CESP, \"Depression and Antidepressants\" team, Faculté de Médecine Paris-Sud, Université Paris Sud, France; Service de Génétique moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France.;INSERM UMR-1178, CESP, \"Depression and Antidepressants\" team, Faculté de Pharmacie de Chatenay-Malabry, Université Paris Sud, France.;Service de Médecine Interne et Immunologie Clinique, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France.;Service Hospitalo-Universitaire de Psychiatrie de Bicêtre, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin Bicêtre, F-94275, France; INSERM UMR-1178, CESP, \"Depression and Antidepressants\" team, Faculté de Médecine Paris-Sud, Université Paris Sud, France.",
"authors": "Colle|Romain|R|;Ait Tayeb|Abd El Kader|AEK|;Mesdom|Pierre|P|;de Menthon|Mathilde|M|;Becquemont|Laurent|L|;Verstuyft|Céline|C|;David|Denis J|DJ|;Lambotte|Olivier|O|;Corruble|Emmanuelle|E|",
"chemical_list": "D015415:Biomarkers; D003622:Dapsone",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jad.2018.12.123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-0327",
"issue": "254()",
"journal": "Journal of affective disorders",
"keywords": "Biomarker; Dapsone; Mania; Methemoglobinemia; Oxydative stress",
"medline_ta": "J Affect Disord",
"mesh_terms": "D015415:Biomarkers; D001714:Bipolar Disorder; D003622:Dapsone; D006801:Humans; D008297:Male; D008708:Methemoglobinemia; D008875:Middle Aged",
"nlm_unique_id": "7906073",
"other_id": null,
"pages": "122-123",
"pmc": null,
"pmid": "30598189",
"pubdate": "2019-07-01",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Methemoglobinemia as a biomarker of dapsone-induced mania severity.",
"title_normalized": "methemoglobinemia as a biomarker of dapsone induced mania severity"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1119641",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "080292",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNE THROMBOCYTOPENIC PURPURA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": null,
"patientonsetage": "54",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Immune thrombocytopenic purpura",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disease recurrence",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "COLLE R, TAYEB AEKA, MESDOM P, DE MENTHON M, BECQUEMONT L, VERSTUYFT C ET AL.. METHEMOGLOBINEMIA AS A BIOMARKER OF DAPSONE-INDUCED MANIA SEVERITY. J. AFFECTIVE DISORD.. 2019?254:122-3",
"literaturereference_normalized": "methemoglobinemia as a biomarker of dapsone induced mania severity",
"qualification": "3",
"reportercountry": "FR"
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"abstract": "BACKGROUND\nThe aim of this study was to evaluate the survival outcomes and toxicity of postoperative chemoradiotherapy with capecitabine and concurrent intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) in patients with stage II and III rectal cancer.\n\n\nMETHODS\nWe recruited 184 patients with pathologically proven, stage II or III rectal cancer. Following total mesorectal excision (TME), the patients were treated with capecitabine and concurrent IMRT/3D-CRT. The treatment regimen consisted of two cycles of oral capecitabine (1600 mg/m2/day), administered twice daily from day 1-14 of radiotherapy, followed by a 7-day rest. The median pelvic dose was 50 Gy in 25 fractions. Oxaliplatin-based adjuvant chemotherapy was administered after the chemoradiotherapy.\n\n\nRESULTS\nThe 5-year overall survival, disease-free survival and locoregional control (LRC) rates were 85.1%, 80% and 95.4%, respectively. Grade 3 and 4 toxicities were observed in 28.3% of patients during treatment. Grade 3 or 4 late toxicity, including neurotoxicity or gastrointestinal toxicity, was only observed in nine patients (4.9%).\n\n\nCONCLUSIONS\nThis study demonstrated that capecitabine chemotherapy with concurrent IMRT/3D-CRT following TME is safe, is well tolerated and achieves superior LRC and favorable survival rates, with acceptable toxicity.",
"affiliations": "Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.;Department of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China.",
"authors": "Lu|Ning-Ning|NN|;Jin|Jing|J|;Wang|Shu-Lian|SL|;Wang|Wei-Hu|WH|;Song|Yong-Wen|YW|;Liu|Yue-Ping|YP|;Ren|Hua|H|;Fang|Hui|H|;Liu|Xin-Fan|XF|;Yu|Zi-Hao|ZH|;Li|Ye-Xiong|YX|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0124601",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2591594810.1371/journal.pone.0124601PONE-D-14-50301Research ArticlePostoperative Capecitabine with Concurrent Intensity-Modulated Radiotherapy or Three-Dimensional Conformal Radiotherapy for Patients with Stage II and III Rectal Cancer Capecitabine with Concurrent IMRT/3D-CRT in Rectal CancerLu Ning-Ning Jin Jing *Wang Shu-Lian Wang Wei-Hu Song Yong-Wen Liu Yue-Ping Ren Hua Fang Hui Liu Xin-Fan Yu Zi-Hao Li Ye-Xiong *\nDepartment of Radiation Oncology, Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing 100021, P. R. China\nSung Shian-Ying Academic Editor\nTaipei Medical University, TAIWAN\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: YXL JJ. Performed the experiments: NNL JJ SLW WHW YWS YPL HR HF XFL ZHY YXL. Analyzed the data: NNL JJ YXL. Contributed reagents/materials/analysis tools: NNL JJ SLW WHW YWS YPL HR HF XFL ZHY YXL. Wrote the paper: NNL JJ YXL.\n\n* E-mail: yexiong12@163.com (YXL); jingjin1025@163.com (JJ)27 4 2015 2015 10 4 e012460113 11 2014 4 3 2015 © 2015 Lu et al2015Lu et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Background\nThe aim of this study was to evaluate the survival outcomes and toxicity of postoperative chemoradiotherapy with capecitabine and concurrent intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3D-CRT) in patients with stage II and III rectal cancer.\n\nPatients\nWe recruited 184 patients with pathologically proven, stage II or III rectal cancer. Following total mesorectal excision (TME), the patients were treated with capecitabine and concurrent IMRT/3D-CRT. The treatment regimen consisted of two cycles of oral capecitabine (1600 mg/m2/day), administered twice daily from day 1–14 of radiotherapy, followed by a 7-day rest. The median pelvic dose was 50 Gy in 25 fractions. Oxaliplatin-based adjuvant chemotherapy was administered after the chemoradiotherapy.\n\nResults\nThe 5-year overall survival, disease-free survival and locoregional control (LRC) rates were 85.1%, 80% and 95.4%, respectively. Grade 3 and 4 toxicities were observed in 28.3% of patients during treatment. Grade 3 or 4 late toxicity, including neurotoxicity or gastrointestinal toxicity, was only observed in nine patients (4.9%).\n\nConclusions\nThis study demonstrated that capecitabine chemotherapy with concurrent IMRT/3D-CRT following TME is safe, is well tolerated and achieves superior LRC and favorable survival rates, with acceptable toxicity.\n\nThis study was funded from the Ministry of Health of the People's Republic of China Grant [07090010, WKJ2005-3-006(21)], and Dr. YXL received the funding; National Natural Science Foundation of China [81402524] which was received by Dr. NNL; and Beijing Hope Run Special Fund [LC2007A17] which was received by Dr. JJ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nRectal cancer is a common malignancy worldwide [1]. Several randomized trials have demonstrated improved locoregional control (LRC) and survival rates with preoperative or postoperative chemoradiotherapy in patients with stage II and III rectal cancer [2–7]. Compared to postoperative chemoradiotherapy, preoperative chemoradiotherapy is associated with lower treatment-related toxicity, less local recurrence and improved disease-free survival (DFS) rates, and may enhance sphincter preservation [8–10]. Although preoperative chemoradiotherapy is considered the standard treatment for patients with locally advanced rectal cancer, postoperative chemoradiotherapy remains the choice of treatment for such patients [10, 11].\n\nConcurrent chemoradiotherapy with 5-fluorouracil (5-FU) is a recommended treatment for stage II and III rectal cancer [2, 3]. However, preliminary trials in patients with metastatic colorectal cancer have indicated that capecitabine may be as effective as standard 5-FU-based chemotherapy in terms of progression-free survival (PFS) and overall survival (OS) rates, while offering a better tolerability profile and a lower incidence of stomatitis [12–18]. Based on these reports, we carried out a phase I trial to evaluate the maximum tolerated dose (MTD) of capecitabine with concurrent postoperative radiotherapy for stage II and III rectal cancer. Consistent with other studies [19, 20], the MTD was 1600 mg/m2/day [21].\n\nAdvanced radiation techniques, such as three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT), are widely used in the treatment of other cancers. Recent dosimetric studies have demonstrated that IMRT/3D-CRT can provide superior target dose distribution and normal tissue protection in patients with rectal cancer [22–26]. However, the long-term outcome of patients with rectal cancer treated by IMRT/3D-CRT has not been determined; therefore, this study was conducted to investigate the toxicity and long-term survival rates of capecitabine and concurrent IMRT/3D-CRT in patients with stage II and III rectal cancer.\n\nPatients and Methods\nPatient selection and evaluation\nPatients in this study were retrospectively selected from our centre. The eligibility and exclusion criteria were similar as the previous phase I study, except for the requirements of IMRT/3D-CRT [21]. Briefly, patients aged 18–75 years with postoperatively pathological confirmed as stage II or III rectal adenocarcinoma with negative recision margin, normal biochemical examinations and good performance status (ECOG 0–1) were recruited for this retrospective analysis. Patients with a history of chemotherapy or radiotherapy were excluded. Patients with significant comorbidities, uncontrolled infections, pregnancy or second primary tumor in situ, other than non-melanoma skin cancer or cervical carcinoma, were also excluded. The study regimen was approved by the Institutional Ethics Committees of Cancer Hospital, Chinese Academy of Medical Sciences, and all patients gave written informed consent prior to the treatment in accordance with the declaration of Helsinki.\n\nPrior to enrollment, a medical history was obtained for each patient, and a physical examination was performed, including blood counts, serum biochemistry, pregnancy testing, chest radiography and a computed tomography (CT) scan of the chest, abdomen and pelvis. A total of 184 patients who had been diagnosed with stage II or III rectal cancer and treated with postoperative concurrent chemoradiotherapy with IMRT/3D-CRT technique between March 2005 and January 2011 were selected and retrospectively analyzed.\n\nTreatment regimen and delivery\nPatients received postoperative chemoradiotherapy with capecitabine and either IMRT (n = 133) or 3D-CRT (n = 51) (patients choice) following TME. The patients were irradiated in a prone position on a belly board, with bladder filling to reduce any intestinal toxicity. Simplified IMRT (sIMRT) is recommended in all patients in order to improve the dose coverage and reduce dose uncertainties during irradiation [27]. The treatment and delivery procedures for sIMRT were similar to those used for IMRT. However, sIMRT involved a five-radiation field, ≤5 segments per beam, a segment area ≥10 cm2 and ≥10 machine monitor units (MU) per segment. The delineation of the clinical target volume (CTV) was based on Roels’s guidelines and included the tumor bed and pelvic lymphatic area, such as the sacrum, the presacral space, the posterior walls of the bladder and prostate or vagina, and the internal iliac lymph nodes without inguinal lymph nodes [28].\n\nThe treatment field has been described previously in the phase I study [21]. Briefly, a 7-mm left-right (LR), 10-mm anteroposterior (AP) and 10-mm superior-inferior (SI) expansion of the CTV was used to create the planning target volume (PTV). A total irradiation dose of 50 Gy without simultaneous boost to the 95% PTV was delivered in 2-Gy daily fractions, from Monday to Friday, over a 5-week period. Organs at risk (OARs) were contoured, including the intestine, bladder and uterus; however, the irradiation dose was allowed to exceed 50 Gy in limited volumes of the small bowel and colon, if they were adjacent to the PTV, but it was not allowed to exceed 52 Gy. The bladder V50 dose limit was below 50%.\n\nAll treatment plans were generated using an inverse IMRT planning system developed by the PHILIPS Corporation, either the Pinnacle3 Version 7.4 or Version 8.0 planning systems. Treatment was delivered using a step-and-shoot technique with 6-MV photons. Portal image or cone-beam CT was acquired daily during the first week, and thereafter once a week.\n\nChemotherapy consisted of two cycles of oral capecitabine, which was 1600 mg/m2/d, administered twice daily from day 1–14 of the radiotherapy, followed by a 7-day rest. The second cycle was continued for the remaining radiotherapy. The first dose of capecitabine was given approximately 2 h before radiotherapy; the second dose was given approximately 12 h between radiotherapy treatments. After the chemoradiotherapy had been completed, 4 to 6 cycles of oxaliplatin-based adjuvant chemotherapy was recommended to patients with high-risk stage II or III disease, referring to patients with positive nodes, tumor nodules, poorly differentiated, or T4 disease. In total, 119/184 (64.7%) patients received adjuvant chemotherapy. The majority of these (108, 90.8%) were treated with oxaliplatin-based chemotherapy; the remaining 11 patients (9.2%) received capecitabine chemotherapy alone. The median number of cycles was six.\n\nPatient follow-up\nPatients were evaluated weekly during treatment, 1 month after the completion of treatment, every 3–6 months for the first 3–5 years and annually thereafter. The median follow-up was 47 months (range, 3 to 91 months). Acute toxicity was scored according to the Common Terminology Criteria for Adverse Events (CTCAE v. 3.0), and late toxicity was graded according to the Late Effects in Normal Tissue—Subjective, Objective, Management and Analytic (LENT-SOMA) system.\n\nOS was measured from the date of surgery to the date of death from any cause, or to the last follow-up date. DFS was measured from the date of surgery to any type of recurrence, or to the date of death as a result of rectal cancer. LRC was measured from the date of surgery to locoregional recurrence or the last follow-up.\n\nStatistical analysis\nPatient characteristics between subgroups were compared using the chi-square test. Survival rates were calculated using the Kaplan-Meier method to construct survival curves. The log-rank test was used to compare survival outcomes. Cox regression was used for multivariate analysis of independent prognostic factors for survival.\n\nResults\nPatient characteristics\nThe clinical features of patients are presented in Table 1. The ratio of males to females was 1.3:1. The median age was 57 years (range, 27–75 years). According to the American Joint Committee on Cancer (AJCC, 6th edition) staging system, 90 (48.9%) patients had stage II disease and 94 (51.1%) patients had stage III disease. Pathological T4 diseases were reported in 2 (1%) patients. A total of 114 (62.0%) patients presented with mid- or low-tumor location. Poor tumor differentiation was reported in 25 (13.6%) patients, and lymphovascular invasion and tumor nodules were reported in 8 (4.3%) and 30 (16.3%) patients, respectively. The median time interval between surgery and radiotherapy was 1.4 months (0.5 to 3 months).\n\n10.1371/journal.pone.0124601.t001Table 1 Clinical characteristics of the study patients with stage II/III rectal cancer.\nCharacteristics\t\tN (%)\t\nSex\t\t\t\nMale\t\t104 (56.5)\t\nAge (years)\t\t\t\nMedian\t57\t\t\nRange\t27–75\t\t\nECOG score\t\t\t\n0–1\t\t172 (93.5)\t\n2\t\t12 (6.5)\t\nTumor level\t\t\t\n≤5 cm\t\t70 (38.0)\t\n5–10 cm\t\t69 (37.5)\t\n>10 cm\t\t45 (24.5)\t\nT stage\t\t\t\nT1–T2\t\t19 (10.3)\t\nT3–T4\t\t165 (89.7)\t\nN stage\t\t\t\nN0\t\t90 (48.9)\t\nN1\t\t60 (32.6)\t\nN2\t\t34 (18.5)\t\nStage (AJCC)\t\t\t\nII\t\t90 (48.9)\t\nIII\t\t94 (51.1)\t\nOperation type\t\t\t\nAPR\t\t42 (22.8)\t\nLAR\t\t142 (77.2)\t\n\nAbbreviations: ECOG, Eastern Cooperative Oncology Group; AJCC, American Joint Committee on Cancer, 6th edition; APR, abdominoperineal resection; LAR, low anterior resection.\n\nOutcome and prognostic factors\nBased on the median follow-up time of 47 months, with a range from 7 to 77 months, the 5-year OS, DFS and LRC rates were 85.1%, 80% and 95.4%, respectively (Fig 1). At the time of last follow-up, 21 (11.4%) patients had died of rectal cancer, and 7 (3.8%) patients were still alive with disease. Twelve patients (6.5%) were lost and included in the analysis.\n\n10.1371/journal.pone.0124601.g001Fig 1 Overall survival (OS), disease-free survival (DFS) and locoregional control (LRC) rates for all patients undergoing postoperative chemoradiotherapy with capecitabine and concurrent intensity-modulated radiotherapy (IMRT)/three-dimensional conformal radiotherapy (3D-CRT).\nClinical features were evaluated to determine their prognostic significance on OS, DFS and LRC rates (Table 2). Univariate analysis revealed that patients with poor or moderately poor differentiation, advanced stage II or III disease, N2 stage disease or tumor nodules had poorer OS. Advanced stage disease and N2 stage disease were also significant prognostic factors for DFS. However, none of the clinicopathologic features were significant prognostic factors for LRC rate, possibly due to the small number of events. Cox regression analysis indicated that advanced N stage was the only poor prognostic factor for OS and DFS rates (Table 3).\n\n10.1371/journal.pone.0124601.t002Table 2 Univariate analysis showing the prognostic significance of clinicopathologic features on the outcomes of the 184 patients recruited in this study.\nVariables\t5-year OS\t\t5-year LRC\t\t5-year DFS\t\t\n\t%\t\nP\n\t%\t\nP\n\t%\t\nP\n\t\nAge\t\t0.582\t\t0.293\t\t0.99\t\n≤60\t86.2\t\t97.2\t\t80.3\t\t\n>60\t82.8\t\t92.1\t\t79.1\t\t\nStage (AJCC)\t\t0.021\t\t0.725\t\t0.035\t\n\t91.4\t\t96.5\t\t86.7\t\t\n\t79.4\t\t94.6\t\t73.6\t\t\nN stage\t\t0.002\t\t0.125\t\t<0.001\t\nN0\t91.4\t\t96.5\t\t86.7\t\t\nN1\t85.2\t\t97.2\t\t83.3\t\t\nN2\t69.2\t\t89.9\t\t56.0\t\t\nT stage\t\t0.712\t\t0.807\t\t0.636\t\nT1–T2\t77.6\t\t91.7\t\t80.5\t\t\nT3–T4\t86.6\t\t96.7\t\t80.1\t\t\nTumor grade\t\t0.05\t\t0.958\t\t0.079\t\nWell\t83.1\t\t94.7\t\t78.2\t\t\nModerately\t87.9\t\t96.3\t\t83.3\t\t\nPoorly\t71.1\t\t91.7\t\t64.9\t\t\nTumor nodules\t\t0.015\t\t0.295\t\t0.056\t\nNo\t87.8\t\t95.9\t\t82.1\t\t\nYes\t70.1\t\t93.0\t\t68.8\t\t\n\nAbbreviations: OS, overall survival; LRC, locoregional control; DFS, disease-free survival; AJCC, American Joint Committee on Cancer, 6th edition\n\n10.1371/journal.pone.0124601.t003Table 3 Multivariate analysis showing the prognostic significance of clinicopathologic features on the outcomes of the 184 patients recruited in this study.\nVariables\tOS\t\tLRC\t\tDFS\t\t\n\tHR(95%CI)\t\nP\n\tHR(95%CI)\t\nP\n\tHR(95%CI)\t\nP\n\t\nAge\t0.78(0.29–2.05)\t0.608\t2.03(0.39–10.59)\t0.403\t0.65(0.31–1.38)\t0.261\t\nGender\t0.51(0.19–1.33)\t0.167\t3.13(0.54–18.14)\t0.202\t0.69(0.34–1.4)\t0.301\t\nOperation\t0.91(0.16–5.3)\t0.919\t0.61(0.02–20.79)\t0.786\t0.67(0.19–2.37)\t0.532\t\nT stage\t0.88(0.22–3.48)\t0.852\t0.75(0.06–9.49)\t0.823\t1.67(0.47–5.91)\t0.430\t\nN stage\t3.21(1.09–9.48)\t0.035\t6.08(0.6–61.59)\t0.128\t4.26(1.76–10.34)\t0.001\t\nDifferentiation\t1.86(0.69–5.05)\t0.223\t0.85(0.16–4.58)\t0.851\t1.7(0.8–3.62)\t0.170\t\nStage\t0.5(0.07–3.66)\t0.491\t0.05(0.00–3.90)\t0.175\t0.27(0.05–1.35)\t0.111\t\nTumor level\t0.64(0.26–1.61)\t0.346\t0.71(0.12–4.06)\t0.700\t0.68(0.35–1.31)\t0.251\t\nLymphovascular invasion\t1.91(0.39–9.35)\t0.427\t0.000\t0.990\t1.46(0.42–5.09)\t0.552\t\nTumor nodules\t1.9(0.59–6.11)\t0.284\t2.69(0.35–20.83)\t0.342\t1.46(0.62–3.43)\t0.382\t\n\nAbbreviations: RT, radiotherapy; OS, overall survival; LRC, locoregional control; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval\n\nTolerance and acute toxicity\nNone of the patients developed grade 5 acute toxicity (Table 4). Grade 3 and 4 toxicities were observed in 52 (28.3%) patients during chemoradiotherapy. The most common of these were diarrhea (42/184, 22.8%), leucopenia (7/184, 3.8%), tenesmus (5/184, 2.7%), dermatitis (4/184, 2.2%) and fatigue (1/184, 0.5%). Dose reduction, due to grade 3 and 4 toxicities was carried out in 19 (10.3%) patients who were receiving adjuvant chemotherapy. Radiotherapy or capecitabine were only interrupted or discontinued in 9 (4.9%) and 11 (6%) patients, respectively, due to treatment-related toxicity. Among them, most patients continued treatment after side effects alleviated. Only 2 patients with stage IIA received pelvic irradiation with dose less than 45 Gy (1 with 34 Gy and another with 44 Gy) and suffered distant metastases at 0.7 year and 1.6 years after surgery, respectively. For patients with treatment interruption, no loco-regional relapse was observed. Pelvic radiation doses ≥45 Gy were received by the majority of patients (182, 98.9%), indicating high tolerance of postoperative capecitabine with concurrent IMRT/3D-CRT.\n\n10.1371/journal.pone.0124601.t004Table 4 Incidence and type of acute toxicity developed in patients receiving postoperative chemoradiotherapy with capecitabine and concurrent IMRT/3D-CRT.\n\t\tGrade;\t\nN (%)\t\t\nToxicity\t1\t2\t3\t4\t\nFatigue\t51 (22.4)\t3 (1.6)\t1 (0.5)\t0 (0)\t\nSkin reaction\t57 (31)\t28 (15.2)\t4 (2.2)\t0 (0)\t\nAnorexia\t54 (29.3)\t5 (2.7)\t0 (0)\t0 (0)\t\nNausea\t32 (17.4)\t4 (2.2)\t0 (0)\t0 (0)\t\nVomiting\t5 (2.7)\t2 (1.1)\t0 (0)\t0 (0)\t\nDiarrhea\t33 (17.9)\t35 (19)\t41 (22.3)\t1 (0.5)\t\nTenesmus\t49 (26.6)\t16 (8.7)\t5 (2.7)\t0 (0)\t\nBody weight decline\t18 (9.8)\t2 (1.1)\t0 (0)\t0 (0)\t\nFood-hand syndrome\t0 (0)\t1 (0.5)\t0 (0)\t0 (0)\t\nLeucopenia\t72 (39.1)\t42 (22.8)\t7 (3.8)\t0 (0)\t\nThrombocytopenia\t7 (3.8)\t2 (1.1)\t0 (0)\t0 (0)\t\nALT elevation\t10 (5.4)\t0 (0)\t0 (0)\t0 (0)\t\nTBIL elevation\t8 (7.2)\t2 (1.1)\t0 (0)\t0 (0)\t\n\nAbbreviations: ALT, aminase; TBIL, total bilirubin level; IMRT, intensity-modulated radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy.\n\nLate toxicities\nLate toxicity was defined as that which occurred ≥3 months after radiotherapy. Only 9 (4.9%) patients presented with grade 3 or 4 late toxicities, including neurotoxicity (n = 1) and gastrointestinal toxicity (n = 8). Other severe late complications or second malignancies were not observed in any of the patients. Colostomies were performed on 6 (3.3%) of the patients with gastrointestinal toxicity.\n\nDiscussion\nThe purpose of this retrospective study was to evaluate the toxicity profile and survival outcomes of postoperative chemoradiotherapy with capecitabine and concurrent IMRT/3D-CRT for patients with stage II or III rectal cancer. Our findings showed that TME followed by capecitabine with concurrent IMRT/3D-CRT resulted in excellent LRC (5 years, 95.4%) with favorable prognosis. Furthermore, the treatment was safe, well-tolerated and caused relatively few severe acute or late toxicities.\n\nThe 5-year incidence of locoregional recurrence in this postoperative chemoradiotherapy study (4.6%) was similar to those reported in preoperative chemoradiotherapy studies, including a German trial (6%) [8] and preoperative capecitabine-based trials (5%–6%) [10, 11, 29]. In contrast, the incidence was lower than most of those reported in other postoperative chemoradiotherapy studies (10%–15%) [8, 11, 30, 31]. The superior LRC rate in this study may be due to the improved quality assurance obtained with TME and better target coverage achieved with IMRT/3D-CRT. Although studies have demonstrated that TME can significantly reduce the incidence of locoregional recurrence [32–34], reports show that it remains high (20%–30%) in patients with stage III disease or distal tumors [33–36].\n\nRecent studies have shown that IMRT provides superior target dose distribution and reduced normal tissue toxicity compared to conventional pelvic radiotherapy or 3D-CRT [22–25]; however, the use of IMRT in rectal cancer remains controversial in clinical practice. This may be due to the dose uncertainty induced by the prolonged treatment time and very small segments or fields. As such, sIMRT, which achieves a uniform dose distribution similar to that obtained with IMRT but with a shorter treatment time [27], has been recommended in our institution since 2005. Our data in this study has demonstrated that sIMRT/3D-CRT can achieve high LRC rates (>90%), which are similar or superior to those obtained with conventional radiotherapy, indicating that the sIMRT technique is safe for use in the clinic. Furthermore, the majority of patients in our study received full-dose pelvic radiotherapy with IMRT/3D-CRT, demonstrating that high LRC rates can also be achieved with concurrent, postoperative, capecitabine-based chemoradiotherapy. In addition, several recent randomized studies have found that compared to 5-FU, capecitabine-based concurrent chemoradiotherapy is better tolerated, associated with lesser toxicity and achieves similar OS rates and better DFS rates [10, 11, 29, 37].\n\nThe incidence of grade 3 or higher acute toxicity for preoperative chemoradiotherapy for rectal cancer ranges from 6% to 27% [8, 29, 37], increasing to 16%–40% for postoperative chemoradiotherapy [8, 9, 29]. The incidence of grade 3 and 4 acute toxicity (28.3%) in this study was lower than the rates reported for postoperative chemoradiotherapy in many studies, such as the German and NSABR-R03 trials [8, 9], but higher than the rates reported for preoperative chemoradiotherapy [25, 29, 37]. Despite moderate acute toxicities, <5% of patients presented severe late toxicities (grade 3 and 4). Further confirmation that postoperative chemoradiotherapy with capecitabine and concurrent IMRT was well tolerated was demonstrated by the observation that approximately 95% of our patients received the prescribed concurrent treatment regimen as planned.\n\nHowever, there is some limitations of this study due to the retrospective analysis. Patient selection bias may be contributed to the better LRC and OS.\n\nIn conclusion, this study demonstrated that patients with stage II and III rectal cancer can be treated safely and efficiently by postoperative chemoradiotherapy with capecitabine and concurrent IMRT/3D-CRT. Although further studies will be required to validate the benefits of precise target dose coverage with IMRT in postoperative chemoradiotherapy, our data shows that superior LRC and improved survival rates can be achieved with capecitabine and concurrent IMRT/3D-CRT following TME.\n==== Refs\nReferences\n1 \nCheng L , Eng C , Nieman LZ , Kapadia AS , Du XL . Trends in Colorectal Cancer Incidence by Anatomic Site and Disease Stage in the United States From 1976 to 2005 . Am J Clin Oncol . 2011 ;34 : 573 –580 . 10.1097/COC.0b013e3181fe41ed \n21217399 \n2 \nGastrointestinal Tumor Study Group . Prolongation of the disease-free interval in surgically treated rectal carcinoma . N Engl J Med . 1985 ;312 : 1465 –1472 .\n2859523 \n3 \nKrook JE , Moertel CG , Gunderson LL , Wieand HS , Collins RT , et al\nEffective surgical adjuvant therapy for high-risk rectal carcinoma . N Engl J Med . 1991 ;324 : 709 –715 .\n1997835 \n4 \nFisher B , Wolmark N , Rocketter H , Redmond C , Deutsch M , et al\nPostoperative adjuvant chemotherapy or radiation therapy for rectal cancer: Results from NSABP protocol R-01 . J Natl Cancer Inst . 1998 ;80 : 21 –29 .\n5 \nWolmark N , Weiand HS , Hyams DM , Colangelo L , Dimitrov NV , et al\nRandomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project protocol R-02 . J Natl Cancer Inst . 2000 ;92 : 388 –396 .\n10699069 \n6 \nTepper J , O’Connell MJ , Niedzwiecki D , Hollis DR , Benson AB 3rd, et al\nAdjuvant therapy in rectal cancer: analysis of stage, sex, and local control—final report of intergroup 0114 . J Clin Oncol . 2002 ;20 : 1744 –1750 .\n11919230 \n7 \nO’Connell MJ , Martenson JA , Wieand HS , Krook JE , Macdonald JS , et al\nImproving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery . N Engl J Med . 1994 ;331 : 502 –507 .\n8041415 \n8 \nSauer R , Becker H , Hohenberger W , Rödel C , Wittekind C , et al\nPreoperative versus postoperative chemoradiotherapy for rectal cancer . N Engl J Med . 2004 ;351 : 1731 –1740 .\n15496622 \n9 \nRoh MS , Colangelo LH , O'Connell MJ , Yothers G , Deutsch M , et al\nPreoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03 . J Clin Oncol . 2009 ;27 : 5124 –5130 . 10.1200/JCO.2009.22.0467 \n19770376 \n10 \nPark JH , Yoon SM , Yu CS , Kim JH , Kim TW , et al\nRandomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with capecitabine for locally advanced rectal cancer . Cancer . 2011 ;117 : 3703 –3712 . 10.1002/cncr.25943 \n21328328 \n11 \nHofheinz RD , Wenz F , Post S , Matzdorff A , Laechelt S , et al\nChemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial . Lancet Oncol . 2012 ;13 : 579 –588 . 10.1016/S1470-2045(12)70116-X \n22503032 \n12 \nVan Cutsem E , Twelves C , Cassidy J , Allman D , Bajetta E , et al\nOral capecitabine compared with intravenous fluorouracil plus leucovorinin patients with metastatic colorectal cancer: Results of a large Phase III study . J Clin Oncol . 2001 ;19 : 4097 –4106 .\n11689577 \n13 \nHoff PM , Ansari R , Batist G , Cox J , Kocha W , et al\nComparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized Phase III study . J Clin Oncol . 2001 ;19 : 2282 –2292 .\n11304782 \n14 \nCassidy J , Twelves C , Van Cutsem E , Hoff P , Bajetta E , et al\nFirst-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/ leucovorin . Ann Oncol . 2002 ;13 : 566 –575 .\n12056707 \n15 \nTwelves C , Wong A , Nowacki MP , Abt M , Burris H 3rd, et al\nCapecitabine as Adjuvant Treatment for Stage III Colon Cancer . N Eng J Med . 2005 ;352 : 2696 –2704 .\n15987918 \n16 \nLembersky BC , Wieand HS , Petrelli NJ , O'Connell MJ , Colangelo LH , et al\nOral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06 . J Clin Oncol . 2006 ;24 : 2059 –2064 .\n16648506 \n17 \nDíaz-Rubio E , Tabernero J , Gómez-España A , Massutí B , Sastre J , et al\nPhase III Study of Capecitabine Plus Oxaliplatin Versus Continuous- Infusion Fluorouracil Plus Oxaliplatin As First-Line Therapy in Metastatic Colorectal Cancer: Final Report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial . J Clin Oncol . 2007 ;25 : 4224 –4230 .\n17548839 \n18 \nPorschen R , Arkenau HT , Kubicka S , Greil R , Seufferlein T , et al\nCapecitabine Plus Oxaliplatin Compared With Fluorouracil and Leucovorin Plus Oxaliplatin: A Randomized Comparison in Metastatic Colorectal Cancer—A Final Report of the AIO Colorectal Study Group . J Clin Oncol . 2007 ;25 : 4217 –4223 .\n17548840 \n19 \nDunst J , Reese T , Sutter T , Zühlke H , Hinke A , et al\nPhase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer . J Clin Oncol . 2002 ;20 : 3983 –3991 .\n12351595 \n20 \nSouglakos J , Androulakis N , Mavroudis D , Kourousis C , Kakolyris S , et al\nMulticenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer . Int J Radiat Oncol Biol Phys . 2003 ;56 : 1284 –1287 .\n12873672 \n21 \nJin J , Li YX , Liu YP , Wang WH , Song YW , et al\nA phase I study of concurrent radiotherapy and capecitabine as adjuvant treatment for operable rectal cancer . Int J Radiat Oncol Biol Phys . 2006 ;64 : 725 –729 .\n16242260 \n22 \nDuthoy W , DeGersem W , Vergote K , Boterberg T , Derie C , et al\nClinical implementation of intensity-modulated arc therapy (IMAT) for rectal cancer . Int J Radiat Oncol Biol Phys . 2004 ;60 : 794 –806 .\n15465196 \n23 \nGuerreroUrbano MT , Henrys AJ , Adams EJ , Norman AR , Bedford JL , et al\nIntensity-modulated radiotherapy in patients with locally advanced rectal cancer reduces volume of bowel treated to high dose levels . Int J Radiat Oncol Biol Phys . 2006 ;65 : 907 –916 .\n16751073 \n24 \nArbea L , Ramos LI , Martinez-Monge R , Moreno M , Aristu J . Intensity- modulated radiation therapy (IMRT) vs. 3D conformal radiotherapy (3DCRT) in locally advanced rectal cancer (LARC): Dosimetric comparison and clinical implications . Radiat Oncol . 2010 ;5 : 17 \n10.1186/1748-717X-5-17 \n20187944 \n25 \nSamuelian JM , Callister MD , Ashman JB , Young-Fadok TM , Borad MJ , et al\nReduced acute bowel toxicity in patients treated with intensity-modulated radiotherapy for rectal cancer . Int J Radiat Oncol Biol Phys . 2012 ;82 : 1981 –1987 . 10.1016/j.ijrobp.2011.01.051 \n21477938 \n26 \nParekh A , Truong MT , Pashtan I , Qureshi MM , Martin NE , et al\nAcute gastrointestinal toxicity and tumor response with preoperative intensity modulated radiation therapy for rectal cancer . Gastrointest Cancer Res . 2013 ;6 : 137 –143 .\n24312687 \n27 \nDeng L , Li YX , Jin J , Jin DW , Dai JR . Comparison of dose distribution with simplified IMRT to different postoperative radiotherapy plans of rectal cancer . Chin J Radiat Oncol . 2008 ;17 : 450 –453 .\n28 \nRoels S , Duthoy W , Haustermans K , Penninckx F , Vandecaveye V , et al\nDefinition and delineation of the clinical target volume for rectal cancer . Int J Radiat Oncol Biol Phys . 2006 ;65 : 1129 –1142 .\n16750329 \n29 \nKim DY , Jung KH , Kim TH , Kim DW , Chang HJ , et al\nComparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer . Int J Radiat Oncol Biol Phys . 2007 ;67 : 378 –384 .\n17097835 \n30 \nQian LT , Song YW , Liu XF , Yu ZH , Qian TN , et al\nPostoperative radiotherapy for stage II and III rectal cancer . Chin J Radiat Oncol . 2003 ;11 : 101 –105 .\n31 \nSebag-Montefiore D , Stephens RJ , Steele R , Monson J , Grieve R , et al\nPreoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial . Lancet . 2009 ;373 : 811 –820 . 10.1016/S0140-6736(09)60484-0 \n19269519 \n32 \nHavenga K , Enker WE , Norstein J , Moriya Y , Heald RJ , et al\nImproved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: an international analysis of 1411 patients . Eur J Surg Oncol . 1999 ;25 : 368 –374 .\n10419706 \n33 \nKapiteijn E , Marijnen CA , Nagtegaal ID , Putter H , Steup WH , et al\nPreoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer . N Engl J Med . 2001 ;345 : 638 –646 .\n11547717 \n34 \nVan Gijn W , Marijnen CA , Nagtegaal ID , Kranenbarg EM , Putter H , et al\nPreoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial . Lancet Oncol . 2011 ;12 : 575 –582 . 10.1016/S1470-2045(11)70097-3 \n21596621 \n35 \nRidgway PF , Darzi AW . The role of total mesorectal excision in the management of rectal cancer . Cancer Control . 2003 ;10 : 205 –211 .\n12794618 \n36 \nPacelli F , Di Giorgio A , Papa V , Tortorelli AP , Covino M , et al\nPreoperative radiotherapy combined with intraoperative radiotherapy improve results of total mesorectal excision in patients with T3 rectal cancer . Dis Colon Rectum . 2004 ;47 : 170 –179 .\n15043286 \n37 \nDas P , Lin EH , Bhatia S , Skibber JM , Rodriguez-Bigas MA , et al\nPreoperative chemoradiotherapy with capecitabine versus protracted infusion 5-fluorouracil for rectal cancer: a matched-pair analysis . Int J Radiat Oncol Biol Phys . 2006 ;66 : 1378 –1383 .\n17056196\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011182:Postoperative Care; D020266:Radiotherapy, Conformal; D050397:Radiotherapy, Intensity-Modulated; D012004:Rectal Neoplasms; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
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"pages": "e0124601",
"pmc": null,
"pmid": "25915948",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19770376;11689577;17548839;10699069;11547717;12873672;3276900;16648506;15465196;16242260;20187944;11304782;17548840;2859523;15987918;10419706;19269519;1997835;17097835;21596621;12056707;17056196;16750329;15496622;21217399;15043286;12794618;16751073;24312687;8041415;22503032;12351595;21477938;11919230;21328328",
"title": "Postoperative Capecitabine with Concurrent Intensity-Modulated Radiotherapy or Three-Dimensional Conformal Radiotherapy for Patients with Stage II and III Rectal Cancer.",
"title_normalized": "postoperative capecitabine with concurrent intensity modulated radiotherapy or three dimensional conformal radiotherapy for patients with stage ii and iii rectal cancer"
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{
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{
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{
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"literaturereference": ", JIN J, WANG S, WANG W, SONG Y, LIU Y, REN H, FANG H, LIU X, YU Z AND LI Y. POSTOPERATIVE CAPECITABINE WITH CONCURRENT INTENSITY-MODULATED RADIOTHERAPY OR THREE DIMENSIONAL CONFORMAL RADIOTHERAPY FOR PATIENTS WITH STAGE II AND III RECTAL CANCER. PLOS ONE 2015 APR 27;10 (4):-.",
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{
"abstract": "BACKGROUND: Langerhans cell histiocytosis (LCH) is a neoplasm of the monocyte-macrophage lineage, characterized by clonal proliferation and dissemination of cells that express CD1a+ and CD207. It is a disorder that predominates in childhood. Although the skin is the second most frequently affected organ (30-60%), isolated cutaneous involvement is rare; its frequency does not exceed 4 to 12 percent of cases. Single system-LCH usually has a good prognosis. We describe a case of LCH with isolated cutaneous involvement that presented in an adult patient and was refractory to polychemotherapy.",
"affiliations": "All authors are with the Department of Dermatology at the Instituto Mexicano del Seguro Social and Centro Médico Nacional La Raza in México City, México.;All authors are with the Department of Dermatology at the Instituto Mexicano del Seguro Social and Centro Médico Nacional La Raza in México City, México.;All authors are with the Department of Dermatology at the Instituto Mexicano del Seguro Social and Centro Médico Nacional La Raza in México City, México.",
"authors": "Lira-Valero|Francisco Javier|FJ|;Pulido-Díaz|Nancy|N|;Quintal-Ramírez|Marissa De Jesús|MJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
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"issn_linking": "1941-2789",
"issue": "13(1)",
"journal": "The Journal of clinical and aesthetic dermatology",
"keywords": "Langerhans cell; cutaneous; histiocytosis",
"medline_ta": "J Clin Aesthet Dermatol",
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"nlm_unique_id": "101518173",
"other_id": null,
"pages": "32-34",
"pmc": null,
"pmid": "32082469",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports",
"references": "27785447;19728332;29599667;24436311;23672541;23909818;26966089;23109216;10326709",
"title": "Langerhans Cell Histiocytosis with Isolated Cutaneous Involvement Refractory to Polychemotherapy: A Case Report.",
"title_normalized": "langerhans cell histiocytosis with isolated cutaneous involvement refractory to polychemotherapy a case report"
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"abstract": "BACKGROUND\nMucormycosis is a rare systemic fungal infection seen in immune-compromised patients. Gastrointestinal tract involvement is not usual.\n\n\nMETHODS\nA 36 years female presented with fever and progressive bilateral leg swelling for 25 days. She was diagnosed as nephrotic syndrome and started on methylprednisolone and cyclophosphamide. She developed hematochezia during hospital stay. On colonoscopy, ulcero-proliferative lesion was noted in caecum. Histopathology examination has confirmed it as mucormycosis of Caecum.\n\n\nCONCLUSIONS\nMucormycosis is an opportunistic angioinvasive disease caused by fungus zygomycosis it is a rare disease and often manifests as a life-threatening condition in immune-compromised patient. Invasion by fungal hyphae leads to arterial thrombosis, tissue infarction, hemorrhage and, necrosis. Diagnosis is confirmed by histopathological examination and culture. It is usually treated by the anti-fungal drug- liposomal amphotericin and surgical debridement.\n\n\nCONCLUSIONS\nMucormycosis is a fatal systemic fungal infection, which can present as lower gastrointestinal bleeding in immunocompromised patients.",
"affiliations": "Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal. Electronic address: gyaneswor89@gmail.com.;Department of GI and General Surgery, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal.;Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal.;Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal.",
"authors": "Shrestha|Gyaneswhor|G|;Maharajan|Narendra|N|;Pradhan|Sumita|S|;Bhandari|Ramesh Singh|RS|",
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"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612\nElsevier\n\nS2210-2612(21)00815-4\n10.1016/j.ijscr.2021.106313\n106313\nCase Report\nMucormycosis-unusual cause of lower GI bleeding: A rare case report\nShrestha Gyaneswhor gyaneswor89@gmail.com\na⁎\nMaharajan Narendra b\nPradhan Sumita a\nBhandari Ramesh Singh a\na Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal\nb Department of GI and General Surgery, Tribhuvan University Teaching Hospital, Institute of Medicine, Kathmandu, Nepal\n⁎ Corresponding author at: Maharajgunj Medical Campus, Institute of Medicine, P.O. Box: 1524, Kathmandu, Nepal. gyaneswor89@gmail.com\n16 8 2021\n9 2021\n16 8 2021\n86 1063138 6 2021\n11 8 2021\n13 8 2021\n© 2021 Published by Elsevier Ltd on behalf of IJS Publishing Group 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/).\nIntroduction\n\nMucormycosis is a rare systemic fungal infection seen in immune-compromised patients. Gastrointestinal tract involvement is not usual.\n\nCase presentation\n\nA 36 years female presented with fever and progressive bilateral leg swelling for 25 days. She was diagnosed as nephrotic syndrome and started on methylprednisolone and cyclophosphamide. She developed hematochezia during hospital stay. On colonoscopy, ulcero-proliferative lesion was noted in caecum. Histopathology examination has confirmed it as mucormycosis of Caecum.\n\nDiscussion\n\nMucormycosis is an opportunistic angioinvasive disease caused by fungus zygomycosis it is a rare disease and often manifests as a life-threatening condition in immune-compromised patient. Invasion by fungal hyphae leads to arterial thrombosis, tissue infarction, hemorrhage and, necrosis. Diagnosis is confirmed by histopathological examination and culture. It is usually treated by the anti-fungal drug- liposomal amphotericin and surgical debridement.\n\nConclusion\n\nMucormycosis is a fatal systemic fungal infection, which can present as lower gastrointestinal bleeding in immunocompromised patients.\n\nKeywords\n\nMucormycosis\nHematochezia\nGastrointestinal tract\nCaecum\nCase report\n==== Body\npmc1 Introduction\n\nMucormycosis is a systemic fungal infection caused by the mucor or rhizopus that belongs to the Mucoraceae family. It is a ubiquitous saprophytic mold which grows in soil and organic matter and produces hyphae after inhalation or ingestion. It represents the third most common angioinvasive fungal infection following candidiasis and aspergillosis [1]. It is common in immune-compromised patients like Diabetes Mellitus, Malignancies, HIV/AIDS, Corticosteroid/Immunosuppressant therapy. There are six types of mucormycosis, namely: rhinocerebral, pulmonary, cutaneous, gastrointestinal tract, disseminated, and miscellaneous (endocarditis, osteomyelitis, renal) [2], [3]. Stomach is the most common site of involvement in gastrointestinal tract (GI) followed by colon and ileum [4]. GI symptoms occur due to colonization of fungus leading to mucosal ulceration, infiltration and vascular invasion. Clinical progression is rapid and almost universally fatal if untreated [5]. It is diagnosed by histopathological examination or tissue culture [6]. It is treated by systemic antifungal drug and surgical debridement or resection. This case report has been reported in line with the SCARE Criteria [7].\n\n2 Case presentation\n\nWe report a case of 39 years lady who presented with fever for one and half month, sore throat followed by swelling of bilateral lower limb 25 days back. Swelling gradually progressed to involve face. Then she noticed cola-colored urine with gradual decrease in urine output. She also gave a history of evening rise in temperature associated with chills and rigor. She gave no any past medical, surgical, psychosocial and family history.\n\nInvestigation showed Total Leucocyte count of 14,000 with Neutrophils 75%, Lymphocytes 20%, Hb-7 g%, Urine Protein 3+. She was evaluated and treated for Nephrotic syndrome with methylprednisolone in nephrology ward. She developed Acute Kidney Injury (AKI) after 7 days of admission and required hemodialysis (HD). Treatment was escalated to immunosuppressant Cyclophosphamide with Regular hemodialysis (HD) for her Nephrotic syndrome induced AKI.\n\nOn 2nd week, there was bleeding per rectum. Proctoscopy followed by Colonoscopy was done for bleeding per rectum which revealed ulceroproliferative growth with friable mucosa in ascending colon and Caecum as shown in Fig. 1, and biopsy was taken in suspicion of malignant pathology.Fig. 1 Ulcerative lesion seen in colonoscopy.\n\nFig. 1\n\nHPE report showed necrotic tissue with lympoplasmacytic infiltrates, granulomas and epitheliod cell with septate fungal hyphae with narrow angle branching suggestive of Mucormycosis. as shown in Fig. 2.Fig. 2 HPE showing fungal hyphae.\n\nFig. 2\n\nCyclophosphamimde was stopped and Liposomal Amphotericin B (1 mg/kg/day) was started. Contrast enhanced computed tomography (CECT) abdomen and pelvis was normal. We proceeded for exploratory laparotomy. Intra operatively firm mass was found at ileocecal junction. Right Standard Hemicolectomy with Double barrel ileo colostomy was done.\n\nOn cut section, circumferential black color ulcerative lesion measuring 1.5 cm width was noted in ileocecal junction with neighboring next lesion measuring 1 × 5 cm size ulcerative lesion in the posterior wall of ascending colon 5 cm distal to IC junction as shown in (Fig. 3). Intra operative course was uneventful.Fig. 3 Cut section of the specimen showing ulcerative lesion around Ileo-ceacal (IC) junction.\n\nFig. 3\n\nPost operatively she was managed in Medical ICU with regular Hemodialysis amd amphotericin B after immediate stabilization in post operative ward for 1 day. Her post operative condition was static with Glassgow Coma Scale of 15 and daily urine output of less than 100 ml over 24 h every day. On POD 10, there was sudden rise in serum creatinine level following which patient required noradrenaline support to maintain her Blood pressure. Gradually her blood pressure was below normal level despite of vasopresser support. She was reintubated on POD12 There was persistent increase of serum creatinine with metabolic acidosis with blood PH of 7.01 and she succumbed on 14th POD.\n\n3 Clinical discussion\n\nMucormycosis is an opportunistic angioinvasive fungal infection belongs to zygomycetes family. Zygomycetes are divided into two orders: the Entophthorales and the Mucorales. Entomophthorales contain rare pathogenic species, whereas Mucorales contain the most common human pathogens specifically Rhizopus, Mucor, Absidia, and Cunninghamellacae. These organisms with low virulence causes disease less frequently and usually present in immunocompromised individuals. The Rhizopus species is the most pathogenic and significantly more virulent than other fungi [5]. Mucormycosis is a rare disease and often life-threatening condition that is commonly seen in patients with risk factors like diabetes, metabolic acidosis, hematological or solid malignancies, neutropenia, trauma, use of corticosteroids, solid organ, or stem cell transplant, iron overload or deferoxamine use, malnourishment, and exposure to newer broad-spectrum antifungals like Echinocadin and Voriconazole like our case was under immunosuppressant [8], [9]. Infection can be of rhinocerebral, pulmonary, cutaneous, gastrointestinal, renal, or disseminated type; gastrointestinal infection comprises only 7% of reported cases so can say our case is rare [2]. Invasion of blood vessels by hyphae leads to arterial thrombosis, tissue infarction, hemorrhage and necrosis. Mechanism of GI tract entry is not clear. Fungi pervasive in environment enters in milieus like nasogastric intubation, ingestion of contaminated food.\n\nClinical features of GI mucormycosis are nonspecific, which includes abdominal pain and distention, nausea and vomiting, hematemesis, hematochezia, and intestinal perforation with peritonitis where our case presented with hematochezia [10]. It may present with bowel obstruction. Biopsy and histopathological examination is the best method to detect mucormycosis, like we found hyphae in HPE of our case. The histopathological hallmark of mucormycosis infection is vascular invasion, causing thrombosis and infarction, or secondary hemorrhages of neighboring tissues; focal areas of granulomatous inflammation are occasionally present [11]. The diagnosis is established histopathologically by the presence of characteristic broad, branching and non-septate hyphae in infected tissues, usually in connotation with angioinvasion, vascular thrombosis and infarction like in our case there was similar features of fungi without identifiable vascular invasion. Histologically it has been categorized into colonization, infiltrative and invasive as in our case its colonized type [6].\n\nRecently published joint clinical guidelines from the European Society for Clinical Microbiology and Infectious Diseases and the European Confederation of Medical Mycology strongly recommend Liposomal amphotericin B as drug of choice and recommend dose is 5 mg/kg daily; the use of amphotericin B deoxycholate was discouraged because of its nephrotoxic side effects [12].\n\n. Besides to antifungal therapy, early surgical debridement improves survival (62% with antifungal alone, 57% with surgery alone, and 70% with both) [5].\n\nHowever, our case could not be recovered despite resection of diseased part and use of systemic antifungal, amphotericin B.\n\n4 Conclusion\n\nGastrointestinal mucormycosis is a fatal disease if not treated in time and aggressively. GI tract Mucormycosis could cause intra lumial bleeding. It could differential diagnosis for GI tract bleeding in patients with high-risk factors though it is rare. Early diagnosis, prompt administration of antifungal therapy and surgical resection of infected and necrotic tissue decrease morbidity and mortality of disease burden.\n\nEthical approval\n\nNot required.\n\nFunding\n\nNone.\n\nGuarantor\n\nGyaneswhor Shrestha.\n\nRegistration of research studies\n\nNot applicable.\n\nProvenance and peer review\n\nNor commissioned, externally peer-reviewed.\n\nConsent for publication\n\nWritten informed consent was obtained from her family member (patient expired) for publication of this case report and accompanying images. A copy of written consent is available for review by the Editor-in Chief of this journal on request.\n\nCRediT authorship contribution statement\n\nGyaneswhor Shrestha: Study concept, data collection surgical therapy for patient.\n\nGyaneswhor Shrestha: Writing-original draft preparation.\n\nNarendra Maharajan: Editing and Writing.\n\nRamesh Singh Bhandari and Sumita Pradhan: Senior author and Manuscript reviewer.\n\nAll the authors read and approved the final manuscript.\n\nDeclaration of competing interest\n\nNone.\n\nAcknowledgement\n\nNone.\n==== Refs\nReferences\n\n1 Torres-Narbona M. Guinea J. Munoz P. Bouza E. Zygomycetes and zygomycosis in the new era of antifungal therapies Rev. Esp. Quimioter. 20 4 2007 375 386 18563211\n2 Lacarriere E. Lacaze L. Schwarz L. Huet E. Lemoine F. Scotte M. First case of gastrointestinal mucormycosis in an immunocompromised patient with gallbladder and duodenum involvement Infection 39 6 2011 595 598 21786018\n3 Lopes J.O. Pereira D.V. Streher L.A. Fenalte A.A. Alves S.H. Benevenga J.P. Cutaneous zygomycosis caused by absidia corymbifera in a leukemic patient Mycopathologia 130 2 1995 89 92 7566062\n4 Agha F.P. Lee H.H. Boland C.R. Bradley S.F. Mucormycoma of the colon: early diagnosis and successful management AJR Am. J. Roentgenol. 145 4 1985 739 741 3875993\n5 Roden M.M. Zaoutis T.E. Buchanan W.L. Knudsen T.A. Sarkisova T.A. Schaufele R.L. Epidemiology and outcome of zygomycosis: a review of 929 reported cases Clin. Infect. Dis. 41 5 2005 634 653 16080086\n6 Vaezi A. Fakhim H. Ilkit M. Faeli L. Fakhar M. Alinejad V. Rapid and low-cost culture-based method for diagnosis of mucormycosis using a mouse model Front. Microbiol. 11 2020 440 32265876\n7 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. Group S The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358\n8 Sedlacek M. Cotter J.G. Suriawinata A.A. Kaneko T.M. Zuckerman R.A. Parsonnet J. Mucormycosis peritonitis: more than 2 years of disease-free follow-up after posaconazole salvage therapy after failure of liposomal amphotericin B Am. J. Kidney Dis. 51 2 2008 302 306 18215708\n9 Petrikkos G. Drogari-Apiranthitou M. Zygomycosis in immunocompromised non-haematological patients Mediterr J. Hematol. Infect. Dis. 3 1 2011 e2011012\n10 Kalva N. Somaraju V. Puli S. A fatal case of gastrointestinal mucormycosis in immunosuppressed host Med. J. Armed Forces India 69 3 2013 285 287 24600124\n11 Spellberg B. Edwards J. Jr. Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management Clin. Microbiol. Rev. 18 3 2005 556 569 16020690\n12 Cornely O.A. Cuenca-Estrella M. Meis J.F. Ullmann A.J. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) fungal infection study group (EFISG) and European Confederation of Medical Mycology (ECMM) 2013 joint guidelines on diagnosis and management of rare and emerging fungal diseases Clin. Microbiol. Infect. 20 Suppl 3 2014 1 4\n\n",
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"literaturereference": "Shrestha G, Maharajan N, Pradhan S, Bhandari RS.. Mucormycosis-unusual cause of lower GI bleeding: A rare case report. International Journal of Surgery Case Reports. 2021;86:1-3",
"literaturereference_normalized": "mucormycosis unusual cause of lower gi bleeding a rare case report",
"qualification": "3",
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},
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}
] |
{
"abstract": "Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that commonly manifests as cutaneous rashes, renal disease, gastrointestinal dysfunction, and cytopenia. Hematological anomalies are frequently associated with drug-induced toxicity in SLE patients. Colony-stimulating factors have been used to treat drug-induced cytopenia in past case reports; however, evidence suggests that colony-stimulating factors can exacerbate autoimmune disorders, including SLE. This case report presents two patients with SLE exacerbations after colony-stimulating factor administration. The first case is a young male with SLE who developed pancytopenia with a white blood cell count (WBC) of 1 × 109 cells/L. The patient was administered filgrastim during his initial admission and presented to the hospital 2 days after discharge in cardiac arrest with a WBC of 66.7 × 109 cells/L. The second case is a 49-year-old female with SLE who was administered sargramostim in response to a WBC count of 9 × 109 cells/L. The patient experienced a drastic increase in WBC followed by a cardiac arrest. These cases highlight the need for more research regarding the safe use of colony-stimulating factors in SLE patients.",
"affiliations": "Department of Pharmaceutical Sciences, 21818Beaumont Hospital, Royal Oak, MI, USA.;Department of Pharmaceutical Sciences, 21818Beaumont Hospital, Royal Oak, MI, USA.",
"authors": "Ragsdale|Morgan E|ME|https://orcid.org/0000-0002-4060-5480;Hall Zimmerman|Lisa G|LG|https://orcid.org/0000-0002-1064-178X",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/08971900211053268",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": null,
"journal": "Journal of pharmacy practice",
"keywords": "G-CSF; GM-CSF; colony-stimulating factor; exacerbation; systemic lupus erythematosus",
"medline_ta": "J Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "8971900211053268",
"pmc": null,
"pmid": "34748466",
"pubdate": "2021-11-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Use of Colony-Stimulating Factors in Patients With Systemic Lupus Erythematosus.",
"title_normalized": "use of colony stimulating factors in patients with systemic lupus erythematosus"
} | [
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},
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}
],
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"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Systemic lupus erythematosus",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Renal impairment",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Vasculitis gastrointestinal",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pancytopenia",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Systemic inflammatory response syndrome",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pseudomembranous colitis",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Tachycardia",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Tachypnoea",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Coagulopathy",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Ragsdale ME, Hall Zimmerman LG. Use of Colony-Stimulating Factors in Patients With Systemic Lupus Erythematosus. J-Pharm-Pract 2021;:no pagination.",
"literaturereference_normalized": "use of colony stimulating factors in patients with systemic lupus erythematosus",
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},
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"receivedate": "20211227",
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},
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"safetyreportversion": 3,
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"senderorganization": "FDA-Public Use",
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnessother": null,
"transmissiondate": "20220720"
},
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP031303",
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},
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},
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{
"abstract": "Bronchospasm (spasm of bronchial muscles) in general anesthesia caused by many reasons. Untreated bronchospasm can cause hypoxia, hypotension and increased morbidity and mortality.\nA 28 years old female scheduled for tonsillectomy surgery. Immediately after induction of anesthesia patient developed with drop in oxygen saturation and difficulty in mechanical ventilation.\nBronchospasm should be considered in differential diagnosis of oxygen saturation drop during general anesthesia. This situation is more common in patients without specific respiratory disorder. Tracheal irritants like sputum and blood can cause bronchospasm. Other causes include histamine or serotonin release.",
"affiliations": "Anesthesia department, Fasa University of Medical Sciences, Fasa, Iran.",
"authors": "Vojdani|Salman|S|",
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"fulltext": "\n==== Front\nGalen Med J\nGalen Med J\nGalen Medical Journal\nGalen Medical Journal\nGMJ\nGalen Medical Journal\n2588-2767\n2322-2379\nSalvia Medical Sciences Ltd\n\n10.22086/gmj.v0i0.846\nCase Report\nBronchospasm During Induction of Anesthesia: A Case Report and Literature Review\nVojdani Salman 1 2 *\n1Anesthesia department, Fasa University of Medical Sciences, Fasa, Iran\n2Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran\nCorrespondence to: Salman Vojdani, Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran Telephone Number: +989397356589 Email address: s.vojdani@fums.ac.ir\n2018\n19 5 2018\n7 e846e846\n17 3 2017\n27 8 2017\n21 9 2017\nCopyright© 2018, Galen Medical Journal.\n2018\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)\nBackground:\n\nBronchospasm (spasm of bronchial muscles) in general anesthesia caused by many reasons. Untreated bronchospasm can cause hypoxia, hypotension and increased morbidity and mortality.\n\nCase report:\n\nA 28 years old female scheduled for tonsillectomy surgery. Immediately after induction of anesthesia patient developed with drop in oxygen saturation and difficulty in mechanical ventilation.\n\nConclusions:\n\nBronchospasm should be considered in differential diagnosis of oxygen saturation drop during general anesthesia. This situation is more common in patients without specific respiratory disorder. Tracheal irritants like sputum and blood can cause bronchospasm. Other causes include histamine or serotonin release.\n\nBronchial Spasm\nGeneral Anesthesia\nRespiratory Hypersensitivity\n==== Body\nIntroduction\n\nBronchospasm like asthma is a feature of reactive airway disease. Patients shows hyperreactive airway responses to irritants. Constriction of bronchial smooth muscle, plugging are pathophysiology of these groups.\n\nIn general anesthesia the incidence of bronchospasm in controlled asthma is approximately 2% and overall incidence is 0.2% [1]. Many patients with bronchospasm in general anesthesia had no history of airway disease. The manifestations of bronchospasm in general anesthesia are expiratory wheeze, drop in oxygen saturation and difficulty in mechanical ventilation, however in severe cases wheeze may be absent.\n\nCase Presentation\n\nA 28-year,60 Kg female, American Society of Anesthesiologists(ASA) Class I was scheduled for tonsillectomy surgery. She had no history of previous surgery or any medical disorder. Chest examination was normal in preoperative anesthesia visit. Anesthesia induced with intravenous midazolam (3 mg), fentanyl (150 μg), propofol (180 mg) and atracurium (35 mg). Nasotracheal intubation performed with mild resistance. Amounts of blood was seen in throat during intubation which suctioning was done. After Nasotracheal intubation chest examination showed lack of breathing sounds. Bag ventilation was difficult to perform. Capnogram revealed prolonged expiratory upstroke, so this was suspected to bronchospasm. Oxygen saturation dropped rapidly, (Spo2:55%) followed by arterial hypotension (from 135/85 to 55/25 mmHg) with a moderate tachycardia (110 beats in minute) in 6 minutes after bronchial spasm. Three intravenous boluses of 100 μg epinephrine administered to correct cardiovascular instability. At the same time suctioning of the airway removed bloody secretions from trachea, then ventilation became easier and audible wheezing over both lung fields was auscultated. By giving intravenous hydrocortisone (200 mg) and aminophylline infusion (250 mg) respiratory symptoms resolved within 30 minutes. Surgery was done with uneventful clinical outcome and in the following day patient was discharged home.\n\nDiscussion\n\nIn a study bronchospasm diagnosed 1.7 times during 1000 anesthesia [1]. Bronchospasm during perioperative period may have multiple causes from IgE-mediated anaphylaxis, non-allergic mechanism triggered by mechanical factors (i.e., orotracheal intubation), drug-induced (i.e., atracurium, morphine and meperidine) to bronchospasm in patients with hyper-reactive airway [2].\n\nLight anesthesia, airway secretions and obstruction of the tube or circuit are other differential diagnosis. Endobronchial intubation present with unilateral wheezing [3].\n\nIf clinical symptoms persist despite appropriate therapy, it may due to pneumothorax or Pulmonary edema [2].\n\nIn cardiovascular system, the results of progressive acute bronchoconstriction are reduction of airflow, lung inflation, increased resistance of pulmonary vessels (PVR) and overload of right ventricle [3]. Propofol with bronchodilating effects considered in allergic patients, histamine-induced contractions in airway smooth muscles reduced with propofol in both healthy and asthmatic patients. Soybean oil and yolk lecithin in propofol formulation induced allergic reaction and should be used with caution in atopic patients.\n\nIn studies about allergic reactions to anesthetic agents the dominant majority were female patients, such as our study [4-6].\n\nOther drugs with histamine release effects are neuromuscular-blocking drugs (NMBDs), intraoperative anaphylaxis often triggered by NMBDs. A few published cases reported bronchospasm triggered after spinal anesthesia. There were no intraoperative deaths [7, 5]. Since in our study Nasotracheal intubation was forceful, causes of bronchospasm may be either blood in bronchial tree or allergic reaction to anesthetic agents.\n\nConclusion\n\nOne of the life threatening emergencies during general anesthesia is severe bronchospasm. In perioperative visit most of the patients had no history of allergy or asthma. Triggering factors like sputum, blood and some anesthetic agents can cause bronchospasm [1]. Selective β2 agonists (Salbutamol) are the drug of choice for treatment. The pharmacodynamics of salbutamol are poorly characterized [8]. Second-line agents include Ipratropium bromide, Magnesium sulphate, Hydrocortisone, Ketamine and in extremis Epinephrine (Nebulized and Intravenous) Extubation under deep anesthesia reduces reflex bronchoconstriction during emergence in this patients [9].\n\nConflict of Interest\n\nNo conflict of interest\n==== Refs\nReferences\n\n1 Olsson G Bronchospasm during anaesthesia A computer-aided incidence study of 136 929 patients Acta Anaesthesiol Scand 1987 31 3 244 52 3577646\n2 Dewachter P Mouton-Faivre C Emala CW Beloucif S Case scenario: bronchospasm during anesthetic induction Anesthesiology 2011 114 5 1200 10 21460703\n3 Woods BD Sladen RN Perioperative considerations for the patient with asthma and bronchospasm Br J Anaesth 2009 103 suppl_1 i57 i65 20007991\n4 Laxenaire M-C Mata-Bermejo E Moneret-Vautrin DA Gueant J-L Life-threatening anaphylactoid reactions to propofol (Diprivan) Anesthesiology 1992 77 2 275 80 1379418\n5 Mertes PM DP, Stenger R. Diseases Summaries. Allergy to Anesthetic Agents. World Allergy Organization [online] (Accessed February 25,2016,at: http://www.worldallergy.org/professional/allergic_diseases_center/anaesthetic_agents).\n6 Nishiyama T Hanaoka K Propofol-induced bronchoconstriction: two case reports Anesth Analg 2001 93 3 645 6 11524333\n7 Rodilla-Fiz AM Gómez-Garrido M Martínez-López F Monsalve-Naharro JÁ Girón-La Casa M López-Pérez A Bronchospasm triggered by spinal anaesthesia Case report and review of the literature rev colomb anestesiol 2016 44 2 179 81\n8 Sottas C Anderson B Holford N Salbutamol has rapid onset pharmacodynamics as a bronchodilator Acta Anaesthesiol Scand 2016 60 9 1328 31 27439596\n9 Parameswara G Anesthetic concerns in patients with hyper-reactive airways Karnataka Anaesth J 2015 1 1 8 16\n\n",
"fulltext_license": "CC BY",
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"journal": "Galen medical journal",
"keywords": "Bronchial Spasm; General Anesthesia; Respiratory Hypersensitivity",
"medline_ta": "Galen Med J",
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"pmid": "34466415",
"pubdate": "2018",
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"title": "Bronchospasm During Induction of Anesthesia: A Case Report and Literature Review.",
"title_normalized": "bronchospasm during induction of anesthesia a case report and literature review"
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"abstract": "Spasmodic dysphonia is a primary task specific focal dystonia affecting the laryngeal muscles during speech. Most medical and surgical approaches to treatment of spasmodic dysphonia are aimed at the denervation of the laryngeal muscles to block symptom expression in the voice. The standard of care for the adductor form of spasmodic dysphonia is botulinum toxin chemodenervation. The common side effects of treatment with Botox are excessive breathiness and aspiration of fluids. We present the report of a delayed presentation of upper airway obstruction due to a complete vocal cords adduction requiring intubation ten days post Botox injection for the adductor form of spasmodic dysphonia. This presentation may be preceded by a change in voice, productive cough, shortness of breath, or odynophagia. We would recommend supportive treatment in an Intensive Care Unit and close liaison with the otolaryngology team for the management of this complication. Acute upper airway obstruction requiring tracheal intubation is a delayed complication of botulinum toxin administration in the adductor form of spasmodic dysphonia.",
"affiliations": "Basingstoke and North Hampshire Hospital, Basingstoke, United Kingdom. danylo.yershov@swft.nhs.uk.;Basingstoke and North Hampshire Hospital, Basingstoke, United Kingdom.",
"authors": "Yershov|Danylo|D|;Partridge|Richard|R|",
"chemical_list": "D019274:Botulinum Toxins, Type A",
"country": "Czech Republic",
"delete": false,
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"issue": "121(2)",
"journal": "Prague medical report",
"keywords": "Botulinum toxin; Dysphonia; Vocal cords",
"medline_ta": "Prague Med Rep",
"mesh_terms": "D019274:Botulinum Toxins, Type A; D055154:Dysphonia; D006801:Humans; D007821:Laryngeal Muscles; D013997:Time Factors; D016896:Treatment Outcome; D064706:Vocal Cord Dysfunction",
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"references": null,
"title": "Life Threatening Delayed Complication of Botulinum Toxin Injection for Treatment of Spasmodic Dysphonia.",
"title_normalized": "life threatening delayed complication of botulinum toxin injection for treatment of spasmodic dysphonia"
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"abstract": "Pancreatic cancer is often detected in late stages, which contributes to its grim prognosis. Although the manifestations of pancreatic cancer most often include nonspecific gastrointestinal complaints, we report a case with the sole initial complaint of halitosis and subsequent diagnostic workup demonstrating a pancreatic mass with secondary pancreatocolonic fistulization. The etiologies of and the radiological findings pertaining to halitosis, the presenting symptoms and imaging studies relevant to the diagnosis of pancreatic cancer, and the imaging and clinical findings of pancreatic fistulization are discussed.",
"affiliations": "Department of Radiology, University of Miami Miller School of Medicine, WW279, 1611 NW 12th Avenue, Miami, FL 33136, USA.;Department of Radiology, University of Miami Miller School of Medicine, WW279, 1611 NW 12th Avenue, Miami, FL 33136, USA.;Department of Radiology, University of Miami Miller School of Medicine, WW279, 1611 NW 12th Avenue, Miami, FL 33136, USA.;Division of Gastroenterology, Department of Internal Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.;Department of Radiology, University of Miami Miller School of Medicine, WW279, 1611 NW 12th Avenue, Miami, FL 33136, USA.;Division of Gastroenterology, Department of Internal Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.",
"authors": "Manov|John|J|;Langston|Michael|M|;Roth|Patrick|P|;Barkin|Jodie|J|;Kuker|Russ|R|;Barkin|Jamie S|JS|",
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"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(17)30422-310.1016/j.radcr.2017.11.011GastrointestinalPancreatocolonic fistulization secondary to pancreatic adenocarcinoma presenting as unexplained halitosis Manov John BSjjm86@med.miami.edua*Langston Michael BSaRoth Patrick MDaBarkin Jodie MDbKuker Russ MDaBarkin Jamie S. MDba Department of Radiology, University of Miami Miller School of Medicine, WW279, 1611 NW 12th Avenue, Miami, FL 33136, USAb Division of Gastroenterology, Department of Internal Medicine, University of Miami Miller School of Medicine, Miami, FL, USA* Corresponding author. jjm86@med.miami.edu25 12 2017 2 2018 25 12 2017 13 1 72 75 12 9 2017 10 11 2017 13 11 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/).Pancreatic cancer is often detected in late stages, which contributes to its grim prognosis. Although the manifestations of pancreatic cancer most often include nonspecific gastrointestinal complaints, we report a case with the sole initial complaint of halitosis and subsequent diagnostic workup demonstrating a pancreatic mass with secondary pancreatocolonic fistulization. The etiologies of and the radiological findings pertaining to halitosis, the presenting symptoms and imaging studies relevant to the diagnosis of pancreatic cancer, and the imaging and clinical findings of pancreatic fistulization are discussed.\n\nKeywords\nPancreatic cancerHalitosisMalignancyFistula\n==== Body\nCase report\nA 77-year-old man with a medical history of long-standing insulin-dependent diabetes mellitus presented to a gastroenterology clinic at the urging of his wife because of her perception that the patient had developed severe, feculent halitosis. This odor had not improved with oral hygiene and dental consultation had not been helpful. The patient noted slight unintentional weight loss over the past 3 months but was otherwise asymptomatic. The patient had a prior episode of reportedly idiopathic acute pancreatitis 7 years previously. Laboratory testing demonstrated normal liver function test results. Amylase and lipase levels were both within normal limits. Fluoroscopic barium esophagography to investigate the possibility of a Zenker diverticulum demonstrated no luminal irregularities or dysmotility. Because of this history of unexplained pancreatitis and weight loss, computed axial tomography of the chest, abdomen, and pelvis was obtained, revealing an irregular, up to 8-cm pancreatic tail mass abutting the stomach and the transverse colon (Fig. 1).Fig. 1 Axial and sagittal projections of the patient's contrast-enhanced computed tomography of the abdomen demonstrate an approximately 7 × 8 × 7 cm mass with central hypodensity arising from the tail of the pancreas. Fat planes between the mass and the stomach, the transverse colon, the spleen, and the left kidney are completely effaced. There is thickening of the walls of the stomach and the transverse colon immediately adjacent to the pancreatic mass.\n\nFig. 1\n\nEndoscopic ultrasonography (EUS) revealed an irregular, hypoechoic mass with poorly defined borders and evidence of invasion into the small bowel, and fine needle aspiration of the pancreatic mass demonstrated adenocarcinoma. Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) was ordered for further characterization of the mass, initial staging, and to serve as a baseline to assess for response to treatment. 18F-FDG PET/CT demonstrated a large, peripherally hypermetabolic and centrally necrotic heterogeneous mass in the left upper abdominal quadrant centered in the tail of the pancreas and inseparable from multiple surrounding structures (Fig. 2). PET/CT did not demonstrate evidence of distant metastatic disease or occult lesions in the liver or distant sites. The lack of distant metastases was one of the justifications for taking the patient to surgery.Fig. 2 Axial fused Fluorine-18 fluorodeoxyglucose positron emission tomography computed tomography of the abdomen show intense peripheral hypermetabolic activity associated with the pancreatic mass, which is inseparable from the spleen and the proximal greater curvature of the stomach. The mass demonstrates central photopenia likely consistent with tumor necrosis.\n\nFig. 2\n\nAfter evaluation by medical and surgical oncology, the patient began chemotherapy with gemcitabine and abraxane, with subsequent tumor progression. The chemotherapy regimen was switched to a combination therapy utilizing fluorouracil, irinotecan, oxaliplatin, and folinic acid. After 6 cycles of FOLFIRINOX, CT demonstrated a decrease in size of the primary tumor and no new areas of disease.\n\nPreoperative imaging after 6 months of neoadjuvant chemotherapy demonstrated an increase in the size of the mass with invasion of the posterior wall of the stomach, the colonic splenic flexure, the anterior aspect of the spleen, and the superior pole of the left kidney (Fig. 3). Additionally, there was a suggestion of fistulization with the transverse colon as evidenced by air within the mass (Fig. 4). The patient underwent exploratory laparotomy, partial gastrectomy, partial colectomy, partial omentectomy, distal pancreatectomy, splenectomy, left nephrectomy, and duodenal resection, with T3N1 disease staging. The presence of a pancreatocolonic fistula was confirmed during surgery. Two months postoperatively, the patient remains with good performance status. Halitosis resolved in the immediate postoperative period without recurrence.Fig. 3 Coronal computed tomography of the abdomen demonstrates a large, ill-defined hypodense mass centered in the region of the pancreatic tail with invasion into the wall of the greater curvature of the stomach, the spleen, and the left kidney. The boxed “A” indicates that this is anterior view from a multiplanar reformat.\n\nFig. 3Fig. 4 CT of the abdomen performed 6 months after the initial scan demonstrates significant interval growth of the patient's centrally necrotic pancreatic tail mass to approximately 8 × 10 × 8 cm. There is fistulization with the transverse colon as evidenced by air within the mass; additionally, there is worsened invasion of the spleen and left kidney.\n\nFig. 4\n\nDiscussion\nPancreatic cancer is a diagnosis with grim 1 and 5-year survival rates [1]. It is generally believed that the poor prognosis in most cases of pancreatic cancer is attributable, in part, to the advanced stage at which most such tumors are detected. The retroperitoneal location of the pancreas allows many pancreatic cancers, especially those outside the head of the pancreas, opportunity for extensive growth and spread before symptoms develop. These symptoms, when present, are often nonspecific gastrointestinal complaints that patients and clinicians can easily ascribe to more common, benign etiologies. In this case, intractable halitosis was the sole complaint motivating this patient to seek care.\n\nThere is controversy as to whether disease of the gastrointestinal tract can contribute to halitosis, as the gastroesophageal junction is usually closed [2]. Zenker diverticulum, a well known but rare cause of halitosis (due to bacterial digestion of retained food) is usually diagnosed by barium swallow or videofluoroscopy [3]. Achalasia and hiatal hernias can also contribute to halitosis, similarly caused by food retention, and can be diagnosed by barium swallow or other modalities [4]. Maldigestion and fermentation from small intestinal bacterial overgrowth or from exocrine pancreatic insufficiency may additionally contribute to halitosis [5]. In this patient, results of the evaluation for all of these causes of extraoral halitosis were negative.\n\nPancreatic cancer is the fourth leading cause of malignancy-related death, among men and women, in the United States. As 85% of these cancers are of exocrine cellular origin, we will restrict our discussion to these cases. The vast majority of patients diagnosed with pancreatic cancer will die from this disease [1]. The only curative modality for pancreatic cancer is surgery, but only 15%-20% of patients are candidates for resection at the time of diagnosis. Even after optimal resection, the 5-year survival rate is only 30% for patients with negative nodes [6].\n\nAlthough the classical presentation of pancreatic head cancer with obstructive jaundice is well known, the symptoms of pancreatic cancer are often vague and subtle. These include pain, typically of a gnawing quality that is felt in the back, anorexia, early satiety, and weight loss. Up to a quarter of patients with pancreatic cancer have no pain at diagnosis, and the presence of pain is associated with disease that is already unresectable. The onset of diabetes mellitus at an advanced age is a distinct sign of possible pancreatic malignancy that is often overlooked [7].\n\nMultiple imaging modalities are useful in the diagnosis of pancreatic adenocarcinoma (PDAC). A recent meta-analysis found that differences in sensitivity, specificity, and diagnostic accuracy between magnetic resonance imaging (MRI), CT, transabdominal ultrasound, and EUS failed to reach statistical significance [8]. Although the sensitivity of transabdominal ultrasound varies throughout the literature, it is still often used as an initial test because of its wide availability and relatively low cost; this is balanced by limitations caused by the technical demands and operator variability inherent to the procedure [8], [9], [10], [11]. CT is the most commonly utilized modality for the evaluation of PDAC; its sensitivity ranges from 89% to 97% for tumors larger than 1.5 cm [12]. Studies have failed to demonstrate differences in the effectiveness of MRI vs CT in the detection of PDAC, although MRI has been suggested to be more useful in small tumors [11]. EUS has been found to have an excellent sensitivity for pancreatic cancer, with a negative predictive value approaching 100%. The of EUS has a key role in cases in which there is strong clinical suspicion, but other modalities have failed to show a lesion [11].\n\nGastrointestinal fistulization is a known complication of acute pancreatitis, which has been reported to occur in up to 5.7% of patients. Kochhar et al. cited the colon and duodenum as the most common locations for fistulization, together accounting for 80% of cases of pancreatic fistulization. Of those with fistulization, only 45% had a history of surgical or percutaneous interventions; thus, 55% were considered spontaneous [13]. In contrast, fistulization resulting from pancreatic masses is rare with only 1 report, in a case of intraductal papillary mucinous neoplasm, encountered on extensive review of the literature [14]. Colonic wall thickening is the hallmark of colonic involvement in acute pancreatitis and may radiographically predict a worse prognosis. Rectally administered, water-soluble contrast enemas may be useful in diagnosing pancreatocolonic fistulae [15].\n\nHalitosis as the sole presenting sign of pancreatic cancer, as in our patient, appears to be quite rare, with only 1 other report found in the literature [16]. Although a meta-analysis by Silva et al. revealed the prevalence of halitosis to be perhaps as high as 31.8% [17], the vast majority (80%-90%) of cases are caused by oral factors confined to the tongue, teeth, and gums [18]. Extraoral causes of halitosis are rare, although the odor may be similar to oral halitosis because of common volatile sulfur compounds produced by certain bacteria [19]. There are many extraoral causes of halitosis; including multiple respiratory and pharyngeal abnormalities, for which imaging studies including CT and chest x-ray may be helpful in the diagnosis, including chronic sinusitis and nasal obstruction [20], pneumonia or pulmonary abscess, bronchiectasis, or tonsilloliths [21].\n\nFor our patient, development of halitosis preceded direct radiological evidence of a fistula, that is, air within the pancreatic mass or identification of a fistula tract. However, there were secondary signs of fistulization with stomach and colonic wall thickening on the patient's initial imaging studies. Pathophysiologically, we propose that microscopic evidence of fistulization or bacterial translocation through a permeable, likely necrotic bowel wall may explain the clinical evidence of halitosis while preceding overt evidence of fistula formation radiographically. It is notable that the patient's halitosis resolved in the immediate postoperative period with obliteration of the fistulous connection between the upper gastrointestinal tract and the large bowel.\n\nIn conclusion, we present a rare case of pancreatic cancer with an initial presentation of severe feculent halitosis. This striking juxtaposition of the common and almost always benign complaint of halitosis with the dire diagnosis of pancreatic malignancy has been reported only once before [16]. Although quite uncommon, in combination with other warning signs such as unintentional weight loss and a history of unexplained pancreatitis, the presence of pancreatointestinal fistulization caused by malignancy should be added to the differential diagnosis. Increased awareness of this uncommon presentation may occasionally result in early detection and improved outcomes for some cases of PDAC.\n==== Refs\nReferences\n1 Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2017 CA Cancer J Clin 67 1 2017 7 30 PubMed PMID 28055103 28055103 \n2 Tangerman A. Halitosis in medicine: a review Int Dent J 52 Suppl. 3 2002 201 206 PubMed PMID 12090453 12090453 \n3 Sooklal S. Sohagia A. Undigested food on awakening with persistent halitosis BMJ Case Rep 2014 PubMed PMID 24913084 PubMed Central PMCID: PMC4054118 \n4 Boeckxstaens G. The European experience of achalasia treatment Gastroenterol Hepatol (N Y) 7 9 2011 609 611 PubMed PMID 22299000 PubMed Central PMCID: PMC3264974 22299000 \n5 Feldman M. Friedman L.S. Brandt L.J. Sleisenger and Fordtran's gastrointestinal and liver disease 10th ed 2010 Elsevier Health Sciences Philadelphia 1824 1831 \n6 Allen P.J. Kuk D. Castillo C.F. Basturk O. Wolfgang C.L. Cameron J.L. Multi-institutional Validation Study of the American Joint Commission on Cancer (8th Edition) Changes for T and N Staging in Patients With Pancreatic Adenocarcinoma Ann Surg 265 1 2017 185 191 PubMed PMID 27163957 NIHMSID: NIHMS838037; PubMed Central PMCID: PMC5611666 27163957 \n7 DiMagno E.P. Pancreatic cancer: clinical presentation, pitfalls and early clues Ann Oncol 10 Suppl. 4 1999 140 142 PubMed PMID 10436807 10436807 \n8 Toft J. Hadden W.J. Laurence J.M. Lam V. Yuen L. Imaging modalities in the diagnosis of pancreatic adenocarcinoma: A systematic review and meta-analysis of sensitivity, specificity and diagnostic accuracy Eur J Radiol 92 2017 17 23 PubMed PMID 28624015 28624015 \n9 Niederau C. Grendell J.H. Diagnosis of pancreatic carcinoma Imaging techniques and tumor markers Pancreas 7 1 1992 66 86 PubMed PMID 1557348 1557348 \n10 Karlson B.M. Ekbom A. Lindgren P.G. Källskog V. Rastad J. Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis Radiology 213 1 1999 107 111 PubMed PMID 10540649 10540649 \n11 Scharwächter C. Haage P. State of the art diagnosis of pancreatic ductal adenocarcinoma Curr Radiol Rep 5 8 2017 38 \n12 Loizou L. Albiin N. Leidner B. Axelsson E. Fischer M.A. Multidetector CT of pancreatic ductal adenocarcinoma: Effect of tube voltage and iodine load on tumour conspicuity and image quality Eur Radiol 26 11 2016 4021 4029 PubMed PMID 26965503 26965503 \n13 Kochhar R. Jain K. Gupta V. Singhal M. Kochhar S. Fistulization in the GI tract in acute pancreatitis Gastrointest Endosc 75 2 2012 436 440 PubMed PMID 22154413 22154413 \n14 Gaujoux S. Dokmak S. Deschamps L. Zappa M. Belghiti J. Pancreatocolonic fistula complicating noninvasive intraductal papillary mucinous tumor of the pancreas Gastroenterol Clin Biol 32 1 Pt 1 2008 79 82 PubMed PMID 18405653 18405653 \n15 Tüney D. Altun E. Barlas A. Yegen C. Pancreatico-colonic fistula after acute necrotizing pancreatitis diagnosis with spiral CT using rectal water soluble contrast media JOP 9 1 2008 26 29 PubMed PMID 18182739 18182739 \n16 Innocent-Ituah I. Halitosis: hindrance or hint? J Miss State Med Assoc 50 12 2009 422 425 PubMed PMID 20806813 20806813 \n17 Silva M.F. Leite F.R.M. Ferreira L.B. Pola N.M. Scannapieco F.A. Estimated prevalence of halitosis: a systematic review and meta-regression analysis Clin Oral Investig 2017 PubMed PMID 28676903 \n18 van den Broek A.M. Feenstra L. de Baat C. A review of the current literature on management of halitosis Oral Dis 14 1 2008 30 39 PubMed PMID 18173446 18173446 \n19 Tangerman A. Winkel E.G. Extra-oral halitosis: an overview J Breath Res 4 1 2010 017003 PubMed PMID 21386205 21386205 \n20 Bhattacharyya N. Contemporary assessment of the disease burden of sinusitis Am J Rhinol Allergy 23 4 2009 392 395 PubMed PMID 19671253 19671253 \n21 Takahashi A. Sugawara C. Kudoh T. Ohe G. Takamaru N. Prevalence and imaging characteristics of palatine tonsilloliths evaluated on 2244 pairs of panoramic radiographs and CT images Clin Oral Investig 21 1 2017 85 91 PubMed PMID 26892471\n\n",
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"abstract": "These case reports focus on a rapid treatment for persistent complex bereavement disorder and posttraumatic stress disorder (PTSD), which appears to activate the mirror neuron network. Simulated reattachment is a technique which has been found to repair phantom limb pain in just a few sessions. The same neuroplasticity that accomplishes phantom pain relief has been found to occur in the treatment of complicated grief and PTSD using similar methods. The simulated reattachment for the client in Case one was found to significantly reduce the symptoms of both complicated grief and obsessive-compulsive disorder (OCD) within one session. In Case two, symptoms of PTSD and depression were significantly reduced in a client with lupus after two sessions of simulated reattachment. In addition, inflammatory markers antinuclear autoantibodies (ANA) and C-reactive protein (CRP) declined from the beginning of treatment to the end.",
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"keywords": "Complicated grief; Lupus; Mirror neuron; Neuroplasticity; OCD; PTSD; Revisioning; Simulated reattachment",
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"mesh_terms": "D000328:Adult; D001601:Bereavement; D003863:Depression; D003866:Depressive Disorder; D005260:Female; D006117:Grief; D006801:Humans; D059167:Mirror Neurons; D009473:Neuronal Plasticity; D009771:Obsessive-Compulsive Disorder; D010591:Phantom Limb; D011613:Psychotherapy; D013313:Stress Disorders, Post-Traumatic",
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"title": "Two Case Reports: Using Simulated Reattachment to Treat Persistent Complex Bereavement Disorder and PTSD.",
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"abstract": "BACKGROUND\nGastrointestinal stromal tumor is the most common malignant mesenchymal tumor of the gastrointestinal tract. The most common sites of metastasis are the liver and the peritoneum, but gastrointestinal stromal tumors rarely metastasize to the skeletal muscles. Only three cases of gastrointestinal stromal tumor metastasizing to skeletal muscle have been reported in the English literature. Here we present an additional case of skeletal muscle metastasis, and the relevant literature is reviewed.\n\n\nMETHODS\nA 54-year-old Japanese man presented with a three-month history of an enlarging mass of the left buttock. An excisional biopsy was performed and the tumor was diagnosed as a leiomyosarcoma. However, careful examination of the gastrointestinal tract revealed a tumor located in the small intestine. Surgical resection of the small intestine tumor was performed; histopathological and immunohistochemical examinations identified it as a primary gastrointestinal stromal tumor arising from the small intestine. Despite receiving both chemotherapy and molecular-targeted therapy, our patient died of gastrointestinal bleeding six months after the initial diagnosis.\n\n\nCONCLUSIONS\nBecause it is a mesenchymal tumor, it is difficult to distinguish a gastrointestinal stromal tumor metastasis to skeletal muscle from other primary soft tissue sarcomas. Although metastasis of gastrointestinal stromal tumor to skeletal muscle is rare, the likelihood of finding metastases in these unusual sites is increasing due to prolonged survival of patients with gastrointestinal stromal tumor after the introduction of imatinib therapy. We should include metastases of gastrointestinal stromal tumors as differential diagnosis of spindle cell tumor, and it is necessary to begin appropriate treatment early.",
"affiliations": "Department of Orthopaedic Surgery, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan. yasuda@med.u-toyama.ac.jp.",
"authors": "Suzuki|Kayo|K|;Yasuda|Taketoshi|T|;Nagao|Kaoru|K|;Hori|Takeshi|T|;Watanabe|Kenta|K|;Kanamori|Masahiko|M|;Kimura|Tomoatsu|T|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-8-2562503794010.1186/1752-1947-8-256Case ReportMetastasis of gastrointestinal stromal tumor to skeletal muscle: a case report Suzuki Kayo 1suzukayo@med.u-toyama.ac.jpYasuda Taketoshi 14yasuda@med.u-toyama.ac.jpNagao Kaoru 2seikei@med.u-toyama.ac.jpHori Takeshi 2seikei@med.u-toyama.ac.jpWatanabe Kenta 1kenta0419@yahoo.co.jpKanamori Masahiko 3kanamori@med.u-toyama.ac.jpKimura Tomoatsu 1tkimura@med.u-toyama.ac.jp1 Department of Orthopaedic Surgery, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan2 Department of Orthopaedic Surgery, Iiyama Red Cross Hospital, Iiyama 226-1, Iiyama, Nagano 389-2295, Japan3 Department of Human Science 1, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan4 Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan2014 18 7 2014 8 256 256 20 2 2014 2 6 2014 Copyright © 2014 Suzuki et al.; licensee BioMed Central Ltd.2014Suzuki et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Introduction\nGastrointestinal stromal tumor is the most common malignant mesenchymal tumor of the gastrointestinal tract. The most common sites of metastasis are the liver and the peritoneum, but gastrointestinal stromal tumors rarely metastasize to the skeletal muscles. Only three cases of gastrointestinal stromal tumor metastasizing to skeletal muscle have been reported in the English literature. Here we present an additional case of skeletal muscle metastasis, and the relevant literature is reviewed.\n\nCase presentation\nA 54-year-old Japanese man presented with a three-month history of an enlarging mass of the left buttock. An excisional biopsy was performed and the tumor was diagnosed as a leiomyosarcoma. However, careful examination of the gastrointestinal tract revealed a tumor located in the small intestine. Surgical resection of the small intestine tumor was performed; histopathological and immunohistochemical examinations identified it as a primary gastrointestinal stromal tumor arising from the small intestine. Despite receiving both chemotherapy and molecular-targeted therapy, our patient died of gastrointestinal bleeding six months after the initial diagnosis.\n\nConclusions\nBecause it is a mesenchymal tumor, it is difficult to distinguish a gastrointestinal stromal tumor metastasis to skeletal muscle from other primary soft tissue sarcomas. Although metastasis of gastrointestinal stromal tumor to skeletal muscle is rare, the likelihood of finding metastases in these unusual sites is increasing due to prolonged survival of patients with gastrointestinal stromal tumor after the introduction of imatinib therapy. We should include metastases of gastrointestinal stromal tumors as differential diagnosis of spindle cell tumor, and it is necessary to begin appropriate treatment early.\n\nGastrointestinal stromal tumorSarcomaSkeletal muscle metastasis\n==== Body\nIntroduction\nGastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal tumors of the gastrointestinal (GI) tract, and account for 1 to 3% of all malignant GI tumors [1]. The precise cellular origin of GISTs recently has been proposed to be the intestinal cell of Cajal, an intestinal pacemaker cell. GISTs are most common in the stomach (60 to 70 percent), followed by the small intestine (25 to 35 percent), the colon and rectum (5 percent), and the esophagus (<2 percent). Based on a population-based sample from Southern Finland, Miettinen et al. originally estimated the incidence of malignant GIST to be four per million and the total incidence to be approximately 40 per million [2]. To the best of our knowledge, only three cases of GIST metastasizing to skeletal muscle have been reported in the English literature [3-5]. Here we present an additional case of skeletal muscle metastasis, and the relevant literature is reviewed.\n\nCase presentation\nIn 2010, three months prior to presentation, a 54-year-old Japanese man noticed an enlarging mass in the soft tissue of his left buttock. An excisional biopsy was performed and the tumor was diagnosed as a leiomyosarcoma composed of cellular bundles of spindle cells (Figure 1). Immunohistochemical stains demonstrated that tumor cells were positive for smooth muscle actin (SMA) and calponin, and negative for S-100, CD34 and epithelial membrane antigen (EMA). Subsequently, a positron emission tomography (PET)-computed tomography (CT) scan was performed. The results showed the existence of multiple metastatic lesions in the skeletal muscle and the absence of metastases in the liver, lung, and lymph nodes (Figure 2). The magnetic resonance (MR) images of the lumbar area and thigh revealed multiple isointense skeletal muscle tumors on T1-weighted with heterogeneous high-signal intensities on T2-weighted images (Figure 3A,B). Our patient was treated with doxorubicin (20g/m2 day 3), and ifosfamide (2,500g/m2 day 3) chemotherapy. Because he developed anemia during chemotherapy, a careful examination of his GI tract was performed, which revealed a bleeding tumor located in the small intestine. Surgical resection of the small intestine tumor was performed. Microscopically, the resected mass was composed of interlacing bundles of spindle and epithelioid mesenchymal cells with morphological features similar to the previously described tumors in his buttock. The mitotic index was 10/high-power field (HPF), and the tumor seemed to be a high-grade spindle cell sarcoma. Immunohistochemical analysis of the tumor cells revealed focal positivity for c-KIT and SMA, and negativity for CD34 and S-100 (Figure 4A-D). Based on these features, additional immunohistochemical analyses of the primary buttock tumor were performed. The buttock tumor cells were negative for c-KIT, but diffusely positive for platelet-derived growth factor receptor-α (PDGFRA) and were definitively diagnosed as a skeletal muscle metastasis of the primary small intestine GIST. Although our patient underwent chemotherapy with imatinib mesylate, death from GI bleeding occurred six months after the initial diagnosis.\n\nFigure 1 Histopathological findings of the buttock mass at open biopsy. Spindle-shaped tumor cells with atypical nuclei have proliferated. The initial diagnosis is a leiomyosarcoma (hematoxylin and eosin staining; scale bar, 50μm).\n\nFigure 2 Positron emission tomography-computed tomography scan. Positron emission tomography-computed tomography scan shows multiple skeletal muscle metastases in the bilateral thighs.\n\nFigure 3 Magnetic resonance imaging findings of the paravertebral muscle and left thigh. Axial T2-weighted imaging reveals high-signal intensity masses in the paravertebral muscle (A) and the left quadriceps (B).\n\nFigure 4 Histopathological findings and immunohistochemical staining of the small intestine tumor. (A) The resected mass shows a tumor with hypercellularity and spindle-shaped cells. The mitotic index is 70 per 50 high-power fields (hematoxylin and eosin stain, scale bar: 50μm). Immunohistochemical stain for c-KIT (B) shows diffuse staining of the cell membrane. CD34 (C) and S-100 (D) staining reveals negativity.\n\nDiscussion\nGISTs are defined as pleomorphic mesenchymal tumors of the GI tract composed of spindle cells, epithelioid cells, or a combination of both, that express the c-KIT protein and, in most cases, CD34, as demonstrated by immunohistochemical staining. However, GISTs negative for c-KIT comprise 5 percent of all GISTs and contain a mutation of the PDGFRA gene that was reported to be related to the oncogenesis of these tumors [6]. Surgical resection of the local disease is the gold standard therapy. The goal is complete resection of the disease without tumor rupture. Tumor size, not negative microscopic surgical margins, determines survival. Complete surgical resection is possible in approximately 85 percent of patients, and 50 percent of patients will develop recurrence or metastasis following complete resection [7]. The five-year survival rate is approximately 50 percent, while the median time to recurrence after resection of primary high-risk GIST is two years. However, after the introduction of the molecular-targeted therapy, imatinib, there was a major improvement in the progression-free survival and overall survival rates. Nevertheless, GISTs have a high risk of metastatic relapse.\n\nSkeletal muscle metastasis of carcinoma is relatively rare. Numerous case reports but few studies or large case series have been reported regarding this occurrence. Surov et al. reported a prevalence of 1.2 percent in 5,170 oncology patients. The frequency of skeletal muscle metastases varied from 0.4 to 4.9 percent for different primary tumors [8]. The most frequent occurrence of skeletal muscle metastasis was in patients with carcinoma of the cervix uteri, malignant melanoma, or ovarian carcinoma. Skeletal muscle metastases from sarcomas are extremely rare, as reported by Plaza et al.[9], who conducted the largest study concerning metastases to soft tissue; 118 patients with metastatic tumors to soft tissue were identified from a total of 7,237 soft tissue tumors and were included in their study (1.6 percent of all soft tissue sarcomas assessed during the same period). Of these 118 cases, 11 had metastases of sarcomatoid elements of primary soft tissue sarcomas from other sites, six had metastases from a uterine leiomyosarcoma, two from bone osteosarcoma, two from uterine malignant mixed Mullerian tumor, and one from ovarian carcinosarcoma. Arpaci et al. proposed to define the radiological imaging features and clinical findings of patients with skeletal muscle metastasis. In their study, the most common source was lung cancer and the muscles mostly affected by metastatic disease were the gluteals (15 percent), psoas (8.7 percent), paravertebral (8.7 percent), rectus abdominis (7.6 percent), and latissimus dorsi (6.5 percent) [10]. On the other hand, Bocchino et al. reported that most skeletal muscle metastases were localized in the psoas (33.3 percent), buttock (33.3 percent), and intercostal muscles (29.6 percent) [11]. Furthermore, Surov et al. showed that most muscle metastases were identified in the iliopsoas (27.5 percent), paravertebral (25 percent), gluteal (16.3 percent), lower extremity (12.5 percent), abdominal wall (10 percent), thoracic wall (5 percent), and upper extremity (3.8 percent) muscles [8].\n\nTo the best of our knowledge, this case is the fourth report of skeletal muscle metastases from a GIST (Table 1) [3-5]. The reports have included two cases of metastasis to muscle of the thigh, one to paravertebral muscle, and the current case, to the gluteal muscle. Although in two of the four cases the GIST had already metastasized to another site aside from skeletal muscle, two cases, including ours (cases one and four) were initially treated as leiomyosarcoma of the uterine or buttock muscle, respectively. Distinguishing between skeletal muscle metastases from GISTs and primary spindle cell sarcoma occurring in skeletal muscle may be challenging. Of a total of 133 rectal and anal GISTs identified in the Armed Forces Institute of Pathology at Washington and in the Haartman Institute of the University of Helsinki, 80 tumors (60 percent) had been originally diagnosed in other centers as leiomyosarcoma, 29 (21.8 percent) as smooth muscle tumors of uncertain malignant potential, 21 (15.8 percent) as leiomyoma and only three (2.25 percent) as GISTs [12]. Differentiating metastatic tumor from GIST and primary leiomyosarcoma in skeletal muscle has often been confusing. Our case was also, morphologically speaking, a spindle cell sarcoma with immunoreactivity for SMA.\n\nTable 1 Clinical characteristics of GIST patients with skeletal muscle metastases\n\nCase\tReference [No.]\tAge/Sex\tPrimary site\tLocation of muscle metastases (years)\n*\n\tInitial DDx\tOther metastases (years)\n*\n\tOutcome (years)\n*\n\t\n1\tPasku et al.[3]\t56/F\tPelvic cavity\tGluteal muscle (2)\tLeiomyosarcoma\tLung (1)\tNED (3)\t\n2\tCichowitz et al.[4]\t23/F\tSmall intestine\tAdductor longus (over 5)\tGIST\tLiver (2)\tAWD (over 5)\t\n3\tBashir et al.[5]\t56/M\tSmall intestine\tUpper back muscle (within 1)\tLeiomyosarcoma\tCardiac adrenal (1)\tAWD (1)\t\n4\tPresent case\t54/M\tSmall intestine\tQuadriceps (at the initial consultation)\tLeiomyosarcoma\tNone\tDOD (0.5)\t\n*Period from the initial diagnosis. GIST, gastrointestinal stromal tumor; DDx, differential diagnosis; F, female; NED, no evidence of disease; AWD, alive with disease; M, male; DOD, died of disease.\n\nEarly recognition and prompt diagnosis will allow the proper treatment to be initiated in a timely fashion. Emmering et al. reported that PET-CT was a sensitive tool for early detection of skeletal muscle metastases and for staging malignant disease [13]. Bocchino et al. reported that 18-fluoro-fluorodeoxyglucose (18F-FDG) uptake in muscle metastatic lesions increased homogeneously reaching a higher maximum standardized uptake value (SUVmax) (mean value 4.2 ± 2.8) than in the liver [11]. Surov et al. reported PET/CT findings of skeletal muscle metastases from different primary tumors [14]. Identified skeletal muscle metastases presented as intramuscular focal abdominal activity with SUVs ranging from 2.4 to 25.9, median SUV 7.8. The median size of the muscle metastases was 2.5cm (0.6 to 6.5cm). In this report, there were no significant correlations between SUV and size of muscle metastases or significant differences between SUVs of muscle metastases and primary tumors. Although MR imaging is not specific for skeletal muscle metastasis, it is an indispensable tool for diagnosis and treatment, the results of which clinicians may use to contemplate the general management of these patients. Surov et al. reported findings of MR imaging of intramuscular metastases [15]. On T2-weighted images, 97 percent of the recognized intramuscular metastases were hyperintense and on T1-weighted images, 91 percent of the intramuscular metastases were homogeneously isointense, in comparison to adjacent muscle tissue. The calculated apparent diffusion coefficient (ADC) values were low or moderate signal intensity in 94 percent of the intramuscular metastases.\n\nIn the current case, the findings of the MR imaging were hyperintensity on T2-weighted and isointensity on T1-weighted images in the identified location of the skeletal muscle metastasis, and according to the MR imaging results, our patient underwent excisional biopsy and the tumor was misdiagnosed as a leiomyosarcoma. We should remember to include metastases of GISTs in the differential diagnosis of spindle cell tumors, and that it is necessary to begin early and appropriate treatment.\n\nConclusions\nIn summary, we present an extremely rare case of skeletal muscle metastasis from a GIST. To the best of our knowledge, there have been only three previously reported cases in the English literature of GIST metastasizing to skeletal muscle. Although skeletal muscle metastases from GIST are rare, the likelihood of finding metastases in these unusual sites has increased due to the prolonged survival of patients with GIST after the introduction of imatinib therapy. We should recognize metastases of GISTs in the differential diagnosis for spindle cell tumors, as it is necessary to begin appropriate treatment in a timely fashion.\n\nConsent\nWritten informed consent was obtained from the patient’s next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nCT: computed tomography; EMA: epithelial membrane antigen; GI: gastrointestinal; GIST: gastrointestinal stromal tumor; HPF: high-power field; MR: magnetic resonance; PDGFRA: platelet-derived growth factor receptor-α; PET: positron emission tomography; SMA: smooth muscle actin; SUV: standardized uptake value.\n\nCompeting interests\nAll authors have disclosed that they have no significant relationships with, or financial interest in, any commercial entity pertinent to this article.\n\nAuthors’ contributions\nKS was the major contributor in writing the manuscript. TY, KN, TH and KW supervised the treatment of our patient and collected case data. TY, MK and TK revised the manuscript. All authors approved the final version of the manuscript.\n\nAcknowledgements\nThis study was supported in part by a Grant-in-Aid for Scientific Research (C) 24592227 (KAKENHI). The authors extend thanks to the patient for allowing participation in his care and presentation of his clinical case.\n==== Refs\nMiettinen M El-Rifai W HL Sobin L Lasota J Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review Hum Pathol 2002 33 478 483 12094372 \nMiettinen M Majidi M Lasota J Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review Eur J Cancer 2002 Suppl 5 S39 S51 12528772 \nPasku D Karantanas A Giannikaki E Tzardi M Velivassakis E Katonis P Bilateral gluteal metastases from a misdiagnosed intrapelvic gastrointestinal stromal tumor World J Surg Oncol 2008 6 139 144 19116036 \nCichowitz A Thomson BNJ Choong PF GIST metastasis to adductor longus muscle ANZ J Surg 2011 81 490 491 22295365 \nBashir U Qureshi A Khan HA Uddin N Gastrointestinal stromal tumor with skeletal muscle, adrenal and cardiac metastases: an unusual occurrence Indian J Pathol Microbiol 2011 54 362 364 21623091 \nHeinrich MC Corless CL Duensing A McGreevey L Chen CJ Joseph N Singer S Griffith DJ Haley A Town A Demetri GD Fletcher CD Fletcher JA PDGFRA activating mutations in gastrointestinal stromal tumors Science 2003 299 708 710 12522257 \nStamatakos M Douzinas E Stefanaki C Safioleas P Polyzou E Levidou G Safioleas M Gastrointestinal stromal tumor World J Surg Oncol 2009 7 61 19646278 \nSurov A Hainz M Holzhausen HJ Arnold D Katzer M Schmidt J Spielmann RP Behrmann C Skeletal muscle metastases: primary tumours, prevalence, and radiological features Eur Radiol 2010 20 649 658 19707767 \nPlaza JA Perez-Montiel D Mayerson J Morrison C Suster S Metastases to soft tissue: a review of 118 cases over a 30-year period Cancer 2008 112 193 203 18040999 \nArpaci T Ugurluer G Akbas T Arpaci RB Serin M Imaging of the skeletal muscle metastases Eur Rev Med Pharmacol Sci 2012 16 2057 2063 23280019 \nBocchino M Valente T Somma F de Rosa I Bifulco M Rea G Detection of skeletal muscle metastases on initial staging of lung cancer: a retrospective case series Jpn J Radiol 2014 32 164 171 24452325 \nMiettinen M Furlong M Sarlomo-Rikala M Burke A Sobin LH Lasota J Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases Am J Surg Pathol 2001 25 1121 1133 11688571 \nEmmering J Vogel WV Stokkel MP Intramuscular metastases on FDG PET-CT: a review of the literature Nucl Med Commun 2012 33 117 120 22124361 \nSurov A Pawelka MK Wienke A Schramm D PET/CT imaging of skeletal muscle metastases Acta Radiol 2014 55 101 106 23884841 \nSurov A Fiedler E Voigt W Wienke A Holzhausen HJ Spielmann RP Behrmann C Magnetic resonance imaging of intramuscular metastases Skeletal Radiol 2011 40 439 446 20697708\n\n",
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"abstract": "OBJECTIVE\nStudies have demonstrated that ECMO leads to pharmacokinetic changes, with alterations in volume of distribution, clearance and drug sequestration by the circuit. We describe a successful dosing approach for daptomycin and micafungin for the treatment of VRE faecium bacteremia and C. glabrata fungemia in a patient receiving veno-venous ECMO and CRRT.\n\n\nMETHODS\nWe report a case of a patient with ARDS on veno-venous ECMO complicated by VRE faecium bacteremia and C. glabrata fungemia. The patient was treated with daptomycin 10 mg/kg every 24 h and micafungin 150 mg every 24 h for 14 days. Key observations included the documented bacteremia and fungemia clearance without the need for ECMO circuit exchange.\n\n\nCONCLUSIONS\nThis case report demonstrates successful bacteremia and fungemia clearance in an adult without the need for ECMO circuit exchange. It also highlights the need for more research to identify optimal antimicrobial dosing strategies in similar scenarios.",
"affiliations": "Department of Pharmacy, Division of Infectious Diseases, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.;Division of Pulmonary Critical Care, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.",
"authors": "Cabanilla|M Gabriela|MG|https://orcid.org/0000-0001-5402-0240;Villalobos|Nicholas|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13482",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": null,
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "\nExtracorporeal membrane oxygenation\n; \ndaptomycin\n; \nmetabolic clearance rates\n; \nmicafungin\n",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34254345",
"pubdate": "2021-07-13",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A successful daptomycin and micafungin dosing strategy in veno-venous ECMO and continuous renal replacement.",
"title_normalized": "a successful daptomycin and micafungin dosing strategy in veno venous ecmo and continuous renal replacement"
} | [
{
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
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"drugauthorizationnumb": "021572",
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"drugdosageform": "INJECTION",
"drugdosagetext": "10 MILLIGRAM/KILOGRAM, Q24H",
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"medicinalproduct": "CUBICIN"
},
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"activesubstance": {
"activesubstancename": "MICAFUNGIN SODIUM"
},
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"drugdosagetext": "150 MILLIGRAM, Q24H",
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"medicinalproduct": "MICAFUNGIN."
}
],
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{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
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},
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"literaturereference": "CABANILLA M.G, VILLALOBOS N.. A SUCCESSFUL DAPTOMYCIN AND MICAFUNGIN DOSING STRATEGY IN VENO?VENOUS ECMO AND CONTINUOUS RENAL REPLACEMENT. CLINICAL PHARMACY AND THERAPEUTICS. 2021",
"literaturereference_normalized": "a successful daptomycin and micafungin dosing strategy in veno venous ecmo and continuous renal replacement",
"qualification": "1",
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},
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"receiptdate": "20210729",
"receivedate": "20210729",
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"receivertype": "6"
},
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"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20211014"
}
] |
{
"abstract": "OBJECTIVE\nIn 2011, an estimated 26.8 million US adults used prescription medications for mental illness.\n\n\nOBJECTIVE\nTo estimate the numbers and rates of adverse drug event (ADE) emergency department (ED) visits involving psychiatric medications among US adults between January 1, 2009, and December 31, 2011.\n\n\nMETHODS\nDescriptive analyses of active, nationally representative surveillance of ADE ED visits using the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance system and of drug prescribing during outpatient visits using the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey.\n\n\nMETHODS\nMedical records from national probability samples of ED and outpatient visits by adults 19 years or older were reviewed and analyzed.\n\n\nMETHODS\nAntidepressants, antipsychotics, lithium salts, sedatives and anxiolytics, and stimulants.\n\n\nMETHODS\nNational estimates of ADE ED visits resulting from therapeutic psychiatric medication use and of psychiatric medication ADE ED visits per 10,000 outpatient visits at which psychiatric medications were prescribed.\n\n\nRESULTS\nFrom 2009 through 2011, there were an estimated 89,094 (95% CI, 68,641-109,548) psychiatric medication ADE ED visits annually, with 19.3% (95% CI, 16.3%-22.2%) resulting in hospitalization and 49.4% (95% CI, 46.5%-52.4%) involving patients aged 19 to 44 years. Sedatives and anxiolytics, antidepressants, antipsychotics, lithium salts, and stimulants were implicated in an estimated 30,707 (95% CI, 23,406-38,008), 25,377 (95% CI, 19,051-31,704), 21,578 (95% CI, 16,599-26,557), 3620 (95% CI, 2311-4928), and 2779 (95% CI, 1764-3794) respective ADE ED visits annually. Antipsychotics and lithium salts were implicated in 11.7 (95% CI, 10.1-13.2) and 16.4 (95% CI, 13.0-19.9) ADE ED visits per 10,000 outpatient prescription visits, respectively, compared with 3.6 (95% CI, 3.2-4.1) for sedatives and anxiolytics, 2.9 (95% CI, 2.3-3.5) for stimulants, and 2.4 (95% CI, 2.1-2.7) for antidepressants. The commonly used sedative zolpidem tartrate was implicated in 11.5% (95% CI, 9.5%-13.4%) of all adult psychiatric medication ADE ED visits and in 21.0% (95% CI, 16.3%-25.7%) of visits involving adults 65 years or older, in both cases significantly more than any other psychiatric medication.\n\n\nCONCLUSIONS\nPsychiatric medications are implicated in many ADEs treated in US EDs. Efforts to reduce ADEs should include adults of all ages but might prioritize medications causing high numbers and rates of ED visits.",
"affiliations": "Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia.;Center for Drug Safety and Effectiveness, The Johns Hopkins University, Baltimore, Maryland3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.;Center for Drug Safety and Effectiveness, The Johns Hopkins University, Baltimore, Maryland4Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.;Center for Drug Safety and Effectiveness, The Johns Hopkins University, Baltimore, Maryland3Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland5Department of Medicine, The Johns Hopkins University School of Med.;Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia.",
"authors": "Hampton|Lee M|LM|;Daubresse|Matthew|M|;Chang|Hsien-Yen|HY|;Alexander|G Caleb|GC|;Budnitz|Daniel S|DS|",
"chemical_list": "D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D006993:Hypnotics and Sedatives; D018020:Lithium Compounds; D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
"doi": "10.1001/jamapsychiatry.2014.436",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-622X",
"issue": "71(9)",
"journal": "JAMA psychiatry",
"keywords": null,
"medline_ta": "JAMA Psychiatry",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D004636:Emergency Service, Hospital; D005260:Female; D006760:Hospitalization; D006801:Humans; D006993:Hypnotics and Sedatives; D018020:Lithium Compounds; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D011619:Psychotropic Drugs; D012737:Sex Factors; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "101589550",
"other_id": "HHSPA748530",
"pages": "1006-14",
"pmc": null,
"pmid": "25006837",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "17909391;19017592;16284208;23187094;15249282;22553074;22362541;23423416;12570945;22297588;20623513;22480592;20559200;23423407;23165956;23385262;20187598;23440257;11844004;23419225;20861593;23614899;17047216;21254289;21680913;22111719;23618545;21769507;22868273;15281899;22116200",
"title": "Emergency department visits by adults for psychiatric medication adverse events.",
"title_normalized": "emergency department visits by adults for psychiatric medication adverse events"
} | [
{
"companynumb": "US-JNJFOC-20141002144",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": null,
"drugadministrationroute": "065",
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"drugdosageform": "Unspecified",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "HALOPERIDOL."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "020272",
"drugbatchnumb": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"medicinalproduct": "RISPERIDONE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Hospitalisation",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Adverse drug reaction",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HAMPTON LM, DAUBRESSE M, CHANG H, ALEXANDER C, BUDNITZ DS. EMERGENCY DEPARTMENT VISITS BY ADULTS FOR PSYCHIATRIC MEDICATION ADVERSE EVENTS. JAMA PSYCHIATRY 2014;71(9):1006-1014.",
"literaturereference_normalized": "emergency department visits by adults for psychiatric medication adverse events",
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},
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},
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"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150528"
}
] |
{
"abstract": "BACKGROUND\nPolycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia.\n\n\nMETHODS\nA middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis. Further morphological analyses of bone marrow and blood smears revealed probable transformation into acute myeloid leukemia. However, there were also cells indicating hairy cell leukemia. Morphological and immunohistochemical analyses later confirmed the presence of hairy cell leukemia in biopsies that had been present for 3 years. Treatment with cladribine temporarily reversed the patient's neutropenia.\n\n\nCONCLUSIONS\nHairy cell leukemia may mimic development to myelofibrosis in patients with polycythemia vera.",
"affiliations": "Department of Haematology, Akershus University Hospital, Lørenskog, Norway.;Department of Haematology, Akershus University Hospital, Lørenskog, Norway.;Department of Pathology, Akershus University Hospital, Lørenskog, Norway.;Department of Pathology, Oslo University Hospital, Oslo, Norway.;Department of Haematology, Oslo University Hospital, Oslo, Norway.;Department of Haematology, Oslo University Hospital, Oslo, Norway.;Department of Haematology, Akershus University Hospital, Lørenskog, Norway. aeadahm@gmail.com.",
"authors": "Habberstad|Andreas Hanssønn|AH|;Tran|Hoa Thi Tuyet|HTT|;Randen|Ulla|U|;Spetalen|Signe|S|;Dybedal|Ingunn|I|;Tjønnfjord|Geir E|GE|;Dahm|Anders Erik Astrup|AEA|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017338:Cladribine; D053614:Janus Kinase 2",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-018-1663-6",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 166310.1186/s13256-018-1663-6Case ReportNeutropenia caused by hairy cell leukemia in a patient with myelofibrosis secondary to polycythemia vera: a case report Habberstad Andreas Hanssønn Andreas.Hanssonn.Habberstad@ahus.no 1Tran Hoa Thi Tuyet htra@ahus.no 1Randen Ulla ulla.randen@ahus.no 2Spetalen Signe uxigsp@ous-hf.no 3Dybedal Ingunn ingdy@online.no 4Tjønnfjord Geir E. gtjonnfj@ous-hf.no 45Dahm Anders Erik Astrup aeadahm@gmail.com 151 0000 0000 9637 455Xgrid.411279.8Department of Haematology, Akershus University Hospital, Lørenskog, Norway 2 0000 0000 9637 455Xgrid.411279.8Department of Pathology, Akershus University Hospital, Lørenskog, Norway 3 0000 0004 0389 8485grid.55325.34Department of Pathology, Oslo University Hospital, Oslo, Norway 4 0000 0004 0389 8485grid.55325.34Department of Haematology, Oslo University Hospital, Oslo, Norway 5 0000 0004 1936 8921grid.5510.1Institute of Clinical Medicine, University of Oslo, Oslo, Norway 24 4 2018 24 4 2018 2018 12 10514 12 2017 21 3 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPolycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia.\n\nCase presentation\nA middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis. Further morphological analyses of bone marrow and blood smears revealed probable transformation into acute myeloid leukemia. However, there were also cells indicating hairy cell leukemia. Morphological and immunohistochemical analyses later confirmed the presence of hairy cell leukemia in biopsies that had been present for 3 years. Treatment with cladribine temporarily reversed the patient’s neutropenia.\n\nConclusions\nHairy cell leukemia may mimic development to myelofibrosis in patients with polycythemia vera.\n\nKeywords\nPolycythemia veraMyelofibrosisHairy cell leukemiaNeutropeniaMyeloproliferative disordersOral ulcerCase reportissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThe BCR-ABL-negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are characterized by excessive production of terminally differentiated and functional blood cells. They clinically overlap, because primary myelofibrosis sometimes presents with thrombocythemia and may be difficult to distinguish from essential thrombocythemia, whereas both essential thrombocythemia and polycythemia vera can progress to myelofibrosis [1]. All three entities have a risk of transformation to acute myeloid leukemia (AML). Polycythemia vera, essential thrombocythemia, and primary myelofibrosis are genetically characterized by clonal mutations in JAK2, CALR, or MPL. The MPN diseases are thought to arise from a somatically mutated hematopoietic stem cell that gives rise to all myeloid cells, B cells, and natural killer cells [2].\n\nPatients with polycythemia vera usually live with the disease for many years, often decades, before it may transform into AML or secondary myelofibrosis [3]. The phase when polycythemia vera is about to transform to myelofibrosis is known as spent phase polycythemia vera and is characterized by reduced erythropoiesis and splenomegaly because of extramedullary hematopoiesis. More than 10% blasts in peripheral blood is unusual and may suggest a blast transformation to AML. Postpolycythemia myelofibrosis, and certainly AML, has a poorer prognosis than polycythemia vera and may therefore be considered for allogeneic stem cell transplant [4].\n\nHairy cell leukemia is a mature, indolent B-cell malignancy. Patients with hairy cell leukemia are characterized by fatigue, splenomegaly, and cytopenia, most often pancytopenia, and some patients may display bone marrow fibrosis [5]. The prognosis is good, and patients usually respond well to purine analogs such as cladribine or pentostatin [6, 7]. Mutation in the BRAF gene leading to a Val-to-Glu substitution in position 600 of the BRAF molecule (V600E) is probably the driving mutation in hairy cell leukemia [8], and a phase II trial testing the BRAF inhibitor vemurafenib in hairy cell leukemia showed promising results, with response in 25 of 26 patients [9]. We report diagnostic and therapeutic difficulties with a patient presenting with myelofibrosis secondary to polycythemia vera, further development to AML, and hairy cell leukemia. This case report illustrates that hairy cell leukemia in a patient with polycythemia vera may be interpreted as secondary myelofibrosis, that monocytopenia could have raised the suspicion of hairy cell leukemia earlier, and that AML does not always present with CD34-positive blasts.\n\nCase presentation\nOur patient was a white man born in 1942, married with no children and without a family history of hematologic disease. He experienced migraine, had a vasectomy in 1980, and had a duodenal ulcer in 1992 treated with triple therapy. In 2009, he underwent prostatectomy for prostate cancer. In 1995, he was diagnosed with polycythemia vera with hemoglobin (Hb) 22.2 g/dl, hematocrit 0.64, white blood cells (WBC) 10.1 × 109/L, and thrombocytes 162 × 109/L. The patient’s main symptom was progressively worsening headache different from his previous migraine. He was treated with phlebotomy and did not receive hydroxyurea. Splenomegaly was not present at diagnosis, but in 2001 ultrasonography revealed a moderately enlarged spleen with maximum diameter of 13 cm. From 2008, his Hb levels were normal with no further need for phlebotomy. The diagnosis of polycythemia vera was supported by a positive JAK2 V617F analysis in 2013.\n\nIn 2009, the patient developed chronic aphthous mouth ulcers and was seen by different dentists and doctors. Biopsies described “a combination of acute and chronic inflammation.” The result of polymerase chain reaction (PCR) analysis for herpes simplex virus was negative. Systemic prednisolone and nonmedical measures were applied without effect.\n\nThe patient’s mouth ulcers persisted, and regular blood counts revealed a steady drop in neutrophils and thrombocytes with normal levels of monocytes, lymphocytes, and Hb from 2010 (Fig. 1). In March 2012, he was referred to the local department of hematology because of leukopenia and thrombocytopenia. A bone marrow biopsy showed mildly increased total cellularity (55%), increased numbers of megakaryocytes, no significant increase in erythropoiesis or granulopoiesis, normal maturing granulopoiesis, no dysplasia, no increase in CD34-positive cells, and fibrosis grade 1 interpreted as spent phase polycythemia vera. The patient’s Hb and thrombocytes decreased during the next year, and a new bone marrow biopsy in April 2013 showed increased total cellularity (60–70%), an abundance of megakaryocytes with mild dysplasia, normal erythropoiesis in numbers with some variation in size and form of nuclei, granulopoiesis with lack of normal maturation, no increase in CD34-positive cells, and fibrosis grade 2–3. Owing to excruciating mouth ulcers, filgrastim 30 million IU/week was started in May 2013. This temporarily increased the number of granulocytes, and the patient’s mouth ulcers healed after a while but later returned despite a normal granulocyte count.Fig. 1 Values of hemoglobin, thrombocytes, leukocytes, and neutrophilic granulocytes during the last 9 years, showing gradual evolution of thrombocytopenia and leukopenia\n\n\n\nIn 2014, the patient again had neutropenia while receiving treatment with filgrastim. Progression of the myelofibrosis or development to AML was suspected. A bone marrow biopsy procured in April 2014 showed osteosclerosis and fibrosis grade 3, monolobulated bizarre megakaryocytes, increased erythropoiesis and myelopoiesis with reduced maturation, but no increase in CD34-positive cells. Ultrasound revealed splenomegaly with diameter 17 cm. Two additional biopsies in July and August 2014 gave similar results. Cytogenetic examination of the bone marrow from May 2014 showed a complex karyotype associated with poor prognosis with 19 different cytogenetic changes including del(7), affection of chromosome 5 and several monosomies, where del(20q) was suggested as the initial chromosomal aberration.\n\nFrom May 2014, the patient was hospitalized almost monthly for fever and neutropenia. No infectional focus or microbiological agents were found. Hence, the patient received empiric antibiotic therapy with penicillin, gentamicin, piperacillin-tazobactam, ciprofloxacin, clindamycin, or meropenem. At one point, fungal infection was suspected on the basis of a positive galactomannan test result in bronchoalveolar lavage, but this result was not confirmed in blood samples. He did, however, receive treatment with voriconazole for a period. Considering progressive myelofibrosis as the main reason for the bone marrow failure, treatment with thalidomide 50 mg/day and prednisolone 30 mg/day was initiated in August 2014 [10]. This was stopped after 1 month, however, owing to a dental abscess/severe infections and no effect on blood counts.\n\nA new bone marrow biopsy in September 2014 disclosed immature myeloid cells with an MPO+, CD15+, CD68+, and CD117+ immunophenotype. Reexamination of previous biopsies also showed immature myeloid cells to be present in April 2014 (Fig. 2). The biopsies were sent for central review, where possible transformation to AML from 2014 was suggested. In addition, there was infiltration of CD20+ lymphocytes positive for cyclin D1, which constituted 15–20% of the bone marrow cells. It was concluded that this cell population was hairy cell leukemia cells (Fig. 3). In reevaluation of biopsies back to 2012, hairy cells were found in all. The patient was considered for allogeneic stem cell transplant, but owing to high risk for recurrence after transplant, it was decided to treat the hairy cell leukemia first. The patient received cladribine 0.11 mg/kg intravenously for 5 days in October 2014. This improved the number of leukocytes temporarily (Fig. 4), as well as the patient’s mouth ulcers. Shortly after this, the patient developed rash and painful edema in both legs. Biopsies confirmed perivascular infiltration of immature myeloid cells. AML then rapidly progressed with increasing bone marrow failure. The patient was given palliative care and died of pneumonia in March 2015. No autopsy was done. Table 1 shows a timeline of the case history.Fig. 2 Bone marrow biopsy with hematoxylin and eosin (H&E) stain. a Fibrosis (left part of the picture) and increased cellularity (right part of the picture) (original magnification × 10). b Myeloid blasts (arrow at example cell) (original magnification × 60)\n\nFig. 3 Bone marrow biopsy with immune coloring for CD20 showing hairy cells positive for CD20 in the bone marrow (brown-colored cells)\n\nFig. 4 Values of leukocytes and neutrophil granulocytes after treatment with cladribine in October 2014\n\nTable 1 Timeline of case report\n\nDate\tSummaries of visits and treatments\tDiagnostic testing\t\n1995\tPolycythemia vera\nPhlebotomy\tHb 22.2 g/dl, Hct 0.64, WBC 10.1 × 109/L, TPK 162 × 109/L\t\n2008\tStable Hb\nPhlebotomy stopped\tHb 13.3 g/dl\t\n2009\tMouth ulcers, prednisolone without effect\tMouth biopsy showed “acute and chronic inflammation.”\t\nMarch 2012\tLeukopenia, thrombocytopenia\tBone marrow biopsy showed fibrosis grade 1, “spent phase” polycythemia vera; in retrospect, also hairy cell leukemia.\nHb 13.2 g/dl, WBC 2.7 × 109/L, neutrophils 1.4 × 109/L, monocytes 0.1 × 109/L, lymphocytes 1.20.1 × 109/L, TPK 102 × 109/L\t\nApril–May 2013\tWorsening of leukopenia, thrombocytopenia\nTemporary effect of filgrastim on neutrophils and partly on mouth ulcers\tBone marrow biopsy: increased cellularity and fibrosis grade 2–3; in retrospect, also hairy cell leukemia\nHb 11.6 g/dl, WBC 2.4 × 109/L, neutrophils 1.1 × 109/L, monocytes 0.1 × 109/L, lymphocytes 1.20.1 × 109/L, TPK 98 × 109/L\t\nApril 2014\tMyelofibrosis\nPancytopenia\tBone marrow biopsy with fibrosis grade 3, osteosclerosis; in retrospect, also AML and hairy cell leukemia\nComplex cytogenetics\nHb 9.7 g/dl, WBC 2.3 × 109/L, neutrophils 0.8 × 109/L, monocytes < 0.1 × 109/L, lymphocytes 1.40.1 × 109/L, TPK 41 × 109/L\t\nMay–August 2014\tRepeated hospitalizations with febrile neutropenia\nThalidomide and prednisolone without effect\t\t\nOctober 2014\tCladribine, temporary effect\tBone marrow biopsy with suggested AML and hairy cell leukemia\t\nMarch 2015\tDeath\t\t\nAbbreviations: Hb Hemoglobin, Hct Hematocrit, TPK Platelet count, AML Acute myeloid leukemia, WBC White blood cells\n\n\n\nDiscussion\nThe present case report is about a man with a long history of polycythemia vera who developed unexplained neutropenia, which we later found was caused by hairy cell leukemia. When we diagnosed the hairy cell leukemia, the patient had also developed secondary myelofibrosis and finally AML. The AML blasts were not CD34-positive, and it therefore took several months before we diagnosed it. We tried treatment with cladribine for the patient’s hairy cell leukemia, with short-term effect on neutropenia, but the patient later died of AML.\n\nPatients with MPN and concomitant hairy cell leukemia have previously been reported a few times (Table 2). In a study of 267 patients with polycythemia vera followed until death, median survival was 13.5 years [11], confirming that polycythemia vera is a slowly progressing disease. In the same study, about 10% of the patients developed myelofibrosis, and 6.8% progressed to AML. Most commonly, secondary AML develops from myelofibrosis, either primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia or polycythemia vera [12]. Therefore, gradual development of cytopenias and splenomegaly in a patient with polycythemia vera is an expected progression of the disease to myelofibrosis. Our patient had an additional cause of neutropenia, myelofibrosis, and splenomegaly (that is, hairy cell leukemia).Table 2 Overview of previous reports of myeloproliferative neoplasms and hairy cell leukemia\n\nReference\tMPN\tHCL\tCytopenia\tOther\t\nMufti et al., 1982 [20]\tPolycythemia vera 1978\t1981\tNeutropenia, thrombocytopenia\t\t\nLishner et al., 1984 [21]\tPolycythemia vera 1967, myelofibrosis 1976\t1982\tThrombocytopenia, anemia,\t\t\nLichtman et al., 1998 [22]\tEssential thrombocythemia 1994\tHCL first, 1986\tThrombocytopenia\t\t\nAzagury et al., 2003 [23]\tEssential thrombocythemia 1995\t1999, symptomatic since 2000\tNeutropenia\t\t\nKelly et al., 2003 [24]\tPolycythemia vera 1976\t2001, HCL variant\tAnemia, thrombocytopenia\t\t\nRazaq et al., 2005 [25]\tPolycythemia vera 1992\t1999, HCL variant\tNo\tAggressive lymphoma in prostate\t\nRumi et al., 2011 [26]\tPolycythemia vera\t\t\tReported in a case series\t\nKotchetkov et al., 2012 [27]\tPolycythemia vera 13 years ago\tHCL variant\tAnemia, thrombocytopenia\tBRAF-negative\t\nIpek et al., 2016 [28]\tPolycythemia vera 3 years after HCL\tHCL first\tAnemia at HCL diagnosis\t\t\nHCL Hairy cell leukemia, MPN Myeloproliferative neoplasms\n\n\n\nIn retrospect, the patient had hairy cell leukemia from 2012 or earlier, as seen in the bone marrow biopsies. A clinical sign that could have raised suspicion was the patient’s monocytopenia, because monocytopenia is found in 90% of patients with hairy cell leukemia [5]. In contrast, patients with polycythemia usually have normal monocyte counts [13]. When our patient was first referred to our department of hematology in 2012, he had monocytes of 0.1 × 109/L, but letters from his general practitioner showed that he had monocytes of 0.3 × 109/L already in 2007. A different treatment strategy could have been to treat the AML first and give the patient cladribine against the hairy cell leukemia later. Nevertheless, the cytogenetic results showed that he had a very poor prognosis even with allogeneic stem cell transplant [14].\n\nNeutropenia is a well-known cause of oral ulcers, and our patient partly responded to granulocyte colony-stimulating factor (G-CSF/filgrastim). Treatment with G-CSF has been suggested to increase the risk of AML; however, the risk is negligible compared with the prophylactic effect on neutropenic fever in patients with cancer [15].\n\nOur patient also had oral ulcers before neutropenia was discovered. Biopsy did not reveal a cause of the ulcers, and no viral infection was detected. Iron deficiency from the phlebotomy for years might have been the cause of the patient’s ulcers [16]. The patient had ferritin 6 μg/L in 2008 and 9 μg/L in 2010. From 2012, the patient had normal iron parameters (Fe 14 μmol/L, transferrin 2.5 g/L, ferritin 44 μg/L, transferrin saturation 23%). Thus, iron deficiency does not appear to be a probable explanation for the patient’s mouth ulcers.\n\nHairy cell leukemia is rarely described in patients with MPN, but there are a few cases reported in the literature (see Table 2 for an overview). It appears not to be a common molecular link between myeloproliferative neoplasms and hairy cell leukemia. The BRAF V600E mutation was not found in a cohort of 402 patients with various myeloid neoplasms, including 90 patients with polycythemia vera [17]. It is, however, reported in an increased frequency of lymphoid malignancies in patients with myeloproliferative diseases [18, 19], suggesting a possible link between myeloproliferative diseases and the risk of lymphoid neoplasms.\n\nConclusions\nOur patient’s case represents a rare presentation of hairy cell leukemia as an unexpected cause of neutropenia in a patient with postpolycythemic myelofibrosis and AML who temporarily responded to cladribine. The patient’s monocytopenia could have raised the suspicion of hairy cell leukemia earlier.\n\nAbbreviations\nAMLAcute myeloid leukemia\n\nG-CSFGranulocyte colony-stimulating factor\n\nHbHemoglobin\n\nHCLHairy cell leukemia\n\nMPNMyeloproliferative neoplasms\n\nTPKPlatelet count\n\nWBCWhite blood cells\n\nAuthors’ contributions\nAHH treated the patient and drafted the manuscript. HTT treated the patient and revised the manuscript. UR reviewed the bone marrow biopsies and reviewed the manuscript. SS reviewed the bone marrow biopsies and reviewed the manuscript. ID reviewed the bone marrow biopsies and the clinical information and revised the manuscript. GET reviewed the bone marrow biopsies and the clinical information and revised the manuscript. AEAD treated the patient and drafted the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nEthical approval was obtained from the Norwegian Regional Committees for Medical and Health Research Ethics (reference number 2015/1882).\n\nConsent for publication\nWritten informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Arber DA Orazi A Hasserjian R Thiele J Borowitz MJ Le Beau MM Bloomfield CD Cazzola M Vardiman JW The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Blood 2016 127 2391 2405 10.1182/blood-2016-03-643544 27069254 \n2. Vainchenker W Kralovics R Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms Blood 2017 129 667 679 10.1182/blood-2016-10-695940 28028029 \n3. Tefferi A Rumi E Finazzi G Gisslinger H Vannucchi AM Rodeghiero F Randi ML Vaidya R Cazzola M Rambaldi A Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study Leukemia 2013 27 1874 1881 10.1038/leu.2013.163 23739289 \n4. Lussana F Rambaldi A Finazzi MC van Biezen A Scholten M Oldani E Carobbio A Iacobelli S Finke J Nagler A Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation Haematologica 2014 99 916 921 10.3324/haematol.2013.094284 24389309 \n5. Jones G Parry-Jones N Wilkins B Else M Catovsky D Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant Br J Haematol 2012 156 186 195 10.1111/j.1365-2141.2011.08931.x 22111844 \n6. Else M Dearden CE Matutes E Forconi F Lauria F Ahmad H Kelly S Liyanage A Ratnayake V Shankari J Rituximab with pentostatin or cladribine: an effective combination treatment for hairy cell leukemia after disease recurrence Leuk Lymphoma 2011 52 Suppl 2 75 78 10.3109/10428194.2011.568650 21504288 \n7. Thompson PA Ravandi F How I manage patients with hairy cell leukaemia Br J Haematol 2017 177 543 556 10.1111/bjh.14524 28146266 \n8. Tiacci E Trifonov V Schiavoni G Holmes A Kern W Martelli MP Pucciarini A Bigerna B Pacini R Wells VA BRAF mutations in hairy-cell leukemia N Engl J Med 2011 364 2305 2315 10.1056/NEJMoa1014209 21663470 \n9. Tiacci E Park JH De Carolis L Chung SS Broccoli A Scott S Zaja F Devlin S Pulsoni A Chung YR Targeting mutant BRAF in relapsed or refractory hairy-cell leukemia N Engl J Med 2015 373 1733 1747 10.1056/NEJMoa1506583 26352686 \n10. Mesa RA Steensma DP Pardanani A Li CY Elliott M Kaufmann SH Wiseman G Gray LA Schroeder G Reeder T A phase 2 trial of combination low-dose thalidomide and prednisone for the treatment of myelofibrosis with myeloid metaplasia Blood 2003 101 2534 2541 10.1182/blood-2002-09-2928 12517815 \n11. Tefferi A Guglielmelli P Larson DR Finke C Wassie EA Pieri L Gangat N Fjerza R Belachew AA Lasho TL Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis Blood 2014 124 2507 2513 10.1182/blood-2014-05-579136 25037629 \n12. Mesa RA Li CY Ketterling RP Schroeder GS Knudson RA Tefferi A Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases Blood 2005 105 973 977 10.1182/blood-2004-07-2864 15388582 \n13. Barraco D Cerquozzi S Gangat N Patnaik MM Lasho T Finke C Hanson CA Ketterling RP Pardanani A Tefferi A Monocytosis in polycythemia vera: clinical and molecular correlates Am J Hematol 2017 92 640 645 10.1002/ajh.24740 28370365 \n14. Armand P Kim HT Logan BR Wang Z Alyea EP Kalaycio ME Maziarz RT Antin JH Soiffer RJ Weisdorf DJ Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation Blood 2014 123 3664 3671 10.1182/blood-2014-01-552984 24744269 \n15. Lyman GH Kuderer NM Granulocyte colony-stimulating factors and risk of acute myeloid leukemia and myelodysplastic syndrome Cancer Treat Res 2011 157 167 178 10.1007/978-1-4419-7073-2_10 21052956 \n16. Scully C Shotts R ABC of oral health: mouth ulcers and other causes of orofacial soreness and pain BMJ 2000 321 162 165 10.1136/bmj.321.7254.162 10894697 \n17. Trifa AP Popp RA Cucuianu A Coada CA Urian LG Militaru MS Banescu C Dima D Farcas MF Crisan TO Absence of BRAF V600E mutation in a cohort of 402 patients with various chronic and acute myeloid neoplasms Leuk Lymphoma 2012 53 2496 2497 10.3109/10428194.2012.668188 22339435 \n18. Vannucchi AM Masala G Antonioli E Chiara Susini M Guglielmelli P Pieri L Maggi L Caini S Palli D Bogani C Increased risk of lymphoid neoplasms in patients with Philadelphia chromosome-negative myeloproliferative neoplasms Cancer Epidemiol Biomark Prev 2009 18 2068 2073 10.1158/1055-9965.EPI-09-0353 \n19. Pettersson H Knutsen H Holmberg E Andreasson B Increased incidence of another cancer in myeloproliferative neoplasms patients at the time of diagnosis Eur J Haematol 2015 94 152 156 10.1111/ejh.12410 25039361 \n20. Mufti GJ Hamblin TJ Stevenson FK Fitchett M Polycythaemia rubra vera and hairy cell leukaemia in the same patient: studies on the spleen J Clin Pathol 1982 35 1312 1315 10.1136/jcp.35.12.1312 7174843 \n21. Lishner M Jutrin I Bar-Sela S Josef D Ravid M Hairy cell leukemia in a patient with polycythemia vera Acta Haematol 1984 72 49 51 10.1159/000206357 6433633 \n22. Lichtman SM Wasil T Ahmad M Brody J Development of essential thrombocythemia in a patient treated with interferon alfa and pentostatin for hairy cell leukemia Leuk Lymphoma 1998 28 423 427 10.3109/10428199809092699 9517515 \n23. Azagury M Martelli JM Morcelet M Duboucher C Flandrin G Development of hairy cell leukemia in a patient treated with cytoreductive agents for essential thrombocythemia Leuk Lymphoma 2003 44 1067 1069 10.1080/1042819031000067990 12854912 \n24. Kelly NP Alkan S Nand S Hairy cell leukemia variant developing in a background of polycythemia vera Arch Pathol Lab Med 2003 127 e209 e211 12683904 \n25. Razaq M Perumandla S Mankan N Sridhar S Sanmugarajah J Fernandez G Hussain S Hairy cell leukemia variant transforming into aggressive lymphoma with prostatic involvement in a patient with polycythemia vera Leuk Lymphoma 2006 47 754 757 16886275 \n26. Rumi E Passamonti F Elena C Pietra D Arcaini L Astori C Zibellini S Boveri E Pascutto C Lazzarino M Increased risk of lymphoid neoplasm in patients with myeloproliferative neoplasm: a study of 1,915 patients Haematologica 2011 96 454 458 10.3324/haematol.2010.033779 21109692 \n27. Kotchetkov R Gupta V Polycythemia vera followed by hairy cell leukemia variant Blood 2012 120 5100 10.1182/blood-2012-07-446260 23387002 \n28. Ipek YH Fehmi H Meliha N Hairy cell leukemia followed by polycythemia vera: report of the first case Oxf Med Case Reports 2016 2016 28 30 10.1093/omcr/omw005 26941958\n\n",
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"keywords": "Case report; Hairy cell leukemia; Myelofibrosis; Myeloproliferative disorders; Neutropenia; Oral ulcer; Polycythemia vera",
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"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001853:Bone Marrow; D017338:Cladribine; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D053614:Janus Kinase 2; D007943:Leukemia, Hairy Cell; D015470:Leukemia, Myeloid, Acute; D007970:Leukopenia; D008297:Male; D009503:Neutropenia; D019226:Oral Ulcer; D011087:Polycythemia Vera; D055728:Primary Myelofibrosis; D013163:Splenomegaly; D013921:Thrombocytopenia",
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"abstract": "We present a case of a 17-year-old girl who developed premenstrual dysphoric disorder (PMDD) after sustaining a severe traumatic brain injury (TBI), and we review the diagnosis of PMDD. The patient developed symptoms of severe depression surrounding her menses months after sustaining severe TBI and was diagnosed with PMDD by a psychiatrist. She ultimately required antipsychotics for optimal symptom resolution. PMDD is a severe form of premenstrual syndrome with symptoms including irritability, anxiety, and nonfatal suicidal behavior. We discuss other potential causes of mood disturbance that are important to screen for after TBI, including depression, anxiety, and hypothalamic-pituitary axis disorders. Rehabilitation medicine providers need to be aware of PMDD in postpubertal female patients with TBI because it can lead to nonfatal suicidal behaviors.\n\n\n\nV.",
"affiliations": "Department of Rehabilitation Medicine, University of Washington, Seattle Children's Hospital, 4800 Sandpoint Way NE, M/S OB.8.410, Seattle, WA 98105.;Department of Rehabilitation Medicine, University of Washington, Seattle Children's Hospital, 4800 Sandpoint Way NE, M/S OB.8.410, Seattle, WA 98105.",
"authors": "Omura|Jaclyn|J|;Osorio|Marisa|M|",
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"mesh_terms": "D000293:Adolescent; D000070642:Brain Injuries, Traumatic; D005260:Female; D006801:Humans; D026741:Physical Therapy Modalities; D065446:Premenstrual Dysphoric Disorder; D012720:Severity of Illness Index; D015599:Trauma Severity Indices",
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"title": "Premenstrual Dysphoric Disorder in a Patient With Traumatic Brain Injury: A Case Presentation.",
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"abstract": "Liver abscess is a rare but serious complication of Crohn's disease. Patients with Crohn's disease are at risk for pyogenic liver abscesses due to immunosuppressive therapy, fistulous disease, and intraabdominal abscesses. Inflammatory bowel disease patients are also known to have a greater prevalence of amebiasis compared to the rest of the population; however, a higher incidence of amebic liver abscess has not been reported. We describe a case of a liver abscess in a patient with Crohn's disease that was initially presumed pyogenic but later determined to be amebic in origin. Epidemiology, clinical presentation, diagnosis, and treatment of amebic and pyogenic liver abscesses are discussed.",
"affiliations": "Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.;Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.;Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.;Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.",
"authors": "Gaut|Daria|D|0000-0002-3808-7258;Shull|Hannah|H|;Bejjani|Anthony|A|;Kahn|Daniel|D|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/9593865Case ReportHepatic Abscess in a Returning Traveler with Crohn's Disease: Differentiating Amebic from Pyogenic Liver Abscess http://orcid.org/0000-0002-3808-7258Gaut Daria dgaut@mednet.ucla.eduShull Hannah Bejjani Anthony Kahn Daniel Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USAAcademic Editor: Masahiro Kohzuki\n\n2018 29 5 2018 2018 959386515 2 2018 6 5 2018 Copyright © 2018 Daria Gaut et al.2018This 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.Liver abscess is a rare but serious complication of Crohn's disease. Patients with Crohn's disease are at risk for pyogenic liver abscesses due to immunosuppressive therapy, fistulous disease, and intraabdominal abscesses. Inflammatory bowel disease patients are also known to have a greater prevalence of amebiasis compared to the rest of the population; however, a higher incidence of amebic liver abscess has not been reported. We describe a case of a liver abscess in a patient with Crohn's disease that was initially presumed pyogenic but later determined to be amebic in origin. Epidemiology, clinical presentation, diagnosis, and treatment of amebic and pyogenic liver abscesses are discussed.\n==== Body\n1. Introduction\nPyogenic and amebic liver abscesses are the two most common types of hepatic abscesses. While both types of hepatic abscesses can present similarly, treatment differs significantly. Despite improvements in therapeutic modalities, pyogenic liver abscess remains a serious condition with a high morbidity and a mortality rate of up to 60% [1]. In contrast, amebic liver abscesses have a good prognosis if diagnosed and treated early. We report a case of liver abscess in a patient with Crohn's disease eventually diagnosed as an amebic abscess by serology that responded well to initial therapy.\n\n2. Case Presentation\nA 28-year-old male with Crohn's disease on azathioprine 100 mg daily in longstanding clinical remission presented to an outpatient gastroenterologist for sudden onset of right upper quadrant abdominal pain 8/10 in severity with radiation to his back. He also endorsed fevers but denied nausea, vomiting, any change in bowel movements, or rectal bleeding. Five months prior to admission, the patient had traveled to northern India and, while there, contracted “traveler's diarrhea,” which was self-limited and treated with loperamide.\n\nAt a gastroenterology clinic, a right upper quadrant ultrasound revealed a 46 mm hypoechoic lesion in the liver, correlating with the area of the patient's pain. The patient was then referred to the emergency room for further evaluation.\n\nIn the emergency room, the patient was afebrile without hypotension or tachycardia. Labs revealed a white blood cell count of 9.91 × 103/μL, hemoglobin of 13.4 g/dL, platelets of 277 × 103/μL, aspartate aminotransferase of 18 U/L, alanine aminotransferase of 22 U/L, total bilirubin of 0.5 mg/dL, alkaline phosphatase of 64 U/L, and C-reactive protein (CRP) of 23.2 mg/dL. Computed tomography (CT) scan of the abdomen/pelvis showed a 6.0 cm × 5.0 cm low/intermediate density lesion in segment 4A/B of the liver with a thick marginal rim and adjacent parenchymal inflammation and biliary prominence (Figure 1). Due to concern for pyogenic abscess, the patient underwent drainage of the abscess by interventional radiology with 110 cc of reported “pus” removed “without anchovy appearance.” A drainage catheter was placed.\n\nFollowing drainage, the patient was started on empiric ertapenem 1 g IV daily and metronidazole 500 mg PO TID. Azathioprine was held. Bacterial, fungal, and acid-fast cultures were negative from the drained fluid. Blood cultures were also negative, except one drawn 2 days into admission that resulted positive for Staphylococcus epidermidis, presumed to be a contaminant. Stool exam for ova and parasites resulted four days after admission with protozoa, later identified as Entamoeba coli trophozoites. The patient's second stool sample was positive for nonpathogenic protozoa, and the third stool sample was negative.\n\nThe patient was discharged on ciprofloxacin 750 mg PO BID and metronidazole 500 mg PO TID for an anticipated three-week antibiotic course from the day of drainage. Entamoeba histolytica IgG antibody returned positive three days after discharge, supporting the diagnosis of amebic liver abscess. The Entamoeba histolytica stool antigen returned negative. Echinococcus and Strongyloides serologies also returned negative. The drain was removed by interventional radiology 1 week after discharge. Repeat CT scan of the abdomen/pelvis 2 weeks after discharge revealed near complete resolution of the abscess with no drainable fluid collection (Figure 2).\n\n3. Discussion\nHepatic abscesses are defined as a suppurative collection within the liver parenchyma infected with either bacterial, parasitic, or less-commonly fungal organisms. Incidence varies according to geographic regions, with amebic being the most common in Southeast Asia and Africa and bacterial (or pyogenic abscess) being the most frequent in Western countries [2]. Amebic liver abscesses are also more common in younger adult males and tend to present with solitary right lobe abscesses [1]. Pyogenic liver abscesses, more common in adults over 50 years old, may result from portal vein pyemia (in the setting of intrabdominal infection), biliary tract disease, or hematogenous seeding and often present with multiple abscesses [1, 3].\n\nSymptoms of pyogenic and amebic liver abscesses are similar and most commonly include fever and abdominal pain. Nausea, vomiting, malaise, and weight loss can also occasionally be seen [4]. Laboratory findings include leukocytosis, elevated CRP, and sometimes liver function test abnormalities [5]. Given that neither symptoms nor laboratory testing are specific, diagnosis relies largely on imaging. Both ultrasound and CT carry a sensitivity of 96–100% for detection of hepatic abscesses; however, they are not able to definitively differentiate the microbiological etiology [5].\n\nSerology can be used to confirm the diagnosis of an amebic liver abscess. Most patients will not have detectable parasites in their stool, as a liver abscess frequently occurs without colitis, but serum antibodies are up to 100% sensitive [6] and 85–95% specific after one or more weeks of symptoms in patients with an amebic liver abscess [3]. As antibodies may persist after acute infection, serologic tests do not have the ability to distinguish past from current infections [3]. In a nonendemic setting, however, a positive serologic test in addition to an imaging finding of liver abscess is strongly suggestive of amebic etiology. Histopathologic samples of abscess fluid can also be used to confirm the diagnosis. Aspirated material from an amebic liver abscess contains acellular, proteinaceous debris with necrotic hepatocytes that form a brown fluid referred to as “anchovy paste” [7]. Trophozoites can also be seen in a minority (<20%) of aspirates [8]. This is in contrast to aspirates from pyogenic liver abscesses which consist of purulent material with bacteria and neutrophils that are readily apparent by Gram stain.\n\nTreatment of pyogenic liver abscess usually involves both antibiotic therapy and adequate drainage, though there have been some studies to suggest that small abscesses 3–5 cm can be treated by antibiotics alone [9]. Amebic liver abscesses generally resolve with just medication. Indications for percutaneous drainage include if the abscess is large (>10 cm in diameter), subcapsular, high risk for rupture, superinfected, or if there is poor response to medical treatment [2].\n\nEmpiric antibiotic choice for a pyogenic abscess should be directed at the microbes typically responsible, which include aerobic enteric Gram-negative bacilli (Escherichia coli and Klebsiella pneumoniae, the latter particularly prevalent in Asia), Gram-positive cocci (most commonly the Streptococcus milleri group but also including Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus spp.), and anaerobes (Bacteriodes, Fusobacterium, Actinomyces, and anaerobic streptococci) [10, 11]. Reasonable single-agent regimens include carbapenems or piperacillin-tazobactam, or a combination regimen of a third-generation cephalosporin plus metronidazole can be used [12]. The latter is preferred in most cases in which drug-resistant bacteria are not strongly suspected or proven [12]. For patients with an amebic liver abscess, metronidazole (500–750 mg orally TID for 7–10 days) is the drug of choice. Following therapy for invasive amebiasis, treatment with a luminal agent (paromomycin, iodoquinol, or nitazoxanide) to eliminate intraluminal cysts is warranted, even if stool microscopy is negative [3]. Patients are otherwise at risk of relapsing from residual infection in the intestine. In stable patients with a hepatic abscess, antibiotics may be deferred until postaspiration/drainage to increase culture yield [13].\n\nLiver abscess is a rare but serious complication of Crohn's disease with an incidence of 114–297 per 100,000 of patients with Crohn's disease [14]. This is higher than the incidence in the general population (8–16 per 100,000) [14]. Patients with Crohn's disease are at risk for pyogenic liver abscess due to immunosuppressive therapy, fistulous disease, and intraabdominal abscesses [15]. Inflammatory bowel disease patients are also known to have a greater prevalence of amebiasis compared to the rest of the population [16]; however, a higher incidence of amebic liver abscesses has not been reported. Our patient was likely predisposed to such an amebic abscess due to a combination of his travel history and immunosuppression.\n\n4. Conclusion\nIn summary, we describe a case of a liver abscess in a patient with Crohn's disease that was initially presumed pyogenic but later determined to be amebic in origin. Distinguishing amebic from pyogenic liver abscess is important because their treatments and prognoses differ. Epidemiology and serology are two ways to help differentiate the two, as clinical presentations are often similar.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this article.\n\nFigure 1 Abdominal CT scan on hospital admission revealing a complex lower attenuating 6.0 cm hepatic segment 4A/B lesion with a thick marginal rim, adjacent parenchymal inflammation, and biliary prominence.\n\nFigure 2 Abdominal CT scan 2 weeks after discharge demonstrating near total resolution of the previously seen hepatic segment 4 abscess without any drainable fluid collection.\n==== Refs\n1 Lodhi S. Sarwari A. R. Muzammil M. Salam A. Smego R. A. Features distinguishing amoebic from pyogenic liver abscess: a review of 577 adult cases Tropical Medicine and International Health 2004 9 6 718 723 10.1111/j.1365-3156.2004.01246.x 2-s2.0-3042633934 15189463 \n2 Lardière-Deguelte S. Ragot E. Amroun K. Hepatic abscess: diagnosis and management Journal of Visceral Surgery 2015 152 4 231 243 10.1016/j.jviscsurg.2015.01.013 2-s2.0-84973414922 25770745 \n3 Wuerz T. Kane J. B. Boggild A. K. A review of amoebic liver abscess for clinicians in a nonendemic setting Canadian Journal of Gastroenterology 2012 26 10 729 733 10.1155/2012/852835 2-s2.0-84867472712 23061067 \n4 Kurland J. E. Brann O. S. Pyogenic and amebic liver abscesses Current Gastroenterology Reports 2004 6 4 273 279 10.1007/s11894-004-0078-2 15245694 \n5 Mavilia M. G. Molina M. Wu G. Y. The evolving nature of hepatic abscess: a review Journal of Clinical and Translational Hepatology 2016 4 2 158 168 10.14218/jcth.2016.00004 27350946 \n6 Fotedar R. Stark D. Beebe N. Marriott D. Ellis J. Harkness J. Laboratory diagnostic techniques for Entamoeba species Clinical Microbiology Reviews 2007 20 3 511 532 10.1128/cmr.00004-07 2-s2.0-34547400970 17630338 \n7 Bhambhani S. Kashyap V. Amoebiasis: diagnosis by aspiration and exfoliative cytology Cytopathology 2001 12 5 329 333 10.1046/j.1365-2303.2001.00333.x 2-s2.0-0035788433 11722513 \n8 Anesi J. A. Gluckman S. Amebic liver abscess Clinical Liver Disease 2015 6 2 41 43 10.1002/cld.488 2-s2.0-84939626420 \n9 Bamberger D. M. Outcome of medical treatment of bacterial abscesses without therapeutic drainage: review of cases reported in the literature Clinical Infectious Diseases 1996 23 3 592 603 10.1093/clind/23.1.592 8879785 \n10 Johannsen E. C. Sifri C. D. Madoff L. C. Pyogenic liver abscesses Infectious Disease Clinics of North America 2000 14 3 547 563 10.1016/s0891-5520(05)70120-3 2-s2.0-0033831481 10987109 \n11 Sabbaj J. Sutter V. L. Finegold S. M. Anaerobic pyogenic liver abscess Annals of Internal Medicine 1972 77 4 p. 629 10.7326/0003-4819-77-4-629 \n12 Solomkin J. S. Mazuski J. E. Bradley J. S. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America Clinical Infectious Diseases 2010 50 2 133 164 10.1086/649554 2-s2.0-73649114948 20034345 \n13 Gyorffy E. J. Frey C. F. Silva J. Jr. McGahan J. Pyogenic liver abscess. Diagnostic and therapeutic strategies Annals of Surgery 1987 206 6 699 705 10.1097/00000658-198712000-00003 3318726 \n14 Mir-Madjlessi S. H. McHenry M. C. Farmer R. G. Liver abscess in Crohn’s disease. Report of four cases and review of the literature Gastroenterology 1986 91 4 987 993 10.1016/0016-5085(86)90704-3 3743974 \n15 Pinarbaşi B. Karaca C. Danalioğlu A. Liver abscess as a rare complication of Crohn’s disease: a case report Turkish Journal of Gastroenterology 2004 15 1 45 48 15264121 \n16 Babić E. Bevanda M. Mimica M. Prevalence of amebiasis in inflammatory bowel disease in University Clinical Hospital Mostar SpringerPlus 2016 5 1 p. 1586 10.1186/s40064-016-3261-7 2-s2.0-84988025143 27652159\n\n",
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"title": "Hepatic Abscess in a Returning Traveler with Crohn's Disease: Differentiating Amebic from Pyogenic Liver Abscess.",
"title_normalized": "hepatic abscess in a returning traveler with crohn s disease differentiating amebic from pyogenic liver abscess"
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"abstract": "BACKGROUND\nEpidural anesthesia is the most commonly used method of pain relief during labor in the USA. It is not classically associated with alterations in level of alertness. Coma during the procedure is rare, with a reported incidence of 0.1-0.3%.\n\n\nMETHODS\nAn otherwise healthy patient experienced almost complete loss of brainstem function following routine epidural anesthesia during delivery. The episode lasted for less than 3 hours and the patient made a full recovery. To our knowledge, this is the most detailed clinical observation to date of this condition.\n\n\nCONCLUSIONS\nClinicians should be aware of this rare and potentially serious complication of epidural anesthesia. The case highlights the need for sensory input to maintain alertness through the activity of the ascending reticular activating system.",
"affiliations": "Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.;Department of Anesthesia, Blackrock Clinic, Dublin, Ireland.;0.",
"authors": "Dardis|Christopher|C|;Lawlor|David|D|;Schusse|Courtney M|CM|",
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"mesh_terms": "D000767:Anesthesia, Epidural; D000779:Anesthetics, Local; D001933:Brain Stem; D003128:Coma; D036861:Delivery, Obstetric; D005260:Female; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D012677:Sensation; D055815:Young Adult",
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"title": "Transient Coma Due To Epidural Anesthesia: The Role of Loss of Sensory Input.",
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"abstract": "BACKGROUND Enterocolitis is an immune-related adverse event associated with nivolumab treatment. Although intravenous corticosteroids and infliximab are recommended as a first-line and second-line therapy, respectively, there is no established treatment for severe enterocolitis that is refractory to these drugs. CASE REPORT A 62-year-old male with non-small cell lung cancer, with multiple brain metastasis, received nivolumab as the eighth-line chemotherapy for his disease. A few days after nivolumab administration, grade 2-3 enterocolitis developed in the patient. The enterocolitis improved to grade 1 after careful observation; however, it was aggravated to grade 3 after resuming nivolumab treatment. After cessation of nivolumab, 3.3 mg of intravenous dexamethasone and 40 mg of methylprednisolone were administered for 16 days and subsequently 30-60 mg of oral prednisolone was administered for 50 days, with little improvement in the patient's colitis. A second-line treatment with 5 mg/kg of infliximab was twice attempted, but the patient had persistent diarrhea. Therefore, 50 mg of oral cyclosporine was started as a third-line therapy. Three days after the start of cyclosporine, the number of diarrhea events decreased, with resolution 2 weeks after cyclosporine administration. CONCLUSIONS Oral cyclosporine treatment can be a third-line therapy for enterocolitis associated with immune-related adverse events.",
"affiliations": "Department of Pharmacy, Jizankai Medical Foundation Tsuboi Cancer Center Hospital, Koriyama, Fukushima, Japan.;Department of Innovative Research and Education for Clinicians and Trainees (DiRECT), Fukushima Medical University Hospital, Fukushima City, Fukushima, Japan.;Department of Pharmacy, Jizankai Medical Foundation Tsuboi Cancer Center Hospital, Koriyama, Fukushima, Japan.;Department of Pharmacy, Jizankai Medical Foundation Tsuboi Cancer Center Hospital, Koriyama, Fukushima, Japan.;Department of Pulmonology, Jizankai Medical Foundation Tsuboi Cancer Center Hospital, Koriyama, Fukushima, Japan.",
"authors": "Iyoda|Tomokazu|T|;Kurita|Noriaki|N|;Takada|Ayumi|A|;Watanabe|Hiroe|H|;Ando|Masahiro|M|",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2958141710.12659/AJCR.908570908570ArticlesResolution of Infliximab-Refractory Nivolumab-Induced Acute Severe Enterocolitis After Cyclosporine Treatment in a Patient with Non-Small Cell Lung Cancer Iyoda Tomokazu ABCDEF1Kurita Noriaki ADEF23Takada Ayumi BC1Watanabe Hiroe BC1Ando Masahiro BCDF4\n1 Department of Pharmacy, Jizankai Medical Foundation Tsuboi Cancer Center Hospital, Koriyama, Fukushima, Japan\n2 Department of Innovative Research and Education for Clinicians and Trainees (DiRECT), Fukushima Medical University Hospital, Fukushima City, Fukushima, Japan\n3 Center for Innovative Research for Communities and Clinical Excellence (CiRC LE), Fukushima Medical University, Fukushima City, Fukushima, Japan\n4 Department of Pulmonology, Jizankai Medical Foundation Tsuboi Cancer Center Hospital, Koriyama, Fukushima, JapanAuthors’ 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: Noriaki Kurita, e-mail: kuritanoriaki@gmail.com2018 27 3 2018 19 360 364 17 12 2017 19 1 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 62\n\nFinal Diagnosis: Enteritis\n\nSymptoms: Diarrhea • enteritis\n\nMedication: Nivolumab\n\nClinical Procedure: —\n\nSpecialty: Oncology\n\nObjective:\nAdverse events of drug therapy\n\nBackground:\nEnterocolitis is an immune-related adverse event associated with nivolumab treatment. Although intravenous corticosteroids and infliximab are recommended as a first-line and second-line therapy, respectively, there is no established treatment for severe enterocolitis that is refractory to these drugs.\n\nCase Report:\nA 62-year-old male with non-small cell lung cancer, with multiple brain metastasis, received nivolumab as the eighth-line chemotherapy for his disease. A few days after nivolumab administration, grade 2–3 enterocolitis developed in the patient. The enterocolitis improved to grade 1 after careful observation; however, it was aggravated to grade 3 after resuming nivolumab treatment. After cessation of nivolumab, 3.3 mg of intravenous dexamethasone and 40 mg of methylprednisolone were administered for 16 days and subsequently 30–60 mg of oral prednisolone was administered for 50 days, with little improvement in the patient’s colitis.\n\nA second-line treatment with 5 mg/kg of infliximab was twice attempted, but the patient had persistent diarrhea. Therefore, 50 mg of oral cyclosporine was started as a third-line therapy. Three days after the start of cyclosporine, the number of diarrhea events decreased, with resolution 2 weeks after cyclosporine administration.\n\nConclusions:\nOral cyclosporine treatment can be a third-line therapy for enterocolitis associated with immune-related adverse events.\n\nMeSH Keywords:\nCyclosporineDrug-Related Side Effects and Adverse ReactionsEnterocolitis\n==== Body\nBackground\nNivolumab, an immune checkpoint inhibitor (ICI), is a humanized anti-PD-1 monoclonal antibody that is used for the treatment for various types of cancer after second-line chemotherapy. Nivolumab may activate T cells to develop anti-tumor effects, but this immune activation sometimes causes immune-related adverse events (irAE), such as pneumonitis, hepatitis, and enterocolitis [1].\n\nEnterocolitis is one form of irAE that decreases the quality-of-life of patients with lung cancer and disrupts treatment with ICIs. Among patients with lung cancer, enterocolitis is common, affecting approximately 8% of treated patients [2,3], and can reach grade 3–4 severity among 1% of patients [3]. Enterocolitis can be managed with cessation of nivolumab and administration of intravenous corticosteroid therapy after hospitalization (methylprednisolone 1–2 mg/kg per day) or administration of 5 mg/kg of infliximab in severe cases [1]. However, there is no standard therapy for enterocolitis that is intractable with corticosteroid therapy or infliximab, and the description of such cases in the literature is scarce, although the use of tacrolimus or mycophenolate has been suggested [4]. Herein, we report a case of severe enterocolitis associated with nivolumab that was refractory to the recommended treatment course (corticosteroid and infliximab) [1], but resolved successfully after cyclosporine treatment.\n\nCase Report\nA 62-year-old male with non-small cell lung cancer and suffering from multiple brain metastases was examined at our clinic. Eleven years before presenting to us, he was diagnosed with stage IIIA (cT3N2M0) lung adenocarcinoma and received cisplatin-based chemoradiotherapy without surgery. Four years before presenting to us, his lung cancer recurred, and he received multiple courses of standard chemotherapy (such as platinum-based chemotherapy and pemetrexed/bevacizumab) after confirmation that the genetic mutation of his tumor was wild-type for the EGFR and the ALK fusion genes. Standard chemotherapy was unable to control the lung lesions and brain metastases; therefore, intravenous nivolumab therapy was started (3 mg/kg intravenous nivolumab for 2 weeks per 1 cycle) as the eighth-line therapy. He received 18 cycles of intravenous nivolumab, and during the treatment, his lung lesions and multiple brain metastases were stable, and the patient followed an uneventful course. At that time, the nineteenth cycle of 3 mg/kg of nivolumab was administered after hospitalization. Four days after this nivolumab administration, grade 2–3 enterocolitis developed in the patient (Figure 1). Endoscopic examination of the colon revealed intestinal inflammation accompanied by edema in the whole colon mucosa, which was consistent with enterocolitis associated with irAE (Figure 2). After improvement of the patient’s enterocolitis to grade 1, nivolumab was again administered. However, the day after resumption of nivolumab, the patient’s enterocolitis became aggravated and worsened to grade 3. Therefore, nivolumab treatment was discontinued, and the recommended treatment for enterocolitis was started: 3.3 mg of intravenous dexamethasone and 40 mg of methylprednisolone (equivalent to 70 mg of prednisolone). After administration of the previously described regimen for 16 days, the treatment was switched to 50 mg of oral prednisolone; however, the patient’s enterocolitis remained grade 2–3. On the 39th day after the onset of diarrhea, 5 mg/kg of infliximab was administered intravenously. However, 2 weeks after infliximab administration the patient’s diarrhea persisted. Thus, a second administration of infliximab was attempted; however, there was no improvement in severe diarrhea symptoms. His diarrhea was severe enough to cause sleep disturbance and depressive mood. Therefore, 50 mg of cyclosporine was started as a third-line therapy. Three days after starting oral cyclosporine (60th day after the onset of enterocolitis), the number of diarrhea events started to decrease, and his enterocolitis became grade 1–2. Two weeks after cyclosporine treatment initiation, diarrhea symptoms resolved, and his stool became solid. Following this, an additional 5 mg/kg of infliximab was administered once. After confirmation of the resolution of the patient’s enterocolitis, he was re-administered nivolumab and discharged to continue outpatient treatment. However, soon after receiving 2 courses of nivolumab, grade 3 diarrhea relapsed and nivolumab administration was withdrawn. Regarding oncologic outcome, computed tomography imaging conducted before patient discharge revealed stable disease, based on the unchanging cancerous lesions of the primary lung focus and multiple brain metastases, suggesting sustained immuno-modulatory effect on cancerous cells despite nivolumab cessation (Figure 3).\n\nDiscussion\nIn this study, we reported the case of a non-small cell lung cancer patient with nivolumab-induced enterocolitis that was refractory to corticosteroid and infliximab, but improved after oral cyclosporine administration. Although his treatment was uneventful during the first 18 cycles of nivolumab administration, he seemed to develop enterocolitis as an irAE associated with nivolumab on the 19th cycle of nivolumab administration. While it is possible that enterocolitis associated with nivolumab could develop during early cycles of nivolumab therapy, studies have shown that there are lung cancer patients who developed enterocolitis associated with nivolumab around the 45th cycle of nivolumab administration [2,3]. Also, regarding the diagnostic accuracy of enterocolitis associated with irAE, the time course of its onset after nivolumab administration, as well as the relapse of enterocolitis after re-administration of nivolumab, support our final diagnosis. Although infectious enteritis [5], such as cytomegalovirus infection, should be a concern for patients with diarrhea during nivolumab therapy, this scenario was unlikely due to a lack of ulcerative lesions on colonoscopy (Figure 2), as well as no aggravation during cyclosporine treatment, which can also sustain immunosuppression. As cyclosporine is an immunosuppressive agent that blocks the transcription of cytokine genes in activated T cells [6], the drug may be effective for irAE involved by T-cell activation.\n\nThe strength of this report is the uniqueness of oral cyclosporine therapy and the subsequent resolution of the refractory enterocolitis. The enterocolitis of our patient seemed refractory, as he did not respond to corticosteroids and infliximab, and suffered from diarrhea during the day and night. However, diarrhea symptoms decreased and eventually subsided after 50 mg of oral cyclosporine. Thus, oral cyclosporine treatment can be a third-line therapy for enterocolitis associated with irAE, considering that treatment recommendations except for corticosteroids as first, and infliximab as second, choice therapies for enterocolitis do not exist [3]. In addition, the use of cyclosporine can be relatively cost effective compared with bio-engineered drugs. A study showed that vedolizumab [7], a humanized monoclonal IgG1 antibody against α4β7 integrin used for the treatment of inflammatory bowel disease, is effective against enterocolitis associated with irAE. In that study, 300 mg of vedolizumab was administered intravenously on days 1, 15, and 43, and then every 8 weeks thereafter. However, a single dose of vedolizumab costs about $5,000 (USD) [8].\n\nSeveral limitations of this study need to be mentioned. First, the case report design does not guarantee the effectiveness of oral cyclosporine treatment for enterocolitis in all cases. Second, our patient may have responded to infliximab treatment in a delayed manner, as his enterocolitis improved to grade 1 to 2 soon after oral cyclosporine administration (i.e., after 3 days). In addition, his diarrhea became grade 0 immediately after the third administration of infliximab. Indeed, although a systematic review has reported that enterocolitis caused by irAE usually improves rapidly after the first infliximab administration, there are cases in which response took approximately 2 weeks after the second administration of infliximab [9]. Therefore, it is possible that cyclosporine and infliximab had a synergistic effect on the patient’s enterocolitis.\n\nConclusions\nWe reported a case of severe enterocolitis associated with nivolumab, which was refractory to corticosteroids and infliximab therapy, but improved after oral cyclosporine administration. Further study is warranted to build evidence of the effectiveness of oral cyclosporine for refractory enterocolitis caused by irAE.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Time course of enterocolitis associated with nivolumab and subsequent treatment. The black solid line shows diarrhea grade, based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The thin light-gray solid line shows dose of prednisolone. The dark gray bar shows cyclosporine dose. The solid circle and triangle show administration of nivolumab and infliximab, respectively.\n\nFigure 2. Endoscopic finding of the colon mucosa. (A–C) The endoscopic images of the ascending colon, the descending colon, and the sigmoid colon, respectively. There was enteritis with mild edema affecting the whole colon mucosa. However, ulcerative lesions were not observed at any site. The findings were compatible with enterocolitis associated with nivolumab. (D) Illustrates the sites of the colon where A–C were taken.\n\nFigure 3. Computed tomography scans of the primary lung focus. (A) Indicates the cancerous lesions measured immediately after withdrawal of nivolumab administration. (B) Indicates the same lesions measured approximately 70 days after withdrawal of nivolumab administration. The size of the lesions remained unchanged.\n==== Refs\nReferences:\n1. Friedman CF Proverbs-Singh TA Postow MA Treatment of the immune-related adverse effects of immune checkpoint inhibitors: A review JAMA Oncol 2016 2 1346 53 27367787 \n2. Brahmer J Reckamp KL Baas P Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer N Engl J Med 2015 373 123 35 26028407 \n3. Borghaei H Paz-Ares L Horn L Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer N Engl J Med 2015 373 1627 39 26412456 \n4. Spain L Diem S Larkin J Management of toxicities of immune checkpoint inhibitors Cancer Treat Rev 2016 44 51 60 26874776 \n5. Prieux-Klotz C Dior M Damotte D Immune checkpoint inhibitor-induced colitis: Diagnosis and management Target Oncol 2017 12 301 8 28540478 \n6. Matsuda S Koyasu S Review mechanisms of action of cyclosporine Immunopharmacology 2000 47 119 25 10878286 \n7. Bergqvist V Hertervig E Gedeon P Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis Cancer Immunol Immunother 2017 66 581 92 28204866 \n8. Erim DO Mahendraratnam N Okafor PN Wheeler SB The value of vedolizumab as rescue therapy in moderate-severe Crohn’s disease patients with adalimumab non-response in the USA J Crohns Colitis 2015 9 669 75 25987351 \n9. Gupta A De Felice KM Loftus EV Khanna S Systematic review: Colitis associated with anti-CTLA-4 therapy Aliment Pharmacol Ther 2015 42 406 17 26079306\n\n",
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"abstract": "This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1-14 along with 375 mg/m(2) of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876.",
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"abstract": "Aromatase inhibitors (AIs) are the indispensible part of hormone-responsive breast cancer treatment. A potential relation between autoimmunity and AIs has been described before. Herein, we report a case of Sjogren's syndrome (SjS) and polyneuropathy which developed during treatment with anastrozole. A 70 years old female patient having a history of breast cancer was referred to our clinic with numbness in both legs for 1 year. She was receiving anastrazole since 2006. She was having sicca symptoms for 3 years. After laboratory evaluation, salivary gland biopsy and electroneuromyography, the patient was evaluated as SjS and polyneuropathy. Intravenous immunoglobulin treatment (400 mg/kg/day, 5 days, 6 months) was initiated. A potential pathogenic linkage between AI therapy and autoimmunity is mentioned. Only few cases of rheumatoid arthritis and SjS related with AIs have been reported. But, our case is the first in the literature having definite SjS and neuropathy in this setting.",
"affiliations": "Department of Internal Medicine, Division of Rheumatology, Eskisehir Yunus Emre State Hospital, Eskisehir, Turkey.;Department of Internal Medicine, Division of Rheumatology, Eskisehir Osmangazi University, Eskisehir, Turkey.",
"authors": "Yasar Bilge|Nazife Sule|NS|;Korkmaz|Cengiz|C|",
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"fulltext": "\n==== Front\nWorld J OncolWorld J OncolElmer PressWorld Journal of Oncology1920-45311920-454XElmer Press 10.14740/wjon695wCase ReportDoes Aromatase Inhibitors Cause Sjogren’s Syndrome and Polyneuropathy? Aromatase InhibitorsYasar Bilge Nazife Sule acKorkmaz Cengiz ba Department of Internal Medicine, Division of Rheumatology, Eskisehir Yunus Emre State Hospital, Eskisehir, Turkeyb Department of Internal Medicine, Division of Rheumatology, Eskisehir Osmangazi University, Eskisehir, Turkeyc Corresponding Author: Nazife Sule Yasar Bilge, Department of Internal Medicine, Division of Rheumatology, Eskisehir Yunus Emre State Hospital, Eskisehir, Turkey. Email: suleyasar@yahoo.com8 2014 25 8 2014 5 4 181 182 24 7 2014 Copyright 2014, Yasar Bilge et al.2014This 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.Aromatase inhibitors (AIs) are the indispensible part of hormone-responsive breast cancer treatment. A potential relation between autoimmunity and AIs has been described before. Herein, we report a case of Sjogren’s syndrome (SjS) and polyneuropathy which developed during treatment with anastrozole. A 70 years old female patient having a history of breast cancer was referred to our clinic with numbness in both legs for 1 year. She was receiving anastrazole since 2006. She was having sicca symptoms for 3 years. After laboratory evaluation, salivary gland biopsy and electroneuromyography, the patient was evaluated as SjS and polyneuropathy. Intravenous immunoglobulin treatment (400 mg/kg/day, 5 days, 6 months) was initiated. A potential pathogenic linkage between AI therapy and autoimmunity is mentioned. Only few cases of rheumatoid arthritis and SjS related with AIs have been reported. But, our case is the first in the literature having definite SjS and neuropathy in this setting.\n\nSjogren’s syndromeBreast cancerAromatase inhibitors\n==== Body\nIntroduction\nAromatase inhibitors (AIs) are the cornerstones of hormone-responsive breast cancer treatment. A pathogenic linkage between autoimmunity and AIs has been described before [1]. Here, we report a case of Sjogren’s syndrome (SjS) and polyneuropathy which developed during treatment with anastrozole, a third generation AI.\n\nCase Report\nA 70 years old female patient was referred to our clinic with numbness in both legs for 1 year. She had a history of breast cancer (invasive ductal carcinom, T2N0Mx) for 6 years and right modified radical mastectomy was performed. She was receiving anastrazole since 2006 after six cycles of chemotherapy (fluorouracil, adriamycin, and cyclophosphamid). She was having sicca symptoms for 3 years. On physical examination, she had dry mouth and superficial sensorial loss in both legs. Her erythrocyte sedimentation rate was 47 mm/h (0 - 20) and C-reactive protein level was 8.87 mg/dL (0 - 8), respectively. Her rheumatoid factor and anti-nuclear antibody (ANA) tests were positive whereas SS-A and SS-B antibodies were negative. Schirmer test was 2 mm in right eye and 3 mm in left eye which was concordant with a positive test. Minor salivary gland biopsy was performed and the results were reported as compatible with SjS. Electroneuromyography showed axonal polyneuropathy. The patient was evaluated as SjS and polyneuropathy. Intravenous immunoglobulin treatment (400 mg/kg/day, 5 days, 6 months) was initiated. Until now she received three cycles and her symptoms improved moderately.\n\nDiscussion\nThe third generation AIs, anastrozole, letrozole and exemestane, have become an important part of both early and advanced hormone-responsive breast cancer treatment in postmenopausal women [2]. They decrease levels of circulating estrogen in postmenopausal women by blocking the action of the aromatase enzyme, which converts androgens to estrogens. The main adverse effects of AIs are reduction of bone mineral density resulting in osteopenia, osteoporosis and fractures, joint symptoms, sexual dysfunction, and reactivation of ovarian function in premenopausal woman [1, 2]. Hormone receptor positivity, obesity, prior chemotherapy and treatment with anastrozole are associated with a higher risk of joint symptoms which may result with interruption of treatment [3]. Musculoskeletal symptoms related to AI therapy include arthralgia, morning stiffness, tenosynovitis, trigger finger and carpal tunnel syndrome. Estrogen deprivation has been accused as the cause of AI-related joint symptoms. A potential pathogenic linkage between AI therapy and autoimmunity is mentioned. Only few cases of rheumatoid arthritis (RA) and SjS related with AIs have been reported [4, 5]. Most of them were cases of incomplete SjS and none of them had neuropathy. In a study by Laroche et al, 24 patients presented with pain while receiving AI therapy were evaluated and 10 patients had sicca symptoms, nine patients had ANA positivity and one had anti-SSA and anti-SSB antibodies positivity. Of the 24 patients, 19 had arthralgia related to AIs but only one had definite RA and one other had definite SjS [5]. An association between estrogen deficiency and increased proinflammatory cytokine secretion is thought to be responsible. Studies about sex hormones and SjS have conflicting results about their relations, making it an intriguing topic [5].\n\nOur case is the first in the literature having definite SjS and neuropathy in this setting. Some scenarios can be suggested for explaining the occurrence of SjS in this patient. SjS and neuropathy may be an adverse effect of chemotherapy which, we believe, is a remote possibility because 6-year interval between chemotherapy administration and occurrence of SjS is a very long period. Another explanation is that autoimmunity as a part of paraneoplastic process due to recurrence of malignancy could have developed. However, the patient was evaluated for this possibility, but no evidence for a relapse was found by oncology department. It is well known that cryoglobulinemia-related vasculitis may cause neuropathy in the course of SjS. The main manifestation of cryoglobulinemia-related vasculitis is palpable purpurae. In this patient, we did not observe any skin lesions that may suggest cryoglobulinemia-related vasculitis. Therefore we did not evaluate the presence of cryoglobulinemia.\n\nAnother mechanism is that AI could have caused SjS and neuropathy or triggered the onset of subclinical SjS in this patient. SjS may have mostly subclinical course, and the diagnosis of SjS is delayed because of this subclinical course. Although it is difficult to remember past medical complaints by the patient, our patient had no SjS-related symptoms prior to the development of breast cancer or when breast cancer was diagnosed. Therefore, it can be speculated that there may be a causal relationship between AI use and SjS and neuropathy. All her symptoms started under the treatment with AI. Presumably, further cases will clarify whether there is a causal relationship between AI use and autoimmune disorders such as SjS and shed light on the pathogenesis of AI-related autoimmune disorders.\n\nConflicts of Interest\nThe authors declare that they have no conflict of interest.\n==== Refs\nReferences\n1 Gaillard S Stearns V Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management Breast Cancer Res 2011 13 2 205 10.1186/bcr2818 21457526 \n2 Din OS Dodwell D Wakefield RJ Coleman RE Aromatase inhibitor-induced arthralgia in early breast cancer: what do we know and how can we find out more? Breast Cancer Res Treat 2010 120 3 525 538 10.1007/s10549-010-0757-7 20157776 \n3 Sestak I Cuzick J Sapunar F Eastell R Forbes JF Bianco AR Buzdar AU Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis Lancet Oncol 2008 9 9 866 872 10.1016/S1470-2045(08)70182-7 18703382 \n4 Morel B Marotte H Miossec P Will steroidal aromatase inhibitors induce rheumatoid arthritis? Ann Rheum Dis 2007 66 4 557 558 10.1136/ard.2006.066159 17360783 \n5 Laroche M Borg S Lassoued S De Lafontan B Roche H Joint pain with aromatase inhibitors: abnormal frequency of Sjogren's syndrome J Rheumatol 2007 34 11 2259 2263 17937464\n\n",
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"drugdosagetext": "10 MG, QD",
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"drugindication": "Pulmonary arterial hypertension",
"drugintervaldosagedefinition": "804",
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"drugstartdateformat": "602",
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MACITENTAN"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SELEXIPAG"
},
"drugadditional": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Pulmonary arterial hypertension",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "202010",
"drugstartdateformat": "610",
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SELEXIPAG"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SELEXIPAG"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1200 MG, BID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Pulmonary arterial hypertension",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1200",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SELEXIPAG"
}
],
"patientagegroup": "5",
"patientonsetage": "64",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Angina pectoris",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Dyspnoea exertional",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Productive cough",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Palpitations",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Oedema peripheral",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": null
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20200901"
}
},
"primarysource": {
"literaturereference": "Proshkina A A, Tsareva N A, Nekludova G V, Avdeev S N. Triple combination therapy with macitentan, riociguat, and selexipag in a patient with idiopathic pulmonary arterial hypertension (functional class III). Cardiology. 2021;61(10):104-107",
"literaturereference_normalized": "triple combination therapy with macitentan riociguat and selexipag in a patient with idiopathic pulmonary arterial hypertension functional class iii",
"qualification": "3",
"reportercountry": "RU"
},
"primarysourcecountry": "RU",
"receiptdate": "20211130",
"receivedate": "20211130",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20131573,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Hepatocellular carcinoma is one of the most common malignant tumors in China and is also a major cause of cancer deaths worldwide. Recent advances in immunotherapy have identified new treatments in which immunotherapy can be combined with antiangiogenic therapy. We report a case of hepatocellular carcinoma with a tumor thrombus at the inferior vena cava-right atrium junction and multiple lung metastases after a multiple-course treatment. Treatment with sintilimab in combination with sorafenib led to a partial remission and immune-related hepatitis.",
"affiliations": "The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.;Department of Liver surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital & Shanghai Medical School, Fudan University, Key Laboratory for Carcinogenesis & Cancer Invasion, The Chinese Ministry of Education, Shanghai, 200032, China.",
"authors": "Liu|Xuhong|X|;Yi|Yong|Y|0000-0003-0847-2590",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.2217/imt-2021-0062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "13(17)",
"journal": "Immunotherapy",
"keywords": "IBI308; anti-PD-1 antibody; hepatitis; hepatocellular carcinoma; immune checkpoint inhibitors; immunotherapy; sintilimab; sorafenib",
"medline_ta": "Immunotherapy",
"mesh_terms": null,
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "1387-1393",
"pmc": null,
"pmid": "34665016",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sintilimab plus sorafenib: a novel regimen for hepatocellular carcinoma.",
"title_normalized": "sintilimab plus sorafenib a novel regimen for hepatocellular carcinoma"
} | [
{
"companynumb": "CN-BAYER-2021A260759",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": "1",
"drugadministrationroute": "048",
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"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "Film-coated tablet",
"drugdosagetext": "400 MG, BID",
"drugenddate": "2020",
"drugenddateformat": "602",
"drugindication": "Hepatocellular carcinoma",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": "202001",
"drugstartdateformat": "610",
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"drugstructuredosageunit": "003",
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"medicinalproduct": "SORAFENIB"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SINTILIMAB"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "200 MG, Q2WK",
"drugenddate": "2020",
"drugenddateformat": "602",
"drugindication": "Hepatocellular carcinoma",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "2",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "202001",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "200",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SINTILIMAB"
}
],
"patientagegroup": "5",
"patientonsetage": "62",
"patientonsetageunit": "801",
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Immune-mediated hepatitis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20200101"
}
},
"primarysource": {
"literaturereference": "Liu XH, Yong Y. Sintilimab plus sorafenib: A novel regimen for hepatocellular carcinoma. Immunotherapy. 2021;13:17:1387-1393",
"literaturereference_normalized": "sintilimab plus sorafenib a novel regimen for hepatocellular carcinoma",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20211208",
"receivedate": "20211208",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20160782,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 1,
"seriousnessother": 2,
"transmissiondate": "20220304"
}
] |
{
"abstract": "OBJECTIVE\nOverweight and obesity represent worldwide a rising health problem. In this context, dietary supplements and herbal preparations are often used as self-medication for weight loss. The aim of this study was to describe the safety profile of dietary supplements for weight control by analyzing spontaneous reports of suspected adverse reactions (ARs) received by the Italian Phytovigilance System, from July 2010 to October 2017.\n\n\nMETHODS\nThe suspected ARs were collected using an ad hoc reporting form, registered in a database at the National Institute of Health and evaluated by a multidisciplinary group of experts. The causality assessment was performed using the WHO-UMC system or the CIOMS/RUCAM score. In case of serious adverse reactions, a feedback is provided to the reporter by e-mail.\n\n\nRESULTS\nSixty-six spontaneous reports were collected. ARs involved cardiovascular system (26%), liver (14%), central nervous system (12%), skin (9%), gastrointestinal system (17%), thyroid (8%), kidney (4%), and other organs/systems (10%). In 64% of cases, the reaction was serious. Dechallenge was positive in 46 cases; three cases of positive rechallenge were reported. After the causality assessment, the association between the product intake and the adverse reaction was judged as possible in the majority of the cases (n = 43; 65%).\n\n\nCONCLUSIONS\nThe data collected confirmed the existence of safety concerns on herbal dietary supplements used for body weight control, mainly related to quality of products and their use as self-medication. In this scenario, spontaneous reports represent the only tools available to monitor safety of these products.",
"affiliations": "Department of Physiology and Pharmacology 'Vittorio Erspamer', Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.;Department of Physiology and Pharmacology 'Vittorio Erspamer', Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy. annabella.vitalone@uniroma1.it.;Centre for Drug Research and Evaluation, National Institute of Health, Viale Regina Elena 299, 00161, Rome, Italy.;Centre for Drug Research and Evaluation, National Institute of Health, Viale Regina Elena 299, 00161, Rome, Italy.",
"authors": "Mazzanti|Gabriela|G|;Vitalone|Annabella|A|http://orcid.org/0000-0002-2055-9755;Da Cas|Roberto|R|;Menniti-Ippolito|Francesca|F|",
"chemical_list": "D028321:Plant Preparations",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-019-02746-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "75(11)",
"journal": "European journal of clinical pharmacology",
"keywords": "Adverse reactions; Dietary supplements; Galenic preparations; Herbal supplements; Weight loss",
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D028321:Plant Preparations; D015431:Weight Loss; D055815:Young Adult",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "1599-1615",
"pmc": null,
"pmid": "31428816",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": "29318131",
"title": "Suspected adverse reactions associated with herbal products used for weight loss: spontaneous reports from the Italian Phytovigilance System.",
"title_normalized": "suspected adverse reactions associated with herbal products used for weight loss spontaneous reports from the italian phytovigilance system"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1026423",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PSEUDOEPHEDRINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "WEIGHT DECREASED",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PSEUDOEPHEDRINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugenddate": null,
"drugenddateformat": null,
"drugindication": "WEIGHT DECREASED",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"medicinalproduct": "BUPROPION."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": "1",
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"medicinalproduct": "METFORMIN"
},
{
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"activesubstance": {
"activesubstancename": "TIRATRICOL"
},
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"drugadministrationroute": null,
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"drugcharacterization": "1",
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"medicinalproduct": "TRIAC"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "075755",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FLUOXETINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLORAZEPATE DIPOTASSIUM"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "WEIGHT DECREASED",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CLORAZEPATE"
}
],
"patientagegroup": null,
"patientonsetage": "38",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Acute coronary syndrome",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "4"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MAZZANTI G? VITALONE A? DA CAS R? MENNITI-IPPOLITO F.. SUSPECTED ADVERSE REACTIONS ASSOCIATED WITH HERBAL PRODUCTS USED FOR WEIGHT LOSS: SPONTANEOUS REPORTS FROM THE ITALIAN PHYTOVIGILANCE SYSTEM. EUR.J.CLIN.PHARMACOL. 2019?75, NO. 11:1599-615",
"literaturereference_normalized": "suspected adverse reactions associated with herbal products used for weight loss spontaneous reports from the italian phytovigilance system",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20200316",
"receivedate": "20200316",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17545235,
"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": "20200409"
}
] |
{
"abstract": "BACKGROUND\nNeuroblastoma is a common abdominal malignancy in children. The chemoresistant and relapsed cases have poor prognosis. The genetic background and the mechanism of resistance remain unelucidated. Next-generation sequence (NGS) is becoming a popular tool to unravel the genetic background and to guide precision medicine in oncology studies as well as in clinical practice.\nHere we report a neuroblastoma case of a boy aged 2 years and 8 months when first diagnosed, with multiple metastatic sites found in both lungs. The metastatic tumors were resistant to chemotherapy and the patient suffered from severe bone marrow suppression. NGS of the whole exon revealed somatic mutations including 9666 single-nucleotide variants (SNVs) from 5148 genes, 55 copy number variations (CNVs), and 140 insertion-deletion variations. The high frequency of SNVs makes it distinguished case. However, no mutation of key tumor driver genes with functional significance was identified. No abnormality was found in nucleic acid synthesis enzymes. No amplification of c-Myc and n-Myc was found by fluorescence in situ hybridization (FISH). Both NGS and immunohistochemistry (IHC) analysis indicated that DNA mismatch repair (MMR) system was intact.\n\n\nMETHODS\nAfter initial diagnosis, the patient received combinational chemotherapy, which includes vindesine, an analogue of adriamycin suggested by NGS data, for 4 months. Radical section of the tumor together with the left kidney and the left adrenal gland was performed 5 months after diagnosis. Postsurgical chemotherapy protocols was similar with the previous.\n\n\nRESULTS\nThe patient died 2 years after initial diagnosis after 8 relapses following combinational chemotherapy.\n\n\nCONCLUSIONS\nThis case of neuroblastoma is with pronounced somatic mutations but unidentified driver gene and therapeutic target. Although NGS is a potentially powerful tool to guide precision medicine, at current stage, its application in the clinic certainly has its limits. The underlying mechanism of the substantially increased SNV number, as well as the malignant behaviors of the tumor, is yet to be revealed.",
"affiliations": "Departments of Central Laboratory, Pathology, Oncology and Radiology, The Children's Hospital of Zhejiang University School of Medicine Institute of Translational Medicine, Zhejiang University The Key Laboratory of Diagnosis and Treatment of Neonatal Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.",
"authors": "Yuan|Lin-Qing|LQ|;Wang|Jin-Hu|JH|;Zhu|Kun|K|;Yang|Min|M|;Gu|Wei-Zhong|WZ|;Lai|Can|C|;Li|Hao-Min|HM|;Shu|Qiang|Q|;Chen|Xi|X|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000008845",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29390274MD-D-17-0524510.1097/MD.0000000000008845088455700Research ArticleClinical Case ReportA highly malignant case of neuroblastoma with substantial increase of single-nucleotide variants and normal mismatch repair system A case reportYuan Lin-Qing MDaWang Jin-Hu MDaZhu Kun MDaYang Min MDaGu Wei-Zhong MDacLai Can MDaLi Hao-Min PhDbcShu Qiang MD, PhDcChen Xi MD, PhDac∗NA. a Departments of Central Laboratory, Pathology, Oncology and Radiology, The Children's Hospital of Zhejiang University School of Medicineb Institute of Translational Medicine, Zhejiang Universityc The Key Laboratory of Diagnosis and Treatment of Neonatal Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.∗ Correspondence: Xi Chen, The Children's Hospital of Zhejiang University School of Medicine, No. 3333 Binsheng Road, Hangzhou 310052, Zhejiang Province, China (e-mail: chchenxi@zju.edu.cn).12 2017 15 12 2017 96 50 e884526 8 2017 29 10 2017 2 11 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nRationale:\nNeuroblastoma is a common abdominal malignancy in children. The chemoresistant and relapsed cases have poor prognosis. The genetic background and the mechanism of resistance remain unelucidated. Next-generation sequence (NGS) is becoming a popular tool to unravel the genetic background and to guide precision medicine in oncology studies as well as in clinical practice.\n\nPatient concerns:\nHere we report a neuroblastoma case of a boy aged 2 years and 8 months when first diagnosed, with multiple metastatic sites found in both lungs. The metastatic tumors were resistant to chemotherapy and the patient suffered from severe bone marrow suppression. NGS of the whole exon revealed somatic mutations including 9666 single-nucleotide variants (SNVs) from 5148 genes, 55 copy number variations (CNVs), and 140 insertion–deletion variations. The high frequency of SNVs makes it distinguished case. However, no mutation of key tumor driver genes with functional significance was identified. No abnormality was found in nucleic acid synthesis enzymes. No amplification of c-Myc and n-Myc was found by fluorescence in situ hybridization (FISH). Both NGS and immunohistochemistry (IHC) analysis indicated that DNA mismatch repair (MMR) system was intact.\n\nInterventions:\nAfter initial diagnosis, the patient received combinational chemotherapy, which includes vindesine, an analogue of adriamycin suggested by NGS data, for 4 months. Radical section of the tumor together with the left kidney and the left adrenal gland was performed 5 months after diagnosis. Postsurgical chemotherapy protocols was similar with the previous.\n\nOutcomes:\nThe patient died 2 years after initial diagnosis after 8 relapses following combinational chemotherapy.\n\nLessons:\nThis case of neuroblastoma is with pronounced somatic mutations but unidentified driver gene and therapeutic target. Although NGS is a potentially powerful tool to guide precision medicine, at current stage, its application in the clinic certainly has its limits. The underlying mechanism of the substantially increased SNV number, as well as the malignant behaviors of the tumor, is yet to be revealed.\n\nKeywords\nDNA mismatch repairMycmultiple drug resistanceneuroblastomanext-generation sequencingprecision medicinesomatic mutationOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nNeuroblastoma is a common abdominal malignancy in children with relatively poor prognosis compared with other childhood tumors. Choice of treatment procedure is made according to the risk stratification based on clinical manifestations and the pathological type. In the international neuroblastoma staging system (INSS) commonly used in the clinic,[1] any primary tumor with dissemination to distant organs is defined as stage IV that requires chemotherapy before and after radical surgery. Common migration sites include the lymph nodes, bone marrow, bone, liver, and skin. Metastasis of neuroblastoma to the lung is rare, with a reported occurrence rate of 3% to 4%,[2] and diffused dissemination to the lung is extremely rare.\n\nThe histological manifestation of neuroblastoma is highly heterogeneous. Its mutational dynamics is to be investigated for the practice of precision medicine. Up to now, only a few studies using next-generation sequencing (NGS) to analyze the genetic background of neuroblastoma have been reported.[3–9] However, the paradigm of classical driver genes including MYC, RAS, and ALK has not been shifted, and not much progress has been made in discovery of applicable therapeutic targets.\n\nThe DNA mismatch repair (MMR) system is a mechanism for genome maintenance. The system is composed of proteins that can recognize and degrade one strand of DNA and use the complementary strand as a repair template to eliminate the mismatch.[10] The MMR system in human is composed of 6 proteins: hMSH2, hMSH3, hMSH6, hMLH1, hMLH3, and hPMS1. Defect of the MMR system substantially elevates spontaneous mutation rates. In pediatrics, constitutional MMR deficiency (CMMRD) syndrome is resulted from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have a high risk to develop a broad spectrum of malignancies, including high-grade glioma, acute myeloid leukemia, or rhabdomyosarcoma.[11] MMR deficiency was found first to contribute to colorectal cancer,[12] later in many other types of cancers, and this pathological condition has been named as Lynch syndrome that is replacing the definition of CMMRD.[13] In pediatric neuroblastoma, analysis of MMR proteins expression levels has been reported.[14] In cultured neuroblastoma cells, MMR deficiency contributes to the malignant behaviors such as colony formation.[15] In this case report, a highly malignant neuroblastoma with lung metastasis and multiple drug resistance (MDR) is reported. The genetics background was analyzed using NGS combined with traditional methods.\n\n2 Materials and methods\n2.1 Sample collection\nThis research was approved by the institutional ethical committee in 2014 and was done in accordance with the Helsinki Declaration of 1975. Signed informed consent forms were obtained from the patient's guardian. Tissue samples were taken after surgery. Neuroblastoma with poor differentiation was diagnosed by postsurgical pathological examinations. Whole blood with anticoagulant was also collected.\n\n2.2 Whole exome sequencing\nNGS was performed by Novogene, Beijing, China. Total DNA was extracted from the tissue and the blood. After building the DNA library, target exome sequences were captured by liquid-phase chips (Agilent) and were sequenced by NGS (Hiseq 2000; Illumina). Somatic SNV was analyzed by muTect (muTect-1.1.4.jar) and by COSMIC plus DBSNP online databases.\n\n2.3 Pathological analysis\nTissues were fixed in 4% paraformaldehyde, embedded in paraffin and cut into 4 μm sections, then subjected to hematoxylin and eosin (HE) staining. Immunohistochemistry (IHC) analysis was performed by primary antibodies against hMSH2 and hMLH1 (Protein Tech) and with a biotinylated peroxidase-conjugated streptavidin system (Bio-Genex Laboratories). IHC of SYN, CD56, vimentin, CD99, Wilms’ tumor 1 (WT1), epidermal growth factor receptor (EMA), and desmin (primary antibodies from Dako, Denmark) were also performed. All specimens were scanned by 3DHistech (Pannoramic, Hungary) with companion software.\n\n2.4 Fluorescence in situ hybridization (FISH)\nAmplification of Myc was detected by commercial kit (Vysis, Abbott) using fluorescent probe against the c-Myc and n-Myc genes in sectioned paraffin-embedded tissue. Based on the guidelines of European neuroblastoma quality assessment (ENQUA),[16] over 100 cells were counted. As the diagnostic criteria, samples with <5% cells with >4 probes bound to the chromosomes were considered negative.\n\n3 Case report\n3.1 Clinical data and treatment procedure\nThe patient was a boy aged 2 years and 8 months when first admitted to the hospital due to palpable left-side abdominal mass. Needle biopsy and pathological examinations diagnosed the patient as neuroblastoma with poor differentiation. No migration to the bone marrow was detected. Computed tomography (CT) revealed multiple migration loci in the lung and pleural fluid (Fig. 1A), but no migration to the liver or to the bone. The patient received chemotherapy for 4 months by combination of vindesine+ifosfamide+etoposide and vindesine+tsprubicine+carboplatin, topotecan, and gemcitabine were also used. Then radical section of the tumor together with the left kidney and the left adrenal gland was performed 5 months after diagnosis. Pathological examinations confirmed neuroblastoma with poor differentiation and massive necrosis. A later CT showed that after first session of chemotherapy, both the number and the size of the high-density loci in the lung were reduced (Fig. 1B). The patient received several postsurgical chemotherapy protocols similar with the previous. He was always developing severe bone marrow suppression upon chemotherapy with low white blood cell and platelet counts, and severe respiratory inflammation. Follow-up CT scans found no relapse of the original tumor in the adrenal gland, but multiple metastatic loci in both lungs, with new loci developed after surgery (Fig. 1C). No metastasis in other organs was detected. The patient died 22 months after diagnosis, 17 months after surgery. The timeline of the reported case from initial diagnosis to death is summarized in Table 1.\n\nFigure 1 CT scans of the metastatic tumors in the lung. (A) Image of a representative window at primary diagnosis. (B) Image of the same window after chemotherapy and surgery. (C) Image of the same window in the follow-up examinations after tumor relapses. Arrows indicate the loci of the metastatic tumors.\n\nTable 1 The timeline of the reported case from initial diagnosis to death.\n\n3.2 Pathology and FISH\nIn the tissue from needle biopsy of the mass from left kidney by HE staining (Fig. 2A), necrosis was commonly seen. Clusters of tumor cells with poor differentiation and with round nuclei could be observed; no anaplastic cells were observed; spindle-like fibers could be observed. The postsurgery specimen was the sectioned left kidney, left adrenal gland together with the tumor. The tumor was located above the kidney, with a size of 7 × 6.5 × 5 cm and massive necrotic area of 5.5 × 5 cm. The tumor had invaded the envelope of the kidney, but not into the renal pelvis and the ureter. Blood congestion, edema, and partial hyaloid degeneration were observed in the fat and fibrous tissues surrounding the tumor mass. Postsurgical pathological examinations revealed similar cellular morphology with significant necrosis and poor differentiation (Fig. 2A).\n\nFigure 2 Expression of Myc gene and MMR proteins in the tumor tissues. (A) HE staining of tumor tissues obtained by needle biopsy and by surgery (200×). (B) IHC of CD56 and Syn, and FISH analysis of c-Myc and n-Myc of tumor tissue sectioned after chemotherapy (400×). (C) IHC of hMLH1 and hMSH2 in this case and a control neuroblastoma case without identified MMR mutation (200×).\n\nIHC showed positive staining for SYN, CD56, vimentin, with Ki-67 >30%, and negative staining for CD99, WT1, EMA, and desmin. FISH showed negative for both c-Myc and n-Myc amplification (Fig. 2B).\n\nIHC revealed positive staining of MMR markers, hMSH2 and hMLH1, in the nucleus region in normal kidney in this case. This was the same result as obtained from tissues of another neuroblastoma case without identified mutation (Fig. 2C), as well as other control tissues (data not shown). No significant decrease in hMSH2 and hMLH1 levels was found in this case.\n\n3.3 Somatic mutations revealed by NGS\nA total of 9666 somatic SNVs from 5148 genes were detected. The number of somatic SNV detected in different regions of the genes is shown in Table 2. Among the 3111 mutations in the exon-coding CDS region, 1469 mutations of missense, stoploss, and stopgain mutations that would cause change of amino acid sequences or the length of proteins. A total of 1171 genes were affected, and 1008 (85.9%) were mapped to 1386 distinct proteins in ConsensusPathDB. In pathway analysis, a total of 608 genes (53.4%) were present in at least one of 19 pathways identified. The 19 pathways enriched in mutated genes/proteins are listed in Table 3. NGS also revelaed 55 copy number variations (CNVs) and 140 insertion–deletion variations (INDELs) in this case.\n\nTable 2 The number of somatic SNV detected in different regions of the genome.\n\nTable 3 The pathways enriched in mutated genes/proteins analyzed by ConsensusPathDB.\n\nTable 4 contains the druggable gene targets predicted by detected mutations. Potentially effective drugs in targeted therapy were anti-EGFR antibodies, and anthracyclines/related substances such as adriamycin. It was also suggested that the tumor cells could be sensitive to HMG-CoA and ACEI, which are nonrelevant to tumor chemotherapy.\n\nTable 4 Therapeutic targets predicted by analysis of mutated genes.\n\nMutation of MSH2 is shown in Table 5. A heterozygous mutation C23T from exon 1 of this gene was identified, leading to a mutation of T8 M in the protein level. The mutation rate was 6.3% (2/48) in this sample.\n\nTable 5 Characteristics of MSH2 mutations identified.\n\n4 Discussion\nHere we report a case of highly malignant neuroblastoma with diffused metastatic loci in the lung. Pathological examination revealed typical undifferentiated neuroblastoma cells. MDR of the metastatic tumors, as well as bone marrow suppression after chemotherapy, has made it an obstinate case in pediatric oncology. To study the genetic background of the tumor and to search for drug targets, NGS was performed to analyze the somatic mutations in the exon region. A substantially increased number of somatic mutations, especially SNVs, were identified. However, the underlying mechanism of the malignacy remained undefined. It is known that severe neuroblastoma cases are frequently associated with amplication of the Myc gene. Other driver genes including p53 and ALK are also frequently involved. However, in this case, even with a powerful tool of NGS, no SNV, INDEL, or CNV mutations of the above key driver genes have been found. On the other hand, a total of 9666 somatic SNVs from 5148 genes were detected, and pathway analysis implies that many cellular functions could be impaired, such as cellular matrix and immune response. The relationship between the many somatic SNVs and the dysregulation of cellular pathways remains unclear.\n\nDefects in the DNA repair system can cause genome instability and increased mutation rate. One important mechanism is the MMR system. Germ-line mutations of MMR-related genes lead to the Lynch syndrome, previously called HNPCC. However, in this case, the genes of all MMR components do not carry mutations except for MSH2 that carried a heterozygous missense SNV mutation. Based on a recent study of functional screening to identify pathogenic MSH2 mutation, the T8 M mutation was proved to be nonpathogenic.[17] Further IHC analysis did not produce evidence of MMR deficiency in the protein level.\n\nAlthough NGS can be a powerful tool to guide personalized precision treatment, at current stage, even without consideration of the relatively high cost, its application in the clinic still has its limits. First, the procedure to obtain representative tumor tissue has intrinsic difficulty because tumors are highly heterogeneous. Sites like lung metastatic loci are not readily accessible for biopsy. In this case, some lung migration sites were responsive to treatment, whereas others manifested different response. Theoretically, it would be informative to compare the genetics of different loci, but is difficult to practice. Second, the number of druggable target molecules is limited. In this case, drug target analysis based on NGS data suggested that the tumor might be sensitive to anti-EGFR antibodies and adriamycin. Although anti-EGFR antibodies are potentially effective, they are not readily available in the clinic of pediatric oncology in China and in many developing countries. Furthermore, there are many potential targets without effective compounds. It is somewhat perplexing that in our clinical protocol, vindesine, an analogue of adriamycin predicted as an effective treatment option, did not result in improved clinical outcome, suggesting the current data interpretation tools could be inadequate. The last but not the least, our knowledge toward the genetics background of neuroblastoma is still very limited. The case reported is an example of pronounced somatic mutations but without identified driver gene and therapeutic target. Deeper understanding of the oncogenetics, as well as optimization of analytical tools, must be achieved before NGS data can provide more diagnostic and therapeutic insight in the clinic.\n\nAcknowledgments\nThe authors thank professor Jian Chen from Institute of Translational Medicine, Zhejiang University, for his help with the analysis of DNA MMR.\n\nAbbreviations: ACEI = angiotension-converting enzyme inhibitors, ALK = anaplastic lymphoma kinase, CDS = coding sequence, CMMRD = constitutional DNA mismatch repair deficiency, CNV = copy number variation, CT = computed tomography, EGFR = epidermal growth factor receptor, EMA = epithelial membrane antigen, ENQUA = European neuroblastoma quality assessment, FISH = fluorescence in situ hybridization, HE = hematoxylin and eosin, hMLH = human MutL homologs, hMSH = human MutS homologs, IHC = immunohistochemistry, INDEL = insertion–deletion variation, INSS = neuroblastoma staging system, MDR = multiple drug resistance, MMR = DNA mismatch repair, ncRNA = noncoding RNA, NGS = next generation sequencing, SNP = single-nucleotide polymorphism, SNV = single-nucleotide variant, SYN = synapsin, TSS = transcription start site, TTS = transcription termination site, UTR = untranslated region, WT1 = Wilms’ tumor 1.\n\nL-QY and J-HW contributed equally to this study.\n\nAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript.\n\nThis research is supported by National Science Foundation of Zhejiang Province, China (LY15H160024) and National Science Foundation of China (No. 81202021).\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Brodeur GM Pritchard J Berthold F \nRevisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment . J Clin Oncol \n1993 ;11 :1466 –77 .8336186 \n[2] Dubois SG London WB Zhang Y \nLung metastases in neuroblastoma at initial diagnosis: a report from the International Neuroblastoma Risk Group (INRG) project . Pediatr Blood Cancer \n2008 ;51 :589 –92 .18649370 \n[3] Theruvath J Russo A Kron B \nNext-generation sequencing reveals germline mutations in an infant with synchronous occurrence of nephro- and neuroblastoma . Pediatr Hematol Oncol \n2016 ;33 :264 –75 .27285993 \n[4] Sanmartin E Munoz L Piqueras M \nDeletion of 11q in Neuroblastomas Drives Sensitivity to PARP Inhibition . Clin Cancer Res \n2017 ;23 :1 –3 .\n[5] Lasorsa VA Formicola D Pignataro P \nExome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression . Oncotarget \n2016 ;7 :21840 –52 .27009842 \n[6] Pugh TJ Morozova O Attiyeh EF \nThe genetic landscape of high-risk neuroblastoma . Nat Genet \n2013 ;45 :279 –84 .23334666 \n[7] Eleveld TF Oldridge DA Bernard V \nRelapsed neuroblastomas show frequent RAS-MAPK pathway mutations . Nat Genet \n2015 ;47 :864 –71 .26121087 \n[8] Lee YH Kim JH Song GG \nGenome-wide pathway analysis in neuroblastoma . Tumour Biol \n2014 ;35 :3471 –85 .24293394 \n[9] Schramm A Koster J Assenov Y \nMutational dynamics between primary and relapse neuroblastomas . Nat Genet \n2015 ;47 :872 –7 .26121086 \n[10] Fishel R \nMismatch repair . J Biol Chem \n2015 ;290 :26395 –403 .26354434 \n[11] Wimmer K Rosenbaum T Messiaen L \nConnections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1 . Clin Genet \n2016 ;91 :507 –19 .\n[12] Kolodner RD Hall NR Lipford J \nHuman mismatch repair genes and their association with hereditary non-polyposis colon cancer . Cold Spring Harb Symp Quant Biol \n1994 ;59 :331 –8 .7587085 \n[13] Ponti G Castellsague E Ruini C \nMismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome . Clin Genet \n2015 ;87 :507 –16 .25345868 \n[14] Idikio HA \nExpression of DNA mismatch repair proteins hMSH2 and hMLH1 and the cyclin G1 inhibitor, p21 (waf1/cip1) in pediatric tumors: correlation with response to therapy . Oncol Rep \n2001 ;8 :965 –71 .11496300 \n[15] Collins SL Herve R Keevil CW \nDown-regulation of DNA mismatch repair enhances initiation and growth of neuroblastoma and brain tumour multicellular spheroids . PLoS One \n2011 ;6 :e28123 .22145025 \n[16] Ambros IM Benard J Boavida M \nQuality assessment of genetic markers used for therapy stratification . J Clin Oncol \n2003 ;21 :2077 –84 .12775732 \n[17] Houlleberghs H Dekker M Lantermans H \nOligonucleotide-directed mutagenesis screen to identify pathogenic Lynch syndrome-associated MSH2 DNA mismatch repair gene variants . Proc Natl Acad Sci USA \n2016 ;113 :4128 –33 .26951660\n\n",
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"mesh_terms": "D000005:Abdomen; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D053843:DNA Mismatch Repair; D017809:Fatal Outcome; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009154:Mutation; D009447:Neuroblastoma; D020641:Polymorphism, Single Nucleotide",
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"title": "A highly malignant case of neuroblastoma with substantial increase of single-nucleotide variants and normal mismatch repair system: A case report.",
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"abstract": "COVID-19 is a novel infectious disease caused by SARS-CoV-2 that emerged in late 2019 and which is now a pandemic. Solid organ transplant recipients are perceived to be at increased risk of severe COVID-19 due to their chronic use of immunosuppressive drugs (ISDs) and to their associated conditions. Scarce data are available on the optimized management of ISDs in these patients and on its impact on presentation, clinical course, viral shedding, and outcome. We report here two cases of COVID-19 in a cohabiting couple of lung transplant recipients for cystic fibrosis, who had different ISDs management and who developed discordant courses of their disease. Our findings suggest that the degree of their immunosuppression might be a reason for their different course and that ISDs might prove partially protective.",
"affiliations": "Service de Pneumologie, Équipe de Transplantation Pulmonaire, Hôpital Nord, Assistance Publique Hôpitaux de Marseille (APHM), Marseille, France.;Service de Pneumologie, Équipe de Transplantation Pulmonaire, Hôpital Nord, Assistance Publique Hôpitaux de Marseille (APHM), Marseille, France.;Service de Pneumologie, Équipe de Transplantation Pulmonaire, Hôpital Nord, Assistance Publique Hôpitaux de Marseille (APHM), Marseille, France.;Clinique des Bronches, Allergie et Sommeil/APHM, Marseille C2VN Center INSERM INRAE UMR1062, Aix-Marseille Université, Marseille, France.;Service de Radiologie, Hôpital Nord, APHM, Marseille, France.;Service de Pneumologie, Équipe de Transplantation Pulmonaire, Hôpital Nord, Assistance Publique Hôpitaux de Marseille (APHM), Marseille, France.;Clinique des Bronches, Allergie et Sommeil/APHM, Marseille C2VN Center INSERM INRAE UMR1062, Aix-Marseille Université, Marseille, France.;Microbes, Evolution, Phylogeny and Infection (MEΦI), Aix-Marseille Université UM63, Institut de Recherche pour le Développement IRD 198, Assistance Publique - Hôpitaux de Marseille (AP-HM), Marseille, France.",
"authors": "Desmazes-Dufeu|Nadine|N|;Coltey|Bérengère|B|;Amari|Lyria|L|;Gouitaa|Marion|M|;Touzery|Camille|C|;Reynaud-Gaubert|Martine|M|;Chanez|Pascal|P|;Cassir|Nadim|N|https://orcid.org/0000-0002-5276-6986",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13410",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "COVID-19; SARS-CoV-2; cystic fibrosis; immunosuppression; lung transplant; viral pneumonia",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D005260:Female; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D000086402:SARS-CoV-2; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13410",
"pmc": null,
"pmid": "32654244",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Discordant courses of COVID-19 in a cohabiting couple of lung transplant recipients.",
"title_normalized": "discordant courses of covid 19 in a cohabiting couple of lung transplant recipients"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1058053",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
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"drugdosagetext": "UNK",
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"drugindication": "HYPERTENSION",
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"medicinalproduct": "AMLODIPINE"
},
{
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"activesubstance": {
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},
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"drugdosagetext": "7 MG, BID, TROUGH OF 10 ?G/ML",
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"drugindication": "IMMUNOSUPPRESSION",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "ENVARSUS XR"
},
{
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"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
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"drugdosagetext": "500 MG, BID, TARGET DOSAGE OF 2.4 ?G/ML",
"drugenddate": null,
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"drugindication": "IMMUNOSUPPRESSION",
"drugintervaldosagedefinition": "804",
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"drugtreatmentduration": null,
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "6 MG, QD",
"drugenddate": null,
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"drugindication": "IMMUNOSUPPRESSION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "6",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": null,
"patientonsetage": "34",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "COVID-19",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DESMAZES?DUFEU N, CASSI N,COLTEY B, AMARI L, GOUITAA M, TOUZERYC,REYNAUD?GAUBERT M ET AL.. DISCORDANT COURSES OF COVID?19 IN A COHABITING COUPLE OF LUNG TRANSPLANT RECIPIENTS.. TRANSPL INFECT DIS. 2020",
"literaturereference_normalized": "discordant courses of covid 19 in a cohabiting couple of lung transplant recipients",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20210907",
"receivedate": "20210907",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19799436,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20211014"
}
] |
{
"abstract": "Young patients with Crohn's disease (CD) show a high prevalence of human papillomavirus (HPV) which is the main cause of high-grade squamous intraepithelial lesions (HSIL). A major complication for patients undergoing immunocompromising therapy is the development of genital dysplasia.\nWe report the case of a 32-year-old patient with recurrent genital dysplasia under long-term therapy for CD with a focus on different drug-related, immunosuppressive mechanisms.\nGynecological examination and biopsy revealed high-grade vulvar intraepithelial neoplasia (VIN) positive for HPV 16 treated with laser vaporization. Due to the combination of HPV positivity, intraoperative multilocularity, and CD, follow-up examinations were performed every 6 months. One year later, the patient showed a VIN at a new location and additionally, a cervical intraepithelial neoplasia (CIN), which were surgically treated. Catch-up HPV vaccination was applied accessorily. After the switch from a TNF-α blocker to vedolizumab, which acts as a gut-selective anti-integrin, the subsequent PAP smear, vulvoscopy, and colposcopy showed no more evidence of dysplasia.\nThis case report highlights that gut-selective immunosuppression with vedolizumab might be favorable in young HPV-positive patients due to a good side effect profile. Regular screening and HPV vaccination are a mainstay of dysplasia prevention and control. The risk for HPV-associated dysplasia in immunosuppressed patients is highly dependent on the choice of immunosuppressive therapy.",
"affiliations": "Department of Gynecology, University Hospital of Zurich, Zurich, Switzerland.;Gastroenterology, Clinic Bethanien, Zurich, Switzerland.;Department of Immunology, University Hospital of Zurich, Zurich, Switzerland.;Department of Gynecology, University Hospital of Zurich, Zurich, Switzerland.;Department of Gynecology, University Hospital of Zurich, Zurich, Switzerland.",
"authors": "Sager|Raphael|R|;Frei|Pascal|P|;Steiner|Urs C|UC|;Fink|Daniel|D|;Betschart|Cornelia|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000502687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2296-9365",
"issue": "4(4)",
"journal": "Inflammatory intestinal diseases",
"keywords": "Crohn's disease; Genital dysplasia; Human papillomavirus; TNF-α blockers",
"medline_ta": "Inflamm Intest Dis",
"mesh_terms": null,
"nlm_unique_id": "101677990",
"other_id": null,
"pages": "154-160",
"pmc": null,
"pmid": "31768388",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "24015171;24752130;29427801;18285688;21697699;23002356;22454089;22126830;19828998;16035255;21875498;26569049;9217656;17036389;28263774;29074187;17315185;18847553;21817920;26294789;25220731;27567553;29126556;26366475;29668916;26028344;29250803;25476713;29551740;29094101;23202792;29029098;25687629;19381021;22431528;8497340",
"title": "Genital Dysplasia and Immunosuppression: Why Organ-Specific Therapy Is Important.",
"title_normalized": "genital dysplasia and immunosuppression why organ specific therapy is important"
} | [
{
"companynumb": "CH-JNJFOC-20191131858",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "058",
"drugauthorizationnumb": "125289",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INJECTION IN PRE-FILLED PEN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CROHN^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "SIMPONI"
}
],
"patientagegroup": null,
"patientonsetage": "32",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cervical dysplasia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Human papilloma virus test positive",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vulval cancer stage 0",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SAGER R, FREI P, STEINER U, FINK D, BETSCHART C. GENITAL DYSPLASIA AND IMMUNOSUPPRESSION: WHY ORGAN-SPECIFIC THERAPY IS IMPORTANT. INFLAMMATORY INTESTINAL DISEASES. 2019 OCT 01?4(4):154-160.",
"literaturereference_normalized": "genital dysplasia and immunosuppression why organ specific therapy is important",
"qualification": "3",
"reportercountry": "CH"
},
"primarysourcecountry": "CH",
"receiptdate": "20191202",
"receivedate": "20191202",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17101948,
"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": "Although relapse of acute leukemia is common, a change of immunophenotype at relapse only occurs rarely. Some of these cases have been labeled \"lineage switch\". In most cases, B-cell lymphoblastic leukemia/lymphoma (B-ALL) relapses as acute myeloid leukemia (AML). We report a rare case of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) relapsing as AML and then returning as T-ALL again in a patient who began her therapy during the third trimester of pregnancy. The patient retained the same cytogenetic and next generation molecular findings in both leukemias. This case provides further evidence of the plasticity of the leukemic stem cell.",
"affiliations": "Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY, USA.;Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY, USA.;Department of Pathology, New York Medical College and Westchester Medical Center, Valhalla, NY, USA.;Department of Pathology, New York Medical College and Westchester Medical Center, Valhalla, NY, USA.;Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY, USA.;Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY, USA.",
"authors": "Aujla|Amandeep|A|;Hanmantgad|Madhura|M|;Islam|Humayun|H|;Shakil|Fouzia|F|;Liu|Delong|D|;Seiter|Karen|K|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/sci.2019.05.02",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2306-9759",
"issue": "6()",
"journal": "Stem cell investigation",
"keywords": "Acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); lineage switch; pregnancy; stem cell plasticity",
"medline_ta": "Stem Cell Investig",
"mesh_terms": null,
"nlm_unique_id": "101672113",
"other_id": null,
"pages": "12",
"pmc": null,
"pmid": "31231669",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10340398;21655072;22685031;22852088;24323992;25891003;27149388;27268298;27460500;28634616;29016570;29164065;29797659;29853461;29898879",
"title": "Lineage switch from T-cell lymphoblastic leukemia/lymphoma to acute myeloid leukemia and back to T-cell lymphoblastic leukemia/lymphoma in a patient diagnosed during pregnancy.",
"title_normalized": "lineage switch from t cell lymphoblastic leukemia lymphoma to acute myeloid leukemia and back to t cell lymphoblastic leukemia lymphoma in a patient diagnosed during pregnancy"
} | [
{
"companynumb": "US-TEVA-2019-US-1084903",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "75493",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "ON DAYS 1, 8, 15, AND 22",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "T-CELL TYPE ACUTE LEUKAEMIA",
"drugintervaldosagedefinition": null,
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"drugstructuredosageunit": "003",
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"medicinalproduct": "VINCRISTINE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "16793",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "100MG/5ML SDV AND 500MG/10ML SDV; 3G/M 2 OVER THREE HOURS ONCE DAILY ON DAYS 1?5,",
"drugenddate": null,
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"drugindication": "T-CELL TYPE ACUTE LEUKAEMIA",
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"medicinalproduct": "CYTARABINE HYDROCHLORIDE"
},
{
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},
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"medicinalproduct": "FLUDARABINE PHOSPHATE."
},
{
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},
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"medicinalproduct": "CLOFARABINE."
},
{
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},
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"drugenddate": null,
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"drugindication": "T-CELL TYPE ACUTE LEUKAEMIA",
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"medicinalproduct": "CYTARABINE HYDROCHLORIDE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "085600",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "T-CELL TYPE ACUTE LEUKAEMIA",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPREDNISOLONE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "81099",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "HIGH DOSE (1G/M2)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "T-CELL TYPE ACUTE LEUKAEMIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHOTREXATE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MITOXANTRONE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "77356",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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] |
{
"abstract": "Acute gastrointestinal (GI) immune-related adverse events (irAE) are commonly reported by patients with cancer undergoing treatment with immune checkpoint inhibitors (CPI); however chronic irAEs are rare. We present a case of a 71-year-old woman with metastatic gastro-oesophageal junction (GOJ) adenocarcinoma who developed delayed-onset chronic intestinal pseudo-obstruction (CIPO) while receiving second-line pembrolizumab. Repeated CT scans of the abdomen/pelvis found no small bowel obstruction, and evaluations for bowel inflammation, infection and paraneoplastic syndrome were negative. Bowel rest and glucocorticoids were associated with transient symptom resolution; however, symptoms recurred within 1 month. The patient was ultimately supported with total parenteral nutrition and intestinal motility agents. After 4 months, the GOJ cancer remained stable with no signs of progression. As CPI use expands, the incidence of rare irAEs, such as CIPO, may increase.",
"affiliations": "Internal Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.;Radiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.;Internal Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.;Internal Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA abullock@bidmc.harvard.edu.",
"authors": "Besaw|Robert J|RJ|;Smith|Martin P|MP|;Zerillo|Jessica A|JA|;Bullock|Andrea J|AJ|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232388",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(12)",
"journal": "BMJ case reports",
"keywords": "gastric cancer; immunology; stomach and duodenum; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D004938:Esophageal Neoplasms; D004943:Esophagogastric Junction; D005260:Female; D006801:Humans; D007418:Intestinal Pseudo-Obstruction; D008207:Lymphatic Metastasis; D014463:Ultrasonography",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31843780",
"pubdate": "2019-12-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Chronic intestinal pseudo-obstruction in a patient with metastatic gastro-oesophageal junction cancer receiving treatment with pembrolizumab.",
"title_normalized": "chronic intestinal pseudo obstruction in a patient with metastatic gastro oesophageal junction cancer receiving treatment with pembrolizumab"
} | [
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],
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"primarysource": {
"literaturereference": "BESAW R.J, SMITH M.P, ZERILLO J.A, BULLOCK A.J. CHRONIC INTESTINAL PSEUDO-OBSTRUCTION IN A PATIENT WITH METASTATIC GASTRO-OESOPHAGEAL JUNCTION CANCER RECEIVING TREATMENT WITH PEMBROLIZUMAB. BMJ CASE REPORTS. 2019?12(12):E232388",
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"transmissiondate": "20200409"
}
] |
{
"abstract": "Corynebacterium striatum, generally considered an opportunistic organism in humans, has recently been known to develop high-level daptomycin resistance (HLDR) shortly after drug exposure. To date, however, only several such clinical isolates have been described in the literature and clinical background of the resistant pathogen remains to be elucidated. Here, we report a case involving a C. striatum strain with HLDR harboring novel nucleotide mutations, together with a review of the relevant literature. To the best of our knowledge, this is the first well-investigated clinical report from Japan including a genetic investigation. Considering the rapid emergence of HLDR C. striatum in vitro experiment, there could be a number of underreporting cases. Scrupulous attention is required when administering daptomycin for the treatment of C. striatum infections, even if the organism has initially exhibited susceptibility.",
"affiliations": "Division of Infection Control and Prevention, Osaka University Hospital, Japan. Electronic address: highgear@hp-infect.med.osaka-u.ac.jp.;Laboratory for Clinical Investigation, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.;Laboratory for Clinical Investigation, Osaka University Hospital, Japan.;Laboratory for Clinical Investigation, Osaka University Hospital, Japan.;Division of Infection Control and Prevention, Osaka University Hospital, Japan.",
"authors": "Hagiya|Hideharu|H|;Kimura|Keigo|K|;Okuno|Hideo|H|;Hamaguchi|Shigeto|S|;Morii|Daiichi|D|;Yoshida|Hisao|H|;Mitsui|Tomomi|T|;Nishi|Isao|I|;Tomono|Kazunori|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017576:Daptomycin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2019.04.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "25(11)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Antimicrobial resistance; Corynebacterium; Daptomycin",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D003352:Corynebacterium; D003354:Corynebacterium Infections; D017576:Daptomycin; D024881:Drug Resistance, Bacterial; D006801:Humans; D007564:Japan; D008297:Male",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "906-908",
"pmc": null,
"pmid": "31101531",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bacteremia due to high-level daptomycin-resistant Corynebacterium striatum: A case report with genetic investigation.",
"title_normalized": "bacteremia due to high level daptomycin resistant corynebacterium striatum a case report with genetic investigation"
} | [
{
"companynumb": "JP-009507513-1905JPN009812",
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{
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},
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"medicinalproduct": "GANCICLOVIR."
},
{
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{
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"medicinalproduct": "MEROPENEM."
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{
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"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
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"medicinalproduct": "DAPTOMYCIN."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MICAFUNGIN SODIUM"
},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MICAFUNGIN."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
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"drugadministrationroute": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "HIGH DOSE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPREDNISOLONE."
}
],
"patientagegroup": null,
"patientonsetage": "68",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pathogen resistance",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Corynebacterium bacteraemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HAGIYA H, KIMURA K, OKUNO H, HAMAGUCHI S, MORII D, YOSHIDA H, ET AL.. BACTEREMIA DUE TO HIGH-LEVEL DAPTOMYCIN-RESISTANT CORYNEBACTERIUM STRIATUM: A CASE REPORT WITH GENETIC INVESTIGATION. JOURNAL OF INFECTION AND CHEMOTHERAPY. 2019",
"literaturereference_normalized": "bacteremia due to high level daptomycin resistant corynebacterium striatum a case report with genetic investigation",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190524",
"receivedate": "20190524",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16352286,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "There is limited data on the use of caplacizumab beyond the initial treatment course. We describe a patient case demonstrating the efficacy of a second course of caplacizumab in a patient with relapsed acquired thrombotic thrombocytopenic purpura (TTP). A 25-year-old female was treated for an initial event of TTP with steroids, plasma exchange, rituximab, and caplacizumab. Caplacizumab was continued 30 days post plasma exchange, which was on day 46 of treatment, at which time platelets had improved to 292 x 109/L. Two weeks after completion of the first caplacizumab course, on day 60, she was readmitted with platelets of 5 x 109/L. Daily plasma exchange and steroids were started on admission, with rituximab added on day 65. On day 67, the decision was made to re-initiate caplacizumab due to a platelet count of 21 x 109/L. By day 72, platelets improved to 273 x 109/L and the patient was able to be discharged and completed her second 30-day post plasma exchange course of caplacizumab without complications or further relapses.",
"affiliations": "Department of Pharmacy, AdventHealth Orlando, Orlando, FL, USA.;Department of Pharmacy, AdventHealth Orlando, Orlando, FL, USA.",
"authors": "Shaffer|Jon|J|;Grove|Angela|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/09537104.2021.1981851",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-7104",
"issue": null,
"journal": "Platelets",
"keywords": "Caplacizumab; thrombotic thrombocytopenic purpura",
"medline_ta": "Platelets",
"mesh_terms": null,
"nlm_unique_id": "9208117",
"other_id": null,
"pages": "1-2",
"pmc": null,
"pmid": "34565299",
"pubdate": "2021-09-26",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Successful use of a second course of caplacizumab in relapsed thrombotic thrombocytopenic purpura.",
"title_normalized": "successful use of a second course of caplacizumab in relapsed thrombotic thrombocytopenic purpura"
} | [
{
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugadministrationroute": "041",
"drugauthorizationnumb": "103705",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "Infusion, Solution",
"drugdosagetext": null,
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"drugindication": "Thrombotic thrombocytopenic purpura",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
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"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"drugstructuredosageunit": "009",
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"medicinalproduct": "RITUXIMAB"
},
{
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN,UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10 MG/KG/DAY FOR 3 DAYS FOLLOWED BY 1 MG/KG/DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Thrombotic thrombocytopenic purpura",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"medicinalproduct": "METHYLPREDNISOLONE"
},
{
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},
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{
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "COVID-19",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Shaffer J, Grove A. Successful use of a second course of caplacizumab in relapsed thrombotic thrombocytopenic purpura.. Platelets 2021;:1-2.",
"literaturereference_normalized": "successful use of a second course of caplacizumab in relapsed thrombotic thrombocytopenic purpura",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20220110",
"receivedate": "20220110",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 20314856,
"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-AMGEN-USASP2021153523",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcumulativedosagenumb": null,
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"drugdosagetext": "375 MILLIGRAM/SQ. METER, QWK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Thrombotic thrombocytopenic purpura",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "1",
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"drugrecurrence": null,
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"drugstartdateformat": null,
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"drugstructuredosageunit": "009",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "RITUXIMAB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN FORMULATION",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Off label use",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "RITUXIMAB"
}
],
"patientagegroup": "5",
"patientonsetage": "25",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Thrombotic thrombocytopenic purpura",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "SARS-CoV-2 test positive",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cerebrovascular accident",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective for unapproved indication",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Shaffer J.; Grove A.. Successful use of a second course of caplacizumab in relapsed thrombotic thrombocytopenic purpura. Platelets. 2021;1-2",
"literaturereference_normalized": "successful use of a second course of caplacizumab in relapsed thrombotic thrombocytopenic purpura",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20211012",
"receivedate": "20211012",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19939581,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Burn patients have numerous risk factors for multidrug resistant organisms (MDROs) and altered pharmacokinetics, which both independently increase the risk of treatment failure. Data on appropriate antimicrobial dosing are limited in this population and therapeutic drug monitoring (TDM) for beta-lactams is impractical at most facilities. 1-3 Technology is available that can detect genetic markers of resistance, but they are not all encompassing, and often require specialized facilities that can detect less common genetic markers. 4-5 Newer antimicrobials can help combat MDROs, but additional resistance patterns may evolve during treatment. Considering drug shortages and antimicrobial formularies, clinicians must remain vigilant when treating infections. This case report describes the development of resistance to ceftazidime-avibactam in a burn patient. The patient was a 54- year-old burn victim with a 58% total body surface area (TBSA) thermal burn who underwent multiple courses of antibiotics for various Pseudomonal infections. The initial Pseudomonal wound infection was sensitive to cefepime, aminoglycosides, and meropenem. A subsequent resistant pseudomonal pneumonia was treated with ceftazidime-avibactam 2.5 grams every 6 hours due to the elevated MIC to cefepime (16mcg/mL) and meropenem (>8mcg/mL). Although, the patient improved over 7 days, the patient again spiked fevers and had increased white blood counts (WBC). Repeat blood cultures demonstrated a multidrug resistant (MDR) Pseudomonas with a minimum inhibitory concentration (MIC) to ceftazidime-avibactam of 16mcg/mL, which is above the Clinical and Laboratory Standards Institute (CLSI) breakpoint of 8mcg/mL. At first, resistance was thought to have occurred due to inadequate dosing, but genetic work demonstrated multiple genes encoding beta-lactamases.",
"affiliations": "Detroit Receiving Hospital, Detroit MI.;University of Mississippi School of Pharmacy, Jackson MS.;Assistant Professor of Surgery, Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Detroit MI.;Assistant Professor of Surgery, Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Detroit MI.;Assistant Professor of Surgery, Michael and Marian Ilitch Department of Surgery, Wayne State University School of Medicine, Detroit MI.;Associate Professor of Surgery, Director of the Hyperbaric and Wound Care Center, Staff Surgeon, Wayne State University School of Medicine/Detroit Medical Center Affiliated Hospitals, Detroit Mi.;Chief of Surgery, Detroit Receiving Hospital, Professor of Surgery, Wayne State University School of Medicine, Detroit MI.;Medical Director of Burn Center, Detroit Receiving Hospital, Detroit MI, Assistant Professor of Surgery, Wayne State University School of Medicine, Detroit MI.;Detroit Receiving Hospital, Detroit MI.",
"authors": "Herbin|Shelbye R|SR|;Barber|Katie E|KE|;Isaacson|Andrew R|AR|;Dolman|Heather S|HS|;McGee|Jessica D|JD|;Baylor|Alfred E|AE|;Tyburski|James G|JG|;White|Michael T|MT|;Faris|Janie|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jbcr/irab160",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1559-047X",
"issue": null,
"journal": "Journal of burn care & research : official publication of the American Burn Association",
"keywords": "antibiotics; burn; ceftazidime-avibactam; pharmacokinetics; resistance",
"medline_ta": "J Burn Care Res",
"mesh_terms": null,
"nlm_unique_id": "101262774",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34427655",
"pubdate": "2021-08-24",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "When More is Still Not Enough: A Case of Ceftazidime-Avibactam Resistance in a Burn Patient.",
"title_normalized": "when more is still not enough a case of ceftazidime avibactam resistance in a burn patient"
} | [
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{
"abstract": "The aim of this work was to to evaluate the incidence and risk factors of adverse events (AEs), focusing on cardiovascular events (CVEs) and hypokalemia, in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials, and their association with survival outcomes.\nThis was a retrospective cohort study of 105 patients treated from 2011 to 2016. Incidence of AEs was descriptively summarized in the whole cohort and by subgroup (pre- versus post-docetaxel). Multivariable Cox proportional hazards models assessed factors associated with progression-free survival (PFS) and overall survival (OS).\nOverall, median PFS and OS were 14.9 and 24.6 months, respectively. Prostate-specific antigen (PSA) ⩾ 10 ng/ml (p = 0.007), Gleason Score >7 (p = 0.008), Eastern Cooperative Oncology Group (ECOG) performance status (PS)1-2 (p = 0.002), duration of androgen deprivation therapy (ADT) ⩽ 43.2 months (p = 0.01), and body mass index (BMI) > 25 (p = 0.03) were associated with worse PFS; presence of pain (p = 0.01), ECOG PS1-2 (p = 0.004), duration of ADT ⩽ 43.2 (p = 0.05), and BMI > 25 (p = 0.042) were associated with worse OS. Incidence of CVEs was as follows: hypertension 17.1%, fluid retention 4.8%, cardiac disorders 8.6%. 16.2% of patients developed hypokalemia. Age ⩾ 75 years was associated with higher probability of cardiac disorders (p = 0.001) and fluid retention (p = 0.03). CVEs did not impact on PFS or OS. Hypokalemia was associated with better median OS (p = 0.036). Similar associations were observed after stratification by subgroup.\nMedian PFS and OS estimates and incidence of CVEs and hypokalemia in our series are consistent with those of pivotal trials of AA plus PDN, confirming the efficacy and safety of this regimen also in the real-world setting. Elderly patients have higher odds of developing/worsening CVEs. However, regardless of age, CVEs were not associated with worse outcomes. Treatment-related hypokalemia seemed to be associated with longer OS, albeit this finding needs confirmation within larger, prospective series.",
"affiliations": "Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Internal Medicine 3, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Internal Medicine 3, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Clinic of Cardiovascular Disease, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy.;Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, L.go R. Benzi 10, 16132, Genoa, Italy.",
"authors": "Cavo|Alessia|A|https://orcid.org/0000-0003-2157-3740;Rubagotti|Alessandra|A|;Zanardi|Elisa|E|;Fabbroni|Chiara|C|;Zinoli|Linda|L|;Di Meglio|Antonio|A|;Arboscello|Eleonora|E|;Bellodi|Andrea|A|;Spallarossa|Paolo|P|;Cattrini|Carlo|C|;Messina|Carlo|C|;Boccardo|Francesco|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1758834017745819",
"fulltext": "\n==== Front\nTher Adv Med OncolTher Adv Med OncolTAMsptamTherapeutic Advances in Medical Oncology1758-83401758-8359SAGE Publications Sage UK: London, England 10.1177/175883401774581910.1177_1758834017745819Original ResearchAbiraterone acetate and prednisone in the pre- and post-docetaxel setting for metastatic castration-resistant prostate cancer: a mono-institutional experience focused on cardiovascular events and their impact on clinical outcomes https://orcid.org/0000-0003-2157-3740Cavo Alessia Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyRubagotti Alessandra Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Health Sciences, School of Medicine, University of Genoa, ItalyZanardi Elisa Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyFabbroni Chiara Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyZinoli Linda Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyDi Meglio Antonio Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyArboscello Eleonora Academic Unit of Internal Medicine 3, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyBellodi Andrea Academic Unit of Internal Medicine 3, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalySpallarossa Paolo Clinic of Cardiovascular Disease, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyCattrini Carlo Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyMessina Carlo Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, ItalyDepartment of Internal Medicine, School of Medicine, University of Genoa, ItalyBoccardo Francesco Academic Unit of Medical Oncology, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, L.go R. Benzi 10, 16132, Genoa, Italyfboccardo@unige.it09 1 2018 2018 10 17588340177458194 5 2017 5 10 2017 © The Author(s), 20182018SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (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).Background:\nThe aim of this work was to to evaluate the incidence and risk factors of adverse events (AEs), focusing on cardiovascular events (CVEs) and hypokalemia, in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials, and their association with survival outcomes.\n\nMethods:\nThis was a retrospective cohort study of 105 patients treated from 2011 to 2016. Incidence of AEs was descriptively summarized in the whole cohort and by subgroup (pre- versus post-docetaxel). Multivariable Cox proportional hazards models assessed factors associated with progression-free survival (PFS) and overall survival (OS).\n\nResults:\nOverall, median PFS and OS were 14.9 and 24.6 months, respectively. Prostate-specific antigen (PSA) ⩾ 10 ng/ml (p = 0.007), Gleason Score >7 (p = 0.008), Eastern Cooperative Oncology Group (ECOG) performance status (PS)1–2 (p = 0.002), duration of androgen deprivation therapy (ADT) ⩽ 43.2 months (p = 0.01), and body mass index (BMI) > 25 (p = 0.03) were associated with worse PFS; presence of pain (p = 0.01), ECOG PS1–2 (p = 0.004), duration of ADT ⩽ 43.2 (p = 0.05), and BMI > 25 (p = 0.042) were associated with worse OS. Incidence of CVEs was as follows: hypertension 17.1%, fluid retention 4.8%, cardiac disorders 8.6%. 16.2% of patients developed hypokalemia. Age ⩾ 75 years was associated with higher probability of cardiac disorders (p = 0.001) and fluid retention (p = 0.03). CVEs did not impact on PFS or OS. Hypokalemia was associated with better median OS (p = 0.036). Similar associations were observed after stratification by subgroup.\n\nConclusions:\nMedian PFS and OS estimates and incidence of CVEs and hypokalemia in our series are consistent with those of pivotal trials of AA plus PDN, confirming the efficacy and safety of this regimen also in the real-world setting. Elderly patients have higher odds of developing/worsening CVEs. However, regardless of age, CVEs were not associated with worse outcomes. Treatment-related hypokalemia seemed to be associated with longer OS, albeit this finding needs confirmation within larger, prospective series.\n\nabiraterone acetatecardiovascular adverse eventshypokalemiametastatic castration-resistant prostate cancerobesitysafetycover-dateJanuary-December 2018\n==== Body\nIntroduction\nProstate cancer is the most common malignancy in men in western countries.1 Androgen deprivation therapy (ADT) represents the cornerstone treatment for metastatic prostate cancer and indeed most patients do benefit from ADT. However, most of them are destined to progress and to become castration-resistant.2 Median survival of metastatic castration-resistant prostate cancer (mCRPC) is highly variable and expected survival among these patients is associated with tumor bulk and disease spread to distant sites other than the skeleton.3 Over the past few years, the increasing knowledge about the driving role of the androgen receptor, even in the castration-resistant setting, has dramatically improved survival for patients developing mCRPC.4 In particular, based on this assumption, new endocrine therapies, such as abiraterone acetate (AA) and enzalutamide, have been developed.4\n\nAbiraterone acetate is a potent, selective inhibitor of steroidogenesis that interferes with androgen synthesis through the inhibition of the cytochrome P450 17α-hydroxylase/17, 20 lyase (CYP17). This enzyme catalyzes two sequential reactions, namely the conversion of pregnenolone and progesterone to their 17α-hydroxy-derivatives (17α-hydroxylase activity), and the subsequent formation of dehydro-epiandrosterone (DHEA) and androstenedione (17, 20-lyase activity). Androstenedione and DHEA are then converted to testosterone (TST) by 17-beta-hydroxy-steroid-dehydrogenase and eventually to dihydrotestosterone (DHT) by 5α reductase.5 Thus, the inhibition of CYP17 decreases circulating and tissue levels of androgens, namely DHEA, TST and DHT, preventing the stimulation of androgen-sensitive neoplastic cell clones. The blockade of steroidogenic enzymes by AA leads to the suppression of adrenocorticotropic feedback, which results in an exceeding production of steroid precursors with high mineralocorticoid activity.5 This effect is responsible for the most frequent adverse events (AEs) occurring during treatment with AA, including hypokalemia, hypertension and fluid overload. Therefore, the concomitant use of low-dose glucocorticoids is required to decrease the frequency and severity of these events and serial monitoring of potassium levels and blood pressure is recommended.6,7\n\nAA plus low-dose prednisone (PDN) was first approved for patients with mCRPC failing prior docetaxel (DX) chemotherapy (CT), based on the COUAA-301 trial results, showing AA plus PDN to be able to improve overall survival (OS) compared with PDN plus placebo [14.8 versus 10.9 months, hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.54–0.77, p < 0.001].7 This drug was subsequently tested in CT-naïve mCRPC, also producing a statistically significant OS benefit (median OS 34.7 versus 30.3 months in the AA and placebo group respectively, HR 0.81, 95% CI 0.70–0.9, p = 0.003) especially in men with asymptomatic or mildly symptomatic disease.8,9 As expected, in both trials, fluid retention, hypokalemia, hypertension and cardiovascular (CV) disorders (cardiac ischemia, rhythm disorders, valvular dysfunctions, stroke, peripheral thrombosis and arterial disease) were the most commonly observed AEs. In the COUAA-301 trial, fluid retention was observed in 33%, hypokalemia in 18%, hypertension in 11% and CV disorders in 16% of treated patients.7 Findings in CT-naïve patients were comparable. In fact, in the COUAA-302 trial, fluid retention was observed in 31% and hypokalemia in 18% of patients. However, the incidence of hypertension (24%) and of CV disorders (22%) was higher.8,9 The higher incidence of CV disorders in CT-naïve patients is likely the result of the longer drug exposure of these patients: median radiologic PFS in the COUAA-302 trial was almost three times as long as that observed in the COUAA-301 trial (16.5 versus 5.6 months).7,9\n\nDespite the widespread use of AA in clinical practice and according to the major guidelines,10–12 few data on the incidence of CV events in ‘real-life’ patients treated with AA and PDN are available, mostly regarding patients failing prior treatment with DX. In the Italian Named Patient Program, the clinical outcomes reported in the AA pivotal trial7 were reproduced but the incidence of toxicities was lower (hypertension was observed only in 2.6% and hypokalemia only in 1.9% of treated patients).13 This difference probably reflects lack of systematic monitoring of patients in this clinical practice setting. One single-institution retrospective study included 51 CRPC patients with concomitant CV risk factors, who were also pretreated with DX. Hypertension was observed in 16% while fluid retention in 18% of patients. Moreover, dose reductions due to unacceptable toxicity were necessary in 9.8% of patients. This study confirms that AA plus PDN can be safely delivered, even to patients bearing risk factors for CV diseases.14 A data update of the same study, with longer follow-up time, confirmed the previously reported safety profile.15 The results of an additional study, also including mCRPC patients previously treated with DX, were presented at the 2016 American Society of Clinical Oncology Annual Meeting.16 This was a prospective study specifically aimed at monitoring cardiac functionality during treatment with AA and PDN. A total of 87 patients underwent electrocardiogram (ECG) and echocardiography with evaluation of left ventricular ejection fraction (LVEF) and diastolic function, both at baseline and at every 6 months until treatment discontinuation. Hypertension was observed in 34.6% of patients, without statistically significant variation of LVEF and diastolic function.\n\nMore recently, the results of two trials exploring the efficacy of AA and PDN (5 mg daily) in hormone-naïve patients were reported.17,18 In both trials the combination of AA plus PDN with ADT was compared with ADT alone, and both ones reported statistically significant and comparable reductions in the HR of all-cause mortality, the primary endpoint for both studies (LATITUDE trial: HR 0.62, 95% CI 0.51–0.76, p < 0.001;17 STAMPEDE trial: HR 0.63, 95% CI 0.52–076, p < 0.00118) as well as in the hazards of all other secondary endpoints. Though these trials were greatly heterogeneous regarding the patient populations accrued, the incidence of AEs, namely hypertension, cardiac disorders and hypokalemia, was comparable across trials. Indeed, hypertension (any grade) occurred in 37% of patients in the LATITUDE trial and in 32% in the STAMPEDE trial among patients in the AA plus PDN arm. The incidence of cardiac disorders (any) was 12% and 10% respectively while hypokalemia (all grades) was recorded in 20% and 12% of patients assigned to AA plus PDN, respectively. The incidence of hypertension, recorded in previous studies (37% and 32%) appears to be higher than the incidence of hypertension in the COUAA-302 trial (24%). However, the incidence of CV events (12% and 10%) and the incidence of hypokalemia (20% and 12%) were quite comparable, if not inferior, to the incidences recorded in the COUAA-302 trial (22% and 18% respectively). These differences are probably due to the different way of reporting AEs, though study population heterogeneity, treatment duration and lower PDN dose might contribute to the differences observed. The LATITUDE and STAMPEDE trials are both destined to soon become ‘practice changing’ and to expand the patient population candidates to receive long-term treatment with AA and PDN. However, both trials included very selected patient populations and ‘real-life’ data concerning AA plus PDN in hormone-naïve patients are not available yet; moreover, it should be better clarified which patients can benefit more from this therapeutic option and which ones, for instance, could better take advantage from adding DX to ADT.19,20 Finally, it will take a few years to obtain the permission of using AA in the castration-sensitive setting, since in most countries, including Italy, the use of AA plus PDN is still limited to CRPC patients. Therefore, we believe that it is still important to report on CRPC patients treated in the real world, outside of clinical trials, not only because they represent the widest setting in everyday clinical practice, but also in the perspective of future comparisons with the results obtained from similar, real-life studies among hormone-naïve patients.\n\nIn view of these premises, we report here the results of a retrospective study evaluating patients affected by mCRPC, who were referred to our unit and treated with AA and PDN, outside clinical trials. Defining the incidence of AEs, with a special focus on CV and biochemical events (including hypokalemia) in a ‘real-life’ mono-institutional patient population, looking for the factors putatively predisposing to them, and evaluating the impact, if any, of CV and biochemical events on patients outcome were study aims. The putative association between baseline clinical–pathological characteristics, the incidence of AEs and patient clinical outcome was also investigated, in the attempt to identify a priori among the patients, candidates to receive treatment with AA and PDN, those at higher risk to develop CV and biochemical events and those destined to derive the greatest benefit from this treatment.\n\nPatients and methods\nWe reviewed the charts of 105 patients affected by mCRPC and consecutively referred to our unit to receive AA and PDN between June 2011 and 2016. Ethics approval and consequent informed consent were not required for this study, according to ‘Authorization n. 9/2016 – General Authorization for the Processing of Personal Data for Scientific Research Purposes – 15 December 2016’ (Published in Gazzetta Ufficiale No 303 of 29 December 2016). On the basis of this authorization, universities, research centers and scientific societies do not have to require ethics approval to perform observational studies on data previously recorded without significant influence on affected patients.\n\nThe following information, recorded at the time AA was started, was collected for each patient: age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), body mass index (BMI), presence or absence of pain (evaluated through the Brief Pain Inventory Short Form scale),21 prostate-specific antigen (PSA) value, type of metastatic sites involved, time on previous ADT, and Gleason score (GS) of primary tumor. Pre-existing cardiac events or CV comorbidities were also recorded. Baseline ECG findings and LVEF were available for all patients, since cardiologic examination before starting treatment with AA and PDN is required by the Italian Drug Agency (AIFA).\n\nAll the patients included in the study cohort received AA orally, 1000 mg daily, and PDN, 5 mg twice daily, until disease progression, symptomatic deterioration, or unacceptable toxicity. Pharmacological suppression of gonadal function was maintained in all patients. The incidence of fluid retention, hypertension, hypokalemia, CV disorders, AST-ALT increase, diabetes and hypercholesterolemia were annotated and scored using Common Terminology Criteria for Adverse Events, version 4.0.22 AE assessment was performed 2 weeks after the beginning of AA plus PDN and at monthly intervals thereafter. In patients at higher risk of developing cardiovascular events (CVEs) and with a baseline LVEF < 50%, assessment was performed every 2 weeks for the first 3 months. Disease progression was defined as per the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, version 1.123 and Prostate Cancer Clinical Trials Working Group 2 criteria.24 Radiographic assessments were performed every 6 months unless required before due to biochemical progression (as defined by an increase in PSA level of 25% or more in respect to nadir value) or clinical deterioration. The date of disease progression was recorded as well as the date of death. The cause of death was recorded whenever we were able to retrieve it. PFS was defined as the time between the initiation of AA plus PDN and the date of disease progression. OS was defined as the time between the initiation of AA plus PDN and the date of death.\n\nStatistical analysis\nAll the patients treated with AA and PDN at our unit between 2011 and 2016 were included in the analysis.\n\nPatient characteristics, the incidence of AEs (namely of CV and biochemical events) in the overall cohort and by subgroup, the association between patient characteristics, the incidence of AEs and patient outcome were descriptively summarized. The predictive value of AEs on treatment outcome was investigated by comparing outcome indicators in patients who developed CV and biochemical events (namely hypokalemia) and in those who did not.\n\nOS and PFS curves were obtained using the Kaplan–Meier product-limit estimator and compared using the log-rank test.25 To evaluate the possible interactions among aforementioned study variables with clinical outcomes, multi-parametric, Cox proportional hazard models were used.26 We obtained separate models for PFS and OS, adjusting for all the covariates that predicted, after univariate analysis, for PFS or OS, as appropriate. The following covariates were included in the PFS models: baseline PSA level (<10 versus ⩾10 ng/ml); ECOG PS (0 versus 1–2); prior ADT duration (⩽43.2 versus >43.2 months); BMI (⩽25 versus >25); Age (<75 versus ⩾75); GS (⩽7 versus >7). In the OS model, we included PSA level (<10 versus ⩾10 ng/ml); ECOG PS (0 versus 1–2); prior ADT duration (⩽43.2 versus >43.2 months); BMI (⩽25 versus >25) and pain (present versus absent). A stepwise procedure was used with a significance level of p = 0.05 to retain variables in the model. HR estimates and their 95% CIs were obtained. The cumulative incidence function was used to describe cause-specific mortality and Fine and Gray’s proportional hazard regression models for competing risks were used to predict for the probabilities of prostate cancer-related and unrelated mortality.27 HRs and respective 95% CIs for group comparisons were obtained after adjusting for baseline PSA value, ECOG PS, ADT duration, BMI and pain presence. The Chi-square test or Fisher’s exact test were used to compare the baseline characteristics between pre and post-DX patients and the incidence and severity of AEs.28 All statistical tests were two-sided. We used the IBM software Statistical Package for Social Sciences (SPSS) version 21.0 for Windows (SPSS Inc. Chicago, Illinois, USA) and Stata/SE 11 (College Station, TX, USA) for data analysis.\n\nSample size calculation\nNo formal calculation of sample size was performed in this retrospective series, as it would not be possible, anyway, to change cohort size since it included all the patients treated with AA and PDN followed at our unit in the time period mentioned above. Moreover, as we have already pointed out in the premises, we intended to perform an explorative study, just to look at the incidence and different distribution of patient features, outcome indicators and AEs (namely CV and hypokalemia) in our cohort, including real-life patients treated outside of clinical trials.\n\nResults\nCohort characteristics\nAs already mentioned, 105 consecutive mCRPC patients treated with AA plus PDN were included in the cohort: 75 had been previously treated with DX while 30 had received AA and PDN as front-line treatment. Median follow up was 26.8 (range 1.4–57.4) months for the whole cohort, 20.9 months (range 3.3–28.4) months for CT-naïve patients and 32.6 months (range 1.4–57.4) for patients previously treated with DX. Patient characteristics are summarized in Table 1. Characteristics of pre- and post-DX patients were comparable. Table 2 shows the prevalence of pre-existing CV disorders and of other conditions that might affect patient survival and treatment safety. Before starting treatment with AA and PDN, most of the patients were affected by hypertension (62.9%) and about half of them was overweight or obese (47.6%). However, again there were no major differences between subgroups.\n\nTable 1. Main characteristic of study patients at AA plus PDN start (disease related).\n\n\tAll patients (N = 105)\tPre-DX (n = 30)\tPost-DX (n = 75)\t\nPSA\t\nMedian, ng/ml (range)\t37.8 (1.97–1572)\t19.02 (1.97–381.8)\t54.4 (2.0–1572)\t\nMetastatic sites\t\nBone only\t34 (32.4%)\t13 (43.3%)\t21 (28.0%)\t\nPelvic nodes only\t21 (20.0%)\t5 (16.7%)\t16 (21.3%)\t\nVisceral only\t2 (1.9%)\t1 (3.3%)\t1 (1.3%)\t\nMultiple sites (bone + others)\t48 (45.7%)\t11 (36.7%)\t37 (49.4%)\t\nECOG PS\t\n0\t85 (81.0%)\t26 (86.7%)\t59 (78.7%)\t\n1–2\t20 (19.0%)\t4 (13.3%)\t16 (21.3%)\t\nPain\t\nAbsent\t82 (78.1%)\t27 (90.0%)Δ\t55 (73.3%)Δ\t\nPresent\t23 (21.9%)\t3 (10.0%)Δ\t20 (26.7%)Δ\t\nGleason score*\t\n⩽7\t50 (47.6%)\t12 (40.0%)\t38 (50.6%)\t\n>7\t55 (52.4%)\t18 (60.0%)\t37 (49.4%)\t\nTreatment of primary\t\nSurgery\t63 (60.0%)\t18 (60.0%)\t45 (60.0%)\t\nRadiotherapy\t23 (21.9%)\t7 (23.4%)\t16 (21.4%)\t\nADT\t19 (18.1%)\t5 (16.6%)\t14 (18.6%)\t\nMedian time on ADT in months (range)\t43.2 (1.9–217.7)\t39.6 (1.9–140.7)\t49.1 (10.4–217.7)\t\n* At initial diagnosis.\n\nΔ p = 0.07.\n\nAA, abiraterone acetate; ADT, androgen deprivation therapy; DX, docetaxel; ECOG, Eastern Cooperative Oncology Group; PDN, prednisone; PS, performance status; PSA, prostate-specific antigen.\n\nTable 2. Main characteristic of study patients at AA plus PDN start (patient related).\n\n\tAll patients (N = 105)\tPre-DX (n = 30)\tPost-DX (n = 75)\t\nMedian age (years) (range)\t74 (47–95)\t78 (55–95)\t73 (47–90)\t\nPre-existing CV disorders\t\nHypertension\t66 (62.9%)\t16 (53.3%)\t50 (66.7%)\t\nCardiac ischemia\t9 (8.6%)\t3 (10.0%)\t6 (8.0%)\t\nRhythm disorders\t17 (16.1%)\t4 (13.3%)\t13 (17.3%)\t\nValvular dysfunctions\t3 (2.8%)\t2 (6.7%)\t1 (1.3%)\t\nStroke\t3 (2.8%)\t1 (3.3%)\t2 (2.7%)\t\nPeripheral thrombosis\t2 (1.9%)\t0 (0.0%)\t2 (2.7%)\t\nPeripheral arterial disease\t5 (4.7%)\t2 (6.7%)\t3 (4.0%)\t\nLVEF (range)\t55% (40–60%)\t55% (40–60%)\t55% (50–60%)\t\nPre-existing dysmetabolic conditions\t\nDiabetes\t14 (13.3%)\t5 (16.7%)\t9 (12.0%)\t\nHypercholesterolemia\t28 (26.7%)\t7 (23.3%)\t21 (28.0%)\t\nBMI\t\n⩽25 (Normal weight)\t55 (52.4%)\t20 (66.7%)\t35 (46.7%)\t\n>25 <30 (Overweight)\t37 (35.2%)\t9 (30.0%)\t28 (37.3%)\t\n⩾30 <40 (Obesity class 1 or 2)\t13 (12.4%)\t1 (3.3%)\t12 (16.0%)\t\nAA, abiraterone acetate; BMI, body mass index; CV, cardiovascular; DX, docetaxel; LVEF, left ventricular ejection fraction; PDN, prednisone.\n\nEfficacy data\nMedian PFS of the whole cohort was 14.9 months (range 1.4–45.7); as expected, PFS was longer in CT-naïve than in post-DX patients: 20.9 (range 1.8–28.4) versus 13.8 (range 1.4–45.7) months respectively. Median OS was 24.6 months (range 1.4–57.4) and it was also longer in CT-naïve patients compared with post-DX patients: 24.8 (range 3.3–28.4) versus 19.9 (range 1.4–57.4) months, respectively (Figure 1). Median time to PSA progression was 9.3 months (range 0.5–41.1) in the whole cohort, 12.2 months (range 0.5–27.9) in CT-naïve and 8.0 months (range 1.2–41.1) in post-DX patients. Patient age at diagnosis (p = 0.04), baseline PSA level (p = 0.002), GS (p = 0.004), ECOG PS (p = 0.017) and duration of prior ADT (p < 0.001) impacted PFS at univariate analysis in the overall cohort and in patients failing prior DX treatment (PSA level p = 0.002; GS p = 0.003; ECOG PS p = 0.003), but not in CT-naïve patients (complete data not shown). Among these variables, baseline PSA level, GS, ECOG PS and prior ADT duration retained statistical significance in multivariable models. Noteworthy, also BMI seemed to predict for PFS after multivariable analysis (Table 3).\n\nFigure 1. PFS and OS curves in all cohort patients and subgroups.\n\nOS, overall survival; PFS, progression-free survival.\n\nTable 3. Multivariable analyses of PFS and OS.\n\n\tPFS\tOS\t\n\tAll patients (N = 105)\tPre-DX (n = 30)\tPost-DX (n = 75)\tAll patients (N = 105)\tPre-DX (n = 30)\tPost-DX (n = 75)\t\n\tHR\t(95% CI)\t\np\n\tHR\t(95% CI)\t\np\n\tHR\t(95% CI)\t\np\n\tHR\t(95% CI)\t\np\n\tHR\t(95% CI)\t\np\n\tHR\t(95% CI)\t\np\n\t\nPSA value\t\n⩾10 ng/ml\t2.94\t(1.35–6.40)\t0.007\t5.67\t(0.76–42.29)\t0.1\t2.70\t(0.99–7.40)\t0.053\t1.98\t(0.90–4.38)\t0.1\t1.28\t(0.20–8.07)\t0.8\t2.22\t(0.82–6.02)\t0.1\t\nECOG PS\t\n1–2\t2.99\t(1.47–6.07)\t0.002\t0.16\t(0.01–3.55)\t0.2\t3.33\t(1.56–7.13)\t0.002\t2.83\t(1.40–5.73)\t0.004\t13.63\t(1.14–162.62)\t0.04\t2.59\t(1.19–5.64)\t0.02\t\nADT duration\t\n>43.2 months\t0.48\t(0.26–0.86)\t0.01\t0.09\t(0.01–1.10)\t0.06\t0.48\t(0.25–0.93)\t0.03\t0.57\t(0.33–1.00)\t0.05\t2.95\t(0.50–17.54)\t0.2\t0.51\t(0.28–0.95)\t0.03\t\nBMI\t\n>25\t1.88\t(1.05–3.36)\t0.03\t2.31\t(0.39–13.82)\t0.4\t1.66\t(0.88–3.14)\t0.1\t1.85\t(1.02–3.36)\t0.042\t21.65\t(1.71–273.73)\t0.018\t1.48\t(0.78–2.81)\t0.2\t\nAge*\t\n⩾75 years\t0.57\t(0.31–1.03)\t0.06\t2.31\t(0.23–23.34)\t0.5\t0.61\t(0.32–1.14)\t0.1\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nGleason score*\t\n>7\t2.16\t(1.22–3.81)\t0.008\t5.84\t(0.77–44.05)\t0.08\t2.01\t(1.06–3.78)\t0.03\t–\t–\t–\t–\t–\t–\t–\t–\t–\t\nPain*\t\nPresent\t–\t–\t–\t–\t–\t–\t–\t–\t–\t2.29\t(1.20–4.37)\t0.01\t1.72\t(0.15–20.03)\t0.7\t1.81\t(0.89–3.67)\t0.1\t\n* Variables not achieving the statistical significance after univariate analysis were not included into the models.\n\nADT, androgen deprivation therapy; BMI, body mass index; CI, confidence interval; DX, docetaxel; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PS, performance status; PSA, prostate-specific antigen.\n\nPresence of pain (p < 0.001), baseline PSA level (p = 0.009) and ECOG PS (p < 0.001) were able to predict for OS duration at univariate analysis in the whole group while GS (p = 0.04) and duration of prior ADT (p = 0.016) were also significant predictors of OS in the post-DX group. Pain (p = 0.01), ECOG PS (p = 0.004), prior ADT duration (p = 0.05) and BMI (p = 0.042) were predictive of the risk of death at multivariable analysis; noteworthy, BMI > 25 was especially associated with a higher risk of death in CT-naïve patients (p = 0.018) (Table 3). Table 4 summarizes the results of multivariable analysis of mortality in the competitive risks model. None of the investigated covariates (baseline PSA value, ECOG PS, ADT duration, BMI value and presence of pain) proved significantly associated with prostate cancer-unrelated mortality, though a trend toward higher risks of death (p = 0.052) was observed for the presence versus the absence of pain.\n\nTable 4. Multivariable analysis of competitive risks of mortality (total patients: N = 105).\n\n\tProstate cancer-related deaths\tProstate cancer-unrelated deaths\t\n\tHR\t(95% CI)\t\np\n\tHR\t(95% CI)\t\np\n\t\nBaseline PSA value\t\n⩾10 versus <10 ng/ml\t3.51\t(0.93–13.28)\t0.06\t0.91\t(0.38–2.17)\t0.8\t\nECOG PS\t\n1–2 versus 0\t2.81\t(0.97–8.12)\t0.056\t1.49\t(0.52–4.31)\t0.4\t\nADT duration\t\n>43.2 versus ⩽43.2 months\t0.41\t(0.19–0.89)\t0.02\t1.79\t(0.73–4.36)\t0.2\t\nBMI\t\n>25 versus ⩽25\t3.96\t(1.60–9.84)\t0.003\t0.54\t(0.23–1.26)\t0.1\t\nPain\t\nPresent versus absent\t1.38\t(0.57–3.31)\t0.5\t2.66\t(0.99–7.11)\t0.052\t\nADT, androgen deprivation therapy; BMI, body mass index; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; PS, performance status; PSA, prostate-specific antigen.\n\nBy contrast, all the variables on study, except for the presence of pain, were independently associated with prostate cancer-specific mortality, particularly BMI (p = 0.003) and duration of ADT (p = 0.02).\n\nSafety data\nTable 5 reports the incidence of AEs developed over the course of treatment in the whole series and in subgroups. As expected, hypertension (17.2%) and hypokalemia (16.2%) were the more commonly observed events, the incidence of both being more elevated in post-DX patients as compared with CT-naïve patients. All the other CV events, including fluid retention and cardiac disorders, were described in <10% of patients (fluid retention in 5/105 patients and cardiac disorders in 9/105 patients). No statistically significant reduction in LVEF compared with baseline was recorded. Worsening of hypertension or of pre-existing cardiac disorders occurred in 16.7% (from G1 to G2 in 9.1% and from G1–G2 to G3–G4 in 7.6%) and 11.1% (from G1 to G2 in 8.3% and from G1–G2 to G3–G4 in 2.8%) of patients, respectively. While 21% of patients affected by diabetes developed further worsening of tolerance to glucose, only 3.6% of patients affected by dyslipidemia showed worsening of this condition.\n\nTable 5. Patients developing at least one AE during treatment.\n\n\tAll patients (N = 105)\tPre-DX (n = 30)\tPost-DX (n = 75)\t\n\tAny grade\tGrade 3–4\tAny grade\tGrade 3–4\tAny grade\tGrade 3–4\t\nAdverse event\t\nFluid retention\t5 (4.8%)\t0 (0%)\t1 (3.3%)\t0 (0%)\t4 (5.3%)\t0 (0%)\t\nHypertension\t18 (17.1%)\t5 (4.8%)\t3 (10.0%)\t0 (0%)\t15 (20.0%)\t5 (6.7%)\t\nHypokalemia\t17 (16.2%)\t1 (0.9%)\t3 (10.0%)\t1 (3.3%)\t14 (18.7%)\t0 (0%)\t\nCardiac disorders*\t9 (8.6%)\t4 (3.8%)\t3 (10.0%)\t0 (0%)\t6 (8.0%)\t4 (5.3%)\t\nALT-AST increase\t5 (4.8%)\t0 (0%)\t2 (6.6%)\t0 (0%)\t3 (4.0%)\t0 (0%)\t\nDiabetes\t5 (4.8%)\t0 (0%)\t1 (3.3%)\t0 (0%)\t4 (5.3%)\t0 (0%)\t\nHypercholesterolemia\t6 (5.7%)\t0 (0%)\t1 (3.3%)\t0 (0%)\t5 (6.7%)\t0 (0%)\t\n* see text.\n\nAE, adverse event; DX, docetaxel.\n\nPresence of baseline hypertension and cardiac disorders was not associated with the development of new hypertensive episodes or cardiac disorders. Conversely, pre-existing diabetes was significantly associated with worsening of glycemic control (p = 0.02). As it is shown in Table 6, patient age was a significant risk factor predisposing to develop cardiac disorders (p = 0.001) or fluid retention (p = 0.03). Unexpectedly, patients with normal BMI showed a higher risk to develop cardiac disorders compared with overweight or obese patients (p = 0.03), even adjusting for baseline cardiac risk factors (p = 0.047). No relationship between baseline ECOG PS, LVEF, presence of pain and AEs occurrence was found (Table 6).\n\nTable 6. Incidence of CV, biochemical and metabolic events during treatment according to age, BMI, ECOG PS and LVEF.\n\n\tAge\tBMI\tECOG PS\tLVEF\t\n\t<75\t⩾75\t⩽25\t>25\t0\t1–2\t⩽55%\t>55%\t\n\tn = 53\tn = 52\tn = 55\tn = 50\tn = 85\tn = 20\tn = 70\tn = 35\t\nDiabetes\t\nNo\t49 (92.5%)\t51 (98.1%)\t52 (94.5%)\t48 (96.0%)\t80 (94.1%)\t20 (100.0%)\t67 (95.7%)\t33 (94.3%)\t\nYes\t4 (7.5%)\t1 (1.9%)\t3 (5.5%)\t2 (4.0%)\t5 (5.9%)\t0 (0.0%)\t3 (4.3%)\t2 (5.7%)\t\nHypercholesterolemia\t\nNo\t52 (98.1%)\t47 (90.4%)\t52 (94.5%)\t47 (94.0%)\t81 (95.3%)\t18 (90.0%)\t65 (92.9%)\t34 (97.1%)\t\nYes\t1 (1.9%)\t5 (9.6%)\t3 (5.5%)\t3 (6.0%)\t4 (4.7%)\t2 (10.0%)\t5 (7.1%)\t1 (2.9%)\t\nFluid retention\t\nNo\t53 (100%)*\t47 (90.4%)*\t51 (92.7%)\t49 (98.0%)\t82 (96.5%)\t18 (90.0%)\t66 (94.3%)\t34 (97.1%)\t\nYes\t0 (0%)*\t5 (9.6%)*\t4 (7.3%)\t1 (2.0%)\t3 (3.5%)\t2 (10.0%)\t4 (5.7%)\t1 (2.9%)\t\nHypokalemia\t\nNo\t45 (84.9%)\t43 (82.7%)\t47 (85.5%)\t41 (82.0%)\t70 (82.4%)\t18 (90.0%)\t59 (84.3%)\t29 (82.9%)\t\nYes\t8 (15.1%)\t9 (17.3%)\t8 (14.5%)\t9 (18.0%)\t15 (17.6%)\t2 (10.0%)\t11 (15.7%)\t6 (17.1%)\t\nHypertension\t\nNo\t45 (84.9%)\t42 (80.8%)\t47 (85.5%)\t40 (80.0%)\t71 (83.5%)\t16 (80.0%)\t57 (81.4%)\t30 (85.7%)\t\nYes\t8 (15.1%)\t10 (19.2%)\t8 (14.5%)\t10 (20.0%)\t14 (16.5%)\t4 (20.0%)\t13 (18.6%)\t5 (14.3%)\t\nCardiac disorders\t\nNo\t53 (100%)**\t43 (82.7%)**\t47 (85.5%)Δ\t49 (98.0%)Δ\t78 (91.8%)\t18 (90.0%)\t63 (90.0%)\t33 (94.3%)\t\nYes\t0 (0%)**\t9 (17.3%)**\t8 (14.5%)Δ\t1 (2.0%)Δ\t7 (8.2%)\t2 (10.0%)\t7 (10.0%)\t2 (5.7%)\t\n* p = 0.03; **p = 0.001; Δp = 0.03.\n\nBMI, body mass index; CV, cardiovascular; ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction; PS, performance status.\n\nNo association between the development of cardiac AEs and PFS or OS duration was observed (Table 7). In particular, patients developing one or more of such events did not appear to progress or to die earlier. No association between hypokalemia and PFS was observed, though a trend was found in favor of patients who developed hypokalemia. However, patients developing hypokalemia appeared to live significantly longer (p = 0.013; Table 7). The association between the occurrence of hypokalemia during treatment and longer OS was confirmed also by multivariable analysis [adjusted HR (95% CI) versus no hypokalemia: 0.40, (0.17–0.94), p = 0.036; Figure 2].\n\nTable 7. PFS and OS as a function of the incidence of all AEs and of CV and biochemical events.\n\n\tPFS\tOS\t\n\tHR (95% CI)\t\np\n\tHR (95% CI)\t\np\n\t\nAll AEs\t\nNo\t1.0\t\t1.0\t\t\nYes\t0.74 (0.43–1.26)\t0.3\t0.65 (0.39–1.10)\t0.1\t\nHypokalemia\t\nNo\t1.0\t\t1.0\t\t\nYes\t0.66 (0.33–1.33)\t0.2\t0.36 (0.15–0.83)\t0.017\t\nHypertension\t\nNo\t1.0\t\t1.0\t\t\nYes\t0.89 (0.45–1.77)\t0.7\t1.05 (0.54–2.03)\t0.9\t\nCardiac disorders\t\nNo\t1.0\t\t1.0\t\t\nYes\t1.19 (0.47–3.02)\t0.7\t1.08 (0.46–2.52)\t0.8\t\nAE, adverse event; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.\n\nFigure 2. PFS and OS curves in patients who developed hypokalemia and in those who did not.\n\nPFS comparison is adjusted for age, PSA value, ECOG PS, ADT, BMI and Gleason score, whereas OS comparison is adjusted for PSA value, ECOG PS, ADT, BMI, pain.\n\nADT, androgen deprivation therapy; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; OS, overall survival; PFS, progression-free survival; PS, performance status; PSA, prostate-specific antigen.\n\nDiscussion\nIn this retrospective analysis, we report our experience about the efficacy and safety of AA plus PDN in mCRPC patients, either CT-naïve or previously treated with DX, focusing on CV, biochemical (i.e. hypokalemia) and metabolic events. Unfortunately, our study is retrospective, includes a relatively small number of patients, which implies a low statistical power, and is unbalanced relative to the proportion of patients receiving AA plus PDN after DX failure compared with the proportion of those receiving these drugs as their front-line treatment. Moreover, observation times recorded in the two groups also differed. Both of the mentioned disproportions reflect the fact that AA was first licensed for the post-DX setting and that it obtained the approval for the management of CT-naïve patients only subsequently. All these factors might bias findings both in the whole cohort and by subgroup, and limit both direct comparisons between subgroups and indirect comparisons with the COU-AA 301 and 302 trial findings. Nevertheless, we believe that our study provides some interesting information regarding the efficacy and safety of AA plus PDN in ‘real-life’ mCRPC patients, which can prove useful in every day practice.\n\nEfficacy data\nOverall, the efficacy results obtained in our series are comparable with those achieved in the two pivotal trials, which contributed to drug approval. Indeed, in post-DX patients, we observed a median PFS of 13.8 months and a median OS of 19.9 months. In the COUAA-301 trial, which comparably accrued post-DX patients, the median duration of PFS and of OS were 5.6 and 15.8 months respectively. The better outcome recorded in our series is probably due to the different selection criteria [patients enrolled in the COUAA-301 trial were younger, had a higher tumor burden (median PSA level was 128.8 versus 54.4 ng/ml in our cohort subgroup) and were more frequently symptomatic] and possibly to the differences in the criteria used to define disease progression. Notably, PSA free-survival duration was comparable in the two series, median PSA free-survival in our series and in the COUAA-301 trial being 8.0 and 10.2 months, respectively.7 Moreover, the choice of subsequent treatment upon progression in the COUAA-301 trial and in our series might differently affect OS duration. Our cohort of patients was, in fact, referred to us for treatment between 2011 and 2016 while the patients enrolled in the COAA-301 trial were recruited between 2008 and 2009. In consideration of this, it is possible that our patients progressing on AA plus PDN had the chance to receive new generation treatments (like cabazitaxel or enzalutamide) which have been proven to significantly prolong the survival of patients affected by CRPC.29,30 This might be the case especially for the patients who had received DX prior to AA and PDN, who represent most of the patients included in our cohort. In the patients who were CT-naïve, we observed a median PFS of 20.9 months and a median OS of 24.8 months. Median time to PSA progression was 12.2 months. Among patients recruited in the COUAA-302 trial, corresponding figures were 16.5, 34.7 and 11.1 months respectively.8,9 Also in this case, there were no major differences between the two series in terms of PFS and PSA free-survival. Apparently, OS duration in our series was much shorter than OS duration in the COUAA-302 trial. However, median follow up of our cohort was also shorter (20.9 versus 49.2 months in COUAA-302) and our survival data are not mature yet. Indeed, the percentages of patients alive at 1 and 2 years in our study (88.4 and 65.2%, respectively) do not differ much from those recorded at the same time points in the COUAA-302 trial (88 and 70%, respectively),9 in spite of differences in patient demography [patients enrolled in the COUAA-302 trial were younger, had a higher tumor burden (median PSA level was 42 ng/ml compared with 19 ng/ml in our cohort subgroup)] and treatment administered upon progression. Therefore, we can state that the effectiveness of AA and PDN in our real-life cohort was substantially comparable with the efficacy figures achieved with this regimen in pivotal trials.\n\nIn the COUAA-301 and COUAA-302 trials, clinical benefits achieved by AA and PDN compared with PDN and placebo were obtained in all patient subgroups. However, these trials were not designed ad hoc to identify the patients who might derive the greatest benefit from AA and PDN.\n\nIn order to answer to this question, we analyzed our PFS and OS results as a function of a number of variables which have been previously shown to significantly predict for patient clinical outcome in mCRPC.31 In our analysis, we also included two additional variables: BMI and duration of prior ADT. BMI was included because it was shown that an elevated BMI is associated both with an increased risk of cancer-specific mortality in healthy people and with a higher risk of biochemical recurrence in prostate cancer patients.32 A trend for an increased risk of progression to CRPC was also observed in patients with a BMI > 25.33 An association between obesity and the aggressiveness of the disease, as well as a higher incidence of complications following ADT, was observed in another study.34 Different mechanisms, involving the insulin/IGF-1 axis, sex hormones and adipokine signaling, have been proposed to explain the association between obesity and aggressiveness of prostate cancer.35 Addressing this issue in detail was not the scope of the present study. However, two additional considerations support our choice of including BMI among the selected covariates: (1) the metabolic dysfunction caused by ADT can accelerate CRPC and increase the risk of CV events; (2) human adipose tissue has been shown to be capable of active androgen synthesis and this, in principle, might interfere with the therapeutic activity of AA.36\n\nDuration of prior ADT has been associated with longer survival in patients receiving AA in a previous study.37 In our study both BMI and the duration of previous ADT were confirmed to be associated with a longer PFS and OS after multivariable analysis. In particular, overweight patients showed a significantly increased risk both to progress and to die, which was even higher for CT-naïve patients. These findings should be interpreted with caution, due to the small numbers and the retrospective nature of our analysis. However, multivariable competitive risks analysis showed that a BMI > 25 was specifically associated with a higher risk of dying for prostate cancer, but it showed no association with prostate cancer-unrelated mortality, independently of the other covariates included in the model. Of course, these findings might deserve confirmation in larger series. As shown in Table 3, we also confirmed that a longer duration of prior ADT almost halved the risk of progression and of death. In contrast to what we expected, visceral metastases were not significantly associated with prognosis in our cohort, but this finding might be due to the limited number of patients with baseline visceral involvement. Duration of response to previous ADT did also predict for prostate cancer mortality in the competing risk model. This and the borderline predictive value of PSA level, confirm that tumor burden and biology are specific determinants of AA efficacy in CRPC. Taken all together, our data suggest that patients with a lower PSA level, an initial GS ⩽ 7, an ECOG PS 0, no pain, a duration of ADT > 43.2 months and a BMI ⩽ 25 are likely to benefit the most from AA plus PDN treatment, independently of their age, the presence of visceral metastasis and of having been previously treated or not with DX.\n\nSafety data\nAA plus PDN proved to be a well tolerated regimen among our cohort. In particular, focusing on CV and biochemical events, in CT-naïve patients we observed a lower incidence of AEs as compared with that reported in the COUAA-302 trial8,9 and only one episode of grade 3–4 hypokalemia. In the post-DX setting, we observed a higher incidence of hypertension (20% versus 10% in the CT-naïve group) which was grade 3–4 in 6.7% of patients. Furthermore, in our post-DX cohort we found a comparable incidence of hypokalemia with respect to COUAA-301 trial findings (18.7% versus 18.0%, respectively).7 Overall, the incidence of fluid retention and cardiac disorders in our series was much lower than the incidence recorded in the two pivotal trials.7,9 Interestingly, pre-existing hypertension and CV disorders were not associated either with an increased risk of worsening CV AEs or the onset of new CV AEs. These results are consistent with those obtained in other real-life experiences; indeed, as already mentioned, one retrospective study in mCRPC patients previously treated with DX, showed that AA plus PDN can be safely administered even in patients bearing CV risk factors.14,15 A prospective evaluation of the incidence of CV events during AA administration in patients with CV comorbidities showed no change in LVEF values during AA treatment, which is consistent with our findings, but it did show worsening of pre-existing hypertension in 30% of patients.16 In our cohort, we also evaluated whether patient age might increase the risk of CV AEs and indeed patients aged ⩾75 showed a significantly increased risk of developing fluid retention (p = 0.03) and cardiac disorders (p = 0.001) as compared with younger ones, regardless of previous administration of CT. A trend toward developing or worsening of dyslipidemia was also observed in elderly patients in our study. Interestingly, this patient subgroup did not prove to be more prone to develop diabetes. Even though a more accurate cardiologic and metabolic monitoring may be advisable among elderly patients, it is certainly reassuring that there was no difference in survival according to age. Moreover, the fact that in our study age >75 was associated with a longer PFS (both at univariate and at multivariable analysis) might suggest that the increased incidence of CV events did not interfere with patient compliance to treatment, probably for the more closely monitoring adopted in elderly patients to control these adverse conditions. Our results confirm the findings of pivotal trials7–9 and of previously mentioned ‘real-life’ experiences where elderly patients treated with AA did not show any difference in survival duration compared with younger ones.38–41 Noteworthy, patient weight did not appear to predict the incidence of CV events. Obese patients showed a slight increase in the probability of developing hypertension but a lower probability of developing CV disorders, though the role played by chance in this association cannot be ruled out, considering the very small numbers of patients developing cardiac disorders in our cohort (n = 9). Most importantly, patients developing CV AEs during treatment with AA and PDN in our cohort did not experience a worse prognosis than those who did not. Conversely, hypokalemia appeared to be associated, even after multivariable analysis, both with a longer PFS (though this trend was not statistically significant) and OS, (Figure 2; Table 7). Neither has this observation been reported before, thus requiring confirmation in larger, prospective studies, nor it is easily explainable; thus, we might only postulate that hypokalemia might represent a marker of treatment activity, to the same extent as hypertension appears to be for anti-angiogenic treatment in other solid tumors, such as renal and colorectal cancer.42,43\n\nConclusion\nOur findings confirm that AA and PDN is an effective and well tolerated regimen also in ‘real-life’ patients, including elderly ones. Though the incidence of AEs, and especially CVEs, was lower with respect to the figures initially reported in pivotal trials, and though no evidence emerged that AEs might imply a worse clinical outcome, appropriate patient selection and monitoring is recommended. Lower PSA levels, an initial GS ⩽ 7, ECOG PS 0, absence of pain, longer duration of previous ADT manipulations and a BMI ⩽ 25 appear to be associated with a greater benefit from AA treatment, independently of patient age, presence of visceral metastasis and of patients having been previously treated or not with DX. Interestingly, patients developing treatment-related hypokalemia seem to have better outcomes as compared with those who did not. However, this finding requires confirmation in larger, possibly prospective trials. Studies focused on more specific markers able to predict for the effectiveness and safety of AA and PDN are needed in order to improve decision-making and patterns of care among patients with mCRPC. Similar studies are also warranted in hormone-naïve patients in view of the results achieved by adding upfront AA and PDN to standard ADT.\n\nThe authors are extremely grateful to Dr Claudia Casella (Descriptive Epidemiology Unit: Tumor Registry, San Martino Polyclinic Hospital, Institute for Cancer Research and Treatment, Genoa, Italy) for helping in data collection.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n\nORCID iD: Alessia Cavo \nhttps://orcid.org/0000-0003-2157-3740\n==== Refs\nReferences\n1 \nSiegel RL Miller KD Jemal A. \nCancer statistics, 2015 . Cancer J Clin \n2015 ; 65 : 5 –29 .\n2 \nProstate Cancer Trialists’ Collaborative Group . Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials . 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BJU Int \n2005 ; 96 : 1241 –1246 .16287438 \n7 \nFizazi K Scher HI Molina A et al \nAbiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study . Lancet Oncol \n2012 ; 13 : 983 –992 .22995653 \n8 \nRyan CJ Smith MR de Bono JS et al \nAbiraterone in metastatic prostate cancer without previous chemotherapy . N Engl J Med \n2013 ; 368 : 138 –148 .23228172 \n9 \nRyan CJ Smith MR Fizazi K et al \nAbiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study . Lancet Oncol \n2015 ; 16 : 152 –160 .25601341 \n10 \nNCCN (National Comprehensive Cancer Network) Guidelines . Prostate Cancer version 2 , 2017 \nhttps://www.nccn.org/professionals/physician_gls/default.aspx#prostate\n11 \nMottet N Bellmunt J Briers E et al \nGuidelines on Prostate Cancer EAU , 2017 \nhttps://uroweb.org/wp-content/uploads/09-Prostate-Cancer_2017_web.pdf\n12 \nAssociazione Italiana di Oncologia Medica (AIOM) \nLinee guida carcinoma della prostata 2017. www.aiom.it › Professionisti › Documenti scientifici › Linee Guida .\n13 \nCaffo O De Giorgi U Fratino L et al \nSafety and clinical outcomes of patients treated with abiraterone acetate after docetaxel: results of the Italian Named Patient Programme . BJU Int \n2015 ; 115 : 764 –771 .24988879 \n14 \nProcopio G Grassi P Testa I et al \nSafety of abiraterone acetate in castration-resistant prostate cancer patients with concomitant cardiovascular risk factors . Am J Clin Oncol \n2015 ; 38 : 479 –482 .24064757 \n15 \nVerzoni E Grassi P Ratta R et al \nSafety of long-term exposure to abiraterone acetate in patients with castration-resistant prostate cancer and concomitant cardiovascular risk factors . Ther Adv Med Oncol \n2016 ; 8 : 323 –330 .27583024 \n16 \nPrati V Ruatta F Gernone A et al \nProspective evaluation of the cardiovascular safety profile of abiraterone acetate (AA) in mCRPC patients (pts) . J Clin Oncol \n2016 ; 34 (Suppl. ): abstract e16534.\n17 \nFizazi K Tran N Fein L et al \nAbiraterone plus prednisone in metastatic, castration-sensitive prostate cancer . N Engl J Med \n2017 ; 377 : 352 –360 .28578607 \n18 \nJames ND de Bono JS Spears MR et al \nAbiraterone for prostate cancer not previously treated with hormone therapy . N Engl J Med \n2017 ; 377 : 338 –351 .28578639 \n19 \nSweeney CJ Chen YH Carducci M et al \nChemohormonal therapy in metastatic hormone-sensitive prostate cancer . N Engl J Med \n2015 ; 373 : 737 –746 .26244877 \n20 \nGravis G Fizazi K Joly F et al \nAndrogen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial . Lancet Oncol \n2013 ; 14 : 149 –158 .23306100 \n21 \nCleeland CS Ryan KM. \nPain assessment: global use of the Brief Pain Inventory . Ann Acad Med Singapore \n1994 ; 23 : 129 –138 .8080219 \n22 \nU.S. Department of Health and Human Services . National Institutes of Health National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 , 2009 .\n23 \nEisenhauer EA Therasse P Bogaerts J et al \nNew response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer (Oxf, Engl: 1990) \n2009 ; 45 : 228 –247 .\n24 \nScher HI Halabi S Tannock I et al \nDesign 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 \n2008 ; 26 : 1148 –1159 .18309951 \n25 \nKaplan EL Meier P. \nNon parametric estimation from incomplete observation . J Am Stat Assoc \n1958 ; 53 : 457 –481 .\n26 \nCox DR. \nRegression models and life tables (with discussion) . J Roy Stat Soc B \n1972 ; 34 : 187 –220 .\n27 \nGray RJ. \nA class of k-sample tests for comparing the cumulative incidence of a competing risk . Ann Stat \n1988 ; 16 : 1141 –1154 .\n28 \nWilson EB Hilferty MM. \nThe distribution of Chi-square . Proc Natl Acad Sci USA \n1931 ; 17 : 684 –688 .16577411 \n29 \nde Bono JS Oudard S Ozguroglu M et al \nPrednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial . Lancet (London, England) \n2010 ; 376 : 1147 –1154 .\n30 \nScher HI Fizazi K Saad F et al \nIncreased survival with enzalutamide in prostate cancer after chemotherapy . N Engl J Med \n2012 ; 367 : 1187 –1197 .22894553 \n31 \nFizazi K Massard C Smith M et al \nBone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer . Eur Urol \n2015 ; 68 : 42 –50 .25449207 \n32 \nCao Y Ma J. \nBody mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis . Cancer Prev Res (Philadelphia, PA) \n2011 ; 4 : 486 –501 .\n33 \nKeto CJ Aronson WJ Terris MK et al \nObesity is associated with castration-resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: results from the SEARCH database . BJU Int \n2012 ; 110 : 492 –498 .22094083 \n34 \nAllott EH Masko EM Freedland SJ. \nObesity and prostate cancer: weighing the evidence . Eur Urol \n2013 ; 63 : 800 –809 .23219374 \n35 \nRoberts DL Dive C Renehan AG. \nBiological mechanisms linking obesity and cancer risk: new perspectives . Annu Rev Med \n2010 ; 61 : 301 –316 .19824817 \n36 \nMontgomery RB Mostaghel EA Vessella R et al \nMaintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth . Cancer Res \n2008 ; 68 : 4447 –4454 .18519708 \n37 \nGiacinti S Carlini P Roberto M et al \nDuration of response to first androgen deprivation therapy, time to castration resistance prostate cancer, and outcome of metastatic castration resistance prostate cancer patients treated with abiraterone acetate . Anti-cancer Drugs \n2017 ; 28 : 110 –115 .27763885 \n38 \nYap YG Camm AJ. \nDrug induced QT prolongation and torsades de pointes . Heart (Brit Card Soc) \n2003 ; 89 : 1363 –1372 .\n39 \nSmith MR Rathkopf DE Mulders PF et al \nEfficacy and safety of abiraterone acetate in elderly (75 years or older) chemotherapy naive patients with metastatic castration-resistant prostate cancer . J Urol \n2015 ; 194 : 1277 –1284 .26151676 \n40 \nSuzman DL Eisenberger MA. \nDetermining the optimal treatment for metastatic castration-resistant prostate cancer: age should not be a factor . Eur Urol \n2014 ; 65 : 884 –886 .24157242 \n41 \nMaines F Caffo O De Giorgi U et al \nSafety and clinical outcomes of abiraterone acetate after docetaxel in octogenarians with metastatic castration-resistant prostate cancer: results of the Italian Compassionate Use Named Patient Programme . Clin Genitourin Cancer \n2016 ; 14 : 48 –55 .26382222 \n42 \nKollmannsberger C. \nSunitinib side effects as surrogate biomarkers of efficacy . Can Urol Assoc J \n2016 ; 10 (Suppl. 7 ): S245 –S247 .28096937 \n43 \nNakaya A Kurata T Yokoi T et al \nRetrospective analysis of bevacizumab-induced hypertension and clinical outcome in patients with colorectal cancer and lung cancer . Cancer Med \n2016 ; 5 : 1381 –1387 .27109438\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1758-8340",
"issue": "10()",
"journal": "Therapeutic advances in medical oncology",
"keywords": "abiraterone acetate; cardiovascular adverse events; hypokalemia; metastatic castration-resistant prostate cancer; obesity; safety",
"medline_ta": "Ther Adv Med Oncol",
"mesh_terms": null,
"nlm_unique_id": "101510808",
"other_id": null,
"pages": "1758834017745819",
"pmc": null,
"pmid": "29383035",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "24064757;14594906;22894553;23219374;18309951;8080219;28578639;20888992;24988879;16577411;25449207;23306100;26382222;26244877;22995653;19824817;21233290;21552559;19097774;21995694;16287438;25559415;27763885;27109438;23228172;25601341;22094083;27583024;18519708;28096937;26151676;24157242;10801170;22291466;28578607",
"title": "Abiraterone acetate and prednisone in the pre- and post-docetaxel setting for metastatic castration-resistant prostate cancer: a mono-institutional experience focused on cardiovascular events and their impact on clinical outcomes.",
"title_normalized": "abiraterone acetate and prednisone in the pre and post docetaxel setting for metastatic castration resistant prostate cancer a mono institutional experience focused on cardiovascular events and their impact on clinical outcomes"
} | [
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"literaturereference": "ALESSIA C, ALESSANDRA R, ELISA Z, CHIARA F, LINDA Z, ANTONIO D, ET AL.. ABIRATERONE ACETATE AND PREDNISONE IN THE PRE- AND POST-DOCETAXEL SETTING FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: A MONO-INSTITUTIONAL EXPERIENCE FOCUSED ON CARDIOVASCULAR EVENTS AND THEIR IMPACT ON CLINICAL OUTCOMES.. THER. ADV. MED. ONCOL.. 2018?10:1-15",
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},
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{
"abstract": "Relapse is a major cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). The aim of this study was to explore the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with minimal-dose decitabine (Dec) on the prevention of HR-AML relapse after allo-HSCT.\n\n\n\nWe conducted a phase II, open-label, multicenter, randomized controlled trial. Two hundred four patients with HR-AML who had received allo-HSCT 60-100 days before randomization and who were minimal residual disease negative were randomly assigned 1:1 to either rhG-CSF combined with minimal-dose Dec (G-Dec group: 100 µg/m2 of rhG-CSF on days 0-5 and 5 mg/m2 of Dec on days 1-5) or no intervention (non-G-Dec group). The primary outcome was relapse after transplantation, and the secondary outcomes were chronic graft-versus-host disease (cGVHD), safety of the treatment, and survival.\n\n\n\nThe estimated 2-year cumulative incidence of relapse in the G-Dec group was 15.0% (95% CI, 8.0% to 22.1%), compared with 38.3% (95% CI, 28.8% to 47.9%) in the non-G-Dec group (P < .01), with a hazard ratio (HR) of 0.32 (95% CI, 0.18 to 0.57; P < .01). There was no statistically significant difference between the G-Dec and non-G-Dec groups in the 2-year cumulative incidence of cGVHD without relapse (23.0% [95% CI, 14.7% to 31.3%] and 21.7% [95% CI, 13.6% to 29.7%], respectively; P = .82), with an HR of 1.07 (95% CI, 0.60 to 1.92; P = .81). After rhG-CSF combined with minimal-dose Dec maintenance, increasing numbers of natural killer, CD8+ T, and regulatory T cells were observed.\n\n\n\nOur findings suggest that rhG-CSF combined with minimal-dose Dec maintenance after allo-HSCT can reduce the incidence of relapse, accompanied by changes in the number of lymphocyte subtypes.",
"affiliations": "Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Department of Health Statistics, College of Military Preventive Medicine, Army Medical University, Chongqing, China.;Department of Hematology, General Hospital of Kunming Military Region of the People's Liberation Army (PLA), Kunming, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Department of Hematology, General Hospital of Chengdu Military Region of the PLA, Chengdu, China.;Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China.;Department of Hematology, the Affiliated Hospital of Xinjiang Medical University, Urumqi, China.;Department of Hematology, General Hospital of Lanzhou Military Region of the PLA, Lanzhou, China.;Department of Hematology, Xinjiang Provincial People's Hospital, Urumqi, China.;Department of Hematology, Affiliated Hospital of Guiyang Medical University, Guiyang, China.;Department of Hematology, Tangdu Hospital, Forth Military Medical University (Air Force Medical University), Xi'an, China.;Department of Hematology, Yunnan Provincial People's Hospital, Kunming, China.;Department of Hematology, Sichuan Provincial People's Hospital, Chengdu, China.;Department of Hematology, General Hospital of Chengdu Military Region of the PLA, Chengdu, China.;Department of Hematology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Department of Hematology, Xinjiang Provincial People's Hospital, Urumqi, China.;Department of Hematology, General Hospital of Lanzhou Military Region of the PLA, Lanzhou, China.;Department of Hematology, the Affiliated Hospital of Xinjiang Medical University, Urumqi, China.;Department of Hematology, General Hospital of Kunming Military Region of the People's Liberation Army (PLA), Kunming, China.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.;Departments of Diabetes Immunology and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA.;Department of Otolaryngology, Keck School of Medicine, University of Southern California, CA.;Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China.",
"authors": "Gao|Lei|L|;Zhang|Yanqi|Y|;Wang|Sanbin|S|;Kong|Peiyan|P|;Su|Yi|Y|;Hu|Jiong|J|;Jiang|Ming|M|;Bai|Hai|H|;Lang|Tao|T|;Wang|Jishi|J|;Liu|Li|L|;Yang|Tonghua|T|;Huang|Xiaobing|X|;Liu|Fang|F|;Lou|Shifeng|S|;Liu|Yao|Y|;Zhang|Cheng|C|;Liu|Hong|H|;Gao|Li|L|;Liu|Jia|J|;Zhu|Lidan|L|;Wen|Qin|Q|;Chen|Ting|T|;Wang|Ping|P|;Rao|Jun|J|;Mao|Min|M|;Wang|Cunbang|C|;Duan|Xianlin|X|;Luo|Le|L|;Peng|Xiangui|X|;Cassady|Kaniel|K|;Zhong|Jiang F|JF|;Zhang|Xi|X|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.19.03277",
"fulltext": "\n==== Front\nJ Clin Oncol\nJ Clin Oncol\njco\nJCO\nJournal of Clinical Oncology\n0732-183X\n1527-7755\nAmerican Society of Clinical Oncology\n\n33108244\n1903277\n10.1200/JCO.19.03277\nORIGINAL REPORTS\nBone Marrow Transplantation\nEffect of rhG-CSF Combined With Decitabine Prophylaxis on Relapse of Patients With High-Risk MRD-Negative AML After HSCT: An Open-Label, Multicenter, Randomized Controlled Trial\nrhG-CSF Plus Decitabine Prevents Relapse in HR-AML After HSCT\nGao Lei MD, PhD 1\nZhang Yanqi PhD 2\nWang Sanbin MD, PhD 3\nKong Peiyan MD, PhD 1\nSu Yi MM 4\nHu Jiong MD 5\nJiang Ming MD 6\nBai Hai MD 7\nLang Tao MD 8\nWang Jishi MD, PhD 9\nLiu Li MD, PhD 10\nYang Tonghua MD 11\nHuang Xiaobing MD 12\nLiu Fang MD 4\nLou Shifeng MD 13\nLiu Yao MD, PhD 1\nZhang Cheng MD, PhD 1\nLiu Hong MM 1\nGao Li MD, PhD 1\nLiu Jia MM 1\nZhu Lidan MM 1\nWen Qin PhD 1\nChen Ting MM 1\nWang Ping MM 1\nRao Jun MD 1\nMao Min MD 8\nWang Cunbang MD 7\nDuan Xianlin MD 6\nLuo Le MD, MM, MS 3\nPeng Xiangui MM 1\nCassady Kaniel PhD 14\nZhong Jiang F. PhD 15\nZhang Xi MD, PhD 1\n1 Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China\n2 Department of Health Statistics, College of Military Preventive Medicine, Army Medical University, Chongqing, China\n3 Department of Hematology, General Hospital of Kunming Military Region of the People’s Liberation Army (PLA), Kunming, China\n4 Department of Hematology, General Hospital of Chengdu Military Region of the PLA, Chengdu, China\n5 Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, China\n6 Department of Hematology, the Affiliated Hospital of Xinjiang Medical University, Urumqi, China\n7 Department of Hematology, General Hospital of Lanzhou Military Region of the PLA, Lanzhou, China\n8 Department of Hematology, Xinjiang Provincial People’s Hospital, Urumqi, China\n9 Department of Hematology, Affiliated Hospital of Guiyang Medical University, Guiyang, China\n10 Department of Hematology, Tangdu Hospital, Forth Military Medical University (Air Force Medical University), Xi’an, China\n11 Department of Hematology, Yunnan Provincial People’s Hospital, Kunming, China\n12 Department of Hematology, Sichuan Provincial People’s Hospital, Chengdu, China\n13 Department of Hematology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China\n14 Departments of Diabetes Immunology and Hematology/Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA\n15 Department of Otolaryngology, Keck School of Medicine, University of Southern California, CA\nXi Zhang, MD, PhD, Medical Center of Hematology, Xinqiao Hospital, The Army Medical University, Chongqing 400037, China; e-mail: zhangxxi@sina.com.\n20 12 2020\n27 10 2020\n38 36 42494259\n4 8 2020\n© 2020 by American Society of Clinical Oncology\n2020\nAmerican Society of Clinical Oncology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/\n\nPURPOSE\n\nRelapse is a major cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). The aim of this study was to explore the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with minimal-dose decitabine (Dec) on the prevention of HR-AML relapse after allo-HSCT.\n\nPATIENTS AND METHODS\n\nWe conducted a phase II, open-label, multicenter, randomized controlled trial. Two hundred four patients with HR-AML who had received allo-HSCT 60-100 days before randomization and who were minimal residual disease negative were randomly assigned 1:1 to either rhG-CSF combined with minimal-dose Dec (G-Dec group: 100 µg/m2 of rhG-CSF on days 0-5 and 5 mg/m2 of Dec on days 1-5) or no intervention (non–G-Dec group). The primary outcome was relapse after transplantation, and the secondary outcomes were chronic graft-versus-host disease (cGVHD), safety of the treatment, and survival.\n\nRESULTS\n\nThe estimated 2-year cumulative incidence of relapse in the G-Dec group was 15.0% (95% CI, 8.0% to 22.1%), compared with 38.3% (95% CI, 28.8% to 47.9%) in the non–G-Dec group (P < .01), with a hazard ratio (HR) of 0.32 (95% CI, 0.18 to 0.57; P < .01). There was no statistically significant difference between the G-Dec and non–G-Dec groups in the 2-year cumulative incidence of cGVHD without relapse (23.0% [95% CI, 14.7% to 31.3%] and 21.7% [95% CI, 13.6% to 29.7%], respectively; P = .82), with an HR of 1.07 (95% CI, 0.60 to 1.92; P = .81). After rhG-CSF combined with minimal-dose Dec maintenance, increasing numbers of natural killer, CD8+ T, and regulatory T cells were observed.\n\nCONCLUSION\n\nOur findings suggest that rhG-CSF combined with minimal-dose Dec maintenance after allo-HSCT can reduce the incidence of relapse, accompanied by changes in the number of lymphocyte subtypes.\n\nSJS Exportv1\n==== Body\npmcINTRODUCTION\n\nThe prognosis of patients with high-risk (HR) acute myeloid leukemia (AML) continues to worsen after treatment. One potentially curative regimen for HR-AML is allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Over the past decade, although considerable advances have been achieved in therapeutic approaches for allo-HSCT, the best survival rate among adults with HR-AML who have undergone allo-HSCT after achieving complete remission (CR) is only approximately 55%, and relapse remains the leading cause of death in patients after allo-HSCT, accounting for 20%-50% of deaths.1-3 Donor lymphocyte infusion (DLI) is one of the most common interventions for AML relapse because donor lymphocytes are expected to promote the graft-versus-leukemia (GVL) effect.4 However, DLI treatment success in AML relapse has been limited, and the reported overall survival (OS) rates at 3 years are only 10%-20%.5 Accordingly, the development of novel regimens to prevent leukemia relapse remains the highest priority in the treatment of HR-AML after allo-HSCT.\n\nCONTEXT\n\nKey Objective\n\nRelapse remains the leading cause of death in patients with high-risk acute myeloid leukemia (HR-AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This open-label, multicenter, randomized, controlled, phase 2 trial examined whether recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with minimal-dose decitabine (Dec) have the effect on preventing AML relapse. It was contained 204 patients and, to our knowledge, is the largest prospective, controlled clinical study to date.\n\nKnowledge Generated\n\nIn this study, we revealed that rhG-CSF combined with minimal-dose Dec maintenance therapy after allo-HSCT can reduce the incidence of relapse, accompanied by changes in the number of lymphocyte subtypes, leading to the acquisition of graft-versus-leukemia and immune tolerance.\n\nRelevance\n\nOur study demonstrated that rhG-CSF combined with minimal-dose Dec maintenance therapy can be selected as the optimal treatment for HR-AML after allo-HSCT. As a result, this maintenance therapy brings survival benefits by reducing the relapse rate.\n\nDecitabine (Dec) is a hypomethylating agent that is currently approved for the treatment of high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, and AML.6,7 Recently, retrospective case series studies and small-sample, prospective, single-arm studies have found that the primary effects of hypomethylating treatment for the prevention of AML relapse after allo-HSCT consist of an increase in the number of T regulatory (Treg) cells and the induction of cytotoxic CD8+ T-cell responsiveness to tumor antigens.8-10 Furthermore, these studies explored the appropriate doses and optimal treatment courses of hypomethylating agents.8,9 However, further optimization of the anti-AML effect while reducing the hematologic toxicities of hypomethylating agents must still be addressed.\n\nImportantly, the demethylating effect of Dec has been shown to be cyclin dependent,11 indicating that the combination of Dec with an agent that promotes cell cycle entry could synergistically promote the elimination of AML and prevent relapse. Notably, granulocyte colony-stimulating factor (G-CSF) is a soluble growth factor that interacts with the G-CSF receptor to promote cell entry into the cell cycle.12 Moreover, G-CSF and Dec have been shown to promote the production and function of cytotoxic CD8+ T cells, natural killer (NK) cells. and Treg cells,8,13 which may promote the GVL effect and reduce graft-versus-host disease (GVHD). We hypothesized that recombinant human G-CSF (rhG-CSF) followed by minimal-dose Dec could effectively prevent AML relapse. To test this hypothesis, we conducted a multicenter, open-label, randomized controlled study to investigate the efficacy, safety, and tolerability of G-CSF combined with minimal-dose Dec for prophylaxis against relapse in patients who underwent allo-HSCT.\n\nPATIENTS AND METHODS\n\nStudy Design and Participants\n\nThis study was a phase II, open-label, multicenter, randomized controlled trial (ChiCTR-IIR-16008182) conducted by the 12 hospitals in Hematopoietic Stem Cell Transplantation–Western China Group. The protocol and all amendments were approved by the China Registered Clinical Laboratory Ethics Committee and the institutional review boards at each of the 12 participating institutions. All of the patients or their legal guardians signed informed consent forms in accordance with the Declaration of Helsinki.\n\nEligible patients with HR-AML included in the trial were categorized as having AML with poor genetic abnormalities,14 primary refractory AML, relapsed AML, or secondary AML.15,16 Eligible patients met the following criteria: established stable donor hematopoiesis; CR and minimal residual disease (MRD) negative; no acute GVHD (aGVHD) or controlled aGVHD for > 60 days after transplantation; and no uncontrolled infections or severe liver, renal, lung, or heart disease. The exclusion criteria were serious organ dysfunction, leukemia combined with other cancers, active systemic infection, GVHD requiring treatment, inability to schedule follow-up, brain dysfunction or severe mental illness preventing compliance with the study protocol, and hypersensitivity to any components of rhG-CSF and/or Dec.\n\nSample Size and Power Analysis\n\nOur primary outcome variable was the cumulative incidence of relapse. The sample size was determined using the log-rank test comparing two cumulative incidences. In the preliminary research, the incidences of relapse in the patients who received rhG-CSF plus Dec (G-Dec group) and the patients who received no treatment (non–G-Dec group) were 12.6% and 32.1%, respectively. We assumed 1 year of enrollment and 2 years of follow-up. With a power of 90% and a two-sided test of α = .05 type I error, a total sample size of 204 patients would be needed, with 102 patients in each arm. With this sample size, if there were no deaths without relapses, 46 relapses would be observed, obtaining a 90% power to test a treatment difference between 67.9% and 87.4% with a hazard ratio (HR) of 0.35. See Data Supplement (online only) for details.\n\nRandomization and Procedure\n\nA stratified block randomization method was used in this study. At each research center, consenting eligible participants were stratified by disease status before HSCT (two levels: CR and MRD negative [CRMRD−] and CR and MRD positive [CRMRD+]/partial remission [PR]/no remission [NR]) and randomly assigned in a 1:1 ratio to the G-Dec group or non–G-Dec group using a computer-generated block randomization schedule. The block size was randomly generated among the numbers 4, 6, 8, and 10.\n\nIn the G-Dec group, patients received six courses of rhG-CSF combined with minimal-dose Dec (rhG-CSF 100 µg/m2 by subcutaneous injection on days 0-5, and Dec at 5 mg/m2 by infusion on days 1-5). No treatment was given to the patients in non–G-Dec group. rhG-CSF and Dec were administered every 6-8 weeks for up to six courses. The maintenance treatment was discontinued if leukemia relapsed, severe chronic GVHD (cGVHD) occurred, or severe adverse effects of the infusion occurred or upon completion of six cycles of infusion. The observation period extended from enrollment to March 21, 2019 or to the time of the patient’s death, whichever occurred first. Both patients and clinicians were aware of the treatment allocation, but the outcome assessors were blinded to the treatment allocation when assessing all primary and secondary end points.\n\nStatistical Analysis\n\nThe primary end point was cumulative incidence of relapse. Secondary end points included the cumulative incidence of cGVHD, cGVHD without relapse, and transplantation-related mortality (TRM); safety of rhG-CSF combined with Dec; OS; and leukemia-free survival (LFS). Exploratory end points were the cell numbers of T, B, NK, and Treg cell subsets during the G-Dec treatment courses. The Mann-Whitney U test, χ2 test, and Fisher’s exact probability test were used to compare the baseline characteristics between the G-Dec and non–G-Dec groups. The competing risk model (Fine and Gray model) was used to estimate 2-year cumulative incidences and HRs with 95% CIs of relapse, cGVHD, and cGVHD without relapse. The Kaplan-Meier method, the log-rank test, and Cox proportional hazard models were used to analyze OS and LFS. Subgroups analysis and interaction P values are shown in a forest plot. In the analysis of T, B, NK, and Treg cell subsets, an analysis of variance of repeated measurement data and t test with Bonferroni corrections were used to assess the differences in the repeated measurement data based on lymphocyte numbers during the G-Dec treatment courses. For details of the statistical analysis, see the Data Supplement.\n\nAll reported P values are two-sided. The sample size and power calculations were performed using PASS software (version 11; NCSS Statistical Software, Kaysville, UT). The statistical analyses were performed using IBM SPSS statistics software version 22 (IBM China, Beijing, China) and the R software package version 2.5.0 (http://www.r-project.org).\n\nRESULTS\n\nA total of 220 patients from 12 transplantation centers were included in the clinical study from April 5, 2016 to January 16, 2017 (Fig 1). The patient characteristics are provided in Table 1, and other patient characteristics are described in the Data Supplement.\n\nFIG 1. Flowchart of the study participants. (*) Observation was stopped according to the visit schedule, and only disease status and survival of the patients were followed. cGVHD, chronic graft-versus-host disease; Dec, decitabine; rhG-CSF, recombinant human granulocyte colony-stimulating factor.\n\nTABLE 1. Patients, Donors, and Graft Characteristics\n\nThe median follow-up time was 28.0 months (range, 2.8-35.9 months) for the G-Dec group and 26.4 months (range, 2.9-35.7 months) for the non–G-Dec group. We found that relapse occurred in 15 (15.0%) of 100 patients in the G-Dec group and 39 (38.2%) of 102 patients in the control group; the estimated 2-year cumulative incidence rates of relapse were 15.0% (95% CI, 8.0% to 22.1%) and 38.3% (95% CI, 28.8% to 47.9%), respectively, with an HR of 0.32 (95% CI, 0.18 to 0.57; P < .01; Fig 2A) . Both in the univariable competing model and the multivariable model after adjustment for possible confounders, treatment and disease status before HSCT were screened out as influencing factors of relapse. The HRs were 0.31 (95% CI, 0.18 to 0.56; P < .01) and 2.77 (95% CI, 1.60 to 4.79; P < .01) in the multivariable model (Data Supplement). We also performed subgroup analyses based on different clinical characteristics. Among the patients with CRMRD−, the 2-year cumulative incidence of relapse in the G-Dec group was lower than that in the non–G-Dec group (5.9% [95% CI, 0.2% to 11.6%] v 31.0% [95% CI, 19.9% to 42.1%], respectively; P < .01), with an HR of 0.16 (95% CI, 0.06 to 0.48; P < .01). For patients with CRMRD+/PR/NR before transplantation, G-Dec maintenance therapy showed a tendency to reduce the 2-year cumulative incidence of relapse after transplantation compared with no G-Dec (34.5% [95% CI, 17.7% to 51.4%] v 52.9% [95% CI, 35.8% to 70.1%], respectively; P = .05), with an HR of 0.48 (95% CI, 0.23 to 0.99; P = .05). There was no interaction between treatment and disease status before HSCT (P = .10). The other clinical characteristics also showed no interaction with the treatment (Appendix Fig A1, online only).\n\nFIG 2. Cumulative incidence of (A) relapse, (B) total chronic graft-versus-host disease (cGVHD), and (C) cGVHD without relapse. G-Dec, recombinant human granulocyte colony-stimulating factor plus decitabine; HR, hazard ratio.\n\nAll patients who survived longer than 100 days after HSCT were evaluated to determine the incidence of cGVHD. In the G-Dec group, cGVHD developed in 34 patients (34.0%) as follows: 30 (30.0%) exhibited mild or moderate cGVHD, whereas four (4.0%) exhibited severe cGVHD. In the non–G-Dec group, cGVHD occurred in 49 patients (48.0%) as follows: 45 (44.1%) exhibited mild or moderate cGVHD, and four (3.9%) exhibited severe cGVHD. The 2-year cumulative incidence rates of cGVHD in the G-Dec and non–G-Dec groups were 34.0% (95% CI, 24.7% to 43.3%) and 48.2% (95% CI, 38.4% to 58.0%), respectively (HR, 0.62; 95% CI, 0.40 to 0.96; P = .03; Data Supplement and Fig 2B). Eleven patients in the G-Dec group and 27 patients in the non–G-Dec group developed cGVHD as a result of the discontinuation of immunosuppressants and DLI during recurrence of the disease. Accordingly, no difference was found between the two groups in the incidence of cGVHD without relapse intervention (23.0% [95% CI, 14.7% to 31.3%] in G-Dec group v 21.7% [95% CI, 13.6% to 29.7%] in non–G-Dec group; HR, 1.07 [95% CI, 0.6 to 1.92]; P = .81; Data Supplement and Fig 2C). The clinical manifestations of cGVHD are described in the Data Supplement.\n\nBefore the study, 20 patients were randomly identified in each group to examine the effect of the G-Dec treatment on lymphocyte subpopulations. The baseline characteristics and representative analysis of 20 patients in each group are provided in the Data Supplement. We monitored the immune cell subtypes, including T cells, B cells, NK cells, and Treg lymphocytes. No significant changes were observed in the numbers of B cells or CD4+ T cells in either the G-Dec group or the non–G-Dec group (P > .05, Figs 3A and 3B). In contrast, the numbers of CD8+ T, NK, and Treg cells increased by the second to third course of G-Dec treatment (P < .05, Figs 3C-3E). Next, for 20 patients in each group, the numbers of CD8+ T, NK, and Treg cells at the end of the last course of G-Dec treatment were used as covariates in a competing risk model to assess the association between increased effector cell numbers and relapse. The univariable competing model revealed that the increase in CD8+ T, NK, and Treg cells reduced the risk of relapse, and their HRs were 0.99 (95% CI, 0.98 to 1.00; P = .02), 0.97 (95% CI, 0.95 to 0.99; P < .01), and 0.96 (95% CI, 0.92 to 1.00; P = .04), respectively. In the multivariable model, the number of NK cells was found to be an independent factor influencing relapse, with an HR of 0.96 (95% CI, 0.94 to 0.99; P < .01; Data Supplement).\n\nFIG 3. Changes in the mean absolute counts of lymphocyte subsets after recombinant human granulocyte colony-stimulating factor (rhG-CSF) plus decitabine (Dec) maintenance treatment (G-Dec group). The number of patients in both the G-Dec group and the non–G-Dec (no treatment) control group was 20. (A) Natural killer (NK) cells. (B) CD19+ B cells. (C) CD3+CD4+ T cells. (D) CD3+CD8+ T cells. (E) CD4+CD25+FOXP3+ T cells. (*) After Bonferroni correction, P < .001 v non–G-Dec group. C, cycle; C1D1, first day in the first cycle before medication; D, day; K, thousand; Treg, regulatory T cell.\n\nEighty-three patients in the G-Dec group and 70 patients in the non–G-Dec group were still alive on January 16, 2019. The 2-year cumulative incidence rates of TRM in the G-Dec and non–G-Dec groups were 3.4% (95% CI, 1.1% to 10.3%) and 1.6% (95% CI, 0.2% to 11.1%), respectively, with an HR of 2.4 (95% CI, 0.25 to 22.97; P = .44). The causes of TRM included severe infections in three patients and recurrent episodes of serious GVHD in two patients. The 2-year rates of LFS in the G-Dec and non–G-Dec groups were 81.9% (95% CI, 72.8% to 88.2%) and 60.7% (95% CI, 50.5% to 69.4%), respectively, with an HR of 0.38 (95% CI, 0.22 to 0.66; P < .01; Fig 4A). The 2-year rates of OS in the G-Dec and non–G-Dec groups were 85.8% (95% CI, 77.1% to 91.3%) and 69.7% (95% CI, 59.6% to 77.8%), respectively, with an HR of 0.45 (95% CI, 0.24 to 0.83; P = .01; Fig 4B).\n\nFIG 4. (A) Leukemia-free survival and (B) overall survival among the patients in the two groups. G-Dec, recombinant human granulocyte colony-stimulating factor plus decitabine; HR, hazard ratio.\n\nAdverse events of any grade regardless of attribution to a trial regimen by an investigator occurred in 93.0% of the patients in the G-Dec group and 83.3% of the patients in the non–G-Dec group. The most common treatment-emergent adverse event was hypoleukocytosis, which mainly occurred during the first two courses of G-Dec treatment (Data Supplement). The nonhematologic toxicities included nausea, vomiting, diarrhea, peripheral edema, abnormal liver function, and abnormal renal function. Most adverse events were grade 1 or 2 and improved after symptomatic treatment (Table 2). No deaths resulted from lethal organ toxicities as a result of G-Dec maintenance therapy in the study.\n\nTABLE 2. Adverse Events of Any Cause in the Two Groups\n\nDISCUSSION\n\nIn this study, we investigated rhG-CSF combined with minimal-dose Dec as a treatment strategy for HR-AML relapse prophylaxis. The incidence of relapse in the G-Dec group was significantly lower than that in the non–G-Dec group. In addition, the relapse rate in patients with CRMRD− before transplantation was significantly decreased after rhG-CSF combined with minimal-dose Dec treatment, indicating that maintenance treatment has a greater benefit for patients with HR-AML who are MRD negative before transplantation.\n\nSelecting the optimal dose is important when administering hypomethylating agents after allo-HSCT. In our study, approximately 97.0% of patients tolerated at least four cycles, and 96.0% of patients completed all six cycles. Although the main dose-limiting toxicity was myelosuppression, only 13.0% of the patients (13 of 100 patients) experienced grade 3 or 4 neutropenia or thrombocytopenia requiring rhG-CSF or recombinant human thrombopoietin support, and 16.0% of patients (16 of 100 patients) experienced grade 3 or 4 anemia requiring an RBC infusion.\n\nBoth our study design and findings differ from those of previous studies using hypomethylation agent maintenance therapy after allo-HSCT. We found that rhG-CSF combined with minimal-dose Dec treatment demonstrated a prominent advantage in the prevention of AML recurrence. rhG-CSF is known to stimulate the production, maturation, and effector functions of granulocytes and co-stimulate early progenitor cells synergistically with several other cytokines.17 Although the use of rhG-CSF in AML has been controversial because it stimulates the in vitro proliferation of leukemic blast cells from most patients with AML,18-20 a large number of clinical studies show that rhG-CSF does not reduce the remission rate of AML chemotherapy.21-25 Furthermore, rhG-CSF combined with Dec and chemotherapy have been proven to improve the remission rate in elderly or refractory patients with AML.26,27 Interestingly, Xiong et al28 found that NK cell populations were expanded in G-CSF–mobilized sources and could also exhibit improved functionality, demonstrating increased GVL capacity. In addition, Dec can enhance NK cell–mediated antibody-dependent cellular cytotoxicity against AML blasts and decrease relapse in patients with AML.29 In our study, the number of NK cells was increased after rhG-CSF combined with Dec treatment. Furthermore, the number of NK cells was found to be an independent factor influencing relapse; with an increasing number of NK cells, the risk of relapse was reduced. This finding suggests that the G-Dec group had a reduced cumulative incidence of relapse as a result of an increase in NK cells. Concomitantly, we found that the number of CD8+ T cells was also increased in patients who received the G-Dec treatment compared with controls. Recently, Ghoneim H.E. et al30 reported that blocking de novo DNA methylation with Dec in activated CD8+ T cells promoted their retention of effector function and inhibited exhaustion. Furthermore, the GVL effects exerted by donor T cells against leukemic-associated antigens also play a crucial role in disease eradication and relapse prevention.31,32 Therefore, we postulate that the effect of G-CSF combined with the Dec maintenance regimen to increase the numbers of NK and CD8+ T cells might be the primary mechanism that reduces relapse in patients with HR-AML after allo-HSCT.\n\nIn the current study, G-CSF therapy combined with a Dec maintenance regimen did not increase the incidence of cGVHD in patients with HR-AML after allo-HSCT. The lymphocyte subset analysis showed that the number of Treg cells significantly increased after the second cycle of treatment. This finding is in agreement with preclinical animal models, in which Treg cells have been shown to suppress GVHD without decreasing the GVL effect.33 Dec and azacytidine (another demethylation drug) have been shown to expand immunomodulatory Treg cells in animal models and in phase I and II clinical trials.8,34 Recently, in vitro experiments have shown that the exposure of T cells to azacytidine leads to demethylation of the FOXP3 promoter, FOXP3 overexpression, and expansion of Treg cells.35 Moreover, G-CSF can promote the expansion and function of Treg cells without diminishing their function, cytokine profiles, or phenotypic characteristics.36-38\n\nIn terms of limitations, the small sample size in some subgroups might have resulted in low test power, and the open-label design might have exaggerated the treatment effect in the G-Dec group. The results require validation in a multicenter, randomized, controlled, double-blind trial with a larger sample size. In addition, only 20 patients were randomly identified in each group to examine the effect of G-Dec treatment on lymphocyte subpopulations and the relationship between lymphocyte subpopulations and relapse. The representativeness of 20 patients is relatively limited. Further studies of lymphocyte subpopulations and functional studies should be performed to show the alloreactivity or anti-AML efficacy in the entire cohort.\n\nAltogether, to our knowledge, our findings demonstrate that rhG-CSF combined with minimal-dose Dec treatment after allo-HSCT could significantly reduce the incidence of HR-AML relapse. The reduction in relapse is associated with increased numbers of NK and CD8+ T cells, which likely promote the GVL effect, and increased numbers of Treg cells, which likely control the development of GVHD. Future studies are required to investigate combinations of other drugs or treatment regimens with minimal-dose Dec for AML relapse prophylaxis in patients who are MRD positive before transplantation.\n\nACKNOWLEDGMENT\n\nWe thank the patients and their families and all investigators and site personnel.\n\nSUPPORT\n\nCLINICAL TRIAL INFORMATION\n\nAUTHOR CONTRIBUTIONS\n\nConception and design: Lei Gao, Yanqi Zhang, Xi Zhang\n\nFinancial support: Lei Gao, Xi Zhang\n\nAdministrative support: Lei Gao, Xi Zhang\n\nProvision of study materials or patients: Lei Gao, Sanbin Wang, Peiyan Kong, Yi Su, Jiong Hu, Ming Jiang, Hai Bai, Tao Lang, Li Liu, Tonghua Yang, Xiaobin Huang, Fang Liu, Shifeng Lou, Yao Liu, Cheng Zhang, Hong Liu, Li Gao, Jia Liu, Lidan Zhu, Qin Wen, Ting Chen, Ping Wang, Min Mao, Cunbang Wang, Xianlin Duan, Le Luo, Xiangui Peng, Xi Zhang\n\nCollection and assembly of data: Lei Gao, Sanbin Wang, Peiyan Kong, Yi Su, Jiong Hu, Ming Jiang, Hai Bai, Tao Lang, Jishi Wang, Li Liu, Tonghua Yang, Xiaobin Huang, Fang Liu, Shifeng Lou, Yao Liu, Cheng Zhang, Hong Liu, Li Gao, Jia Liu, Lidan Zhu, Qin Wen, Ting Chen, Ping Wang, Jun Rao, Min Mao, Cunbang Wang, Xianlin Duan, Le Luo, Xiangui Peng, Xi Zhang\n\nData analysis and interpretation: Lei Gao, Yanqi Zhang, Kaniel Cassady, Jiang F. Zhong, Xi Zhang\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\n\nEffect of rhG-CSF Combined With Decitabine Prophylaxis on Relapse of Patients With High-Risk MRD-Negative AML After HSCT: An Open-Label, Multicenter, Randomized Controlled Trial\n\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.\n\nOpen Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).\n\nKaniel Cassady\n\nEmployment: Regeneron\n\nStock and Other Ownership Interests: Regeneron\n\nNo other potential conflicts of interest were reported.\n\nAPPENDIX\n\nFIG A1. Forest plot summarizing hazard ratios for the G-Dec group versus the non-G-Dec group in the subgroup analyses with a test for interaction. ACNU, nimustine; Ara-C, cytarabine; ATG, thymoglobulin; BU, busulfan; CRMRD−, complete remission and minimal residual disease negative; CY, cyclophosphamide; HSCT, hematopoietic stem-cell transplantation.\n\nSupported by the National Key Research and Development Program of China (Grants No. 2016YFA0202104 and 2017YFA0105502), the Chinese National Natural Science Foundation (Grants No. 81370593, 81570131, 81570097, and 81873424), the Chongqing Social Undertakings, People’s Livelihood Guarantee and Technology Innovation Foundation (Grant No. cstc2016shms-ztzx10003), the Chongqing Key Project of Basic and Frontier Research Program (Grant No. cstc2015jcyjBX0077), the Chongqing National Natural Science Key Foundation (Grant No. cstc2019jcyj-zdxmX0023), the Research Fund from the Clinical Foundation of Army Medical University (Grants No. 2018JSLC0034 and 2018XLC1006), and Xinqiao Hospital (Grant No. 2018YQYLY007). This article is the authors’ own work and not an official position of the institution or funder.\n\nChiCTR-IIR-16008182\n\nLei Gao, Yanqi Zhang, and Sanbin Wang contributed equally to this work.\n==== Refs\nREFERENCES\n\n1. Ruggeri A Labopin M Sanz G , et al : Comparison of outcomes after unrelated cord blood and unmanipulated haploidentical stem cell transplantation in adults with acute leukemia. Leukemia 29 :1891-1900, 2015 25882700\n2. Tsai SB Rhodes J Liu H , et al : Reduced-intensity allogeneic transplant for acute myeloid leukemia and myelodysplastic syndrome using combined CD34-selected haploidentical graft and a single umbilical cord unit compared with matched unrelated donor stem cells in older adults. Biol Blood Marrow Transplant 24 :997-1004, 2018 29288821\n3. Xu L Chen H Chen J , et al : The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China: Recommendations from the Chinese Society of Hematology. J Hematol Oncol 11 :33, 2018 29495966\n4. Wang Y Chen H Chen J , et al : The consensus on the monitoring, treatment, and prevention of leukemia relapse after allogeneic hematopoietic stem cell transplantation in China. Cancer Lett 438 :63-75, 2018 30217562\n5. Schmid C Labopin M Nagler A , et al : Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: A retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 25 :4938-4945, 2007 17909197\n6. Yun S Vincelette ND Abraham I , et al : Targeting epigenetic pathways in acute myeloid leukemia and myelodysplastic syndrome: A systematic review of hypomethylating agents trials. Clin Epigenetics 8 :68, 2016 27307795\n7. Li J Chen Y Zhu Y , et al : Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia. Oncotarget 6 :6448-6458, 2015 25749041\n8. Goodyear OC Dennis M Jilani NY , et al : Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 119 :3361-3369, 2012 22234690\n9. Pusic I Choi J Fiala MA , et al : Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 21 :1761-1769, 2015 26055299\n10. Han S Kim YJ Lee J , et al : Model-based adaptive phase I trial design of post-transplant decitabine maintenance in myelodysplastic syndrome. J Hematol Oncol 8 :118, 2015 26497198\n11. Wen XM Lin J Yang J , et al : Double CEBPA mutations are prognostically favorable in non-M3 acute myeloid leukemia patients with wild-type NPM1 and FLT3-ITD. Int J Clin Exp Pathol 7 :6832-6840, 2014 25400766\n12. Gao L Wen Q Chen X , et al : Effects of priming with recombinant human granulocyte colony-stimulating factor on conditioning regimen for high-risk acute myeloid leukemia patients undergoing human leukocyte antigen-haploidentical hematopoietic stem cell transplantation: A multicenter randomized controlled study in southwest China. Biol Blood Marrow Transplant 20 :1932-1939, 2014 25109850\n13. Franzke A : The role of G-CSF in adaptive immunity. Cytokine Growth Factor Rev 17 :235-244, 2006 16807060\n14. National Comprehensive Cancer Network: NCCN clinical practice guidelines in oncology (NCCN guidelines): Acute myeloid leukemia. https://www.nccn.org/professionals/physician_gls/default.aspx\n15. Estey EH : How to manage high-risk acute myeloid leukemia. Leukemia 26 :861-869, 2012 22116555\n16. Schiller GJ : High-risk acute myelogenous leukemia: Treatment today ... and tomorrow. Hematology Am Soc Hematol Educ Program 2013 :201-208, 2013 24319182\n17. Yong KL : Granulocyte colony-stimulating factor (G-CSF) increases neutrophil migration across vascular endothelium independent of an effect on adhesion: Comparison with granulocyte-macrophage colony-stimulating factor (GM-CSF). Br J Haematol 94 :40-47, 1996 8757506\n18. Welte K Gabrilove J Bronchud MH , et al : Filgrastim (r-metHuG-CSF): The first 10 years. Blood 88 :1907-1929, 1996 8822908\n19. Nara N Murohashi I Suzuki T , et al : Effects of recombinant human granulocyte colony-stimulating factor (G-CSF) on blast progenitors from acute myeloblastic leukaemia patients. Br J Cancer 56 :49-51, 1987 3497662\n20. Usuki K Iki S Endo M , et al : Granulocyte colony-stimulating factor in acute myeloid leukemia. Stem Cells 13 :647-654, 1995 8590866\n21. Heil G Hoelzer D Sanz MA , et al : A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. Blood 90 :4710-4718, 1997 9389686\n22. Dombret H Chastang C Fenaux P , et al : A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. N Engl J Med 332 :1678-1683, 1995 7539109\n23. Godwin JE Kopecky KJ Head DR , et al : A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: A Southwest Oncology Group study (9031). Blood 91 :3607-3615, 1998 9572995\n24. Bradstock K Matthews J Young G , et al : Effects of glycosylated recombinant human granulocyte colony-stimulating factor after high-dose cytarabine-based induction chemotherapy for adult acute myeloid leukaemia. Leukemia 15 :1331-1338, 2001 11516093\n25. Goldstone AH Burnett AK Wheatley K , et al : Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 98 :1302-1311, 2001 11520775\n26. Li L Zhang X Yu H , et al : Low-dose hypomethylating agent decitabine in combination with aclacinomycin and cytarabine achieves a better outcome than standard FLAG chemotherapy in refractory/relapsed acute myeloid leukemia patients with poor-risk cytogenetics and mutations. Onco Targets Ther 11 :6863-6870, 2018 30349319\n27. Huang J Hong M Zhu Y , et al : Decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin is as effective as standard dose chemotherapy in the induction treatment for patients aged from 55 to 69 years old with newly diagnosed acute myeloid leukemia. Leuk Lymphoma 59 :2570-2579, 2018 29616840\n28. Xiong Y Mouginot M Reppel L , et al : Modification of NK cell subset repartition and functions in granulocyte colony-stimulating factor-mobilized leukapheresis after expansion with IL-15. Immunol Res 65 :1130-1138, 2017 29019081\n29. Vasu S He S Cheney C , et al : Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts. Blood 127 :2879-2889, 2016 27013443\n30. Ghoneim HE Fan YP Moustaki A , et al . De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell 170 : 142-157, 2017 28648661\n31. Rücker-Braun E Link CS Schmiedgen M , et al : Longitudinal analyses of leukemia-associated antigen-specific CD8+ T cells in patients after allogeneic stem cell transplantation. Exp Hematol 44 :1024-1033.e1, 2016 27473564\n32. Ni X Song Q Cassady K , et al : PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells. J Clin Invest 127 :1960-1977, 2017 28414296\n33. Del Papa B Ruggeri L Urbani E , et al : Clinical-grade-expanded regulatory T cells prevent graft-versus-host disease while allowing a powerful T cell-dependent graft-versus-leukemia effect in murine models. Biol Blood Marrow Transplant 23 :1847-1851, 2017 28729148\n34. Wang L Liu Y Beier UH , et al : Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity. Blood 121 :3631-3639, 2013 23444399\n35. Cooper ML Choi J Karpova D , et al : Azacitidine mitigates graft-versus-host disease via differential effects on the proliferation of T effectors and natural regulatory T cells in vivo. J Immunol 198 :3746-3754, 2017 28330901\n36. MacDonald KPA Le Texier L Zhang P , et al : Modification of T cell responses by stem cell mobilization requires direct signaling of the T cell by G-CSF and IL-10. J Immunol 192 :3180-3189, 2014 24585878\n37. D’Aveni M Rossignol J Coman T , et al : G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease. Sci Transl Med 7 :281ra42, 2015\n38. Ukena SN Velaga S Goudeva L , et al : Human regulatory T cells of G-CSF mobilized allogeneic stem cell donors qualify for clinical application. PLoS One 7 :e51644, 2012 23251603\n\n",
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"abstract": "We describe 5 cases of immediate-type reactions to systemic corticosteroids observed during the last 2 decades in boys aged 2, 4, 8, 9, and 10 years. Symptoms ranged from generalized urticaria and angioedema to anaphylactic shock immediately after administration. Oral betamethasone was implicated in 2 cases, oral prednisolone in 2 cases, and intravenous prednisolone in 1 case. The parents of patient 5 refused the skin tests. The remaining patients underwent skin prick tests with the following undiluted corticosteroids: parenteral prednisolone, oral prednisolone, parenteral methylprednisolone, parenteral dexamethasone, parenteral hydrocortisone, and oral betamethasone. If the results were negative, intradermal tests were performed with the same drugs at increasing concentrations. Skin test results were positive for all suspect corticosteroids, thus indicating an immunoglobulin E-mediated mechanism. Two patients had positive skin test results to other corticosteroids, suggesting cross-reactivity. An oral challenge test was performed with deflazacort in 4 cases and with betamethasone in 1 case; the results were negative.",
"affiliations": "Immunoallergy Department, CUF-Descobertas Hospital, Lisbon, Portugal. nunogasparsousa@gmail.com",
"authors": "de Sousa|N Gaspar|NG|;Santa-Marta|C|C|;Morais-Almeida|M|M|",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D006801:Humans; D006969:Hypersensitivity, Immediate; D008297:Male; D012882:Skin Tests",
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"references": null,
"title": "Systemic corticosteroid hypersensitivity in children.",
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"abstract": "Intramural pregnancy is a rare type of ectopic pregnancy with an unclear etiology. It may be associated with uterine wall injury and/or abnormal uterine conditions, such as adenomyosis, in certain cases. In the present report, a case of intramural pregnancy associated with adenomyosis is discussed. The patient was 34 years old and presented with amenorrhea for 40 days. Ultrasonography and magnetic resonance imaging revealed a mixed echogenic mass located within the posterior wall of the uterine fundus with abundant blood flow. In addition, the patient's β-human chorionic gonadotropin levels were markedly elevated; however, these levels demonstrated a declining tendency. Clinically, it was difficult to distinguish the diagnosis of the case between intramural pregnancy and choriocarcinoma. Following initial treatment with methotrexate-based chemotherapy, a laparotomy was performed to confirm the diagnosis and excise the lesion. Pathological analysis confirmed a diagnosis of intramural pregnancy and adenomyosis within the uterine wall. The results of the present case report suggest that surgical intervention should be the first action performed when intramural pregnancy is suspected, in order to confirm the diagnosis and treat the disease.",
"affiliations": "Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China.;Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China.;Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China.;Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.;Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China.;Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China.;Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China.;Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China.",
"authors": "Su|Shan|S|;Chavan|Devendra|D|;Song|Kun|K|;Chi|Dennis|D|;Zhang|Guiyu|G|;Deng|Xiaohui|X|;Li|Li|L|;Kong|Beihua|B|",
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"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2017.5737OL-0-0-5737ArticlesDistinguishing between intramural pregnancy and choriocarcinoma: A case report Su Shan 12*Chavan Devendra 1*Song Kun 1Chi Dennis 3Zhang Guiyu 1Deng Xiaohui 12Li Li 12Kong Beihua 11 Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China2 Reproductive Medicine Center, Qilu Hospital Affiliated to Shandong University, Jinan, Shandong 250012, P.R. China3 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USACorrespondence to: Dr Li Li, Department of Obstetrics and Gynecology, Qilu Hospital Affiliated to Shandong University, 107 Wenhuaxi Road, Jinan, Shandong 250012, P.R. China, E-mail: bzlily@163.com* Contributed equally\n\n4 2017 14 2 2017 14 2 2017 13 4 2129 2132 13 10 2015 06 12 2016 Copyright: © Su et al.2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Intramural pregnancy is a rare type of ectopic pregnancy with an unclear etiology. It may be associated with uterine wall injury and/or abnormal uterine conditions, such as adenomyosis, in certain cases. In the present report, a case of intramural pregnancy associated with adenomyosis is discussed. The patient was 34 years old and presented with amenorrhea for 40 days. Ultrasonography and magnetic resonance imaging revealed a mixed echogenic mass located within the posterior wall of the uterine fundus with abundant blood flow. In addition, the patient's β-human chorionic gonadotropin levels were markedly elevated; however, these levels demonstrated a declining tendency. Clinically, it was difficult to distinguish the diagnosis of the case between intramural pregnancy and choriocarcinoma. Following initial treatment with methotrexate-based chemotherapy, a laparotomy was performed to confirm the diagnosis and excise the lesion. Pathological analysis confirmed a diagnosis of intramural pregnancy and adenomyosis within the uterine wall. The results of the present case report suggest that surgical intervention should be the first action performed when intramural pregnancy is suspected, in order to confirm the diagnosis and treat the disease.\n\nintramural ectopic pregnancychoriocarcinomaadenomyosis\n==== Body\nIntroduction\nIntramural ectopic pregnancy refers to a pregnancy located within the uterine wall, without a connection to the fallopian tubes or endometrial cavity. Intramural pregnancy is a rare condition that constitutes <1% of ectopic pregnancies (1). The etiology of intramural pregnancy is unclear. A previous medical history of uterine surgical procedures, such as cesarean section, myomectomy, curettage or hysteroscopy, are considered to be risk factors for intramural pregnancy (2). Other pre-disposing factors include the following: A history of ectopic pregnancy and tubal surgery; smoking; in vitro fertilization and embryo transfer (IVF-ET); endometriosis; diethylstilbestrol exposure; and intrauterine device placement (3). The clinical symptoms of intramural pregnancy are nonspecific, as patients may present with no obvious symptoms, mild vaginal bleeding and abdominal pain or, conversely, hypovolemic shock due to a uterine rupture.\n\nChoriocarcinoma is a highly malignant epithelial tumor caused by trophoblastic proliferation, which may be secondary to any type of pregnancy. While the uterus is frequently affected, choriocarcinoma may metastasize to other organs, such as the lung, vagina, liver and brain. It is difficult to diagnosis intramural pregnancies at an early stage due to their varied manifestations, which can mimic trophoblastic disorders, uterine fibroids and other uterine wall conditions. Life-threatening complications, such as uterine ruptures, can develop if intramural pregnancies are not diagnosed and treated at an early stage.\n\nCase report\nA 34-year-old woman, gravida 2 para 1, was referred to the Department of Obstetrics and Gynecology at Qilu Hospital Affiliated to Shandong University with suspected gestational trophoblastic disease (GTD) in April 2015. The patient's first pregnancy was uncomplicated there was no past history of miscarriage or termination. Menstrual history was unremarkable and the last menstrual period had occurred 40 days prior to admission. The physical examination revealed no abnormalities. An ultrasonography (USG) scan performed upon admission revealed a mixed echogenic mass measuring 5.1×4.6 cm located within the posterior wall of the uterine fundus with an abundant blood supply. The mass was separate from the uterine cavity (Fig. 1). The patient's serum β-human chorionic gonadotropin (β-hCG) level was 14,153 mIU/ml. On the second day of admission, the patient's serum β-hCG level had dropped to 7,991 mIU/ml; however, all other blood test results remained normal. Enhanced pelvic magnetic resonance imaging (MRI) demonstrated an intramural mass that had partially invaded the myometrium and the posterior wall of the uterine fundus, and was isolated from the uterine cavity (Fig. 2). Since the patient's β-hCG levels had significantly decreased, they were kept under observation and had their β-hCG levels were monitored regularly. Serum progesterone was 2.3 ng/ml.\n\nOne week later, a USG scan identified a heterogeneous mass measuring 4.9×4.8 cm in the left wall of the uterine fundus reaching the serosa, with several anechoic areas inside the mass demonstrating significant circumferential vascularity. A preliminary diagnosis of choriocarcinoma was made; however, intramural pregnancy was not excluded. The decision to initiate chemotherapy was made in order to reduce the activity of trophoblastic cells, followed by exploratory surgery to confirm the diagnosis. A 5-day regimen of intramuscular methotrexate (MTX; 20 mg/day) injections was prescribed. Following the 1st day of MTX treatment, the patient's serum β-hCG level had decreased to 3,893 mIU/ml, and a USG scan revealed an increase in mass size (5.6×4.9 cm) in the left uterine wall with substantial vascularity and tortuous vessels around the uterus. Three days following the initiation of chemotherapy, the patient exhibited fever, fatigue, mouth ulcers and loss of appetite; in addition, the patient's white blood cell count had decreased from 7.64×109 to 2.02×109 cells/l. On the 7th day of chemotherapy, the patient's serum alanine transaminase level had increased from 35 to 71 U/l and their platelet count had decreased from 245×109 to 76×109 platelets/l.\n\nDue to a minimal reduction in mass size and the evident side effects of chemotherapy, including severe bone marrow suppression, the decision was made to perform a hysteroscopy and exploratory laparotomy. No intrauterine pregnancy tissue was observed during the hysteroscopy and the left ostium of the fallopian tube was not easily delineated. Total blood loss did not exceed 10 ml. The laparotomy revealed a cystic projection measuring 4×4 cm that was located on the left horn of uterus with a purplish-blue colored surface. In addition, the vascular vessels surrounding the left side of the uterus were convoluted with both adnexa considered normal (Fig. 3A and B). Following ligation of the uterine vessels, the lesion was completely removed. The lesion tissue was sectioned (thickness, 3 µm) and stained using hematoxylin and eosin prior to visualization using light microscopy. Pathological examination revealed a cystic lesion, centered with an edema vesicle-like structure of ~1 cm in diameter, covered with honeycomb-like hemorrhages infiltrating the myometrium, with normal myometrium at the periphery (Fig. 3C). Placental villi identified in the myometrium supported a diagnosis of intramural pregnancy (Fig. 3D). Furthermore, the presence of ectopic endometrial tissue within the myometrium supported an additional diagnosis of adenomyosis. A total of 1 day following surgery, the patient's β-hCG level was 352.8 mIU/ml and 5 days post-operatively their β-hCG levels had decreased to 45.02 mIU/ml, at which point the patient was discharged. A follow-up 1 week following discharge demonstrated that the patient's β-hCG level had returned to normal (<30 mIU/ml).\n\nDiscussion\nIn the case discussed in the present report, it was difficult to distinguish between intramural pregnancy and choriocarcinoma based on the clinical assessment. This is likely due to the rareness of intramural pregnancies experienced by medical professionals in clinical practice. A comprehensive text search on PubMed (National Center for Biotechnology Information, Bethesda MD, USA) using the query terms ‘intramural ectopic pregnancy’ returned 63 studies, of which the majority were case reports and frequently described interstitial pregnancy as intramural pregnancy. Intramural pregnancy should only include cases with elements of ectopic pregnancy within the myometrium, without any connection to the endometrial cavity or fallopian tubes. At present, there is no precise definition of intramural ectopic pregnancy. Intramural pregnancy should be treated as a specific type of ectopic pregnancy, similarly to interstitial pregnancy, caesarean scar pregnancy and cervical pregnancy, or should broadly include all of these conditions.\n\nCurrently, the etiology of intramural pregnancy is unclear and several hypotheses exist. The most accepted theory is that the embryo implants into the myometrium through a microscopic fistula, which may be the consequence of previous uterine surgery, such as a caesarean section or myomectomy (1). Similarly, the embryo may implant into the myometrium together with ectopic endometrial tissues during the development of adenomyosis (4). Another scenario is that the embryo may be implanted inside the myometrium artificially during IVF-ET (5). All the conditions mentioned above, except adenomyosis, were excluded in the present case report. There are several reports discussing the co-existence of adenomyosis with intramural pregnancy (4,6). However, whether adenomyosis is the method of pathogenesis or serves as a high-risk factor for intramural pregnancy remains unclear.\n\nNumerous studies have reported the early diagnosis of intramural pregnancy based on transvaginal USG and/or MRI (2,7–10). Memtsa et al (2) suggested several sets of criteria for the ultrasonographic diagnosis of intramural pregnancy and proposed a simple classification system that is useful in clinical practice. However, in the present case neither USG nor MRI could exclude the presence of choriocarcinoma. Furthermore, the results of the present case report suggest that the diagnosis of intramural pregnancy should be based on post-operative pathology results. The differential diagnosis between intramural pregnancy and GTD is clinically important due to their different treatment regimes. GTDs are a group of malignant disorders that require systemic chemotherapy. Choriocarcinoma should be considered if β-hCG levels continue to rise or do not decrease to an acceptable level post-partum or post-abortion. Metastasis of choriocarcinoma to other organs will induce corresponding symptoms, such as intracranial hemorrhage and hemoptysis (11). Although serum β-hCG levels may be increased in intramural pregnancy and choriocarcinoma, they are higher in choriocarcinoma compared with ectopic pregnancy, the latter of which rarely exceeds 10,000 mIU/l. Dousias et al (12) and Hsieh et al (13) reported two separate cases of intramural pregnancy with a negative maternal serum β-hCG. In the present case, the patient's previous menstrual cycles were regular with a recent history of amenorrhea for 40 days, which suggested a possible pregnancy. However, ultrasound examination revealed an empty uterine cavity. A high initial β-hCG concentration that declined (from 14,153 to 7,991 mIU/ml) excluded a diagnosis of tubal pregnancy and choriocarcinoma, respectively. Furthermore, the patient did not present with any typical ectopic pregnancy or miscarriage symptoms, such as abdominal pain or vaginal bleeding. USG and MRI scan results did not differentiate between GTD and intramural pregnancy.\n\nThe treatment for patients with intramural pregnancy should be individualized, depending on the location of the lesion, depth of muscular invasion, gestational age and the desire for future fertility (2). Reported successful treatment options for intramural pregnancy include the following: MTX-based chemotherapy, which can be delivered locally under ultrasound guidance (6), systemically (14) or injected directly into the embryo in combination with potassium chloride(8); laparoscopic surgical removal of lesions (15), although this option should be used with caution since the local blood flow is abundant and bleeding may be difficult to regulate; and uterine artery embolization (16). However, choriocarcinoma requires multiple cycles of chemotherapy compared with the MTX-based treatment for intramural pregnancy. As clinical and radiological results could not direct a final diagnosis in the current case, MTX-based chemotherapy was firstly chosen to reduce the activity of trophoblastic cells, as it is able to treat choriocarcinoma and intramural pregnancy. In the present case, unsatisfactory reductions in mass size and the side effects of chemotherapy resulted in the decision to perform a hysteroscopy and exploratory laparotomy. To prevent excessive blood loss during surgery, the ascending uterine artery was ligated, blocking blood flow to the bilateral infundibulopelvic ligament prior to excision of the lesion. In the majority of cases, conservative treatment of intramural pregnancy has poor efficacy and eventually leads to the need for surgery. The laparotomy performed confirmed a final diagnosis of intramural pregnancy with adenomyosis and treated the lesion effectively.\n\nIn conclusion, the present case report demonstrates that it is difficult to distinguish intramural pregnancy from choriocarcinoma. Under such circumstances, earlier surgical intervention would be an appropriate choice to diagnose and treat the disease simultaneously. In addition, surgical intervention reduces the potential toxic side effects of excessive chemotherapy due to a misdiagnosis of choriocarcinoma. Although intramural pregnancy is a rare condition, it is essential to establish a precise definition and classification system, in addition to diagnostic and treatment guidelines, for intramural pregnancy in order to effectively treat sufferers.\n\nAcknowledgements\nThe present study was supported by the National Natural Science Foundation of China (grant no. 81172488) and the Outstanding Young Scientists Foundation of Shandong Province (grant no. BS2013YY035).\n\nFigure 1. Ultrasonographic images of the lesion. (A) Transvaginal ultrasonography revealed a solid cystic lesion completely confined to the myometrium of left uterine wall with no connection to the endometrial cavity. The black arrow indicates the gestation sac. (B) Doppler images revealed abundant perilesional vascularity.\n\nFigure 2. MRI images of the lesion. MRI imaging revealed a mass with (A) low signal intensity on T1WI and (B) high signal intensity on T2WI. (C) T2WI, sagittal plane. (D) T2WI, coronal plane. Arrows indicate the lesion. T1WI, T1-weighted image; T2WI, T2-weighted image; MRI, magnetic resonance imaging.\n\nFigure 3. Lesion appearance, schema chart and pathological section. (A) Laparotomy revealed a mass inside the left posterior lateral aspect of the uterus. (B) Image of the mass removed. (C) Schema chart of the lesion section: a, normal muscle tissue in the outer layer; b, blood clot surrounding the vesicle; and c, edematous vesicle. (D) Pathological section demonstrating villi inside the uterine wall isolated from the uterine cavity, as demonstrated by the black arrow (hematoxylin and eosin stained; magnification, ×400).\n==== Refs\nReferences\n1 Lu HF Sheu BC Shih JC Chang YL Torng PL Huang SC Intramural ectopic pregnancy. Sonographic picture and its relation with adenomyosis Acta Obstet Gynecol Scand 76 886 889 1997 10.3109/00016349709024372 9351419 \n2 Memtsa M Jamil A Sebire N Jauniaux E Jurkovic D Diagnosis and management of intramural ectopic pregnancy Ultrasound Obstet Gynecol 42 359 362 2013 10.1002/uog.12437 23417903 \n3 Tulandi T Ectopic Pregnancy A Clinical Casebook Springer International Publishing Switzerland 115 122 2015 \n4 Karakök M Balat O Sari I Kocer NE Erdogan R Early diagnosed intramural ectopic pregnancy associated with adenomyosis: Report of an unusual case Clin Exp Obstet Gynecol 29 217 218 2002 12519047 \n5 Khalifa Y Redgment CJ Yazdani N Taranissi M Craft IL Intramural pregnancy following difficult embryo transfer Hum Reprod 9 2427 2428 1994 10.1093/oxfordjournals.humrep.a138463 7714169 \n6 Choi DH Kwon H Kim YS Kim JH Intramural pregnancy associated with adenomyosis after in vitro fertilization and embryo transfer: A case report J Reprod Med 54 255 258 2009 19438169 \n7 Wang J Xie X Sonographic diagnosis of intramural pregnancy J Ultrasound Med 32 2215 2217 2013 10.7863/ultra.32.12.2215 24277907 \n8 Ko HS Lee Y Lee HJ Park IY Chung DY Kim SP Park TC Shin JC Sonographic and MR findings in 2 cases of intramural pregnancy treated conservatively J Clin Ultrasound 34 356 360 2006 10.1002/jcu.20245 16869015 \n9 Ong C Su LL Chia D Choolani M Biswas A Sonographic diagnosis and successful medical management of an intramural ectopic pregnancy J Clin Ultrasound 38 320 324 2010 20544869 \n10 Katano K Ikuta K Matsubara H Oya N Nishio M Suzumori K A case of successful conservative chemotherapy for intramural pregnancy Fertil Steril 72 744 746 1999 10.1016/S0015-0282(99)00330-1 10521123 \n11 Soper JT Mutch DG Schink JC American College of Obstetricians and Gynecologists Diagnosis and treatment of gestational trophoblastic disease: ACOG Practice Bulletin No. 53 Gynecol Oncol 93 575 585 2004 10.1016/j.ygyno.2004.05.013 15196847 \n12 Dousias V Stefos T Chouliara S Stefanou D Kamina S Lolis D Intramural pregnancy with negative maternal serum b-HCG Eur J Obstet Gynecol Reprod Biol 111 94 95 2003 10.1016/S0301-2115(03)00200-8 14557021 \n13 Hsieh YY Chang CC Tsai HD Yeh LS Hsu TY Yang TC Intramural pregnancy with negative maternal serum beta-hCG. A case report J Reprod Med 43 468 470 1998 9610475 \n14 Ko HS Lee Y Lee HJ Park IY Chung DY Kim SP Park TC Shin JC Sonographic and MR Findings in 2 case of intramural pregnancy treated conservatively J Clin Ultrasound 34 356 360 2006 10.1002/jcu.20245 16869015 \n15 Ye Kuang Chen XH Si Y Kong XC Preoperative diagnosis and successful laparoscopic management of intramural pregnancy: Case report Eur J Obstet Gynecol Reprod Biol 171 385 386 2013 10.1016/j.ejogrb.2013.09.013 24183350 \n16 Zhuang Y Huang L Uterine artery embolization compared with methotrexate for the management of pregnancy implanted within a cesarean scar Am J Obstet Gynecol 201 152.e1 e3 2009 10.1016/j.ajog.2009.04.038 19527897\n\n",
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{
"abstract": "Disruption of blood brain barrier (BBB) with subsequent subarachnoid contrast extravasation and cerebral edema is a rare complication of intra-arterial contrast administration. We report a patient with end-stage renal disease (ESRD) who developed such a complication. A 63-year-old man with a history of left orbital apex syndrome on hemodialysis (HD) was admitted with massive epistaxis. A pseudo-aneurysm of the left internal carotid artery (ICA) required a cerebral arteriogram with coil embolization; a total of 910 ml of isosmolar intra-arterial contrast was used. Shortly thereafter, the patient developed severe alteration in his mental status. A CT study without contrast of the head showed bilateral subarachnoid hyper-attenuation with diffuse cerebral edema consistent with contrast-induced encephalopathy syndrome. The patient was urgently and repetitively dialyzed to remove the contrast leading to a remarkable improvement in his mental status and resolution of both subarachnoid hyper-attenuation and brain edema. The large volume of intra-arterial contrast that may be required in neurologic interventional procedures is occasionally associated with breakdown of BBB leading to subarachnoid accumulation and cerebral edema resulting in a severe encephalopathy syndrome. Hemodialysis seems particularly well suited for the patient who has renal failure in whom this syndrome develops.",
"affiliations": "Renal Section, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, Texas, USA.",
"authors": "Yan|Jingyin|J|;Ramanathan|Venkat|V|",
"chemical_list": "D003287:Contrast Media",
"country": "United States",
"delete": false,
"doi": "10.1111/sdi.12061",
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"issn_linking": "0894-0959",
"issue": "26(2)",
"journal": "Seminars in dialysis",
"keywords": null,
"medline_ta": "Semin Dial",
"mesh_terms": "D017541:Aneurysm, False; D001812:Blood-Brain Barrier; D001929:Brain Edema; D002340:Carotid Artery Diseases; D002533:Cerebral Angiography; D003287:Contrast Media; D003937:Diagnosis, Differential; D004621:Embolization, Therapeutic; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8911629",
"other_id": null,
"pages": "203-7",
"pmc": null,
"pmid": "23406363",
"pubdate": "2013",
"publication_types": "D016429:Clinical Conference; D016428:Journal Article",
"references": null,
"title": "Severe encephalopathy following cerebral arteriogram in a patient with end-stage renal disease.",
"title_normalized": "severe encephalopathy following cerebral arteriogram in a patient with end stage renal disease"
} | [
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{
"abstract": "Splenic rupture due to any cause is a life-threatening complication and commonly attributed to trauma. Atraumatic splenic rupture is very rarely reported, and the incidence is currently unknown. Anticoagulants and dual anti-platelet medication can increase the chances of a splenic rupture. Surgical removal of the spleen may be warranted to prevent a life-threatening bleeding. Early identification and intervention are required for most patients as only a few qualify for medical management.",
"affiliations": "Texas Tech University Health Sciences Center, El Paso, TX, USA.;Texas Tech University Health Sciences Center, El Paso, TX, USA.;Texas Tech University Health Sciences Center, El Paso, TX, USA.;Texas Tech University Health Sciences Center, El Paso, TX, USA.;Texas Tech University Health Sciences Center, El Paso, TX, USA.;Texas Tech University Health Sciences Center, El Paso, TX, USA.;Texas Tech University Health Sciences Center, El Paso, TX, USA.;Texas Tech University Health Sciences Center, El Paso, TX, USA.",
"authors": "Natarajan|Piruthiviraj|P|0000-0003-2702-7476;Thangarasu|Sudhagar|S|;Ruck|Lela|L|;Estrada|Paul|P|;Gajendran|Mahesh|M|;Renganathan|Gowri|G|;Prakash|Bharat Ved|BV|;Aduroja|Olufemi|O|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban",
"country": "United States",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n34148386\n10.1177/23247096211026492\n10.1177_23247096211026492\nCase Report\nAtraumatic Splenic Rupture in a Patient on Apixaban and Dual Antiplatelet Therapy\nhttps://orcid.org/0000-0003-2702-7476\nNatarajan Piruthiviraj MD 1\nThangarasu Sudhagar MD, FACP 1\nRuck Lela MD 1\nEstrada Paul MD 1\nGajendran Mahesh MD, MPH 1\nRenganathan Gowri MD 1\nPrakash Bharat Ved MD 1\nAduroja Olufemi MD, MPH 1\n1 Texas Tech University Health Sciences Center, El Paso, TX, USA\nPiruthiviraj Natarajan, MD, Department of Internal Medicine—Transmountain Campus, Texas Tech University Health Sciences Center El Paso, 2000 B Transmountain Road, Suite B476, El Paso, TX 79911, USA. Email: Piruthiviraj@gmail.com\n21 6 2021\nJan-Dec 2021\n9 2324709621102649226 3 2021\n24 5 2021\n1 6 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nSplenic rupture due to any cause is a life-threatening complication and commonly attributed to trauma. Atraumatic splenic rupture is very rarely reported, and the incidence is currently unknown. Anticoagulants and dual anti-platelet medication can increase the chances of a splenic rupture. Surgical removal of the spleen may be warranted to prevent a life-threatening bleeding. Early identification and intervention are required for most patients as only a few qualify for medical management.\n\natraumatic splenic rupture\napixaban\ndual antiplatelet therapy\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nIntroduction\n\nSplenic ruptures are potentially fatal, mostly attributed to trauma and less commonly to atraumatic etiology. In the absence of a defining abdominal pain or signs of peritonitis the diagnosis can be easily missed. Atraumatic splenic rupture (ASR) is reportedly associated with apixaban 1 and dual antiplatelet therapy 2 but neither was concurrently associated in the same patient. Atrial fibrillation is independently reported 3 to be associated with spontaneous rupture of the spleen. An appropriate clinical examination and computed tomography (CT) of the abdomen are vital for diagnosis and management. 4 Early risk stratification of patients to determine those eligible for active surgical and vascular interventions is warranted to minimize morbidity and mortality. ASRs are managed similarly to other splenic ruptures, whereas most of the lower grade ruptures can be medically managed. Recently, nonsurgical management is preferred for select patients to protect immunologic function following splenectomy. 5\n\nCase Presentation\n\nAn 81-year-old male with a past medical history of hypertension, diabetes mellitus type 2, coronary artery disease, atrial fibrillation, and myasthenia gravis presented to the hospital with complaints of left-sided abdominal pain for few hours. He denied any trauma or fall. The abdominal pain had an intensity of 6 out of 10 on the pain scale, with no aggravating or relieving factors. It was associated with dry cough without any fever. He underwent left main coronary artery stenting 60 days prior to the presentation and was taking apixaban, clopidogrel, and aspirin for the management of the atrial fibrillation and coronary artery disease. He had minimal left upper quadrant tenderness on palpation without any guarding or rigidity. A CT of the abdomen (Figure 1) revealed splenic laceration, hemoperitoneum, and grade 2 perisplenic hematoma according to the American Association for the Surgery of Trauma splenic injury scale. Serum hemoglobin ranged from 8.1 to 9.3 g/dL throughout the hospital stay. He was monitored in the critical care unit for hemodynamic instability and surgical intervention was deferred due to stable hematoma. The patient’s apixaban, aspirin, and clopidogrel were held during the hospital stay. Repeat CT of the abdomen showed interval resolution of the perisplenic hematoma. At discharge, only clopidogrel was resumed.\n\nFigure 1. Spleen shown with white arrows showing splenic injury.\n\nDiscussion\n\nWe report the first case of ASR in a patient on apixaban and dual antiplatelet therapy in the absence of any other inciting risk factors. Splenic rupture is a well-known life-threatening condition, with a mortality risk ranging from 12% to 20%.6,7 A vast majority of splenic injuries are traumatic in origin, with a small proportion of patients presenting with ASR. Other major causes of nontraumatic rupture of spleen reported are neoplasm, infections, inflammatory diseases, medications, and medical treatment, mechanical causes such as direct abdominal trauma and idiopathic.8,9 Depending on the severity of the splenic rupture, clinical symptoms range from mild to very severe abdominal pain often associated with clinical signs suggestive of hemorrhagic shock. Ultrasound of the abdomen (57.1%) is less sensitive when compared with a contrast-enhanced CT of the abdomen (85.7%) in diagnosing ASR. 10 Hemodynamic and hemoglobin monitoring is critical to assess for ongoing blood loss. Etiologic factors, splenic injury grading, and clinical progression determines the need for surgery.6,11 The etiology of splenic rupture has been reported to be recognized in around 38% of cases before surgery and 50% during or after surgery. Total splenectomy is the primary treatment of choice for patients with hemodynamic instability or high-grade rupture or those with a pathologically altered spleen. Temporary measures including splenic artery embolization are reserved for candidates who are bleeding and unable to tolerate surgery. Very few patients qualify for nonsurgical treatment since conservative management is reported to have high failure rates. 7 Even though enoxaparin is reported to accumulate in the spleen preferentially,12,13 the data on apixaban or its mechanism is currently unavailable. Multiple systemic diseases like polycythemia vera, chronic pancreatitis, pancreatic cancer, or splenic flexure colon tumor can affect and damage the architecture of the spleen making it fragile and vulnerable to minor trauma. 11 Some older patients with baseline spleen damage may not recognize the inciting trauma. 14 Surgical management is also recommended in patients with unclear etiology of splenic injury so the spleen can be sent for pathologic evaluation to rule out systemic diseases, especially malignancy. 7 Although the emergent nature of splenectomy does not allow adequate time for vaccine prophylaxis, some nonsurgical candidates may benefit from vaccination in anticipation of a nonfunctional spleen and a possible surgery later.\n\nConclusion\n\nPatients on apixaban and dual antiplatelet therapy are at high risk for ASR and the management is based on the grade of splenic rupture. For ASR, appropriate treatment stratification is necessary as some patients qualify for early surgical management. The literature on restarting anticoagulation or antiplatelet medication after splenic rupture is currently very limited.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed consent: Verbal informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.\n\nORCID iD: Piruthiviraj Natarajan https://orcid.org/0000-0003-2702-7476\n==== Refs\nReferences\n\n1 Basnet S Mohanty E Mir I Dhital R Koirala A Tachamo N. Atraumatic splenic rupture associated with apixaban. SAGE Open Med Case Rep. 2019;7 :2050313X19832490.\n2 Grifoni E Paniccia R Giusti B , et al . Non-traumatic splenic rupture on dual antiplatelet therapy with aspirin and ticagrelor after stenting for acute coronary syndrome. J Cardiol Cases. 2015;12 :65-67.30524542\n3 Matykiewicz J Głuszek S. Spontaneous rupture of the spleen—a rare case. Pol Przegl Chir. 2011;83 :105-107.22166289\n4 Malaki M Mangat K. Hepatic and splenic trauma. Trauma. 2011;13 :233-244.\n5 Coccolini F Montori G Catena F , et al . Splenic trauma: WSES classification and guidelines for adult and pediatric patients. World J Emerg Surg. 2017;12 :40.28828034\n6 Renzulli P Hostettler A Schoepfer AM Gloor B Candinas D. Systematic review of atraumatic splenic rupture. Br J Surg. 2009;96 :1114-1121.19787754\n7 Moore EE Cogbill TH Jurkovich GJ Shackford SR Malangoni MA Champion HR. Organ injury scaling: spleen and liver (1994 revision). J Trauma. 1995;38 :323-324.7897707\n8 Akoury T Whetstone DR. Splenic rupture. In: StatPearls. StatPearls; 2021. Accessed December 19, 2020. http://www.ncbi.nlm.nih.gov/books/NBK525951/\n9 Clancy AA Tiruta C Ashman D Ball CG Krikpatrick AW. The song remains the same although the instruments are changing: complications following selective non-operative management of blunt spleen trauma: a retrospective review of patients at a level I trauma centre from 1996 to 2007. J Trauma Manag Outcomes. 2012;6 :4.22410104\n10 Sortland O Nerdrum HJ Solheim K. Computed tomography and scintigraphy in the diagnosis of splenic injury. Acta Chir Scand. 1986;152 :453-461.3766033\n11 Liu J Feng Y Li A Liu C Li F. Diagnosis and treatment of atraumatic splenic rupture: experience of 8 cases. Gastroenterol Res Pract. 2019;2019 :5827694.30809256\n12 Colas Linhart N Laforest MD Guiraud-Vitaux F , et al . Pharmacokinetics and tissue distribution of 99mTc-labelled enoxaparin in the rat: evaluation of dosimetry parameters. Biomed Pharmacother Biomedecine Pharmacother. 1990;44 :317-323.\n13 Kim JC Tae G. The modulation of biodistribution of stem cells by anchoring lipid-conjugated heparin on the cell surface. J Control Release. 2015;217 :128-137.26342662\n14 Tzankov A Adams H Sterlacci W. Rupture of the spleen. Clinicopathological correlations and diagnostic procedures [in German]. Pathologe. 2008;29 :148-157.17929019\n\n",
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"issn_linking": "2324-7096",
"issue": "9()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "apixaban; atraumatic splenic rupture; dual antiplatelet therapy",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D006801:Humans; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D011728:Pyridones; D012422:Rupture, Spontaneous; D013161:Splenic Rupture",
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"references": "22410104;7897707;30815265;3766033;26342662;30524542;19787754;28828034;30809256;2171691;22166289;17929019",
"title": "Atraumatic Splenic Rupture in a Patient on Apixaban and Dual Antiplatelet Therapy.",
"title_normalized": "atraumatic splenic rupture in a patient on apixaban and dual antiplatelet therapy"
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"abstract": "Optimal treatment of prosthetic joint infection and chronic osteomyelitis consists of surgical removal of biofilm-embedded bacteria, followed by a 6-12 week course of antimicrobial therapy. However, when optimal surgery is not feasible, oral prolonged suppressive antibiotic therapy (PSAT) is recommended to prevent prosthesis loosening and/or relapse of infection. Since 2010, we have used infection salvage therapy using off-label subcutaneous (sc) injection of a β-lactam as PSAT for patients in whom oral PSAT is not possible.\n\n\n\nA single-centre prospective cohort study (2010-18) reporting treatment modalities, efficacy and safety in all patients receiving sc PSAT. NCT03403608.\n\n\n\nThe 10 included patients (median age 79 years) had polymicrobial (n = 5) or MDR bacterial (n = 4) prosthetic joint infection (knee, n = 4; hip, n = 3) or chronic osteomyelitis (n = 3). After initial intensive therapy, seven patients received ertapenem, three patients received ceftriaxone and one patient received ceftazidime by sc injection (one patient received 8 days of ceftriaxone before receiving ertapenem). In one patient, sc PSAT failed with recurrent signs of infection under treatment. In three patients, sc PSAT had to be discontinued due to side effects; in only one of these was the sc route implicated (skin necrosis following direct sc injection and not gravity infusion). Median treatment duration was 433 days. In six patients, sc PSAT was successful with favourable outcome at the time of writing. Interestingly, three patients with MDR bacterial carriage at baseline lost this under PSAT during follow-up.\n\n\n\nAs salvage therapy, sc PSAT delivered by gravity infusion is a safe and interesting alternative when an optimal surgical strategy is not feasible and no oral treatment is available.",
"affiliations": "Service de Maladies Infectieuses, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.;Service de Maladies Infectieuses, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.;Université Claude Bernard Lyon 1, Lyon, France.;Université Claude Bernard Lyon 1, Lyon, France.;Service de Maladies Infectieuses, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.;Service de Maladies Infectieuses, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.;Université Claude Bernard Lyon 1, Lyon, France.;Université Claude Bernard Lyon 1, Lyon, France.;Université Claude Bernard Lyon 1, Lyon, France.;Service de Maladies Infectieuses, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.;Service de Maladies Infectieuses, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.;Service de Maladies Infectieuses, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France.",
"authors": "Pouderoux|Cécile|C|;Becker|Agathe|A|;Goutelle|Sylvain|S|;Lustig|Sébastien|S|;Triffault-Fillit|Claire|C|;Daoud|Fatiha|F|;Fessy|Michel Henry|MH|;Cohen|Sabine|S|;Laurent|Frédéric|F|;Chidiac|Christian|C|;Valour|Florent|F|;Ferry|Tristan|T|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkz104",
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"issue": "74(7)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D015331:Cohort Studies; D003131:Combined Modality Therapy; D004333:Drug Administration Routes; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010019:Osteomyelitis; D011379:Prognosis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "2060-2064",
"pmc": null,
"pmid": "31220276",
"pubdate": "2019-07-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Subcutaneous suppressive antibiotic therapy for bone and joint infections: safety and outcome in a cohort of 10 patients.",
"title_normalized": "subcutaneous suppressive antibiotic therapy for bone and joint infections safety and outcome in a cohort of 10 patients"
} | [
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{
"abstract": "Ehlers-Danlos syndrome (EDS) is a heterogeneous heritable connective tissue disorder with various neurological manifestations, including chronic pain. The neurological manifestations in EDS are often regarded as being caused by the associated musculoskeletal disorders or polyneuropathy. Here, we present two patients with hypermobile EDS (hEDS), presenting with relapsing central nervous system (CNS) manifestations. Although the two patients showed relapsing signs of CNS manifestations like multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), they were unique in that they had widespread opioid-dependent chronic pain, which is not consistent with the symptoms of MS/NMOSD. Unexpectedly, the serious pain of unknown origin was remarkably mitigated by plasmapheresis, and magnetic resonance imaging (MRI) examinations conducted for one of the patients were negative. Collectively, we speculate that hEDS may be more susceptible to 'normal-appearing imaging, neuroimmunologically justified, autoimmune-mediated encephalomyelitis (NINJA).' Analysis of the presented cases and an additional three patients with EDS with chronic pain indicates that treatable immune-mediated mechanisms deserve considerations for neurological symptoms observed in hEDS.",
"affiliations": "Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, Japan.;Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, Japan.;Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.;Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, Japan.;Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, Japan.",
"authors": "Araki|Manabu|M|https://orcid.org/0000-0001-7371-7983;Lin|Youwei|Y|;Ono|Hirohiko|H|;Sato|Wakiro|W|;Yamamura|Takashi|T|",
"chemical_list": null,
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"fulltext": "\n==== Front\nTher Adv Neurol DisordTher Adv Neurol DisordTANsptanTherapeutic Advances in Neurological Disorders1756-28561756-2864SAGE Publications Sage UK: London, England 10.1177/175628641879376610.1177_1756286418793766Case SeriesApplication of immunotherapy for neurological manifestations in hypermobile Ehlers–Danlos syndrome https://orcid.org/0000-0001-7371-7983Araki Manabu Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, JapanDepartment of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, JapanLin Youwei Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, JapanDepartment of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, JapanDepartment of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, JapanOno Hirohiko Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, JapanSato Wakiro Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, JapanDepartment of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, JapanYamamura Takashi Multiple Sclerosis Center, National Center of Neurology and Psychiatry, Tokyo, JapanDepartment of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japanyamamura@ncnp.go.jp18 8 2018 2018 11 175628641879376622 2 2018 9 6 2018 © The Author(s), 20182018SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (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).Ehlers–Danlos syndrome (EDS) is a heterogeneous heritable connective tissue disorder with various neurological manifestations, including chronic pain. The neurological manifestations in EDS are often regarded as being caused by the associated musculoskeletal disorders or polyneuropathy. Here, we present two patients with hypermobile EDS (hEDS), presenting with relapsing central nervous system (CNS) manifestations. Although the two patients showed relapsing signs of CNS manifestations like multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), they were unique in that they had widespread opioid-dependent chronic pain, which is not consistent with the symptoms of MS/NMOSD. Unexpectedly, the serious pain of unknown origin was remarkably mitigated by plasmapheresis, and magnetic resonance imaging (MRI) examinations conducted for one of the patients were negative. Collectively, we speculate that hEDS may be more susceptible to ‘normal-appearing imaging, neuroimmunologically justified, autoimmune-mediated encephalomyelitis (NINJA).’ Analysis of the presented cases and an additional three patients with EDS with chronic pain indicates that treatable immune-mediated mechanisms deserve considerations for neurological symptoms observed in hEDS.\n\nhypermobile Ehlers–Danlos syndromeimmunotherapyneurological manifestationsneuropathic painplasmapheresiscover-dateJanuary-December 2018\n==== Body\nIntroduction\nThe Ehlers–Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders preferentially characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Patients with EDS are currently classified into 13 subtypes.1 Mutations in collagen type V genes (COL5A1, COL5A2) are reported to cause the classical EDSs; COL3A1, vascular EDS; genes encoding extracellular matrix proteins, other rare EDSs; and transforming growth factor beta superfamily (TGFBR1/2 and SMAD3), a pathogenic variant of EDS.2 In contrast to these subtypes, the molecular basis of hypermobile EDS (hEDS) remains to be identified.\n\nOf note, neurological symptoms are frequently observed in EDS,3 and are commonly attributed to the associated musculoskeletal disorders or polyneuropathy,4 unless coexistence of CNS diseases such as multiple sclerosis (MS) is identified.5 Chronic pain is a common manifestation of EDS and more frequent in patients with hEDS.6 Here, we present two cases of hEDS with the following relapsing neurological manifestations: paraplegia, visual impairment, diplopia, and intractable nausea and vomiting. Despite the provisional diagnosis of MS or seronegative neuromyelitis optica spectrum disorder (NMOSD), these were not regarded NMOSD cases, as the chronic pain was widespread and neurological paralysis and pain reversibility was higher than achieved after plasmapheresis. Based on the clinical course and measurement of plasmablasts in the peripheral blood, we speculate that the clinical features of these patients resemble those of ‘normal-appearing imaging, neuroimmunologically justified, autoimmune-mediated encephalomyelitis (NINJA).’ We indicate that intractable chronic pain in hEDS should be regarded as immune-mediated pain and immunotherapy be provided.\n\nMethods\nThe Ethics Committee of the National Center of Neurology and Psychiatry on human experimentation approved the present study (approval number: A2014-082), which conformed to the tenets of the Declaration of Helsinki. Written informed consent for the publication of patient information was obtained from all participants. The plasmablast frequency (CD19+CD27highCD38highCD180− cells) was measured using flow cytometry (FACS Canto II, BD Biosciences, San Jose, CA, USA) and defined as the proportions (%) of CD19+ cells among peripheral blood mononuclear cells, as described previously.7\n\nCase reports\nCase 1: the patient was a 41-year-old homemaker. She had noticed joint hypermobility and had experienced pain since a young age. She had shoulder and finger subluxation since the age of 6 years. Cardiac ablation was performed for supraventricular tachycardia at the age of 24 years, and pacemaker implantation for bradycardia at the age of 28 years. She was initially diagnosed with vascular EDS (vEDS) at the age of 29 years, because a skin biopsy revealed low levels of collagen type III. However, since no known genetic basis was identified,1 she was diagnosed with hEDS at the age of 34 years by EDS experts, based on the clinical criteria.1 There was no family history of EDS. Opioids were initiated at the age 30 years for intractable chronic pain, which had been widespread and uncontrollable.\n\nHer first neurological symptom, except for chronic pain, was paraplegia, which occurred at the age of 22 years. Although slow paced, the recovery from the paraplegia was almost complete within 1 year, and she entered a state of remission. Subsequently, she experienced a few relapses, which were thought to support the diagnosis MS or NMOSD (MS/NMOSD). She was diagnosed with MS/NMOSD during the third paraplegia attack at the age of 34 years. Brain and spinal cord magnetic resonance imaging (MRI) studies were not conducted owing to pacemaker implantation. Computed tomography showed neither spinal cord atrophy nor spinal diseases including atlantoaxial instability. Based on the clinical diagnosis of MS/NMOSD, oral prednisolone was initiated, but she experienced several attacks of paraplegia, visual impairment, and dysphagia under the treatment, with an interval ranging from a few to several months. At the age of 36 years, she had severe nausea, vomiting, and dizziness, which were resistant to corticosteroid therapy, and was admitted to our hospital. Objective neurological findings on admission were as follows: left horizontal nystagmus, diplopia, entire muscle weakness of extremities and trunk, distal hypoesthesia of extremities, hyper-reflexia of the upper and lower limbs, bilateral finger flexor and left extensor plantar reflex, and urinary retention. She was bedridden due to severe dizziness, which was resistant to several courses of intravenous methylprednisolone (IVMP). None of the following autoantibodies (auto-Abs) were detected in the patient’s sera: antiaquaporin 4 (AQP4) Ab; antimyelin-oligodendrocyte glycoprotein (MOG) Ab; antinuclear antibody (ANA); anti-Ro/SSA Ab; anti-La/SSB Ab; antithyroid Ab. AQP4 and MOG Abs were examined using a cell-based assay. Cerebrospinal fluid (CSF) exhibited neither pleocytosis nor elevated protein levels. The immunoglobulin G (IgG) index was within normal limits and oligoclonal bands were not found. Nerve conduction study was normal. However, prolonged visual evoked potential (P100: 152.1 ms, bilateral flash) and I–V interpeak intervals of auditory brainstem responses (right: 4.7 ms; left: 4.5 ms) were suggestive of CNS demyelination. Sequential treatment with seven courses of immunoadsorption plasmapheresis (IAPP) followed by high-dose intravenous Ig (400 mg/kg/day for 3 days) had an obvious effect on the refractory neurological symptoms. Of note, chronic neuropathic pain of the lower limbs and trunk, which had persisted for more than 6 years, was greatly mitigated after IAPP or plasma exchange (PLEX), which resulted in the discontinuation of oral opioid and tapered opioid plaster. She experienced neurological exacerbations at 1.5, 4, and 5 years after first admission, but improved with IAPP or PLEX on all occasions.\n\nCase 2: the patient was a 42-year-old female office worker. She had noticed joint hypermobility since a young age. Her eldest sister had died of brainstem hemorrhage at the age of 32 years; the precise etiology was not confirmed. She had repeated dislocations and meniscal tears since adolescence. During operations, at the age of 16, 20, and 24 years, anesthetic agent-induced anaphylactic shocks had occurred. She also showed allergies to nonsteroidal anti-inflammatory drugs, pilins, antibiotics, and gel patches, food (melon, mango, and peach), and metals (silver and gold plating). She was suspected to have EDS based on a comorbid molluscoid pseudotumor in her lumbar region; however, no clear EDS family history or known genetic abnormalities were revealed. Based on clinical characteristics that met the major criteria of hEDS, she was diagnosed with hEDS at the age of 24 years. Opioids were initiated at the age of 36 years for refractory chronic pain, for which no causal lesion was identified.\n\nIntractable vomiting and hiccups had often occurred since the age of 34 years. Visual impairment and diplopia at the age of 36 years were the first neurological manifestations. She received a single course of IVMP, resulting in the improvement of symptoms. Oral corticosteroid and tacrolimus were administered to prevent the attack. Loxoprofen for chronic pain could be discontinued under the treatment of steroid and immunosuppressant. Her second attack occurred at the age of 41 years. Due to severe visual impairment and diplopia resistant to two courses of IVMP, she was admitted to our hospital for further treatment. Her neurological findings were as follows: decreased visual acuity, diplopia, distal muscle weakness, hyperreflexia, and spasticity of lower limbs, hypoesthesia on the foot in the L5 dermatome and further, and decreased deep sensation of the lower limbs. Brain and spinal cord MRI showed neither demyelinating lesions nor spinal diseases. None of the following auto-Abs were detected in the patient’s serum: anti-AQP4 Ab; anti-MOG Ab; ANA; anti-Ro/SSA Ab; anti-La/SSB Ab; antithyroid Ab. CSF and visual evoked potential (VEP) were not tested as per her request. She received seven courses of IAPP, which resulted in improvement of the visual disturbances. Furthermore, her intractable chronic pain also improved after plasmapheresis; the numerical rating score (NRS) of 6 before IAPP reduced to 3 after IAPP.\n\nWe further investigated the clinical histories and immunological analysis of a series of five patients with hEDS, including the presented cases (Table 1). Allergy to drugs, foods, and metals was identified in four patients (patient 1, 2, 3, and 5). In addition to the present cases (patient 1 and 2), patient 3 and 4 also had comorbid hEDS and other autoimmune diseases. The four patients with autoimmune diseases showed a high frequency of plasmablasts, which has the potential to produce pathogenic autoantibodies.\n\nTable 1. Demographics of five patients with hypermobile Ehlers–Danlos syndrome.\n\nCase\tAge (years)\tSex\tAllergy\tNeurological manifestations\tImmune disease\tImmunotherapy\tPlasmablast\n(cut-off value: 3.9%)\t\n1\t41\tF\tDrug+\tVisual impairment\nNausea and vomiting\nDizziness\nChronic pain\nDystonia\t–\tPSL + TAC\t4.5\t\n2\t42\tF\tDrug+\nFood+\nMetal+\tVisual impairment\nDiplopia\nHeadache\nNausea and hiccup\nChronic pain\tIdiopathic hypogammaglobulinemia\tPSL + TAC\nPeriodic IVIg\t5.1\t\n3\t44\tF\tFood+\tChronic pain\tSpondylarthritis\tPSL + MTX\t4.0\t\n4\t23\tF\t\tChronic pain\nMonoparesis\tBehcet’s disease, \nCongenital immunodeficiency\tPeriodic IVIg\t6.5\t\n5\t27\tF\tPollen+\tChronic pain\t–\t–\t1.0\t\nIVIg, intravenous immunoglobulin; MTX, methotrexate; PSL, prednisolone; TAC, tacrolimus.\n\nDiscussion\nThe two patients with hEDS showed MS/NMOSD-like CNS manifestations that were responsive to corticosteroid and plasmapheresis treatment. They may correspond to a clinical category of NINJA8 although other possibilities remain. Notably, four EDS patients were identified among 1892 patients with MS in a previous study.5 The authors argued that an increased prevalence of EDS in MS was suggestive of a possible causal relationship in terms of a connective-tissue-level abnormality leading to a higher susceptibility of MS. We noted two major clinical dissimilarities on comparing the CNS manifestations in the present cases with those in patients with MS/NMOSD. Firstly, the paraplegia in the two patients was much more reversible than expected, compared with the 600 MS/NMOSD patients previously treated at our hospital. In general, if paraplegia or tetraplegia reoccurs in MS/NMOSD patients, the usual outcome is severe physical impediment such as a wheelchair-bound or bedridden state. However, although both patient 1 and 2 had entered the bedridden state following a severe attack, they gradually improved after immunotherapy, and were eventually able to walk without any assistance. Secondly, the distribution and characteristics of chronic pain was different between the two EDS cases and MS/NMOSD. In MS/NMOSD, the patients experience girdle sensation and neuropathic pain in the extremities, which is attributed to spinal dermatome. In contrast, the chronic pain in our EDS patients was not localized but widespread. Furthermore, although chronic pain tends to be refractory to pain medications or immunotherapy in MS/NMOSD, chronic widespread pain in case 1 dramatically mitigated after plasmapheresis. A satisfactory reduction of chronic pain after plasmapheresis was also observed in case 2.\n\nIt has recently been proposed that the diverse clinical features of EDS, including neurological and immunological manifestations, can be attributed to mast cell activation.9,10 Roles of mast cells have also been indicated in the pathogenesis of autoimmune diseases, MS, and rheumatoid arthritis.11 On the other hand, elevated basal serum tryptase levels have been exclusively associated with duplication of the TPSAB1 gene encoding α-tryptase, followed by mast cell activation.12 In both the present cases, serum tryptase levels were normal, with the blood samples obtained not in the exacerbation but in the remission phase.\n\nThese case reports and case series suggest that the pathogenesis of hEDS can be partly associated with an autoimmune mechanism. While the underlying mechanisms of hEDS remain unclear, autoimmunity and mast cell activation may play key roles. Further clinical investigations are needed to elucidate how autoimmune mechanisms influence the pathogenesis of hEDS and evaluate the efficacy of immunotherapy.\n\nWe thank Dr Miho Murata, Dr Yuji Takahashi and Dr Tomoko Okamoto for their administrative support, and Dr Tomoki Kosho from the Department of Medical Genetics, Shinshu University School of Medicine, Ms Maito Wakui, President of Japan Ehlers–Danlos syndrome Fellowship Association, for providing the clinical information on hEDS. We also thank Dr Toshiyuki Takahashi from the Department of Neurology and Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, for measuring the titer of anti-AQP-4 and anti-MOG antibodies.\n\nAuthor contributions: Study concept and design: MA, LY, TY; data acquisition and analysis: HO, WS; drafting and revising the manuscript: MA, TY.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n\nORCID iD: Manabu Araki \nhttps://orcid.org/0000-0001-7371-7983\n==== Refs\nReferences\n1 \nMalfait F Francomano C Byers P et al \nThe 2017 international classification of the Ehlers-Danlos syndromes . Am J Med Genet C Semin Med Genet \n2017 ; 175 : 8 –26 .28306229 \n2 \nWeerakkody RA Vandrovcova J Kanonidou C et al \nTargeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome . Genet Med \n2016 ; 18 : 1119 –1127 .27011056 \n3 \nHenderson FC Sr.Austin C Benzel E et al \nNeurological and spinal manifestations of the Ehlers-Danlos syndromes . Am J Med Genet C Semin Med Genet \n2017 ; 175 : 195 –211 .28220607 \n4 \nVoermans NC Van Alfen N Pillen S et al \nNeuromuscular involvement in various types of Ehlers-Danlos syndrome . Ann Neurol \n2009 ; 65 : 687 –697 .19557868 \n5 \nVilisaar J Harikrishnan S Suri M et al \nEhlers-Danlos syndrome and multiple sclerosis: a possible association . Mult Scler \n2008 ; 14 : 567 –570 .18208891 \n6 \nVoermans NC Knoop H Bleijenberg G et al \nPain in Ehlers-Danlos syndrome is common, severe, and associated with functional impairment . J Pain Symptom Manage \n2010 ; 40 : 370 –378 .20579833 \n7 \nChihara N Aranami T Sato W et al \nInterleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica . P Natl Acad Sci USA \n2011 ; 108 : 3701 –3706 .\n8 \nTakewaki D Lin Y Sato W et al \nNormal brain imaging accompanies neuroimmunologically justified, autoimmune encephalomyelitis . Neurol Neuroimmunol Neuroinflamm \n2018 ; 5 : e456 .29616233 \n9 \nTheoharides TC Valent P Akin C. \nMast cells, mastocytosis, and related disorders . N Engl J Med \n2015 ; 373 : 163 –172 .26154789 \n10 \nSeneviratne SL Maitland A Afrin L. \nMast cell disorders in Ehlers-Danlos syndrome . Am J Med Genet C Semin Med Genet \n2017 ; 175 : 226 –236 .28261938 \n11 \nBenoist C Mathis D. \nMast cells in autoimmune disease . Nature \n2002 ; 420 : 875 –878 .12490961 \n12 \nLyons JJ Yu X Hughes JD et al \nElevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number . Nat Genet \n2016 ; 48 : 1564 –1569 .27749843\n\n",
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"title": "Application of immunotherapy for neurological manifestations in hypermobile Ehlers-Danlos syndrome.",
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"abstract": "A 22-year-old woman presented to the emergency room with right lower abdominal pain. A CT scan suggested potential appendicitis and perforation. She had no relevant medical or surgical history, and she last had vaginal sex 4 years prior to admission. During surgery, turbid fluid, secondary inflammatory changes, and dilated, fluid-filled fallopian tubes pointed to a diagnosis of pelvic inflammatory disease (PID), so she was started on azithromycin, metronidazole and piperacillin/tazobactam. The following day, she continued to have abdominal pain and developed tachycardia, hypotension, a marked leukemoid response, haemoconcentration, third space fluid accumulation and acidosis. Culture results led to her being further diagnosed with Clostridium perfringens PID with peritonitis and toxic shock syndrome. A gynaecological infection of C. perfringens leading to toxic shock syndrome is both extremely rare and highly fatal. Her antibiotics were changed to meropenem and clindamycin, and she slowly made a full recovery.",
"affiliations": "Department of Medical Education, Texas A&M University System Health Science Center College of Medicine, Bryan, Texas, USA bcovin@exchange.tamu.edu.;Department of Medical Education, Texas A&M University System Health Science Center College of Medicine, Bryan, Texas, USA.;Department of Medical Education, Texas A&M University System Health Science Center College of Medicine, Bryan, Texas, USA.",
"authors": "Covin|Brianna Danielle|BD|;Chapa|Hector|H|;Pham|Nastassia|N|",
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"mesh_terms": "D000328:Adult; D001064:Appendicitis; D003016:Clostridium perfringens; D005260:Female; D006801:Humans; D000292:Pelvic Inflammatory Disease; D010538:Peritonitis; D012772:Shock, Septic; D055815:Young Adult",
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"title": "Clostridium perfringens of unclear origin causing pelvic inflammatory disease and toxic shock syndrome in a previously healthy young woman.",
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"abstract": "Ectopic male breast cancer is very rare. Consequently, there is a lack of prospective clinical trials, and most recommendations for treatment are based on the experiences of clinicians and data from female breast cancer patients. The United States Food and Drug Administration has recently approved palbociclib combined with endocrine therapy for advanced male breast cancer because of the positive results of its use in metastatic female breast cancer. Therefore, it is worth considering cyclin-dependent kinase 4/6 inhibitors as alternatives to conventional chemotherapies for advanced male breast cancer patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative cancers. The present case report introduces the use of palbociclib plus letrozole as first-line therapy for an elderly male patient with relapsed ectopic breast cancer, notwithstanding the limitations of the current national health insurance policy.",
"affiliations": "Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.;Department of Pathology, Kyungpook National University Chilgok Hospital, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.;Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.;Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.",
"authors": "Baek|Dong Won|DW|https://orcid.org/0000-0003-4446-1549;Park|Jee Young|JY|https://orcid.org/0000-0002-1857-813X;Lee|Soo Jung|SJ|https://orcid.org/0000-0003-0066-4109;Chae|Yee Soo|YS|https://orcid.org/0000-0002-8585-4982",
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"fulltext": "\n==== Front\nJ Breast Cancer\nJ Breast Cancer\nJBC\nJournal of Breast Cancer\n1738-6756 2092-9900 Korean Breast Cancer Society \n\n10.4048/jbc.2020.23.e39\nCase Report\nThe Therapeutic Effect of Cyclin-Dependent Kinase 4/6 Inhibitor on Relapsed Ectopic Male Breast Cancer\nhttps://orcid.org/0000-0003-4446-1549Baek Dong Won 1 https://orcid.org/0000-0002-1857-813XPark Jee Young 2 https://orcid.org/0000-0003-0066-4109Lee Soo Jung 1 https://orcid.org/0000-0002-8585-4982Chae Yee Soo 1 1 Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.\n2 Department of Pathology, Kyungpook National University Chilgok Hospital, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.\nCorrespondence to Yee Soo Chae. Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, 807 Hoguk-ro, Buk-gu, Daegu 41404, Korea. yschae@knu.ac.kr\n10 2020 \n30 6 2020 \n23 5 560 566\n22 3 2020 09 6 2020 © 2020 Korean Breast Cancer Society2020Korean Breast Cancer SocietyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Ectopic male breast cancer is very rare. Consequently, there is a lack of prospective clinical trials, and most recommendations for treatment are based on the experiences of clinicians and data from female breast cancer patients. The United States Food and Drug Administration has recently approved palbociclib combined with endocrine therapy for advanced male breast cancer because of the positive results of its use in metastatic female breast cancer. Therefore, it is worth considering cyclin-dependent kinase 4/6 inhibitors as alternatives to conventional chemotherapies for advanced male breast cancer patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative cancers. The present case report introduces the use of palbociclib plus letrozole as first-line therapy for an elderly male patient with relapsed ectopic breast cancer, notwithstanding the limitations of the current national health insurance policy.\n\nBreast neoplasmsMalePalbociclib\n==== Body\nINTRODUCTION\nMale breast cancer accounts for less than 1% of all breast cancers [1]. Although much progress has been made regarding the diagnosis and treatment of female breast cancer over the years, there have been insufficient studies on male breast cancer because of its rarity. Moreover, only a few cases of ectopic breast cancer, a congenital anomaly of breast cancer located in various sites, have been reported [2]. Because ectopic male breast cancer is quite rare, prospective clinical trials are lacking, and most of the treatment approaches are based on the experience of the clinicians and data on female breast cancer. Although the treatment efficacy between men and women may be inconsistent in many aspects due to biological differences, strategies gleaned from cases of female breast cancer may be helpful [3]. Therefore, curative surgical resection followed by adjuvant chemotherapy is regarded as a standard treatment for non-metastatic male breast cancer, and adjuvant treatment, which includes chemotherapeutic agents and endocrine therapy in hormone receptor-positive cases, is similar to that for female breast cancer [456].\n\nMeanwhile, as a systemic treatment for metastatic female breast cancer, the use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors such as palbociclib along with endocrine therapy has been shown to improve clinical outcomes [7]. There have been no clinical trials of CDK4/6 inhibitors in male breast cancer, partially because the Korean health insurance does not cover the cost of these inhibitors for the treatment of male breast cancer. However, the United States Food and Drug Administration (FDA) recently approved palbociclib combined with endocrine therapy for the treatment of advanced male breast cancer [8]. Therefore, CDK4/6 inhibitors should be considered as an alternative to conventional chemotherapies for advanced male breast cancer. Since the multidisciplinary treatment board of the Kyungpook National University Chilgok Hospital has permitted the use of palbociclib plus letrozole for metastatic male breast cancer patients who are hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative, we would like to share our experience of administering palbociclib plus letrozole to treat an elderly male patient with relapsed ectopic breast cancer.\n\nCASE REPORT\nA 69-year-old Korean male was transferred from a nearby clinic after presenting with metastatic adenocarcinoma of unknown primary site confirmed with a perineal mass biopsy. At the time of admission to the oncology department on March 2016, the patient's general condition was good with an Eastern Cooperative Oncology Group performance status of 1, and he did not have any specific disease history. He complained of a palpable left inguinal mass (Figure 1), and histology of the resected inguinal mass revealed invasive breast cancer of ectopic breast origin. Immunohistochemistry analysis revealed it to be hormone receptor-positive and HER2-negative. The tumor was 28 mm in size, and the resection margin was clear. Subcutis and muscle involvement were noted, but there was no lymphovascular or perineural invasion. The tumor cells had an estrogen receptor (ER) score of 8, a progesterone receptor (PR) score of 8, and a Ki-67 labeling index of 10%. The histologic grade was 3 (Figure 2). The patient had no family history of breast or ovarian cancer, and no pathogenic germline breast cancer susceptibility gene (BRCA) 1/2 mutations were identified in the peripheral blood. However, an unclassified genetic variation of BRCA2 was detected (Table 1). Although 4 cycles of doxorubicin plus cyclophosphamide (AC) regimen followed by twelve cycles of weekly paclitaxel were planned as adjuvant chemotherapy, the patient completed only 8 cycles of weekly paclitaxel after 4 cycles of AC because he developed grade 2 neuropathy. Thereafter, tamoxifen was started without evidence of disease relapse at that time.\n\nFigure 1 PET-CT scan of the patients at the time of diagnosis. PET-CT scan showing a solitary left inguinal mass, measuring approximately 3 cm, shown to be invasive breast cancer of ectopic breast origin (March 2016).\nPET-CT = positron emission tomography-computed tomography.\n\nFigure 2 Representative features and immunohistochemical findings. (A) Irregular infiltration of tumor cell clusters suspended in extracellular mucin at the sub-epidermal tissue (H&E stain; ×20 on magnification). (B) Tumor cell clusters showing intermediate nuclear grade and extracellular mucin production (H&E stain; ×200). (C) Estrogen receptor positivity (> 95%; Allred score, 8 = 5 + 3, IHC; ×200). (D) Progesterone receptor positivity (> 90%; Allred score, 8 = 5 + 3, IHC; ×200). (E) ERBB2 (human epidermal growth factor receptor 2) incomplete staining (1+, IHC; ×200). (F) Low Ki-67 proliferation index (less than 2%, IHC; ×200).\nH&E = hematoxylin and eosin; IHC = Immunohistochemistry.\n\nTable 1 \nBRCA2 unclassified variation was detected\nExon\tBIC nomenclature\tHGVS nomenclature\tEffect on amino acid\tVariation type\t\n14\t7280C > G\tc.7052C > G\tp.Ala2351Gly\tUnclassified variation\t\nBIC = breast cancer information; HGVS = human genome variation society.\n\nIn October 2016, enlargement of the left inguinal mass was noted, and further analysis revealed adenocarcinoma with abundant mucin pools. The recurrent tumor cells showed an ER score of 8, a PR score of 8, HER2-negative, and a Ki-67 labeling index of 10%. After undergoing radiation therapy for local relapse, tamoxifen treatment was continued because there was no evidence of disease relapse and his health insurance did not cover for the use of aromatase inhibitors at that time. In September 2018, a 1-cm sized single nodule was identified in the right upper lung during a routine follow-up imaging study; this nodule was considered evidence of metastasis. The patient underwent stereotactic radiosurgery, but other metastatic nodules were found in both lobes of the lung. After receiving permission from the institutional multidisciplinary board, the patient was started on letrozole (2.5 mg orally once daily) plus goserelin (3.6 mg subcutaneously every 4 weeks) and palbociclib (125 mg orally once daily for 21 days followed by 7 days off treatment in 28-day cycles) in March 2019 based on the cumulative evidence of its benefits in female breast cancers. Recently, the patient completed his 12th cycle of palbociclib, letrozole, and goserelin combination therapy without any severe toxicity, and follow-up chest computed tomography showed a slight decrease in metastatic lung lesions (Figure 3). This study was approved by the Institutional Review Board of Kyungpook National University Chilgok Hospital (KNUCH 2020-04-012), and informed consent was obtained.\n\nFigure 3 Timeline of treatment and lung nodules. (A) Summary of the overall treatment administered. (B) CT scan showing right upper lung mass (arrowhead). (C) The right upper lung mass (arrowhead) was slightly decreased after letrozole plus palbociclib and goserelin combination therapy. (D) CT scan showing left upper lung mass (arrow). (D) The left upper lung mass (arrow) was also decreased after treament, demonstrating a stable disease.\nCT = computed tomography.\n\nDISCUSSION\nGenerally, the diagnosis of male breast cancer tends to be delayed when compared with that in women due to the lack of adequate screening and clinician awareness. Therefore, male breast cancer patients are more likely to be diagnosed at a more advanced stage than female breast cancer patients [1]. Besides, de novo metastatic disease has been reported in more than 4% of all male breast cancer cases; the most common sites are the bones, lungs, and distant lymph nodes [9]. The most common histological subtype is invasive ductal carcinoma, and individuals can present with various symptoms, such as painless masses and ulceration. If a male patient is diagnosed with breast cancer, it is important to investigate their family history for possible genetic abnormalities [10]. In fact, more than 15% of male breast cancer patients have a family history of breast or ovarian cancer, and approximately 10% of patients showed a hereditary breast cancer-related genetic mutation such as a BRCA mutation. In particular, a BRCA2 mutation is a known risk factor for breast cancer in the male population [11].\n\nEctopic breast cancer can present anywhere along the milk line as a result of incomplete normal embryological development of the breast bud. Ectopic breast cancer is rare and accounts for less than 1% of all breast cancers. More than 90% of all ectopic breast cancer cases are diagnosed in female patients [12]. The axillar is the most frequent site identified as a primary tumor, and histologically, invasive ductal carcinoma is the most common type. The regimens for postoperative adjuvant therapy for ectopic breast cancer are similar to those for breast cancer [13]. However, the treatment response and prognosis of ectopic breast cancer are difficult to determine because of the limited patient population and lack of clinical trials.\n\nPalbociclib is a CDK4/6 inhibitor, and preclinical studies have shown its ability to inhibit the growth of ER-positive breast cancer cells, acting synergistically with antiestrogens [14]. In a phase II study (PALOMA-2) on previously untreated ER-positive and HER2-negative advanced breast cancer, palbociclib combined with letrozole showed significantly longer progression-free survival than letrozole alone [7]. In the United States, the FDA has already approved the use of CDK4/6 inhibitor and letrozole combination regimens for patients with ER-positive and HER2-negative advanced breast cancer [15]. All of these promising results were obtained in female patients; unfortunately, there is a lack of clinical trials for male breast cancer patients. However, clinicians should consider palbociclib plus letrozole combination therapy as an alternative for ER-positive, HER2-negative advanced male breast cancer because efficacy and safety have already been demonstrated with the use of palbociclib in breast cancer.\n\nMale breast cancer may appear similar to female breast cancer in many characteristics, but subtle differences exist. There have been many valuable studies on female breast cancer, and we can apply these results to create treatment strategies for male patients with breast cancer. However, well-designed studies for novel agents such as CDK4/6 inhibitors, mammalian target of rapamycin inhibitors, and PARP inhibitors, alone or as combined regimens, are still necessary, and clinical investigators should be encouraged to enroll male breast cancer patients in clinical trials. Herein, we reported the successful use of palbociclib with letrozole to treat relapsed ectopic breast cancer in a 69-year-old man. Palbociclib should be considered as a treatment for advanced male breast cancer irrespective of the limitations posed by the current national health insurance policy.\n\nConflicts of Interest: The authors declare that they have no competing interests.\n\nAuthor Contributions:\nConceptualization: Baek DW, Lee SJ, Chae YS.\n\nData curation: Baek DW.\n\nFormal analysis: Baek DW.\n\nInvestigation: Baek DW, Chae YS.\n\nSoftware: Baek DW.\n\nSupervision: Lee SJ, Chae YS.\n\nValidation: Lee SJ, Chae YS.\n\nVisualization: Baek DW, Park JY.\n\nWriting - original draft: Baek DW, Park JY, Lee SJ, Chae YS.\n\nWriting - review & editing: Baek DW, Chae YS.\n==== Refs\n1 Siegel RL Miller KD Jemal A Cancer statistics, 2017 CA Cancer J Clin 2017 67 7 30 28055103 \n2 Ortiz-Mendoza CM Axillary ectopic breast tissue fibroadenoma: report of three cases and review of the literature Ginecol Obstet Mex 2012 80 99 103 22519219 \n3 Anderson WF Althuis MD Brinton LA Devesa SS Is male breast cancer similar or different than female breast cancer? Breast Cancer Res Treat 2004 83 77 86 14997057 \n4 Cardoso F Bartlett JMS Slaets L van Deurzen CHM van Leeuwen-Stok E Porter P Characterization of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG international male breast cancer program Ann Oncol 2018 29 405 417 29092024 \n5 Culell P Solernou L Tarazona J Roma J Martí E Miguel A Male breast cancer: a multicentric study Breast J 2007 13 213 215 17319872 \n6 Cutuli B Le-Nir CC Serin D Kirova Y Gaci Z Lemanski C Male breast cancer. Evolution of treatment and prognostic factors. Analysis of 489 cases Crit Rev Oncol Hematol 2010 73 246 254 19442535 \n7 Finn RS Martin M Rugo HS Jones S Im SA Gelmon K Palbociclib and letrozole in advanced breast cancer N Engl J Med 2016 375 1925 1936 27959613 \n8 Wedam S Fashoyin-Aje L Bloomquist E Tang S Sridhara R Goldberg KB FDA approval summary: palbociclib for male patients with metastatic breast cancer Clin Cancer Res 2020 26 1208 1212 31649043 \n9 Korde LA Zujewski JA Kamin L Giordano S Domchek S Anderson WF Multidisciplinary meeting on male breast cancer: summary and research recommendations J Clin Oncol 2010 28 2114 2122 20308661 \n10 Vermeulen MA Slaets L Cardoso F Giordano SH Tryfonidis K van Diest PJ Pathological characterisation of male breast cancer: results of the EORTC 10085/TBCRC/BIG/NABCG international male breast cancer program Eur J Cancer 2017 82 219 227 28292559 \n11 Tai YC Domchek S Parmigiani G Chen S Breast cancer risk among male BRCA1 and BRCA2 mutation carriers J Natl Cancer Inst 2007 99 1811 1814 18042939 \n12 Shin SJ Sheikh FS Allenby PA Rosen PP Invasive secretory (juvenile) carcinoma arising in ectopic breast tissue of the axilla Arch Pathol Lab Med 2001 125 1372 1374 11570920 \n13 Fracchioli S Puopolo M De La Longrais IA Scozzafava M Bogliatto F Arisio R Primary “breast-like” cancer of the vulva: a case report and critical review of the literature Int J Gynecol Cancer 2006 16 Suppl 1 423 428 \n14 Finn RS Crown JP Lang I Boer K Bondarenko IM Kulyk SO The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study Lancet Oncol 2015 16 25 35 25524798 \n15 Dickler MN Tolaney SM Rugo HS Cortés J Diéras V Patt D MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+ /HER2- metastatic breast cancer Clin Cancer Res 2017 23 5218 5224 28533223\n\n",
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"abstract": "Dyskeratosis congenita (DC) is characterized by reticular skin pigmentation, oral leukoplakia and abnormal nails. Patients with DC have very short telomeres and approximately one-half have mutations in telomere biology genes. A majority of patients with DC develop BM failure (BMF). Hematopoietic cell transplantation (HCT) represents the only known cure for BMF in DC, but poses significant toxicities. We report six patients who underwent allogeneic HCT with a novel nonmyeloablative conditioning regimen specifically designed for DC patients. Graft sources included related PBSCs (1), unrelated BM (2) and unrelated double umbilical cord blood (3). Complete donor engraftment was achieved in five of six patients. One patient had initial autologous hematopoietic recovery, which was followed by a second transplant that resulted in 88% donor chimerism. With a median follow-up of 26.5 months, four patients are alive, three of whom were recipients of unrelated grafts. We conclude with this small study that encouraging short-term survival can be achieved with HCT in patients with DC using a preparative regimen designed to promote donor engraftment and minimize life-threatening disease-specific complications such as pulmonary fibrosis. Long-term follow-up will be crucial with respect to individualized patient care with each of the transplanted individuals.",
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{
"abstract": "Before approval of andexanet alfa, off-label treatment with 4-factor prothrombin complex concentrate (4F-PCC) was often utilized for the management of life-threatening hemorrhages associated with oral factor Xa inhibitors. We evaluated the operational processes and outcomes of patients with oral factor Xa inhibitor-associated intracranial hemorrhages (ICH) treated with andexanet alfa or 4F-PCC.\n\n\n\nWe performed a retrospective, single-center case series of rivaroxaban or apixaban-associated ICH between 2016-2019 treated with andexanet alfa or 4F-PCC. Good or excellent hemostatic effectiveness, good functional outcome (Glasgow Outcome Score [GOS]> 3) at hospital discharge, and incidence of thrombosis within 30 days were reported.\n\n\n\nEighteen patients were included in the andexanet alfa cohort and 11 in the 4F-PCC cohort. Excellent or good hemostasis occurred in 88.9% of andexanet alfa-treated patients and 60% of 4F-PCC-treated patients. Good functional outcome on discharge occurred in 55.6% of andexanet alfa-treated patients and 9.1% of 4F-PCC-treated patients. Thrombotic complications occurred in 16.7% of andexanet alfa-treated patients and 9.1% of 4F-PCC-treated patients. Median order-to-administration time was 1.1 hours [0.8-1.4] versus 0.5 hours [0.1-0.8] in the andexanet alfa and 4F-PCC group, respectively. The median cost of therapy was $29970/patient versus $6925/patient in the andexanet alfa and 4F-PCC group, respectively.\n\n\n\nWe observed higher rates of occurrence of good or excellent hemostasis and GOS > 3 on hospital discharge and increased incidence of thrombosis in patients who received andexanet alfa compared to 4F-PCC for oral factor Xa inhibitor reversal. However, patients receiving 4F-PCC had lower pre-reversal Glasgow Coma Scale (GCS)score and larger pre-reversal ICH volume.",
"affiliations": "Department of Pharmacy, Massachusetts General Hospital, Boston, MA, USA.;Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Department of Pharmacy, Massachusetts General Hospital, Boston, MA, USA.;Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Department of Medicine, Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Department of Pharmacy, Massachusetts General Hospital, Boston, MA, USA.;Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Department of Pharmacy, Massachusetts General Hospital, Boston, MA, USA.",
"authors": "Barra|Megan E|ME|;Das|Alvin S|AS|;Hayes|Bryan D|BD|;Rosenthal|Eric S|ES|;Rosovsky|Rachel P|RP|;Fuh|Lanting|L|;Patel|Aman B|AB|;Goldstein|Joshua N|JN|;Roberts|Russel J|RJ|",
"chemical_list": "D001779:Blood Coagulation Factors; D065427:Factor Xa Inhibitors; C580915:PRT064445; D011720:Pyrazoles; D011728:Pyridones; D011994:Recombinant Proteins; C025667:prothrombin complex concentrates; C522181:apixaban; D000069552:Rivaroxaban; D015951:Factor Xa",
"country": "England",
"delete": false,
"doi": "10.1111/jth.14838",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-7836",
"issue": "18(7)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "antithrombotic drugs; hemostasis; intracranial hemorrhage; thrombosis",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D001779:Blood Coagulation Factors; D015951:Factor Xa; D065427:Factor Xa Inhibitors; D006801:Humans; D020300:Intracranial Hemorrhages; D011720:Pyrazoles; D011728:Pyridones; D011994:Recombinant Proteins; D012189:Retrospective Studies; D000069552:Rivaroxaban",
"nlm_unique_id": "101170508",
"other_id": null,
"pages": "1637-1647",
"pmc": null,
"pmid": "32291874",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of andexanet alfa and four-factor prothrombin complex concentrate (4F-PCC) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages.",
"title_normalized": "evaluation of andexanet alfa and four factor prothrombin complex concentrate 4f pcc for reversal of rivaroxaban and apixaban associated intracranial hemorrhages"
} | [
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"abstract": "Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infection that sometimes occurs in immunocompromised patients with human immunodeficiency virus (HIV). Here, we report two extremely rare cases of PCP in non-HIV pregnant women who underwent chemotherapy for malignant lymphoma. Case 1 is a 34-year-old primigravida who was diagnosed with Hodgkin's lymphoma. She received ABVD chemotherapy and developed PCP at 37 weeks of gestation. After the onset of PCP, emergent cesarean section was performed due to a nonreassuring fetal status. Case 2 is a 31-year-old multigravida with diffuse large B-cell lymphoma who was administered R-CHOP chemotherapy. At 34 weeks of gestation, she complained of dyspnea and developed PCP. She delivered her baby vaginally immediately after the onset of symptoms. Both patients were treated with sulfamethoxazole-trimethoprim (ST) and recovered shortly thereafter. The babies' courses were also uneventful. PCP remains a serious cause of death, especially in non-HIV patients, and, therefore, appropriate prophylaxis and a prompt diagnosis are imperative.",
"affiliations": "Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.;Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.",
"authors": "Fukutani|Yuki|Y|;Chigusa|Yoshitsugu|Y|0000-0001-9629-5912;Kondoh|Eiji|E|;Kawasaki|Kaoru|K|;Io|Shingo|S|;Matsumura|Noriomi|N|0000-0002-4512-7975",
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"fulltext": "\n==== Front\nCase Rep Obstet GynecolCase Rep Obstet GynecolCRIOGCase Reports in Obstetrics and Gynecology2090-66842090-6692Hindawi 10.1155/2017/1073146Case Report\nPneumocystis Pneumonia in Non-HIV Pregnant Women Receiving Chemotherapy for Malignant Lymphoma: Two Case Reports Fukutani Yuki http://orcid.org/0000-0001-9629-5912Chigusa Yoshitsugu \n*\nKondoh Eiji Kawasaki Kaoru Io Shingo http://orcid.org/0000-0002-4512-7975Matsumura Noriomi Department of Gynecology and Obstetrics, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan*Yoshitsugu Chigusa: chigusa@kuhp.kyoto-u.ac.jpAcademic Editor: Akihide Ohkuchi\n\n2017 28 8 2017 2017 10731462 4 2017 28 7 2017 2 8 2017 Copyright © 2017 Yuki Fukutani et al.2017This 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.\nPneumocystis pneumonia (PCP) is a life-threatening opportunistic infection that sometimes occurs in immunocompromised patients with human immunodeficiency virus (HIV). Here, we report two extremely rare cases of PCP in non-HIV pregnant women who underwent chemotherapy for malignant lymphoma. Case 1 is a 34-year-old primigravida who was diagnosed with Hodgkin's lymphoma. She received ABVD chemotherapy and developed PCP at 37 weeks of gestation. After the onset of PCP, emergent cesarean section was performed due to a nonreassuring fetal status. Case 2 is a 31-year-old multigravida with diffuse large B-cell lymphoma who was administered R-CHOP chemotherapy. At 34 weeks of gestation, she complained of dyspnea and developed PCP. She delivered her baby vaginally immediately after the onset of symptoms. Both patients were treated with sulfamethoxazole-trimethoprim (ST) and recovered shortly thereafter. The babies' courses were also uneventful. PCP remains a serious cause of death, especially in non-HIV patients, and, therefore, appropriate prophylaxis and a prompt diagnosis are imperative.\n==== Body\n1. Introduction\n\nPneumocystis pneumonia (PCP) is one of the most prevalent opportunistic infections in immunocompromised patients, especially in those infected with the human immunodeficiency virus (HIV). Lately, the incidence of PCP in non-HIV immunosuppressed patients has also been on the rise. These cases include hematological malignancies and patients who undergo chemotherapy for cancer or immunosuppressive drugs. In terms of PCP during pregnancy, most cases are HIV immunosuppressed patients, and non-HIV cases are extremely rare. Importantly, compared with HIV-positive patients, PCP in HIV-positive patients is associated with a higher mortality rate and poorer prognosis [1]. However, the standard prophylaxis and strategy for the treatment of PCP that develops in HIV-negative pregnant women have not yet been established.\n\nThis article describes two cases of PCP during pregnancy that occurred in patients receiving chemotherapy due to malignant lymphoma. We also reviewed the relevant literature to reveal the proper management of this life-threatening opportunistic infection in HIV-negative pregnant women.\n\n2. Case Reports\n2.1. Case 1\nA 34-year-old woman, gravida 0, complained of a swollen lymph node on the left side of the neck and underwent a biopsy of the neck and mediastinal lymph nodes at 20 weeks of gestation. Pathological diagnosis was classical stage IIA (Ann Arbor staging system) Hodgkin's lymphoma, with involvement of the left supraclavicular and mediastinal nodes. ABVD (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2) chemotherapy was started at 23 weeks of gestation. After 4 cycles of ABVD, at 37 weeks and 0 days of gestation, she experienced a cough and slight dyspnea. Chest X-ray showed high density areas in both lower lobes, which were detected as diffuse ground-glass patterns on computed tomography (CT) (Figure 1(a)). We included interstitial pneumonia caused by bleomycin as well as PCP in the differential diagnosis, and oral prednisone was administered. We did not prescribe sulfamethoxazole-trimethoprim (ST) because the safety of ST in pregnancy was unclear at that time. At 37 weeks and 1 day of gestation, fetal movement was profoundly decreased, and repeated variable deceleration was observed on the fetal heart rate monitor. Consequently, emergent cesarean section due to nonreassuring fetal status and breech presentation was performed, and she delivered a 2596 g male baby. After surgery, she was treated with ST based on the clinical suspicion of PCP. Eventually, she was diagnosed with PCP by a PCR method that detects Pneumocystis jirovecii-specific DNA in the sputum. After a 3-week treatment with ST and prednisone, she recovered and thereafter received two additional cycles of ABVD. She has had no sign of disease relapse, and the subsequent clinical course of the baby has been uneventful.\n\n2.2. Case 2\nA 31-year-old woman, gravida 1, para 1, who had undergone conization due to stage IA1 uterine cervical cancer, noticed swelling of the right side of the pharynx shortly after she conceived; as a result, she visited an otolaryngologist. The tonsil biopsy at 13 weeks of gestation showed diffuse large B-cell lymphoma (DLBCL). The patient had multiple swollen lymph node groups on the same side of the diaphragm and was therefore classified as stage II according to the Cotswold modification of the Ann Arbor staging system. In all, 6 cycles of R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 100 mg/body) every 3 weeks were administered. At 32 weeks of gestation, she was hospitalized due to rapidly shortening cervical length (15 mm), and tocolysis with ritodrine was started. At 34 weeks and 0 days of gestation, she suddenly complained of dyspnea and a nonproductive cough, and chest CT showed a ground-glass pattern on both sides of the lungs (Figure 1(b)). Pneumocystis pneumonia was highly suspected in view of her history and CT findings, and she was presumptively treated with sulfamethoxazole-trimethoprim (ST), azithromycin, and oral prednisone. Then, tocolysis was stopped and she delivered a 1939 g female baby at 34 weeks and 1 day of gestation. Although Pneumocystis jirovecii was not observed in bronchoalveolar lavage (BAL) fluid by Grocott stain, Pneumocystis jirovecii-specific DNA was detected by PCR using BAL fluid. She recovered and was discharged home 14 days later, and her baby's course was uneventful. She has shown no signs of DLBCL recurrence.\n\n3. Discussion\nIn the present report, we described two cases of PCP during pregnancy. Numerous cases of PCP in HIV-infected pregnant individuals have been reported. However, our cases are extremely rare in that both occurred in pregnant women without HIV. To the best of our knowledge, only one similar case of PCP has been reported thus far, and, in that case, PCP developed in a pregnant woman who was infected with human T lymphotropic virus type 1 (HTLV-1) [2].\n\nWith increasing maternal age, the incidence of cancer and the opportunity to administer chemotherapy during pregnancy also increase. Malignant lymphoma, which is the fourth most common malignancy diagnosed in pregnancy, is estimated to occur in 1 : 6,000 pregnancies [3]. Basically, chemotherapy in pregnant women with lymphoma should be similar to that in nonpregnant individuals, although it remains unclear whether the increased plasma volume and renal clearance of drugs during pregnancy might necessitate different doses of chemotherapy. The available existing data suggest that ABVD for Hodgkin's disease and CHOP for non-Hodgkin's disease during the second and third trimester can be administered safely without severe fetal outcomes [4]. In addition, compared with CHOP, rituximab with CHOP (R-CHOP) was revealed to be more effective and to lead to a better prognosis in patients (aged 18 to 60 years) with DLBCL [5]. Rituximab, which is a monoclonal antibody against CD20, is considered to be relatively safe for pregnant women although it may be associated with preterm birth [6, 7]. Based on these views, ABVD was given from 23 weeks of gestation in case 1, and R-CHOP was given from 16 weeks of gestation in case 2. In terms of R-CHOP, however, to our knowledge, only nine patients thus far have received that particular therapy [6–8], and more cases are necessary to analyze the safety of R-CHOP in pregnancy.\n\nGenerally, chemotherapy treatment for cancer can cause opportunistic infections, and patients with hematologic malignancies are particularly susceptible to a different set of infections [9]. However, the occurrence of PCP in patients who are administered R-CHOP or ABVD is infrequent. Hardak et al. reported that the incidence of PCP among patients treated with R-CHOP was 2.6% [10] in spite of the finding that R-CHOP includes a high dose of prednisone. Moreover, the frequency of PCP in patients who are given ABVD is currently unknown. The only literature that we found involved five patients with PCP and Hodgkin's lymphoma who were treated with ABVD [11]. Nevertheless, we have encountered two cases of PCP following ABVD or R-CHOP therapy. Presumably, PCP is more likely to occur in pregnant women who undergo cancer chemotherapy since pregnancy itself can give rise to immunosuppression [12].\n\nAlthough PCP during pregnancy in HIV-negative patients is very rare, it is notable that the mortality rate of patients with PCP in the absence of HIV is higher (30 to 60%) than that in patients with HIV (10 to 20%) [13]. Moreover, PCP in HIV-negative patients has an abrupt onset that consists of respiratory insufficiency, and patients can deteriorate rapidly. Therefore, the appropriate prophylaxis is necessary to reduce the risk of PCP, even among HIV-negative pregnant women. Sulfamethoxazole-trimethoprim (ST), also known as cotrimoxazole, has already been demonstrated to be effective for the prevention of PCP in patients with HIV [14], while ST has been recommended for HIV-infected pregnant women with a low CD4 cell count. According to the systematic review and meta-analysis regarding the safety of cotrimoxazole conducted by Ford et al., the overall prevalence of congenital abnormalities in those exposed to cotrimoxazole was not significantly higher than the reported rates in the general population [15]. Thus, patients with hematological cancers, such as lymphoma and leukemia, are at risk for PCP because they are treated with cytotoxic chemotherapy, which sometimes causes immunosuppression. In addition, chronic corticosteroid administration is one of the most common risk factors for PCP in patients without HIV infection. For nonpregnant women, therefore, it is recommended that prophylaxis with ST be considered for those with hematological malignancies who are treated with chemotherapy, and for those who are treated with more than 20 mg/day of prednisone for longer than 1 month [16]. This recommendation may be pertinent to pregnant women as well.\n\nIn addition to prophylaxis, prompt diagnosis and appropriate treatment are essential for a good prognosis of PCP. However, PCP is sometimes difficult to diagnose, as the patients present nonspecific symptoms such as fever, dyspnea, and nonproductive cough. Although the final diagnosis of PCP should be made based on the microscopic detection of Pneumocystis from specimens of sputum or bronchoalveolar fluid, the PCR method that is used to detect Pneumocystis jirovecii-specific nucleic acids has also become available, which has a higher diagnostic sensitivity. Moreover, chest CT is more sensitive and superior as a diagnostic tool compared with chest radiography. Indeed, in our two cases, expeditious CT revealed typical features of PCP, such as a ground-glass attenuation, which encouraged us to initiate treatment with sulfamethoxazole-trimethoprim. The fetal radiation doses from chest CT are very low, since this type of scan does not involve direct irradiation, but rather it results in scattered radiation. The maximum estimated conceptus radiation dose from chest CT is less than 1 mGy [17], and the average dose is 0.22 mGy [18]. Therefore, physicians should not hesitate to perform chest CT examination, even during pregnancy, when PCP is suspected.\n\nIn summary, we described two rare cases of PCP after chemotherapy was administered for lymphoma during pregnancy. PCP remains a serious cause of death in immunocompromised patients, and, therefore, appropriate prophylaxis and prompt diagnosis are imperative.\n\nConsent\nWritten informed consent was obtained from both patients for the publication of this case report and its accompanying images.\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nFigure 1 Chest X-ray (left) and computed tomography (CT) (right) images of case 1 (a) and case 2 (b). Chest X-ray showed a high density area in the lower lobes, which was detected as a diffuse ground-glass pattern on CT in both cases.\n==== Refs\n1 Mansharamani N. G. Garland R. Delaney D. Koziel H. Management and outcome patterns for adult Pneumocystis carinii pneumonia, 1985 to 1995: comparison of HIV-associated cases to other immunocompromised states Chest 2000 118 3 704 711 10.1378/chest.118.3.704 2-s2.0-0033801225 10988192 \n2 Tamaki Y. Higa F. Tasato D. Pneumocystis jirovecii pneumonia and alveolar hemorrhage in a pregnant woman with human T cell lymphotropic virus type-1 infection Internal Medicine 2011 50 4 351 354 2-s2.0-79951641394 10.2169/internalmedicine.50.4482 21325770 \n3 Brenner B. Avivi I. Lishner M. Haematological cancers in pregnancy The Lancet 2012 379 9815 580 587 2-s2.0-84856914452 10.1016/S0140-6736(11)61348-2 \n4 Avilés A. Neri N. Hematological malignancies and pregnancy: A final report of 84 children who received chemotherapy in utero Clinical Lymphoma 2001 2 3 173 177 2-s2.0-0035691599 10.3816/CLM.2001.n.023 11779294 \n5 Pfreundschuh M. Trümper L. Österborg A. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group The Lancet Oncology 2006 7 5 379 391 10.1016/S1470-2045(06)70664-7 2-s2.0-33646004738 16648042 \n6 Chakravarty E. F. Murray E. R. Kelman A. Farmer P. Pregnancy outcomes after maternal exposure to rituximab Blood 2011 117 5 1499 1506 2-s2.0-79551617381 10.1182/blood-2010-07-295444 21098742 \n7 Lee E. J. Ahn K. H. Hong S. C. Lee E. H. Park Y. Kim B. S. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy for diffuse large B-cell lymphoma in pregnancy may be associated with preterm birth Obstetrics & Gynecology Science 2014 57 6 526 529 10.5468/ogs.2014.57.6.526 25469343 \n8 Mandal P. K. Dolai T. K. Bagchi B. Ghosh M. K. Bose S. Bhattacharyya M. B cell suppression in newborn following treatment of pregnant diffuse large B-cell lymphoma patient with rituximab containing regimen Indian Journal of Pediatrics 2014 81 10 1092 1094 10.1007/s12098-013-1336-9 2-s2.0-84919844558 24562617 \n9 Zembower T. R. Epidemiology of infections in cancer patients Cancer Treatment and Research 2014 161 43 89 2-s2.0-84902087539 10.1007/978-3-319-04220-6_2 24706221 \n10 Hardak E. Oren I. Dann E. J. The increased risk for pneumocystis pneumonia in patients receiving rituximab-CHOP-14 can be prevented by the administration of trimethoprim/sulfamethoxazole: a single-center experience Acta Haematologica 2012 127 2 110 114 10.1159/000334113 2-s2.0-83455250642 22178955 \n11 Kalin M. Kristinsson S. Y. Cherif H. Lebbad M. Björkholm M. Fatal pneumocystis jiroveci pneumonia in ABVD-treated Hodgkin lymphoma patients Annals of Hematology 2010 89 5 523 525 2-s2.0-77950571344 10.1007/s00277-009-0833-4 19768459 \n12 Luppi P. How immune mechanisms are affected by pregnancy Vaccine 2003 21 24 3352 3357 10.1016/S0264-410X(03)00331-1 2-s2.0-0037708024 12850338 \n13 Thomas C. F. Jr. Limper A. H. Pneumocystis pneumonia The New England Journal of Medicine 2004 350 24 2487 2498 10.1056/nejmra032588 2-s2.0-2942518018 15190141 \n14 Bozzette S. Finkelstein D. M. Spector S. A. A randomized trial of three antipneumocystis agents in patients with advanced human immunodeficiency virus infection The New England Journal of Medicine 1995 332 11 693 699 10.1056/NEJM199503163321101 7854375 \n15 Ford N. Shubber Z. Jao J. Abrams E. J. Frigati L. Mofenson L. Safety of cotrimoxazole in pregnancy: a systematic review and meta-analysis Journal of Acquired Immune Deficiency Syndromes 2014 66 5 512 521 10.1097/QAI.0000000000000211 2-s2.0-84904504141 24853309 \n16 Limper A. H. Knox K. S. Sarosi G. A. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients American Journal of Respiratory and Critical Care Medicine 2011 183 1 96 128 10.1164/rccm.2008-740st 2-s2.0-78650794568 21193785 \n17 Goldberg-Stein S. Liu B. Hahn P. F. Lee S. I. Body CT during pregnancy: Utilization trends, examination indications, and fetal radiation doses American Journal of Roentgenology 2011 196 1 146 151 2-s2.0-78650825587 10.2214/AJR.10.4271 21178060 \n18 Lazarus E. DeBenedectis C. North D. Spencer P. K. Mayo-Smith W. W. Utilization of imaging in pregnant patients: 10-year review of 5270 examinations in 3285 patients - 1997–2006 Radiology 2009 251 2 517 524 10.1148/radiol.2512080736 2-s2.0-66149105525 19293204\n\n",
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"abstract": "To report a case of temporary bilateral corneal denting in a patient who underwent cardiovascular surgery under general anesthesia.\nA 71-year-old male with no history of ophthalmological disease experienced bilateral corneal denting immediately after undergoing surgery for aneurysm of the thoracic aorta under general anesthesia. Anesthesia was induced with propofol and maintained with rocuronium bromide and remifentanil hydrochloride. The initial examination revealed significant denting on the surface of both the corneas and ocular hypotension. Visual evaluation could not be performed due to the patient's low level of consciousness resulting from delayed emergence from anesthesia. After applying tropicamide and phenylephrine ophthalmic solution for fundus examination, the ocular morphology improved. Ocular pressure was normal on the day after surgery, and creasing on the surface of the corneas had disappeared.\nand Importance: We experienced a patient with bilateral corneal denting following a cardiovascular surgery under general anesthesia. The dents could be attributed to augmentation of ocular hypotension using several types of anesthesia at relatively high doses.",
"affiliations": "Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.",
"authors": "Obata|Satsuki|S|;Miki|Akiko|A|;Imai|Hisanori|H|;Nakamura|Makoto|M|",
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"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(18)30008-210.1016/j.ajoc.2018.04.011Case reportBilateral corneal denting after surgery under general anesthesia: A case report☆ Obata Satsuki Miki Akiko acacyey@med.kobe-u.ac.jp∗Imai Hisanori Nakamura Makoto Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan∗ Corresponding author. Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. acacyey@med.kobe-u.ac.jp19 4 2018 6 2018 19 4 2018 10 290 292 5 1 2018 22 2 2018 17 4 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report a case of temporary bilateral corneal denting in a patient who underwent cardiovascular surgery under general anesthesia.\n\nObservations\nA 71-year-old male with no history of ophthalmological disease experienced bilateral corneal denting immediately after undergoing surgery for aneurysm of the thoracic aorta under general anesthesia. Anesthesia was induced with propofol and maintained with rocuronium bromide and remifentanil hydrochloride. The initial examination revealed significant denting on the surface of both the corneas and ocular hypotension. Visual evaluation could not be performed due to the patient's low level of consciousness resulting from delayed emergence from anesthesia. After applying tropicamide and phenylephrine ophthalmic solution for fundus examination, the ocular morphology improved. Ocular pressure was normal on the day after surgery, and creasing on the surface of the corneas had disappeared.\n\nConclusions\nand Importance: We experienced a patient with bilateral corneal denting following a cardiovascular surgery under general anesthesia. The dents could be attributed to augmentation of ocular hypotension using several types of anesthesia at relatively high doses.\n\nKeywords\nGeneral anesthesiaCornea dentingComplicationCardiovascular surgery\n==== Body\n1 Introduction\nOcular complications after general anesthesia are uncommon.1 Ocular surface disease such as dry eye is a most common finding.1 It is also reported that patients who underwent coronary artery bypass graft surgery could develop retinal infarction or retinal emboli.2\n\nOn the other hand, corneal denting is a quite rare complication in connection with general anesthesia and has been reported only once by Hasegawa et al.3 so far.\n\nHere, we report a similar case of temporary bilateral corneal denting after surgery for aneurysm of the thoracic aorta under general anesthesia.\n\n2 Case report\nA 71-year-old male (height 156.0 cm, weight 40.0 kg) underwent ascending aorta and aortic arch replacement surgery for aneurysm of the thoracic aorta under general anesthesia. He remained under anesthesia for 10 h 20 min. Anesthesia was induced with propofol maintained with rocuronium bromide and remifentanil hydrochloride. In addition, artificial cardiopulmonary bypass was performed during the surgery; however, no diuretic drugs were used. The patient was consulted to the department of ophthalmology because ocular denting was observed after surgery. His medical history was left cerebral infarction, stenosis of the right internal carotid artery, and no history of ophthalmological disease. At initial examination, we observed denting and creasing on the surface of the corneas of both eyes. The anterior chambers were thin but maintained, and no fundal abnormalities were detected on non-dilated observation. The patient was not completely conscious during the initial examination and postoperative course; therefore, it was challenging to perform a visual acuity evaluation. In addition, ocular hypotension rendered the evaluation of ocular pressure challenging (Fig. 1).Fig. 1 Anterior chamber findings at initial examination. Significant corneal denting and creasing observed in both eyes.\n\nFig. 1\n\nAfter applying tropicamide and phenylephrine ophthalmic solution for fundus examination, we observed gradual improvement in the ocular morphology. Two hours after applying the ophthalmic solution, the corneal denting markedly improved and reduced to only slight creasing on the surfaces of the corneas. We did not find corneal edema in either eyes. The fundus examination did not indicate abnormal findings such as swelling of the optic disc or hemorrhage (Fig. 2).Fig. 2 Anterior chamber and fundus findings 2 h after the application of tropicamide and phenylephrine ophthalmic solution. Significant improvement in corneal denting, and normal fundus findings confirmed.\n\nFig. 2\n\nOn the day after surgery, the creasing on the surface of the corneas had disappeared and ocular pressure was normal (15 mmHg on the right and 14 mmHg on the left) (Fig. 3). We did not find apparent corneal endothelial cell damage in either eyes. In addition, the findings of the fundus examination were normal. Because our patient experienced delayed recovery from anesthesia, the assessment of visual function was impossible. Subsequently, he experienced septic shock and died 18 days after the surgery.Fig. 3 Anterior chamber findings on the day following surgery. Creasing on the corneal surfaces has disappeared.\n\nFig. 3\n\n3 Discussion\nOur patient experienced bilateral corneal denting after cardiovascular surgery under general anesthesia. A previous report3 has discussed a case wherein the patient underwent blood vessel prosthesis implantation surgery under general anesthesia for acute aortic dissection and developed bilateral corneal denting immediately after the surgery. Similarities between that report and our report include the patient's advanced age, low body weight (Body mass index (BMI) < 18.5), and onset after long-term cardiovascular surgery.\n\nThe previous report3 attributed the corneal denting to the following three factors: the effect of decreased ocular pressure because of general anesthesia (barbiturates), the possibility of excessive dose of mannitol for the body type during surgery, and the possibility of corneal denting because of the maintenance of corneal curvature radius by intraocular lens. However, the differences between the previous report and our report are the types of anesthetic agents used, high dose of diuretics, and history of cataract surgery in the previous study. Therefore, other factors may have been involved in the denting in the present case.\n\nIn the present case, multiple anesthetics, such as propofol, remifentanil, and sevoflurane, which have the effect of decreasing ocular pressure, were utilized and may have augmented the ocular hypotension. All these anesthetic agents reportedly cause ocular hypotension.4,5 In addition, the following mechanism of ocular hypotension caused by anesthesia has been reported6: aqueous outflow, which is regulated by intraocular pressure regulation center in the diencephalon, is promoted, and hypotonia of the extraocular muscles promotes decreased ocular tension and aqueous outflow. In addition, our patient experienced sympathetic nerve inhibition because of propofol, which, along with simultaneous decreases in the aqueous humor production, may have caused temporary excessive aqueous outflow.\n\nExcessive doses of general anesthesia could also have been a cause of the corneal denting. In addition, our patient experienced delayed recovery from anesthesia, which may be attributed to the prolonged effect of excessive doses of anesthesia and muscle relaxants.5,7 We also observed a likelihood of relatively excessive doses because of the patient's advanced age, low BMI, liver and renal functional disorders, and low cardiac function.8,9 Because our case involved a patient with a low body weight who underwent cardiovascular surgery at a relatively advanced age, it is possible that relatively excessive doses of anesthesia were administered.\n\nAnother explanation for corneal denting might be the unbalance of pressure between anterior chamber and atomic pressure. The similar corneal denting infrequently takes place during cataract surgery when infusion does not catch up with aspiration, leading to a negative pressure in the anterior chamber compared with the atomic pressure. Such a negative pressure in the anterior chamber must have given rise for some reason in this patient during or after the cardiovascular surgery. General anesthetics may have negatively affected the partial pressure in the anterior chamber by passive diffusion into the aqueous humor.\n\nThe corneal morphology improved after applying tropicamide and phenylephrine ophthalmic solution. It may be because that the dilating drops containing phenylephrine increase the resistance of aqueous outflow via the relaxation of ciliary muscle. Or there was also an inverse pressure gradient between the anterior and posterior chamber, and thus pupillary dilation may have released the reverse pupillary block. If so, an injection of physiological saline may be another option to treat this condition. It is also suggested that ocular morphology naturally became to its original state with time.\n\n4 Conclusions\nWe report a case of bilateral corneal denting after surgery under general anesthesia. This case suggests that using multiple and relatively excessive doses of anesthetics increases the risk of corneal denting because of the augmentation of intraocular hypotension.\n\nPatient consent\nThe patient's legal guardian consented to publication of the case in orally.\n\nFunding\nNo funding or grant support.\n\nConflicts of interest\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nAcknowledgements\nNone.\n\n☆ This case was presented at the 70th Annual Congress of Japan Clinical Ophthalmology.\n==== Refs\nReferences\n1 Kara-Junior N. Espindola R.F. Valverde Filho J. Rosa C.P. Ottoboni A. Silva E.D. Ocular Risk Management in Patients Undergoing General Anesthesia: An Analysis of 39,431 Surgeries Clinics (Sao Paulo) vol. 70 2015 541 543 8 \n2 Shaw P.J. Bates D. Cartlidge N.E. Neuro-ophthalmological complications of coronary artery bypass graft surgery Acta Neurol Scand 76 1 1987 1 7 3498286 \n3 Hasegawa T. Matsui Y. Morita M. Dented corneas related to cardiovascular surgery under general anesthesia Graefes Arch Clin Exp Ophthalmol 50 3 2012 465 466 \n4 Sator-Katzenschlager S. Deusch E. Dolezal S. Sevoflurane and propofpl decrease intraocular pressure equally during non-ophthalmic surgery and recovery Br J Anaesth 89 5 2002 764 766 12393777 \n5 Hanna S.F. Ahmad F. Pappas A.L. The effect of propofol/remifentanil rapid-induction technique without muscle relaxants on intraocular pressure J Clin Anesth 22 6 2010 437 442 20868965 \n6 Schäfer R. Klett J. Auffarth G. Intraocular pressure more reduced during anesthesia with propofol than with sevoflurane: both combined with remifentanil Acta Anaesthesiol Scand 46 6 2002 703 706 12059895 \n7 Ullhas S.M. Joshi Suchita Annasaheb Shaikh Mudassir Mohd Delayed recovery from anesthesia: a postgraduate educational review Anesth Essays 10 2 2016 164 172 \n8 Bowie M.W. Slattum P.W. Pharmacodynamics in older adults: a review Am J Geriatr Pharmacother 5 3 2007 263 303 17996666 \n9 Tsai H.J. Chen C.C. Chang K.Y. Patients and surgery-related factors that affect time to recovery of consciousness in adult patients undergoing elective cardiac surgery J Chin Med Assoc 74 8 2011 345 349 21872814\n\n",
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"keywords": "Cardiovascular surgery; Complication; Cornea denting; General anesthesia",
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{
"abstract": "To describe a case of corneal ulceration associated with Nivolumab use.\nAn 80-year-old woman treated with Nivolumab for metastatic melanoma developed an intractable corneal ulcer in her left eye, refractory to all therapies - including surgery to cover the ulcer with a conjunctival flap - until topical prednisolone acetate was tried, which was curative.\nNivolumab use may be associated with a form of steroid-responsive corneal ulceration.",
"affiliations": "Parker Cornea, 1720 University Blvd Suite 503, Birmingham, AL, 35233, USA.;Alabama Eye Ophthalmology Associates, 1009 Montgomery Hwy #200, Birmingham, AL, 35216, USA.;Alabama Oncology Brookwood, 2022 Medical Center Drive, Suite 628, Birmingham, AL, 35209, USA.;University of Alabama at Birmingham School of Medicine, 1670 University Blvd, Birmingham, AL, 35233, USA.;Parker Cornea, 1720 University Blvd Suite 503, Birmingham, AL, 35233, USA.",
"authors": "Parker|Jack S|JS|;Feagin|Wyatt|W|;Wang|Christopher|C|;Heersink|Marius|M|;Parker|John S|JS|",
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"doi": "10.1016/j.ajoc.2019.01.013",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(18)30103-810.1016/j.ajoc.2019.01.013Case ReportCorneal ulceration associated with Nivolumab use Parker Jack S. jack.parker@gmail.comab∗Feagin Wyatt cWang Christopher dHeersink Marius eParker John S. aa Parker Cornea, 1720 University Blvd Suite 503, Birmingham, AL, 35233, USAb Netherlands Institute for Innovative Ocular Surgery (NIIOS), Laan op Zuid 88 - 3071 AA Rotterdam, Rotterdam, NL, the Netherlandsc Alabama Eye Ophthalmology Associates, 1009 Montgomery Hwy #200, Birmingham, AL, 35216, USAd Alabama Oncology Brookwood, 2022 Medical Center Drive, Suite 628, Birmingham, AL, 35209, USAe University of Alabama at Birmingham School of Medicine, 1670 University Blvd, Birmingham, AL, 35233, USA∗ Corresponding author. Parker Cornea, Birmingham, AL, USA. jack.parker@gmail.com07 2 2019 6 2019 07 2 2019 14 26 27 17 3 2018 8 7 2018 30 1 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo describe a case of corneal ulceration associated with Nivolumab use.\n\nObservations\nAn 80-year-old woman treated with Nivolumab for metastatic melanoma developed an intractable corneal ulcer in her left eye, refractory to all therapies – including surgery to cover the ulcer with a conjunctival flap – until topical prednisolone acetate was tried, which was curative.\n\nConclusions and importance\nNivolumab use may be associated with a form of steroid-responsive corneal ulceration.\n\nKeywords\nCorneaCorneal ulcerNivolumabOpdivoPeripheral ulcerative keratitis\n==== Body\n1 Introduction\nNivolumab is an immunomodulatory agent with a broadening list of indications including first-line medical treatment for metastatic melanoma and second line for non-small cell lung cancer.1 The drug is a monoclonal antibody that targets the PD-1 receptor, and it functions by upregulating the number and activity of circulating T-cells.2 Stemming from this mechanism, a number of “immune related adverse events” have been described, including polymyalgia rheumatica, insulin-dependent diabetes, and immune-related pneumonitis, colitis, myocarditis, hepatitis, nephritis, encephalitis, and others.2 Ocular side effects have also been reported including conjunctivitis, uveitis, and dry eye syndrome.2, 3, 4, 5 Here, we present a ocular adverse association with Nivolumab use – corneal ulceration – and describe its features, clinical behavior, and potential importance to oncologists as a harbinger of more serious systemic sequelae.\n\n2 Case description\nAn 80-year-old white female with no past ocular history and a medical history significant for metastatic mucosal melanoma – treated initially with Nivolumab at the standard dosage (every-other-week infusions of 240mg for a duration of 4 months prior to seeing ophthalmological care) – presented to our clinic complaining of redness, pain, and decreased vision in her left eye of one-month's duration. On exam, her left eye manifested a best-corrected visual acuity (BCVA) of 20/40, moderate injection of the bulbar conjunctiva, and a limbus-involving corneal epithelial defect with underlying infiltrate (Fig. 1). The right eye was asymptomatic with a normal exam and a BCVA of 20/20. Bacterial and fungal cultures and HSV PCR were negative. Corneal sensation was normal bilaterally. Nevertheless, for suspected HSV-keratitis, ganciclovir ophthalmic gel (0.15%) was initiated five times daily in the left eye along with oral Valcyclovir 1 gm three times daily. Ten weeks of such treatment produced no improvement in the appearance of the ulcer, nor did one subsequent week of loteprednol etabonate ophthalmic gel (0.5%) applied twice daily, and – as a result of continuing pain– the patient underwent a conjunctival flap procedure along with corneal biopsy. The surgery itself was uneventful; at one day, week, and month postoperatively, the eye was comfortable and the flap appeared in good position. Meanwhile, the results of the corneal biopsy (including tissue gram stain, culture, and viral PCR for herpes simplex, zoster, and cytomegalovirus) were negative. However, by the two-month postoperative visit, the ulcer had recurred at the central edge of the conjunctival flap (Fig. 2). Viral and bacterial cultures were repeated, oral Valcyclovir at 1 gm three times daily was resumed (which had been discontinued after surgery), and topical ciprofloxacin (0.3%) ophthalmic solution was initiated at a frequency of one drop every hour around the clock. Three days later – with all cultures again negative, and the patient's signs and symptoms unimproved – a decision was made to stop all topical and oral therapy and instead proceed with topical prednisolone acetate ophthalmic solution (1%) four times daily. Four days later, the epithelial defect had completely healed; two weeks later, topical steroids were discontinued. Two months later, secondary to interstitial pneumonitis, declining pulmonary function, and the development of atrial fibrillation and brittle, insulin-dependent diabetes, Nivolumab infusions were halted (which were ongoing throughout the entirety of her ophthalmic treatment course). Through 12 months of subsequent follow-up, the patient's left eye has remained asymptomatic without evidence of ulcer recurrence.Fig. 1 Peripheral cornea ulcer.\n\nFig. 1Fig. 2 Recurrent ulcer at the central edge of the conjunctival flap.\n\nFig. 2\n\n3 Discussion and conclusions\nWith Nivolumab rapidly increasing in popularity for a number of different malignancies, a number of inflammatory ocular side effects have been attributed to its use. These include conjunctivitis, anterior uveitis, immune retinopathy, endothelitis, and corneal allograft reaction with graft rejection.2, 3, 4, 5 Dry eye syndrome is believed to be the most common related ocular adverse event and, recently, Nguyen et al. described a severe example of which culminating in corneal perforation.6 Even more recently, Reddy et al. made the first report of Nivolumab associated retinopathy.7 Here, we describe Nivolumab associated corneal ulceration which appears to be immune, not exposure, related.\n\nThat our patient's ulcer arose at the corneal limbus, rather than in the inferior or interpalpebral cornea, suggests an inflammatory etiology, akin to a peripheral ulcerative keratitis, rather than an exposure keratopathy, as does the ulcer's unilaterality (and the paucity of dry-eye findings in the contralateral eye), its recurrence at the edge of the conjunctival flap, and its prompt resolution following the administration of topical prednisolone acetate (but, interestingly, not loteprednol etabonate). These findings also argue against a diagnosis of Rosacea-related keratitis, which has been reported to produce a sterile corneal ulceration.8\n\nAlthough our initial suspicion was a herpetic keratitis based on the lesion's morphology, the patient's lack of response to extended medical (and surgical) therapy called this diagnosis into question, as did the multiple negative culture and biopsy results. Moreover, Nivolumab may actually be an effective treatment for herpetic keratitis, since it upregulates and activates the body's T-cell population, making our original diagnosis additionally unlikely and suggesting an etiology of true auto-immune keratitis.9 Whether our patient had a predisposition to developing ocular autoimmune problems is unknown, because the required laboratory investigations to inform upon that issue were not performed. However, it is possible that some individuals may be uniquely susceptible to such complications.\n\nIt is also noteworthy that our patient's systemic side effects of Nivolumab use which forced her to discontinue the medication crescendoed within four months of the appearance of her corneal ulcer. In patients with rheumatoid arthritis, peripheral ulcerative keratitis is often resistant to topical steroid therapy and is a well-known harbinger of severe morbidity and mortality risk. It is conceivable that peripheral ulceration in patients using Nivolumab likewise presages upcoming systemic events.10\n\n4 Patient Consent\nConsent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nAcknowledgments and disclosures\nNo funding or grant support.\n\nNo author has a financial or proprietary interest in any material or method mentioned.\n\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n==== Refs\nReferences\n1 Ramamurthy C. Godwin J.L. Borghaei H. Immune checkpoint inhibitor therapy: what line of therapy and how to choose? Curr Treat Options Oncol 18 2017 33 28534248 \n2 Zimmer L. Goldinger S.M. Hofmann L. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy Eur J Cancer 60 2016 210 225 27084345 \n3 Richardson D.R. Ellis B. Mehmi I. Leys M. Bilateral uveitis associated with nivolumab therapy for metastatic melanoma: a case report Int J Ophthalmol 10 2017 18 1183 1186 28730129 \n4 Baughman D.M. Lee C.S. Snydsman B.E. Jung H.C. Bilateral uveitis and keratitis following nivolumab treatment for metastatic melanoma Med Case Rep 3 2017 pii: 8 \n5 Le Fournis S. Gohier P. Urban T. Jeanfaivre T. Hureaux J. Corneal graft rejection in a patient treated with nivolumab for primary lung cancer Lung Canc 102 2016 28 29 \n6 Nguyen A.T. Elia M. Materin M.A. Sznol M. Chow J. Cyclosporine for dry eye associated with nivolumab: a case progressing to corneal perforation Cornea 35 2016 399 401 26771550 \n7 Reddy M. Chen J.J. Kalevar A. Terribilini R. Agarwal A. Immune retinopathy associated with nivolumab administration for metastatic non-small cell lung cancer Retin Cases Brief Rep 2017 Nov 22 [Epub ahead of print] \n8 Brouwer N. Haanen J. Jager M. Development of ocular Rosacea following combined ipilimumab and nivolumab treatment for metastatic malignant skin melanoma Ocul Oncol Pathol 3 2017 188 192 29071268 \n9 Jun H. Seo S.K. Jeong H.Y. B7-H1 (CD274) inhibits the development of herpetic stromal keratitis (HSK) FEBS Lett 579 2005 7 6259 6264 16253242 \n10 Foster C.S. Forstot S.L. Wilson L.A. Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immunosuppression Ophthalmology 91 1984 1253 1263 6514289\n\n",
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"keywords": "Cornea; Corneal ulcer; Nivolumab; Opdivo; Peripheral ulcerative keratitis",
"medline_ta": "Am J Ophthalmol Case Rep",
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"pages": "26-27",
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"pmid": "30815619",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "16253242;26771550;27084345;27987584;28534248;28730129;28856338;29071268;29176534;6514289",
"title": "Corneal ulceration associated with Nivolumab use.",
"title_normalized": "corneal ulceration associated with nivolumab use"
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"literaturereference": "WANG C, PARKER J, FEAGIN W, HEERSINK M, PARKER J. CORNEAL ULCERATION ASSOCIATED WITH NIVOLUMAB USE. AMERICAN JOURNAL OF OPHTHALMOLOGY CASE REPORTS. 2019?14:26?7",
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{
"abstract": "BACKGROUND\nAcetazolamide has been studied extensively in post-hypercapnic alkalosis as a tool to facilitate ventilator weaning in chronic obstructive pulmonary disease (COPD). It has also been utilized to facilitate respiratory drive in nonmechanically ventilated patients with COPD. Although this is generally a forgiving intervention, providers must carefully select patients for this medication, as it can cause severe acidosis and deterioration of clinical status in severe COPD cases. The present report describes two cases of patients who developed worsening acidosis and hypercapnia after receiving acetazolamide in acute respiratory failure.\n\n\nMETHODS\nCase 1 was a 72-year-old obese male with COPD who was dependent on supplemental oxygen and presented to the emergency department (ED) with acute on chronic hypercapnic respiratory failure. He was given a one-time dose of acetazolamide in the ED for \"respiratory failure made worse by severe metabolic alkalosis.\" His arterial blood gas (ABG) worsened overnight, accompanied by decreased mental status: pH 7.32, paCO2 82 mm Hg, paO2 50 mm Hg, HCO3 41.7 mmol/L, FiO2 32% to pH 7.21, paCO2 91.7 mm Hg, paO2 59 mm Hg, HCO3 36.6 mmol/L, and FiO2 32%. Case 2 was a 62-year-old male with COPD who was dependent on supplemental oxygen and presented to the ED with acute on chronic hypercapnic respiratory failure. He was given acetazolamide in the ED with similar results: ABG on presentation pH 7.37, paCO2 79.3 mm Hg, paO2 77.6 mm Hg, HCO3 45.5 mmol/L, and FiO2 32%. The next morning, ABG was pH 7.29, paCO2 79 mm Hg, paO2 77 mm Hg, HCO3 45.5 mmol/L, and FiO2 32%. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Acetazolamide given early in the uncompensated setting can worsen acidosis and potentiate clinical deterioration.",
"affiliations": "Veterans Healthcare System of the Ozarks, Fayetteville, Arkansas.",
"authors": "Cole|Jennifer L|JL|",
"chemical_list": "D000086:Acetazolamide; D010100:Oxygen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2020.01.019",
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"issn_linking": "0736-4679",
"issue": "58(6)",
"journal": "The Journal of emergency medicine",
"keywords": "COPD; acetazolamide; mixed acid–base disorders",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000086:Acetazolamide; D000138:Acidosis; D000368:Aged; D006801:Humans; D006935:Hypercapnia; D008297:Male; D008875:Middle Aged; D010100:Oxygen; D061214:Patient Safety; D029424:Pulmonary Disease, Chronic Obstructive",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "953-958",
"pmc": null,
"pmid": "32241707",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acetazolamide Causes Worsening Acidosis in Uncompensated COPD Exacerbations: Increased Awareness Needed for Patient Safety.",
"title_normalized": "acetazolamide causes worsening acidosis in uncompensated copd exacerbations increased awareness needed for patient safety"
} | [
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},
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{
"actiondrug": "6",
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},
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{
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"medicinalproduct": "ACETAZOLAMIDE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THEOPHYLLINE ANHYDROUS"
},
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"drugindication": "RESPIRATORY FAILURE",
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"drugstructuredosageunit": "003",
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"medicinalproduct": "THEOPHYLLINE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugindication": "INFECTION",
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"drugrecurreadministration": "3",
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"medicinalproduct": "CEFTRIAXONE."
}
],
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"patientonsetageunit": "801",
"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Metabolic acidosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypercapnia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "COLE JL. ACETAZOLAMIDE CAUSES WORSENING ACIDOSIS IN UNCOMPENSATED COPD EXACERBATIONS:INCREASED AWARENESS NEEDED FOR PATIENT SAFETY. J EMERG MED. 2020?JAN 58(6):953?958",
"literaturereference_normalized": "acetazolamide causes worsening acidosis in uncompensated copd exacerbations increased awareness needed for patient safety",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200910",
"receivedate": "20200910",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18253201,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20201103"
}
] |
{
"abstract": "Intravenous immunoglobulin (IVIG) is a standard therapy for Kawasaki disease (KD), because it prevents formation of coronary artery aneurysm, a major complication of KD. Herein, we report a 3-year-old boy with KD complicated by haemolytic anaemia (HA) which developed following two courses of IVIG. Although both direct and indirect antiglobulin tests and anti-M antibodies were positive in his blood obtained after the onset of HA, indirect antiglobulin tests and anti-M antibodies were negative either in the blood sample before the treatment or the same lot of IVIG products as those used for the therapy, suggesting autoimmune mechanism. This is, to our knowledge, the first report of autoimmune HA caused by anti-M autoantibodies after IVIG therapy in KD.",
"affiliations": "Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.;Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan.",
"authors": "Shimomura|Masaki|M|0000-0002-6569-2381;Okura|Yuka|Y|0000-0003-1050-2103;Ohta|Osamu|O|;Takahashi|Yutaka|Y|;Kobayashi|Ichiro|I|0000-0003-4956-4010",
"chemical_list": "D001323:Autoantibodies; D016756:Immunoglobulins, Intravenous",
"country": "England",
"delete": false,
"doi": "10.1080/24725625.2019.1681654",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2472-5625",
"issue": "4(1)",
"journal": "Modern rheumatology case reports",
"keywords": "Anti-M antibody; Kawasaki disease; haemolytic anaemia; intravenous immunoglobulin",
"medline_ta": "Mod Rheumatol Case Rep",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D001323:Autoantibodies; D015551:Autoimmunity; D002675:Child, Preschool; D003298:Coombs Test; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "101761026",
"other_id": null,
"pages": "99-101",
"pmc": null,
"pmid": "33086950",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Autoimmune haemolytic anaemia caused by anti-M antibody in a patient with Kawasaki disease.",
"title_normalized": "autoimmune haemolytic anaemia caused by anti m antibody in a patient with kawasaki disease"
} | [
{
"companynumb": "JP-SHIRE-JP202005767",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "1255960",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "2 GRAM PER KILOGRAM",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "KAWASAKI^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "HUMAN NORMAL IMMUNOGLOBULIN"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLURBIPROFEN"
},
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FLURBIPROFEN."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFOTAXIME SODIUM"
},
"drugadditional": null,
"drugadministrationroute": null,
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"medicinalproduct": "CEFOTAXIME"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Autoimmune haemolytic anaemia",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHIMOMURA, M.? OKURA, Y.? OHTA, O.? TAKAHASHI, Y.? KOBAYASHI, I.. AUTOIMMUNE HAEMOLYTIC ANAEMIA CAUSED BY ANTI-M ANTIBODY IN A PATIENT WITH KAWASAKI DISEASE. MODERN RHEUMATOLOGY CASE REPORTS. 2020?4 (1):99-101",
"literaturereference_normalized": "autoimmune haemolytic anaemia caused by anti m antibody in a patient with kawasaki disease",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200220",
"receivedate": "20200220",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17441915,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "BACKGROUND\nCitalopram is a selective serotonin reuptake inhibitor (SSRI) with cardiac and neurologic toxicities as well as the potential for serotonin syndrome. In most instances, patients recover fully from toxic ingestions of SSRIs. We describe a fatal case of a citalopram overdose.\n\n\nMETHODS\nA 35-year-old woman presented to the emergency department after having witnessed seizures at home. An empty citalopram prescription bottle was located, and an intentional overdose was suspected. At the scene, she was found to be in cardiac arrest with pulseless electrical activity and underwent cardiopulmonary resuscitation, including intravenous epinephrine and bicarbonate. In the emergency department, her physical exam was notable for cough and gag reflexes and movement in all extremities with increased muscle tone and tachycardia. Her initial postresuscitation ECG showed sinus rhythm with QRS 92 ms and QTc 502 ms. Her temperature was initially normal, but she rapidly became febrile to 41.8 °C shortly after admission. She was treated symptomatically and with cyproheptadine for suspected serotonin syndrome (SS) but became increasingly hemodynamically unstable over the next 6 h and then developed torsades des pointes (TdP) progressing to pulseless, wide complex tachycardia. She underwent cardiopulmonary resuscitation (CPR) for approximately 50 min but ultimately expired. Postmortem serum analysis revealed a citalopram concentration of 7300 ng/mL (therapeutic range 9-200 ng/mL) and THC, but no other non-resuscitation drugs or substances.\n\n\nMETHODS\nCitalopram overdoses often have only mild to moderate symptoms, particularly with ingestions under 600 mg in adults. However, with higher doses, severe manifestations have been described, including QTc prolongation, TdP, and seizures. Serotonin syndrome has also been described in SSRI overdose, and our patient exhibited signs consistent with SS, including increased muscle tone and autonomic dysregulation. Our patient's serum concentration suggests a massive overdose, with major clinical effects, possible SS, and death.\n\n\nCONCLUSIONS\nAlthough most patients recover from citalopram overdose, high-dose ingestions can produce severe effects and fatalities may occur. In this case, it is likely that the patient's delayed presentation also contributed significantly to her death. The clinician must be aware of the potential for large ingestions of citalopram to produce life-threatening effects and monitor closely for the neurologic, cardiovascular, and other manifestations that, in rare cases, can be fatal.",
"affiliations": "University of New Mexico Health Sciences Center, MSC09 5080, 1 University of New Mexico, Albuquerque, NM, 87131-0001, USA.",
"authors": "Kraai|Erik P|EP|;Seifert|Steven A|SA|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D015283:Citalopram",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-014-0441-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "11(2)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": null,
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000328:Adult; D016887:Cardiopulmonary Resuscitation; D015283:Citalopram; D062787:Drug Overdose; D004562:Electrocardiography; D017809:Fatal Outcome; D005260:Female; D006323:Heart Arrest; D006801:Humans; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D013405:Suicide",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "232-6",
"pmc": null,
"pmid": "25326372",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8709713;18520609;22996077;16304470;18570170;24554467;23167578;24020938;14980340;24455378;20833944;9140316;12925718;11164765;10863884;9696181;15362595;12884999;12902002;10706996",
"title": "Citalopram Overdose: a Fatal Case.",
"title_normalized": "citalopram overdose a fatal case"
} | [
{
"companynumb": "US-FRI-1000070432",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "020822",
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"drugcharacterization": "1",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CITALOPRAM"
}
],
"patientagegroup": null,
"patientonsetage": "35",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": "82.5",
"reaction": [
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Serotonin syndrome",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Electrocardiogram QT prolonged",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Torsade de pointes",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KRAAI E. CITALOPRAM OVERDOSE: A FATAL CASE. CLINICAL TOXICOLOGY. 2014;.",
"literaturereference_normalized": "citalopram overdose a fatal case",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "DK",
"receiptdate": "20141031",
"receivedate": "20140910",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 10445744,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150528"
},
{
"companynumb": "US-TEVA-508023USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "77048",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INTENTIONAL OVERDOSE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CITALOPRAM"
}
],
"patientagegroup": null,
"patientonsetage": "35",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cardiac arrest",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Liver injury",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Torsade de pointes",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Serotonin syndrome",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Renal injury",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KRAII E. CITALOPRAM OVERDOSE: A FATAL CASE.. JOURNAL OF MEDICAL TOXICOLOGY - OFFICIAL JOURNAL OF THE AMERICAN COLLEGE OF MEDICAL TOXICOLOGY. 2014 OCT 18;11:232-236.",
"literaturereference_normalized": "citalopram overdose a fatal case",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150722",
"receivedate": "20140916",
"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20151125"
},
{
"companynumb": "US-APOTEX-2014AP004470",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional": null,
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"abstract": "In November 2012, a 72-year old patient was diagnosed with left eye wet age-related macular degeneration. The patient received three monthly intravitreal injections of ranibizumab, with complete resolution of retinal hemorrhage and edema and reinstatement of visual acuity. In May 2015, symptomatic relapse was detected. The patient was again treated with intravitreal ranibizumab, with overall six injections till the end of February 2016. In May 2016, the patient complained of left hand resting tremor, bradykinesia, and postural rigidity of head and trunk. A diagnosis of clinically established PD was made based on new criteria of the Movement Disorders Society. Single Photon Emission Computerized Tomography of the Dopamine Transporter with (123I) ioflupane documented a low Dopamine Transporter (DAT) uptake mostly in the right striatum. Due to the documented protective role of vascular endothelial growth factor (VEGF) on the dopaminergic neurons, intensive intravitreal injections of the anti-VEGF agent ranibizumab may have played as an additional risk factor accelerating the neurodegeneration process related to PD and the onset of the related clinical signs and symptoms.",
"affiliations": "Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy.;Unit of Clinical Pharmacology, Azienda Ospedaliera Universitaria Policlinico \"G. Martino\" - Messina, Italy.;Unit of Clinical Pharmacology, Azienda Ospedaliera Universitaria Policlinico \"G. Martino\" - Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy.;Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy.;Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.",
"authors": "Trifirò|Gianluca|G|;Marcianò|Ilaria|I|;Cutroneo|Paola M|PM|;Spina|Edoardo|E|;Mirabelli|Eliana|E|;Trombetta|Costantino J|CJ|;Morgante|Francesca|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2018.00608",
"fulltext": "\n==== Front\nFront PharmacolFront PharmacolFront. Pharmacol.Frontiers in Pharmacology1663-9812Frontiers Media S.A. 10.3389/fphar.2018.00608PharmacologyCase ReportLong-Term Intravitreal Ranibizumab as a Potential Additional Risk Factor for Neurodegeneration in Parkinson’s Disease: A Case Report Trifirò Gianluca 1*Marcianò Ilaria 2Cutroneo Paola M. 2Spina Edoardo 3Mirabelli Eliana 1Trombetta Costantino J. 1Morgante Francesca 341Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy2Unit of Clinical Pharmacology, Azienda Ospedaliera Universitaria Policlinico “G. Martino” – Messina, Italy3Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy4Neurosciences Research Centre, Molecular and Clinical Sciences Research Institute, St George’s University of London, London, United KingdomEdited by: Fabiana Novellino, Consiglio Nazionale delle Ricerche, Italy\n\nReviewed by: Sulev Kõks, University of Tartu, Estonia; Giulia Donzuso, Università degli Studi di Catania, Italy\n\n*Correspondence: Gianluca Trifirò, trifirog@unime.itThis article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology\n\n08 6 2018 2018 9 60804 2 2018 21 5 2018 Copyright © 2018 Trifirò, Marcianò, Cutroneo, Spina, Mirabelli, Trombetta and Morgante.2018Trifirò, Marcianò, Cutroneo, Spina, Mirabelli, Trombetta and MorganteThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.In November 2012, a 72-year old patient was diagnosed with left eye wet age-related macular degeneration. The patient received three monthly intravitreal injections of ranibizumab, with complete resolution of retinal hemorrhage and edema and reinstatement of visual acuity. In May 2015, symptomatic relapse was detected. The patient was again treated with intravitreal ranibizumab, with overall six injections till the end of February 2016. In May 2016, the patient complained of left hand resting tremor, bradykinesia, and postural rigidity of head and trunk. A diagnosis of clinically established PD was made based on new criteria of the Movement Disorders Society. Single Photon Emission Computerized Tomography of the Dopamine Transporter with (123I) ioflupane documented a low Dopamine Transporter (DAT) uptake mostly in the right striatum. Due to the documented protective role of vascular endothelial growth factor (VEGF) on the dopaminergic neurons, intensive intravitreal injections of the anti-VEGF agent ranibizumab may have played as an additional risk factor accelerating the neurodegeneration process related to PD and the onset of the related clinical signs and symptoms.\n\nanti-vascular endothelial growth factorsranibizumabParkinson’s diseaseintravitrealneurodegeneration\n==== Body\nIntroduction\nAge-related macular degeneration (AMD) is a chronic progressive disorder of the retina, representing the main cause of irreversible vision loss in elderly people (de Jong, 2006) in both Western and Eastern Countries.\n\nThe neovascular or “wet” AMD is characterized by choroidal neovascularization and vascular leakage, associated with up-regulation of angiogenic factors, such as vascular endothelial growth factor (VEGF), a cytokine that promotes vascular permeability and angiogenesis. Through reduction of edema and new blood vessel growth, VEGF inhibitors administered by intravitreal injection are an established treatment for “wet” AMD and include bevacizumab (only as off-label use), pegaptanib, and, more recently, ranibizumab and aflibercept.\n\nRecent studies revealed that VEGF displays a key role in neuronal survival and proliferation (Drake and Little, 1995; Silverman et al., 1999; Storkebaum and Carmeliet, 2004), with neuroprotective effects, due to apoptosis inhibition, stimulation of neurogenesis, and activation of antioxidants (Zachary, 2005; Krum et al., 2008; Nowacka and Obuchowicz, 2012; Quittet et al., 2015). This effect has been highlighted also on dopaminergic (DA) neurons and on both in vitro and in vivo pre-clinical studies on Parkinson’s disease (PD) models (Yasuhara et al., 2004, 2005a,b; Yasuda et al., 2007; Falk et al., 2011; Piltonen et al., 2011; Yue et al., 2014). Inhibition of the neuroprotective effects associated to VEGF may theoretically play a role in the development of neurodegenerative disorders involving dopamine transmission, including PD.\n\nWe report a case of PD which occurred after long-term treatment with intravitreal injections of ranibizumab for the treatment of wet AMD.\n\nCase Report\nIn November 2012, a 72-year old man was diagnosed with wet AMD in his left eye, based on fundus examination and optical coherence tomography (OCT), which was requested for the onset of metamorphopsia. At that time, he was treated with combination of angiotensin converting enzyme inhibitor plus thiazide diuretic for a 20-year history of well controlled hypertension.\n\nHis best-corrected visual acuity in the right and left eyes was 10/10 and 8/10, respectively. On slit-lamp examination, both anterior chambers showed clear aqueous humor and no inflammatory reaction. Dilated fundus examination revealed a subretinal whitish mass and adjacent subretinal hemorrhage. OCT confirmed the presence of a subretinal lesion and intraretinal edema. After obtaining informed consent, the patient was monthly treated with intravitreal administration of 0.5 mg ranibizumab for three months, without any complication and with complete retinal hemorrhage and edema resolution and increased visual acuity of left eye (10/10). Thereafter, the patient underwent routine follow-up visits, on a 2-month basis, including fundus examination and OCT which did not document any abnormal finding. In May 2014, a reduction of visual acuity (from 10/10 to 7/10) was registered. The patient was periodically followed-up but not treated with anti-VEGF drugs as there was no sign of neovascularization. In May 2015, visual acuity further reduced to 3/10 and both fundus examination and OCT revealed a reactivation of the neovascular membrane, edema and pigment epithelial detachment. For this reason, the patient was again treated with intravitreal injections of ranibizumab (0.5 mg), firstly on a monthly basis and thereafter using treat and extend approach, with overall six injections till the end of February 2016, when visual acuity increased to 6/10. At the follow-up visit in May 2016, the neovascular membrane appeared inactive and the visual acuity was stable at 6/10, so the ophthalmologist decided for a pro re nata approach (i.e., as needed).\n\nIn the same period, the patient referred to the Movement Disorders Clinic due to intermittent tremor on the left hand, started around February 2016. He did not complain non-motor symptoms.\n\nNeurological examination disclosed resting tremor on the left hand, mild bradykinesia of left lower limb, and mild rigidity of head and trunk. His motor Unified Parkinson’s Disease Rating Scale (UPDRS) was 11/108.\n\nThe patient had no family history of PD or other neurodegenerative diseases nor had he been ever exposed to pesticides. Magnetic Resonance Imaging of the brain showed rare small subcortical white matters hyperintensities on T2 (mainly periventricular and frontal) and some bilateral hypointensities in T1 in the striatum, more prominent on the right, compatible with small ischemic lesions.\n\nSingle Photon Emission Computerized Tomography (SPECT) of the Dopamine Transporter (DAT) with 123I-ioflupane documented a significant and clear low uptake of DAT, mostly in the right striatum (Figure 1). A diagnosis of clinically established PD was made based on new criteria of the Movement Disorders Society (Postuma et al., 2015).\n\nFIGURE 1 (A) Bilateral hypointensities in T1 in the striatum, more prominent on the right side and (B) rare small subcortical white matters hyperintensities on T2 (mainly periventricular and frontal) on Magnetic Resonance Imaging of the brain. (C) Single Photon Emission Computerized Tomography of the Dopamine Transporter (DAT) with 123I-ioflupane showing a significant low uptake of DAT, mostly in the right striatum.\n\nA treatment with levodopa/carbidopa (300 mg/daily) was started at the beginning of 2017, due to worsening of tremor and bradykinesia leading to gait impairment and fatigue (motor UPDRS = 15/108). At follow-up examination in May 2017, response to levodopa was demonstrated by improvement of motor symptoms (motor UPDRS = 6/108), particularly of gait. Up to November 2017 other two injections of ranibizumab were intravitreally administered with visual acuity equal to 3/10 and the patient was in stable treatment with levodopa/carbidopa (300 mg/daily).\n\nDiscussion\nWe described the development of PD in a patient without any genetic and environmental risk factor for PD, who received repeated intravitreal injections of ranibizumab for wet AMD over the previous year. The clinical picture with lack of atypical features is consistent with the clinical diagnosis of PD. The DAT SPECT evidence of pre-synaptic dopamine loss supports the presence of neurodegeneration in the nigro-striatal pathway, typical of neurodegenerative Parkinsonism. Moreover, brain MRI did not disclose areas of cortical and subcortical atrophy, suggesting the diagnosis of atypical Parkinsonism. The presence of vascular lesions in the basal ganglia at brain MRI does not exclude the diagnosis of idiopathic PD, as they have been described in PD patients with vascular risk factors, such as hypertension (Antonini et al., 2012). On the other hand, there is a strong biological plausibility and temporal relationship between intensive intravitreal administration of ranibizumab and onset of PD-related signs and symptoms which may suggest a role of the anti-VEGF drug as additional risk factor resulting potentially in accelerating the PD-related neurodegeneration process.\n\nPD is a multi-systemic neurodegenerative disease, primarily affecting DA neurons of substantia nigra, and characterized by intracellular accumulation of the protein α-synuclein (Poewe et al., 2017). Mechanisms of neurodegeneration hypothesized in PD include abnormal α-synuclein degradation by the ubiquitin–proteasome system and the lysosomal autophagy system, propagation of α-synuclein with a prion-like mechanism, mitochondrial dysfunction, oxidative stress, and neuroinflammation (Poewe et al., 2017). Recent studies demonstrated in PD patients the presence of α-synuclein in the retina (Bodis-Wollner et al., 2014) as well the presence of specific OCT abnormalities, such as reduced parafoveal thickness (Slotnick et al., 2015). The retina has several molecular and cellular features in common with the brain, such as neurons, glial cells, connected vasculature, and a blood barrier (Trost et al., 2016). The most liable mechanisms potentially explaining the relationship between AMD and PD are related to neurodegenerative processes and chronic inflammation: the activation of microglia cells in the retina and nervous system may trigger the inflammatory response and aggravate both the retinal and DA degeneration (Whitton, 2007). Ranibizumab is a humanized recombinant monoclonal antibody fragment targeted against human VEGF. It binds with high affinity to the VEGF-A isoforms, thus preventing binding of VEGF-A to its receptors (European Medicines Agency. Lucentis – Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000715/WC500043546.pdf. Accessed 01 Feb 2018). Ranibizumab maintains effective retinal concentrations for around 1 month, being able to reach low concentrations in the serum compartment as well (Stewart, 2012; Gibson and Gibson, 2014). Based on the Summary of Product Characteristics (European Medicines Agency. Lucentis – Summary of Product Characteristics. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000715/WC500043546.pdf. Accessed 01 Feb 2018), following monthly intravitreal injections in AMD patients, serum concentrations of ranibizumab generally range between 0.79 and 2.90 ng/ml. Such concentrations are below the drug concentration necessary to inhibit the VEGF activity by 50% (IC50 = 11–27 ng/ml). Serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal ranibizumab concentrations. Results from clinical trials documented no significant reduction in serum VEGF levels within the first 1 month of treatment (Zehetner et al., 2015), but a significant decline in systemic VEGF levels was detected after 1 and 2 years (Enders et al., 2015). The resulting systemic VEGF inhibition after intravitreal injections may lead to systemic effects (Gibson and Gibson, 2014). Clinical trials on ranibizumab showed a high incidence of stroke, myocardial infarction and non-ocular hemorrhage (Brown et al., 2006; Rosenfeld et al., 2006), further confirmed by recent observational studies (Kemp et al., 2013; Pratt et al., 2014). Furthermore, a meta-analysis of randomized trials on ranibizumab for AMD treatment identified a stronger relationship of systemic vascular adverse events and intravitreal administration of VEGF inhibitors in case of more intensive treatment schedule (Ueta et al., 2014).\n\nRecent evidence suggested that the VEGF signal pathway may directly and indirectly improve DA neuron survival (Silverman et al., 1999; Pitzer et al., 2003; Yasuhara et al., 2004). VEGF administration inhibits DA neurons loss in PD models, especially in the substantia nigra and in the striatum (Sheikh et al., 2017), thus representing a potential therapeutic target for prevention of DA neuron death and PD progression. Functional polymorphisms of the VEGF gene expression have been associated with an increased risk of developing PD in the Chinese Ham population (Wu et al., 2016). It has been postulated that reduced VEGF levels may cause neurodegeneration, by impairing neural tissue perfusion, thus causing ischemia and production of free radicals (Storkebaum and Carmeliet, 2004). This hypothesis is consistent with a recent autopsy study in patients with dementia with Lewy body, in whom VEGF deficiency has been associated with a loss of microvessels and low occipital blood flow (Miners et al., 2014). On the other hand, VEGF is up-regulated by ischemic and inflammatory stimulation, which accompany neurodegeneration. The state of brain hypoxia up-regulates VEGF and its subsequent higher levels mediate angiogenesis, causing microvascular leakage and fragility. These changes lead to edema, bleeding, and impair neural tissue perfusion. The resultant hypoxia then further up-regulate VEGF levels again (Storkebaum and Carmeliet, 2004).\n\nVEGF shows neuroprotective effects, due to apoptosis inhibition, stimulation of neurogenesis, and activation of antioxidants (Zachary, 2005; Krum et al., 2008; Nowacka and Obuchowicz, 2012; Quittet et al., 2015). Specifically, ranibizumab binds to the VEGF-A, one of the five isoforms of the VEGF family and one of the strongest inducers of vascular permeability (Yla-Herttuala et al., 2007), which showed neuroprotective effects in several in vitro and in vivo PD models (Silverman et al., 1999; Pitzer et al., 2003; Yasuhara et al., 2004; Tian et al., 2007; Yue et al., 2014). A recent study on the Italian ADR Spontaneous Reporting System showed 3 reports of “extrapyramidal syndrome” due to intravitreal bevacizumab and 1 to intravitreal aflibercept (Cutroneo et al., 2017). Similarly, in the Food and Drug Administration’s Adverse Event Reporting System, three cases of neurodegenerative disorders have been reported following bevacizumab use (Shamloo et al., 2012). On the other hand, the onset of such disorders may be due to vascular events and/or stroke, which are well known and listed risks of intravitreal therapy with anti-VEGF drugs in general, including ranibizumab. Finally, a meta-analysis of randomized trials on ranibizumab for AMD treatment identified a stronger relationship of systemic vascular adverse events and intravitreal administration of VEGF inhibitors in case of more intensive treatment schedule (Ueta et al., 2014).\n\nAll the above described experimental and epidemiological evidence raise the hypothesis that persistent and intensive VEGF inhibition concurred to DA degeneration in our patient. AMD may be considered as a neurodegeneration of the retina (de Jong, 2006), thus potentially sharing with PD common biological pathways, such as oxidative stress and inflammation (Ding et al., 2009; Poewe et al., 2017). Chung et al. (2014) investigated the risk of developing PD within 3 years after the AMD diagnosis in a retrospective cohort, population-based, claims database study in Taiwan . Adjusting for several vascular risk factors (i.e., coronary heart disease, hypertension, diabetes, and hyperlipidemia), subjects with AMD had a significant higher risk of developing PD than AMD-free patients during follow-up. On the contrary, a case-control study found no statistically significant differences in the frequency of AMD between patients with idiopathic PD and healthy subjects (Nowacka et al., 2014). Using claims databases from the United States, Brilliant et al. (2016) found that around 70% of the levodopa users started the drug treatment after AMD diagnosis . However, the use of anti-VEGF drugs, which are on the market since 2005, was not considered in any of the studies and it cannot be excluded that anti-VEGF drugs rather than AMD itself triggered the clinical manifestation of PD.\n\nConclusion\nIn conclusion, our case report points out to VEGF inhibition as a possible additional risk factor of neurodegeneration of DA neurons in PD.\n\nAccording to the Naranjo causality assessment scale (Naranjo et al., 1981), the causal relationship between use of ranibizumab and PD development was scored as “possible”.\n\nIn particular, we hypothesize that long-term treatment with intravitreal ranibizumab led to a persistent inhibition of VEGF activity which played an important compensatory neuroprotective role in older patient with AMD, ultimately triggering PD.\n\nEthics Statement\nA signed statement of informed consent to publish the case description was obtained from the patient.\n\nAuthor Contributions\nEM, CT, and FM collected the data and performed the investigation. GT, IM, PC wrote the manuscript in collaboration. ES and FM critically reviewed the manuscript for important intellectual content and suggested valuable comments, which improved the quality of the manuscript.\n\nConflict of Interest Statement\nFM declares she receives royalties from publication of the book “Disorders of Movement” (Springer 2016). She has been part of advisory boards of Medtronic, Merz, and UCB Pharma. She has received honoraria for speaking from UCB Pharma, Medtronic, Chiesi, Abbvie, Allergan, Merz, and Zambon. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\nAntonini A. Vitale C. Barone P. Cilia R. Righini A. Bonuccelli U. (2012 ). The relationship between cerebral vascular disease and parkinsonism: the VADO study. \nParkinsonism Relat. 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Neurol. \n206 \n308 –317 . 10.1016/j.expneurol.2007.05.012 \n17604022 \nYasuhara T. Shingo T. Kobayashi K. Takeuchi A. Yano A. Muraoka K. (2004 ). Neuroprotective effects of vascular endothelial growth factor (VEGF) upon dopaminergic neurons in a rat model of Parkinson’s disease. \nEur. J. Neurosci. \n19 \n1494 –1504 . 10.1111/j.1460-9568.2004.03254.x \n15066146 \nYasuhara T. Shingo T. Muraoka K. Kameda M. Agari T. Wen Y. (2005a ). Neurorescue effects of VEGF on a rat model of Parkinson’s disease. \nBrain Res. \n1053 \n10 –18 . 10.1016/j.brainres.2005.05.027 \n16045899 \nYasuhara T. Shingo T. Muraoka K. wen Ji Y. Kameda M. Takeuchi A. (2005b ). The differences between high and low-dose administration of VEGF to dopaminergic neurons of in vitro and in vivo Parkinson’s disease model. \nBrain Res. \n1038 \n1 –10 . 10.1016/j.brainres.2004.12.055 \n15748867 \nYla-Herttuala S. Rissanen T. T. Vajanto I. Hartikainen J. (2007 ). 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Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age-related macular degeneration: a randomised, prospective trial. \nActa Ophthalmol. \n93 \ne154 –e159 . 10.1111/aos.12604 \n25488124\n\n",
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"abstract": "Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.",
"affiliations": "Division of Cardiology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.;Division of Genomic Medicine, Department of Pathology, Children's Hospital Los Angeles and Keck-USC School of Medicine, Los Angeles, California.;Division of Medical Genetics, A. I. du Pont Hospital for Children, Wilmington, Delaware.;Division of Craniofacial Medicine, Seattle Children's Hospital, Seattle, Washington.;Department of Pediatrics, Cooper Medical School at Rowan University, Camden, New Jersey.;Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Division of Cardiology, Department of Pediatrics, Maine Medical Center, Portland, Maine.;Division of Genetics, Department of Pediatrics, Maine Medical Center, Portland, Maine.;The Heart Institute, Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana.;Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts.;Division of Medical Genetics, Sanford Health, Sioux Falls, South Dakota.;Department of Pediatrics, Section of Cardiology, University of Colorado School of Medicine, Aurora, Colorado.;Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts.",
"authors": "Levin|Mark D|MD|0000-0002-2241-9828;Saitta|Sulagna C|SC|;Gripp|Karen W|KW|;Wenger|Tara L|TL|;Ganesh|Jaya|J|;Kalish|Jennifer M|JM|0000-0003-1500-9713;Epstein|Michael R|MR|;Smith|Rosemarie|R|;Czosek|Richard J|RJ|;Ware|Stephanie M|SM|;Goldenberg|Paula|P|;Myers|Angela|A|;Chatfield|Kathryn C|KC|;Gillespie|Matthew J|MJ|;Zackai|Elaine H|EH|;Lin|Angela E|AE|",
"chemical_list": "C117307:KRAS protein, human; D020837:SOS1 Protein; C000632287:SOS1 protein, human; D004077:Digoxin; D011433:Propranolol; D019908:Proto-Oncogene Proteins c-raf; C000627598:Raf1 protein, human; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000638:Amiodarone; D002118:Calcium",
"country": "United States",
"delete": false,
"doi": "10.1002/ajmg.a.38854",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4825",
"issue": "176(8)",
"journal": "American journal of medical genetics. Part A",
"keywords": "Calcium; Costello syndrome; Noonan syndrome; Noonan syndrome with multiple lentigines; RAS/MAPK signaling pathway; ectopic atrial tachycardia; multifocal atrial tachycardia",
"medline_ta": "Am J Med Genet A",
"mesh_terms": "D000638:Amiodarone; D001145:Arrhythmias, Cardiac; D002118:Calcium; D002312:Cardiomyopathy, Hypertrophic; D056685:Costello Syndrome; D004077:Digoxin; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D044542:LEOPARD Syndrome; D008297:Male; D009634:Noonan Syndrome; D011433:Propranolol; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras); D020837:SOS1 Protein; D013612:Tachycardia, Ectopic Atrial; D018631:ras Proteins",
"nlm_unique_id": "101235741",
"other_id": null,
"pages": "1711-1722",
"pmc": null,
"pmid": "30055033",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "15183628;16567565;3964904;15073377;19330009;19835880;25858058;21339642;19376813;9440591;7732989;24534818;12752577;4064786;20358587;11499730;25648700;2110551;23290139;19467855;24925317;20004664;16439621;17603483;3662276;1561973;23875798;23281408;25274603;25180280;21344638;25651172;3719928;772700",
"title": "Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.",
"title_normalized": "nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in rasopathy patients"
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"abstract": "BACKGROUND\nEarly combination antiretroviral therapy (cART) initiation at the time of primary HIV-1 infection could restrict the establishment of HIV reservoirs. We aimed to assess the effect of a cART regimen intensified with raltegravir and maraviroc, compared with standard triple-drug cART, on HIV-DNA load.\n\n\nMETHODS\nIn this randomised, open-label, phase 3 trial, we recruited patients from hospitals across France. Inclusion criteria were primary HIV-1 infection (an incomplete HIV-1 western blot and detectable plasma HIV-RNA), with either symptoms or a CD4+ cell count below 500 cells per μL. Patients were randomly assigned (1:1) to an intensive, five-drug cART regimen (raltegravir 400 mg and maraviroc 150 mg twice daily, and a fixed-dose combination of tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) or a standard triple-drug cART regimen (tenofovir disoproxil fumarate 300 g plus emtricitabine 200 g, darunavir 800 g, and ritonavir 100 g once daily) using a predefined randomised list generated by randomly selected variable block sizes. The primary endpoint was the median number of HIV-DNA copies per 10(6) peripheral blood mononuclear cells (PBMC) at month 24, analysed in the modified intention-to-treat population, defined as all patients who started their assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01033760.\n\n\nRESULTS\nBetween April 26, 2010, and July 13, 2011, 110 patients were enrolled, of whom 92 were randomly assigned and 90 started treatment (45 in each treatment group). Six (13%) patients in the intensive cART group and two (4%) in the standard cART group discontinued before month 24. At month 24, HIV-DNA loads were similar between groups (2·35 [IQR 2·05-2·50] log₁₀ per 10(6) PBMC in the intensive cART group vs 2·25 [1·71-2·55] in the standard cART group; p=0·21). Eight grade 3-4 clinical adverse events were reported in seven patients in the intensive cART group and seven grade 3-4 clinical adverse events were reported in seven patients in the standard cART group. Three serious clinical adverse events occurred: two (pancreatitis and lipodystrophy) in the standard cART group, which were regarded as treatment related, and one event (suicide attempt) in the intensive cART group that was unrelated to treatment.\n\n\nCONCLUSIONS\nAfter 24 months, cART intensified with raltegravir and maraviroc did not have a greater effect on HIV blood reservoirs than did standard cART. These results should help to design future trials of treatments aiming to decrease the HIV reservoir in patients with primary HIV-1 infection.\n\n\nBACKGROUND\nInserm-ANRS, Gilead Sciences, Janssen Pharmaceuticals, Merck, and ViiV Laboratories.",
"affiliations": "EA 7327, Paris Descartes University - Sorbonne Paris Cité, Paris, France; Infectious Diseases Department, Tourcoing Hospital, Tourcoing, France; Internal Medicine Department, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France. Electronic address: antoinecheret@free.fr.;INSERM U1018, Faculty of Medicine, Paris-Sud University, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France.;EA 7327, Paris Descartes University - Sorbonne Paris Cité, Paris, France; Virology Laboratory, AP-HP, Necker Hospital, Paris, France.;Infectious Diseases Department, AP-HP, Saint-Louis Hospital, Paris, France.;Infectious Diseases Department, AP-HP, Tenon Hospital, Paris, France.;Infectious Diseases Department, Croix Rousse Hospital, Lyon, France.;Infectious Diseases Department, AP-HP, Bichat Claude-Bernard Hospital, Paris, France.;Infectious Diseases Department, CHU de Fort de France, Martinique, France.;EA 7327, Paris Descartes University - Sorbonne Paris Cité, Paris, France; Virology Laboratory, AP-HP, Necker Hospital, Paris, France.;INSERM U1012, Faculty of Medicine, Paris-Sud University, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France.;EA 7327, Paris Descartes University - Sorbonne Paris Cité, Paris, France; Virology Laboratory, AP-HP, Necker Hospital, Paris, France.;Infectious Diseases Department, AP-HP, Saint-Louis Hospital, Paris, France; INSERM U941, University of Paris Diderot, Paris, France.;Infectious Diseases Department, AP-HP, La Pitié-Salpêtrière Hospital, Paris, France.;Internal Medicine Department, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France; INSERM U1018, Faculty of Medicine, Paris-Sud University, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France.;Virology Laboratory, AP-HM, La Timone Hospital, Marseille, France.;Collège des Universitaires des Maladies Infectieuses et Tropicales (CMIT), Paris, France.;Infectious Diseases Department, Font-Pré Hospital, Toulon, France.;Infectious Diseases Department, Gui de Chauliac Hospital, Montpellier, France.;Infectious Diseases Department, AP-HM, La Timone Hospital, Marseille, France.;Infectious Diseases Department, CHU Ricou Hospital, Pointe à Pître, France.;Internal Medicine Department, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France.;INSERM U1018, Faculty of Medicine, Paris-Sud University, AP-HP, Bicêtre Hospital, Le Kremlin-Bicêtre, France.;EA 7327, Paris Descartes University - Sorbonne Paris Cité, Paris, France; Virology Laboratory, AP-HP, Necker Hospital, Paris, France.",
"authors": "Chéret|Antoine|A|;Nembot|Georges|G|;Mélard|Adeline|A|;Lascoux|Caroline|C|;Slama|Laurence|L|;Miailhes|Patrick|P|;Yeni|Patrick|P|;Abel|Sylvie|S|;Avettand-Fenoel|Véronique|V|;Venet|Alain|A|;Chaix|Marie-Laure|ML|;Molina|Jean-Michel|JM|;Katlama|Christine|C|;Goujard|Cécile|C|;Tamalet|Catherine|C|;Raffi|François|F|;Lafeuillade|Alain|A|;Reynes|Jacques|J|;Ravaux|Isabelle|I|;Hoën|Bruno|B|;Delfraissy|Jean-François|JF|;Meyer|Laurence|L|;Rouzioux|Christine|C|;|||",
"chemical_list": "D044966:Anti-Retroviral Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-3099",
"issue": "15(4)",
"journal": "The Lancet. Infectious diseases",
"keywords": null,
"medline_ta": "Lancet Infect Dis",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D023241:Antiretroviral Therapy, Highly Active; D005260:Female; D005602:France; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101130150",
"other_id": null,
"pages": "387-96",
"pmc": null,
"pmid": "25701561",
"pubdate": "2015-04",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open-label, phase 3 trial.",
"title_normalized": "intensive five drug antiretroviral therapy regimen versus standard triple drug therapy during primary hiv 1 infection optiprim anrs 147 a randomised open label phase 3 trial"
} | [
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"abstract": "Propofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.",
"affiliations": "Department of Medicine, Summa Health Systems, Barberton, OH.;Department of Gastroenterology, Summa Health Systems, Akron, OH.",
"authors": "Parekh|Akarsh|A|;Zhang|Howard|H|",
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"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253\nWolters Kluwer Maryland, MD\n\n33490299\nACGCR-20-0310\n10.14309/crj.0000000000000528\n00016\nCase Report\nPancreas\nPropofol-Induced Severe Necrotizing Pancreatitis\nParekh Akarsh MD 12akarsh_ed@hotmail.com\n\nZhang Howard MD 3\n1 Department of Medicine, Summa Health Systems, Barberton, OH\n2 Northeast Ohio Medical University, Rootstown, OH\n3 Department of Gastroenterology, Summa Health Systems, Akron, OH\nCorrespondence: Howard Zhang, MD (zhangh@summahealth.org).\n1 2021\n19 1 2021\n8 1 e0052803 4 2020\n04 9 2020\n© 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.\n2021\nThis is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nABSTRACT\n\nPropofol is a widely used sedative for gastrointestinal endoscopic procedures. Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition. Propofol-induced pancreatitis is an extremely rare phenomenon. We present a 22-year-old healthy man who underwent esophagogastroduodenoscopy with propofol as a sedative. Soon after, he developed acute upper gastrointestinal symptoms and was diagnosed with pancreatitis. His prolonged hospital course was complicated with necrotizing pancreatitis, acute respiratory distress syndrome, septic shock, and other end-organ damages. We hope to increase awareness of a life-threatening adverse event of a commonly used anesthetic such as propofol.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\n\nPropofol, 2,6-diisopropylphenol, is a commonly used agent for induction and maintenance of anesthesia. It has also gained wide-spread popularity for gastrointestinal (GI) endoscopic procedures because it is short-acting and has fewer side effects.1,2 Drug-induced pancreatitis is a relatively rare disease possibly because of poor recognition.3 However, propofol-induced pancreatitis has been reported, although a seemingly rare phenomenon.3 We present a case of severe necrotizing pancreatitis with multiorgan failure, attributed to delayed reaction after receiving propofol for an elective esophagogastroduodenoscopy (EGD) procedure.\n\nCASE REPORT\n\nA 22-year-old white man with a medical history of gastroesophageal reflux disease and past cholecystectomy underwent EGD evaluation for intermittent esophageal dysphagia of many years. His only home medication was omeprazole. He had no EGD, previous exposure to propofol, or known drug and environmental allergies. He did not use tobacco, drink alcohol, or use any illicit drugs. He had no family history of significant medical conditions. EGD was accomplished without any immediate complications. For procedural sedation, he received a total of 150 mg of intravenous propofol. EGD revealed mild esophageal stricture at the esophagogastric junction, which was dilated to 20 mm using a balloon dilator. Esophageal mucosal changes, including ringed esophagus, feline appearance, and longitudinal furrows, were also found in the middle and lower third of the esophagus. Biopsies were taken from the esophagus which showed eosinophilic esophagitis. The remainder examined upper GI tract was otherwise unremarkable.\n\nHe tolerated the procedure and anesthesia well. However, about 90 minutes after his discharge, he called and reported a sudden onset of severe epigastric pain and several episodes of emesis that started after a meal. He was instructed to go to the emergency department immediately for further evaluation. In the emergency department, he was found to have marked elevation of his lipase at about 14,000 U/L and a total leukocyte count of 30,000 cells per liter with no eosinophilia, high neutrophils, and normal lymphocyte counts. His triglycerides level was 79 mg/dL. Initial abdominal and pelvic computed tomography showed peripancreatic fluid without any evidence of cyst, abscess, or necrosis. He was initially admitted to the general medical floor for intravenous fluid hydration and pain control but was soon transferred to the intensive care unit (ICU) because of deterioration and development of hypoxia and hemodynamic instability.\n\nIn the ICU, he developed acute hypoxic respiratory failure due to acute respiratory distress syndrome requiring intubation and mechanical ventilation. Subsequently, he developed septic shock, requiring vasopressor support and broad-spectrum antibacterial and antifungal agents; significant pleural effusion, requiring thoracentesis and chest tube placement; and acute kidney injury that improved gradually without the need for dialysis. Repeat abdominal and pelvic computed tomography 10 days later demonstrated pancreatic necrosis with extensive peripancreatic fluid extending to post-pararenal space along with retroperitoneal fluid collection, requiring percutaneous drain placement and ultimately pancreatic necrosectomy (Figure 1). To complicate matters further, the patient also developed severe ischemic colitis because of shock, requiring a subtotal colectomy. The patient had had a prolonged course of hospitalization, mostly in the ICU setting at 2 tertiary care centers for over 6 months, receiving cares from multiple medical and surgical specialties. He was then transferred to rehab facility and is currently doing well.\n\nFigure 1. Abdominal displaying pancreatitis with peripancreatic fluid collection (red arrows).\n\nExhaustive diagnostic workup had been performed to exclude other causes of pancreatitis. This patient had a cholecystectomy 2 years ago. His initial abdominal imaging and laboratory work ruled out gallstone pancreatitis and pancreatic divisum. He had no history of alcohol use. Extensive and repeated laboratory tests and microbiology excluded common infectious pathogens. A nasopharyngeal respiratory viral polymerase chain reaction testing was positive for human rhinovirus; however, serum testing was negative, which rules out a viral cause for the patient's pancreatitis. Autoimmune etiology was ruled out because immunoglobulin levels were normal. He had initial unremarkable blood work, including normal serum triglyceride level, except for elevated lipase level and total white count at presentation. His only home medication was omeprazole that he had been taking for multiple years. He had no previous trauma or exposure to drugs or toxins. Testing for rare causes such as cystic fibrosis and myotonic dystrophy was also negative. He had no history of vascular disease or vasculitis. He had no known history of drug or environmental allergies. Given the chronological association of propofol administration and immediate development of acute pancreatitis without any other causes, it was concluded that the patient had propofol-induced severe necrotizing pancreatitis.\n\nDISCUSSION\n\nPropofol is lipophilic and a global central nervous depressant with a rapid onset of sedation, dose-related hypnotic effect, and a quick recovery profile.4 Although extensive use of propofol has increased patient satisfaction and acceptability in GI procedures, risks of over-sedation and complications are not negligible.5,6 Deeper sedation levels can increase the risk of procedural hypotension, colonic perforation, and aspiration pneumonia.5,7,8 Moreover, propofol may lead to increase in mortality and morbidity from cardiopulmonary complications in elderly compared with younger patients probably because of reduced renal clearance.9\n\nCase reports have been published over the years that showed propofol as a rare causative agent for pancreatitis.1,4,10–13 The mechanism of this drug-induced pancreatitis is largely unknown, although propofol-induced hypertriglyceridemia, hypersensitivity, or direct pancreatic toxicity had been suggested as possible culprit.3,14 We present a case of severe necrotizing pancreatitis within hours of after single dosage of propofol exposure that ultimately led to multiorgan failure. Initial triglyceride levels were normal, and all other causes of pancreatitis were systematically ruled out. Hence, the mechanism of propofol-induced pancreatitis in our case remains unidentified, suggesting an idiosyncratic reaction.\n\nAlthough propofol-induced pancreatitis is a rare phenomenon, the exact incidence is unclear and potentially much higher due in part to possible poor recognition, especially for mild cases. We hope that this case report will help increase pancreatitis awareness as a potentially life-threatening adverse event associated with propofol sedation and not assume postprocedural abdominal pain to be secondary to abdominal dilation from periprocedural air insufflation. The debate is likely to continue as to the cost, risks, and benefits of ever-popular propofol-induced deep sedation vs conventional benzodiazepines and opioid-induced conscious sedation for GI endoscopic procedures. We would like to make the clinicians aware of the rare but potentially fatal complication of propofol, and they should consider other alternative sedatives.\n\nDISCLOSURES\n\nAuthor contributions: All authors contributed equally to this manuscript. H. Zhang is the article guarantor.\n\nFinancial disclosure: None to report.\n\nPrevious presentation: This case was presented at the Michigan Osteopathic Association, May 17, 2019; Southfield, Michigan.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n\n1. Jawaid Q Presti ME Neuschwander-Tetri BA Burton FR Case report: Acute pancreatitis after single-dose exposure to propofol: A case report and review of literature. Dig Dis Sci 2002;47 (3 ):614–8.11911351\n2. Muniraj T Aslanian H Hypertriglyceridemia independent propofol-induced pancreatitis. JOP 2012;13 (4 ):451–3.22797405\n3. Csomor J Murínová I Broulíková K Propofol-induced acute pancreatitis. J Clin Pharm Ther 2017;42 (4 ):495–8.28393377\n4. Gottschling S Meyer S Krenn T Effects of short-term propofol administration on pancreatic enzymes and triglyceride levels in children. Anaesthesia 2005;60 (7 ):660–3.15960715\n5. Goudra B Singh PM Gouda G Borle A Carlin A Yadwad A Propofol and non-propofol based sedation for outpatient colonoscopy-prospective comparison of depth of sedation using an EEG based SEDLine monitor . J Clin Monit Comput 2016;30 (5 ):551–7.26364193\n6. Lovett P Gómez V Hodge DO Ladlie B Propofol versus midazolam/fentanyl sedation for colonoscopy in the elderly patient population. J Perianesth Nurs 2017;32 (3 ):210–4.28527548\n7. Adeyemo A Bannazadeh M Riggs T Shellnut J Barkel D Wasvary H Does sedation type affect colonoscopy perforation rates? Dis Colon Rectum 2014;57 (1 ):110–4.24316954\n8. Basavana Goudra AN Nuzat A Singh PM Borle A Carlin A Gouda G Association between type of sedation and the adverse events associated with gastrointestinal endoscopy: An analysis of 5 years' data from a tertiary center in the USA. Clin Endosc 2017;50 (2 ):161.27126387\n9. Horiuchi A Nakayama Y Tanaka N Ichise Y Katsuyama Y Ohmori S Propofol sedation for endoscopic procedures in patients 90 years of age and older. Digestion 2008;78 (1 ):20–3.18765935\n10. Donmez A Arslan G Pirat A Demirhan B Is pancreatitis a complication of propofol infusion? Eur J Anaesthesiol 1999;16 (6 ):367–70.10434163\n11. Gottschling S Larsen R Meyer S Graf N Reinhard H Acute pancreatitis induced by short-term propofol administration. Paediatr Anaesth 2005;15 (11 ):1006–8.16238566\n12. Ting TW Lee JH Acute pancreatitis after propofol infusion in a teenage patient. Anaesth Intensive Care 2012;40 (3 ):561–2.22577931\n13. Donmez A Sener M Candan S Arslan G Can we blame Propofol for pancreatitis? Pharmacotherapy 1999;19 (10 ):1181–2.10512069\n14. Asghar MU Cheema HA Tanveer K Leinwand J Propofol infusion and acute pancreatitis: A review. Am J Ther 2020;27 (4 ):e3711–4.\n\n",
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"abstract": "Microbial keratitis is a common corneal condition, with many known risk factors. We present a case of an 88-year-old female patient with a multidrug-resistant Achromobacter xylosoxidans corneal ulcer in a previously failed second penetrating keratoplasty, successfully managed with topical meropenem drops administered hourly around the clock, for five days preceding and then hourly day only, for five days following a repeat third penetrating keratoplasty. Topical meropenem 50 mg/mL was prepared by mixing a 500 mg vial of meropenem with 10 mL of sterile water with pharmacy advice that administration should be within an hour. To the best of our knowledge, this is the first report of the use of topical meropenem in the management of A.xylosoxidans keratitis. This case highlights the importance of the mean inhibitory concentrations for antibiotics when considering sensitivities. Topical meropenem may be a useful treatment option for multidrug-resistant bacterial corneal ulcers that are resistant to conventional therapy.",
"affiliations": "Cornea, Anterior Segment and Refractive Surgery, Bristol Eye Hospital, Bristol, UK.;Cornea, Anterior Segment and Refractive Surgery, Bristol Eye Hospital, Bristol, UK.;Microbiology and Infectious Diseases, Bristol Royal Infirmary, Bristol, UK.;Cornea, Anterior Segment and Refractive Surgery, Bristol Eye Hospital, Bristol, UK.",
"authors": "Tavassoli|Shokufeh|S|;Gunn|David|D|;Williams|O Martin|OM|;Darcy|Kieren|K|",
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"keywords": "eye; ophthalmology",
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"mesh_terms": "D042441:Achromobacter denitrificans; D060433:Administration, Ophthalmic; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003320:Corneal Ulcer; D018432:Drug Resistance, Multiple; D024901:Drug Resistance, Multiple, Bacterial; D015818:Eye Infections, Bacterial; D005260:Female; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D015948:Keratoplasty, Penetrating; D000077731:Meropenem; D011300:Preoperative Care; D013845:Thienamycins",
"nlm_unique_id": "101526291",
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"pmid": "30021738",
"pubdate": "2018-07-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "The successful treatment of a multidrug-resistant Achromobacter xylosoxidans corneal ulcer with topical meropenem.",
"title_normalized": "the successful treatment of a multidrug resistant achromobacter xylosoxidans corneal ulcer with topical meropenem"
} | [
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{
"abstract": "A cornerstone of the management of Acquired Haemophilia A (AHA) involves inhibitor eradication. First line immunosuppressive agents are usually steroids, either alone or in combination with cyclophosphamide. We present the use of Rituximab, cyclophosphamide, vincristine and prednisolone (RCVP) combination as immunosuppressant in AHA in a small cohort of patients in order to control their symptoms and eradicate inhibitors. This was a retrospective analysis of all AHA patients treated at the Northern Ireland Haemophilia centre over a six year period. During this time, a total of six patients were newly diagnosed with AHA. Four of these patients failed to respond conventional therapy of steroids and cyclophosphamide, they were however successfully treated with RCVP/ RCV. All patients achieved complete remission with this regimen after 1 to 2 cycles of treatment. Remission has been maintained for an extended time period (range 33-69 months). As AHA is related to immune modulation and, in some cases, underlying malignancy we decided to use this regime as it is effective in either condition. From our experience, we demonstrate that RCVP combination is a promising treatment in patients with AHA who fail to respond to steroids alone or who have been on pre-existing immunosuppression.",
"affiliations": "Northern Ireland Regional haemophilia Centre, Belfast City Hospital, Belfast, Northern Ireland.;Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, Northern Ireland.;Northern Ireland Regional haemophilia Centre, Belfast City Hospital, Belfast, Northern Ireland.",
"authors": "Sarah|Lawless|L|;Prantik|Das|D|;Gary|Benson|B|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D005938:Glucocorticoids; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069283:Rituximab; D014750:Vincristine; D003520:Cyclophosphamide",
"country": "Northern Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-6193",
"issue": "85(3)",
"journal": "The Ulster medical journal",
"keywords": "RCVP; acquired haemophilia; inhibitor eradication",
"medline_ta": "Ulster Med J",
"mesh_terms": "D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D003520:Cyclophosphamide; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006467:Hemophilia A; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D008297:Male; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "0417367",
"other_id": null,
"pages": "187-192",
"pmc": null,
"pmid": "27698522",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "6792737;17236786;15494430;2496636;11921026;17047148;23889317;19731307;8128430;17124095;12670328;11336065;6791677;14996701;22517903;17212724;18463353;9245226",
"title": "Systemic Therapy In Acquired Haemophilia - A Single Institute Experience.",
"title_normalized": "systemic therapy in acquired haemophilia a single institute experience"
} | [
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"medicinalproduct": "PREDNISOLONE."
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{
"actiondrug": "5",
"activesubstance": {
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},
"drugadditional": "3",
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"drugdosageform": null,
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"drugenddateformat": null,
"drugindication": "PEMPHIGOID",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISOLONE."
}
],
"patientagegroup": null,
"patientonsetage": "66",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Blood glucose fluctuation",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia aspiration",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SARAH L, PRANTIK D, GARY B. SYSTEMIC THERAPY IN ACQUIRED HAEMOPHILIA - A SINGLE INSTITUTE EXPERIENCE. ULSTER-MED-J 2016;85(3):187-192.",
"literaturereference_normalized": "systemic therapy in acquired haemophilia a single institute experience",
"qualification": "1",
"reportercountry": "GB"
},
"primarysourcecountry": null,
"receiptdate": "20161209",
"receivedate": "20161209",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 13013733,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170207"
}
] |
{
"abstract": "Flexible laryngoscopes are common outpatient surveillance tools. Cleansing of these scopes between patients must be quick, effective, and safe. One sterilant that largely meets these criteria is ortho-phthalaldehyde (OPA); however, infrequently, patients may develop allergic reactions to it. We present three cases of patients who developed significant allergic reactions following repeated laryngoscopic examinations. Subsequent intradermal allergy testing confirmed sensitivity to OPA. In addition, we reviewed the current literature, which includes 17 similar reactions reported in nine patients across disciplines. Allergic reaction to OPA is uncommon, but a potentially under-reported severe complication of repeated endoscopy.",
"affiliations": "NYU Voice Center, Department of Otolaryngology-Head and Neck Surgery, New York University School of Medicine, New York, New York, U.S.A.;ENT and Allergy Associates, New York, New York, U.S.A.;NYU Voice Center, Department of Otolaryngology-Head and Neck Surgery, New York University School of Medicine, New York, New York, U.S.A.;NYU Voice Center, Department of Otolaryngology-Head and Neck Surgery, New York University School of Medicine, New York, New York, U.S.A.;NYU Voice Center, Department of Otolaryngology-Head and Neck Surgery, New York University School of Medicine, New York, New York, U.S.A.",
"authors": "Atiyeh|Kimberly|K|;Chitkara|Ajay|A|;Achlatis|Stratos|S|;Branski|Ryan C|RC|;Amin|Milan R|MR|",
"chemical_list": "D004202:Disinfectants; D009764:o-Phthalaldehyde",
"country": "United States",
"delete": false,
"doi": "10.1002/lary.25421",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-852X",
"issue": "125(10)",
"journal": "The Laryngoscope",
"keywords": "Laryngoscopy; allergy; ortho-phthalaldehyde; voice",
"medline_ta": "Laryngoscope",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell; D004202:Disinfectants; D004203:Disinfection; D004342:Drug Hypersensitivity; D006258:Head and Neck Neoplasms; D006801:Humans; D007822:Laryngeal Neoplasms; D007828:Laryngoscopy; D008297:Male; D008875:Middle Aged; D000077195:Squamous Cell Carcinoma of Head and Neck; D009764:o-Phthalaldehyde",
"nlm_unique_id": "8607378",
"other_id": null,
"pages": "2349-52",
"pmc": null,
"pmid": "26199135",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Allergic reaction to ortho-phthalaldehyde following flexible laryngoscopy.",
"title_normalized": "allergic reaction to ortho phthalaldehyde following flexible laryngoscopy"
} | [
{
"companynumb": "US-JNJFOC-20151010235",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "019835",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"medicinalproduct": "CETIRIZINE HYDROCHLORIDE."
},
{
"actiondrug": "5",
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"activesubstancename": "CETIRIZINE HYDROCHLORIDE"
},
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "PREMEDICATION",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"medicinalproduct": "CETIRIZINE HYDROCHLORIDE."
}
],
"patientagegroup": "6",
"patientonsetage": "67",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
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"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ATIYEH K, CHITKARA A, ACHLATIS S, BRANSKI RC, AMIN MR. ALLERGIC REACTION TO ORTHO-PHTHALALDEHYDE FOLLOWING FLEXIBLE LARYNGOSCOPY. LARYNGOSCOPE 2015?125:2349-2352.",
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"qualification": "1",
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160304"
}
] |
{
"abstract": "Vitamin D-mediated hypercalcemia is an uncommon complication of Pneumocystis infection. A granulomatous response resulting from Pneumocystis infection is also atypical. In this report, we describe an exceptional case of granulomatous Pneumocystis pneumonia associated with vitamin D-mediated hypercalcemia, in a patient who presented unusually late after renal transplantation. The patient's hypercalcemia resolved with treatment of the infection.",
"affiliations": "Department of Internal Medicine, Division of Infectious Disease, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;Department of Internal Medicine, Division of Infectious Disease, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.",
"authors": "Taylor|Lindsay N|LN|;Aesif|Scott W|SW|;Matson|Kristine M|KM|https://orcid.org/0000-0002-4853-6125",
"chemical_list": "D000935:Antifungal Agents; D014807:Vitamin D; D002981:Clindamycin; D011319:Primaquine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13081",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "21(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nPneumocystis\n; granuloma; hypercalcemia; renal transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D058186:Acute Kidney Injury; D000935:Antifungal Agents; D002981:Clindamycin; D006099:Granuloma; D006801:Humans; D006934:Hypercalcemia; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D011319:Primaquine; D013997:Time Factors; D016896:Treatment Outcome; D014807:Vitamin D",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13081",
"pmc": null,
"pmid": "30892756",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "A case of Pneumocystis pneumonia, with a granulomatous response and vitamin D-mediated hypercalcemia, presenting 13 years after renal transplantation.",
"title_normalized": "a case of pneumocystis pneumonia with a granulomatous response and vitamin d mediated hypercalcemia presenting 13 years after renal transplantation"
} | [
{
"companynumb": "US-ROCHE-2350088",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
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},
{
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"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
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"drugindication": "INFECTION PROPHYLAXIS",
"drugintervaldosagedefinition": "805",
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},
{
"actiondrug": "5",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
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"drugauthorizationnumb": "050722",
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
{
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"activesubstancename": "CYCLOSPORINE"
},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CYCLOSPORINE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
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"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PNEUMOCYSTIS JIROVECII PNEUMONIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"medicinalproduct": "SULFAMETHOXAZOLE/TRIMETHOPRIM"
}
],
"patientagegroup": null,
"patientonsetage": "53",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hypercalcaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pneumocystis jirovecii pneumonia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TAYLOR L, AESIF S AND MATSON K. A CASE OF PNEUMOCYSTIS PNEUMONIA, WITH A GRANULOMATOUS RESPONSE AND VITAMIN D-MEDIATED HYPERCALCEMIA, PRESENTING 13 YEARS AFTER RENAL TRANSPLANTATION. TRANSPLANT INFECTIOUS DISEASE 2019 JUN?21 (3):1-6.",
"literaturereference_normalized": "a case of pneumocystis pneumonia with a granulomatous response and vitamin d mediated hypercalcemia presenting 13 years after renal transplantation",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190709",
"receivedate": "20190709",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16542898,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191004"
}
] |
{
"abstract": "Methadone, an opioid agonist, is the recommended treatment for pregnant women with opioid use disorder (OUD). Fetal/neonatal autopsy findings as well as placental changes in the setting of maternal OUD or methadone maintenance therapy (MMT) are not well-characterized. Here we present a case of a neonate who had exposure to MMT while in utero and died shortly after birth and was subsequently found to have multifocal calcified renal vein thrombosis, a recent inferior vena cava thrombus, and placental features of fetal vascular malperfusion at autopsy.",
"affiliations": "Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.;Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Pathology, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Pathology, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.;Department of Pathology, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.",
"authors": "Guerrero|J C|JC|https://orcid.org/0000-0001-7876-6602;Kim|Joseph|J|https://orcid.org/0000-0003-1773-0758;Santi|Mariarita|M|;Ruchelli|Eduardo|E|;Carreon|Chrystalle Katte|CK|",
"chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1177/1093526620962062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1093-5266",
"issue": "24(1)",
"journal": "Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society",
"keywords": "delayed villous maturation; fetal vascular malperfusion; methadone maintenance therapy; neonatal demise; opioid use disorder; renal vein thrombosis",
"medline_ta": "Pediatr Dev Pathol",
"mesh_terms": "D000701:Analgesics, Opioid; D001344:Autopsy; D005260:Female; D005313:Fetal Death; D005333:Fetus; D006801:Humans; D008691:Methadone; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011247:Pregnancy; D012082:Renal Veins; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis",
"nlm_unique_id": "9809673",
"other_id": null,
"pages": "56-61",
"pmc": null,
"pmid": "32970505",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Thrombosis of the Renal Vein and Inferior Vena Cava Associated With Placental Fetal Vascular Malperfusion in a Neonate Exposed to Methadone Maintenance Therapy In Utero.",
"title_normalized": "thrombosis of the renal vein and inferior vena cava associated with placental fetal vascular malperfusion in a neonate exposed to methadone maintenance therapy in utero"
} | [
{
"companynumb": "US-TEVA-2021-US-1924543",
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{
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"activesubstance": {
"activesubstancename": "FENTANYL"
},
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"drugdosagetext": "ADMINISTERED UPON PRESENTATION TO THE HOSPITAL",
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"drugindication": "Product used for unknown indication",
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{
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"medicinalproduct": "MORPHINE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
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"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "THE MOTHER HAD BEEN RECEIVING METHADONE MAINTENANCE THERAPY FOR 2 YEARS.",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Drug use disorder",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "METHADONE"
}
],
"patientagegroup": "1",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Renal vein thrombosis",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Vena cava thrombosis",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Foetal vascular malperfusion",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Neonatal respiratory failure",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Encephalopathy neonatal",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Extramedullary haemopoiesis",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nucleated red cells",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
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{
"abstract": "Between 2000 and 2014, five patients received bilateral hand (n = 3), bilateral forearm (n = 1), and unilateral hand (n = 1) transplants at the Innsbruck Medical University Hospital. We provide a comprehensive report of the long-term results at 20 years. During the 6-20 years follow-up, 43 rejection episodes were recorded in total. Of these, 27.9% were antibody-related with serum donor-specific alloantibodies (DSA) and skin-infiltrating B-cells. The cell phenotype in rejecting skin biopsies changed and C4d-staining increased with time post-transplantation. In the long-term, a change in hand appearance was observed. The functional outcome was highly depending on the level of amputation. The number and severity of rejections did not correlate with hand function, but negatively impacted on the patients´ well-being and quality of life. Patient satisfaction significantly correlated with upper limb function. One hand allograft eventually developed severe allograft vasculopathy and was amputated at 7 years. The patient later died due to progressive gastric cancer. The other four patients are currently rejection-free with moderate levels of immunosuppression. Hand transplantation remains a therapeutic option for carefully selected patients. A stable immunologic situation with optimized and individually adopted immunosuppression favors good compliance and patient satisfaction and may prevent development of DSA.",
"affiliations": "Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.;Department of Psychiatry, Psychotherapy and Psychosomatic, Center for Advanced Psychology in Plastic and Transplant Surgery, Medical University of Innsbruck, Innsbruck, Austria.;Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Plastic, Reconstructive and Aesthetic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Pathology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Dermatology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Plastic, Reconstructive and Aesthetic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Plastic, Reconstructive and Aesthetic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.;Department of Plastic, Reconstructive and Aesthetic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department for Trauma Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department for Trauma Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Vascularized Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.;Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.",
"authors": "Hautz|Theresa|T|0000-0003-0388-0202;Messner|Franka|F|0000-0003-2100-6914;Weissenbacher|Annemarie|A|;Hackl|Hubert|H|;Kumnig|Martin|M|;Ninkovic|Marina|M|;Berchtold|Valeria|V|;Krapf|Johanna|J|;Zelger|Bettina G|BG|;Zelger|Bernhard|B|;Wolfram|Dolores|D|;Pierer|Gerhard|G|;Löscher|Wolfgang N|WN|;Zimmermann|Robert|R|;Gabl|Markus|M|;Arora|Rohit|R|;Brandacher|Gerald|G|0000-0001-7790-441X;Margreiter|Raimund|R|;Öfner|Dietmar|D|;Schneeberger|Stefan|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/tri.13752",
"fulltext": "\n==== Front\nTranspl Int\nTranspl Int\n10.1111/(ISSN)1432-2277\nTRI\nTransplant International\n0934-0874 1432-2277 John Wiley and Sons Inc. Hoboken \n\n32970891\n10.1111/tri.13752\nTRI13752\nOriginal Article\nOriginal Articles\nLong‐term outcome after hand and forearm transplantation – a retrospective study\n20 years hand transplantationHautz et al.Hautz Theresa https://orcid.org/0000-0003-0388-0202\n1\n\n*\ntheresa.hautz@i-med.ac.at Messner Franka https://orcid.org/0000-0003-2100-6914\n1\n\n*\n Weissenbacher Annemarie \n1\n Hackl Hubert \n2\n Kumnig Martin \n3\n Ninkovic Marina \n1\n Berchtold Valeria \n1\n Krapf Johanna \n4\n Zelger Bettina G. \n5\n Zelger Bernhard \n6\n Wolfram Dolores \n4\n Pierer Gerhard \n4\n Löscher Wolfgang N. \n7\n Zimmermann Robert \n4\n Gabl Markus \n8\n Arora Rohit \n8\n Brandacher Gerald https://orcid.org/0000-0001-7790-441X\n9\n Margreiter Raimund \n1\n Öfner Dietmar \n1\n Schneeberger Stefan \n1\ntheresa.hautz@i-med.ac.atstefan.schneeberger@i-med.ac.at \n1 \nDepartment of Visceral, Transplant and Thoracic Surgery\nCenter of Operative Medicine\nMedical University of Innsbruck\nInnsbruck\nAustria\n\n\n2 \nDivision of Bioinformatics\nBiocenter\nMedical University of Innsbruck\nInnsbruck\nAustria\n\n\n3 \nDepartment of Psychiatry, Psychotherapy and Psychosomatic\nCenter for Advanced Psychology in Plastic and Transplant Surgery\nMedical University of Innsbruck\nInnsbruck\nAustria\n\n\n4 \nDepartment of Plastic, Reconstructive and Aesthetic Surgery\nCenter of Operative Medicine\nMedical University of Innsbruck\nInnsbruck\nAustria\n\n\n5 \nDepartment of Pathology\nMedical University of Innsbruck\nInnsbruck\nAustria\n\n\n6 \nDepartment of Dermatology\nMedical University of Innsbruck\nInnsbruck\nAustria\n\n\n7 \nDepartment of Neurology\nMedical University of Innsbruck\nInnsbruck\nAustria\n\n\n8 \nDepartment for Trauma Surgery\nCenter of Operative Medicine\nMedical University of Innsbruck\nInnsbruck\nAustria\n\n\n9 \nVascularized Composite Allotransplantation (VCA) Laboratory\nDepartment of Plastic and Reconstructive Surgery\nJohns Hopkins University School of Medicine\nBaltimore\nMD\nUSA\n\n* Correspondence\n\nTheresa Hautz MD, PhD and Stefan Schneeberger MD, Department of Visceral, Transplant and Thoracic Surgery, D. Swarovski Research Laboratory, Medical University Innsbruck, Anichstr. 35, A‐6020 Innsbruck, Austria.\n\nTel.: 0043 512 504 22601;\n\nfax: 0043 512 504 22602;\n\ne‐mails: theresa.hautz@i-med.ac.at (T.H.) and stefan.schneeberger@i-med.ac.at (S.S.)\n* Authors contributed equally to this work.\n\n\n10 11 2020 \n12 2020 \n33 12 10.1111/tri.v33.121762 1778\n12 7 2020 04 8 2020 14 9 2020 © 2020 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOTThis 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.Summary\nBetween 2000 and 2014, five patients received bilateral hand (n = 3), bilateral forearm (n = 1), and unilateral hand (n = 1) transplants at the Innsbruck Medical University Hospital. We provide a comprehensive report of the long‐term results at 20 years. During the 6–20 years follow‐up, 43 rejection episodes were recorded in total. Of these, 27.9% were antibody‐related with serum donor‐specific alloantibodies (DSA) and skin‐infiltrating B‐cells. The cell phenotype in rejecting skin biopsies changed and C4d‐staining increased with time post‐transplantation. In the long‐term, a change in hand appearance was observed. The functional outcome was highly depending on the level of amputation. The number and severity of rejections did not correlate with hand function, but negatively impacted on the patients´ well‐being and quality of life. Patient satisfaction significantly correlated with upper limb function. One hand allograft eventually developed severe allograft vasculopathy and was amputated at 7 years. The patient later died due to progressive gastric cancer. The other four patients are currently rejection‐free with moderate levels of immunosuppression. Hand transplantation remains a therapeutic option for carefully selected patients. A stable immunologic situation with optimized and individually adopted immunosuppression favors good compliance and patient satisfaction and may prevent development of DSA.\n\ncomplicationsdonor‐specific antibodieshand and forearm transplantationimmunosuppressionrejectionvascularized composite allotransplantation source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:23.12.2020\n==== Body\nIntroduction\nHand and forearm transplantation are therapeutic options for patients suffering from amputation. While the first successful case was performed 21 years ago [1], the total number of upper limb transplantations remains small and the progress of the field slow. This is sobering since conceptually, the idea to replace a missing limb with an allograft is attractive and the early functional results were very good [2, 3, 4. The long‐term outcomes are only slowly emerging and include early and late graft losses [5, 6, 7, development of chronic rejection and graft vasculopathy [6, 8, donor‐specific alloantibodies (DSA), antibody‐mediated rejection (ABMR) [11, 12, and side effects of long‐term immunosuppression (IS). Despite immunologic problems, psychological well‐being, psychosocial factors, compliance, and a more selective evaluation process to determine the “ideal” candidate for a vascularized composite allograft (VCA) have come into focus and require attention in the field.\n\nClose patient monitoring and detailed, transparent reporting of the outcome remain key for the field and may help to eventually make this procedure safe and successful in the long run. We herein report and critically reflect the outcomes (mean 13 years) of nine limbs transplanted in five patients at the Innsbruck Medical University Hospital between March 2000 and March 2014. This report focuses on the occurrences and challenges in the long‐term.\n\nMaterials and methods\nPatients\nEarlier reports describe the patient details and the early post‐transplant course [13, 14, 15, 16, 17, 18. Patient characteristics and the immunologic risk profile are provided in Table 1. Five male patients were given a bilateral (n = 4) or unilateral (n = 1) hand or forearm transplantation following traumatic hand loss. Time from amputation to transplantation was 5.0 ± 1.16 years (mean ± standard deviation) and time on the waiting list was 10.0 ± 4.7 months. No IRB approval was required since this is a retrospective data analysis.\n\nTable 1 Patient characteristics.\n\nCharacteristics\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\t\nSex\tM\tM\tM\tM\tM\t\nAmputation year\t1994\t2000\t2000\t2004\t2009\t\nAmputation cause\tExplosion\tElectric current accident\tExplosion\tTimber machine accident\tCar accident\t\nAge at Tx (year)\t47\t41\t23\t55\t55\t\nTx date\t07.03.2000\t17.02.2003\t29.05.2006\t22.07.2009\t26.03.2014\t\nType\tBilateral\tBilateral\tBilateral\tUnilateral®\n\tBilateral\t\nLevel\tDistal forearm\tProximal forearm\tMid forearm\tWrist\tr: metacarpal, l: wrist\t\nUse of myoelectric prostheses\tYes\tYes\tNo\tYes\tNo\t\nCMV status (rec/don)\tneg/pos\tpos/pos\tpos/pos\tneg/neg\tneg/neg\t\nPRA pre‐Tx (%)\t5\t0\t0\t0\t0\t\nHLA mismatch (A/B/DR)\t2/2/2\t1/2/1\t1/1/1\t2/2/2\t2/2/2\t\nLymphocytotoxic crossmatch\tneg\tneg\tneg\tneg\tneg\t\nPerfusion solution\tUW\tUW\tHTK\tHKT\tHTK\t\nCold ischemia time (min)\tr:150, l:170\tr: 155, l: 153\tr: 183, l: 195\t200\tr: 368, l: 399\t\nInduction therapy\tATG\tATG\tAlemtuzumab\tAlemtuzumab\tAlemtuzumab\t\nEarly maintenance IS\ttac/MMF/ster\ttac/MMF/ster\ttac/MMF/ster\ttac/MMF\ttac/MMF/ster\t\nFollow‐up (year)\t19\t16\t13\t7*\n\t5\t\nATG, antithymocyte globulin; CMV, cytomegalovirus; HLA, human leukocyte antigens; HTK, histidine‐tryptophan‐ketoglutarate solution; IS, immunosuppression; l, left; M, male; MMF, mycophenolate mofetil; PRA, panel reactive antibodies; r, right; ster, steroids; tac, tacrolimus; Tx, transplantation; UW, University of Wisconsin solution.\n\n* Graft had to be amputated 7 years post‐transplantation.\n\nJohn Wiley & Sons, LtdSurgery and immunosuppression\nDetails of surgical techniques have been reported earlier [3, 13, 14, 15, 19. Intra‐ and postoperative IS consisted of induction and maintenance treatment (Table 1). Reduction of overall IS including steroid withdrawal, reduction of tacrolimus trough levels and conversion from tacrolimus to mTOR‐inhibitors sirolimus or everolimus was cautiously aimed for in all patients. In patient 5, belatacept (Nulojix) has been successfully introduced to the IS protocol [5], while in patients 2 and 3 balatacept was only added transiently and discontinued after 3 years. IS was adjusted under close surveillance of skin appearance, skin histology, metabolic, and kidney function parameters.\n\nHistology and immunohistochemistry\nSkin biopsies were collected according to a previously published protocol [20]. Paraffin embedded and hematoxylin&eosin (H&E)‐stained sections were graded according to the Banff 2007‐guidelines [21] with particular attention to luminal narrowing/occlusion. Immunohistochemical staining for CD3, CD4, CD8, CD20, CD68, Foxp3, and C4d was routinely performed. CD3, CD4, CD8, CD20, and CD68‐stainings were read as percentage of the cellular infiltrate. Foxp3‐staining was graded as 0 (0–<2%), 1 (2–10%), and 2 (>10% positive stained infiltrating cells). Endothelial C4d‐staining was graded as follows: 0 (no/unspecific staining), 1 (mild/noncircumferential staining in some vessels), 2 (intense/circumferential staining in most vessels).\n\nImaging modalities\nTo monitor bone healing and integrity, vessel patency and muscle texture, X‐ray and ultrasound were performed at close intervals during the first year and annually thereafter. Angiography and computed tomography angiography with three‐dimensional reconstruction of graft vessels were undertaken annually after year 1. Functional magnetic resonance imaging (fMRI) was performed in patient 2 at 5‐, 9‐, and 15‐year post‐transplant.\n\nRehabilitation program and evaluation of hand function\nDetails on the specific rehabilitation program were published earlier [18, 22. Among others, the following tests were applied to evaluate and document hand function: Thumb opposition – Kapandji score, key pinch strength, grip strength, static 2‐point discrimination (s‐2PD) test, and total active range of motion (TAROM) measurement. Functional results and subjective assessment were evaluated utilizing the disabilities of the arm, shoulder and hand (DASH) score, the action research arm test (ARAT) and the hand transplant score system (HTSS) score.\n\nElectrophysiological studies\nMotor and sensory nerve conduction studies were performed regularly according to standard procedures. For measurement of compound motor action potentials (CMAP) disposable surface electrodes were placed on the abductor pollicis brevis and abductor digiti minimi muscle after stimulation of the median and ulnar nerve proximal to the level of hand/forearm transplantation. Compound sensory action potentials (CSAP) were recorded from the index and the fifth finger with band electrodes.\n\nPsychological evaluation\nThe “Innsbruck Psychological Screening Program for Reconstructive Transplantation (iRT‐PSP)” [23] was applied for evaluation and follow‐up. The iRT‐PSP protocol highlights areas that are specific for hand transplantation and is a useful tool for the development of interventions that help patients to enhance coping strategies, manage life stress, and support their innate resilience to best adapt to life post‐transplant [23, 24.\n\nStatistical analysis\nImmunohistochemical data are expressed as mean ± standard error of the mean (SEM). The comparisons of the phenotype at three time‐periods post‐transplant (early: 0–3 years, n = 54 skin samples; late: 3–10 years, n = 88; very late: after year 10, n = 12) were carried out using one‐way analysis of variance with the Bonferroni post hoc test. Wilcoxon rank sum test was used to assess for differences in hand function and psychological parameters/scores during (value minus patient side median centered no rejection) and in the absence of rejection (median). Spearman’s rank correlation rho or Kendall’s tau b was used for correlation analysis. P‐values were adjusted based on the false discovery rate (FDR) according to the Benjamini–Hochberg method [25]. Loess (locally weighted scatterplot smoothing) plots were used to depict trends in hand function over time, values were related to the 5‐year results. A P‐value < 0.05 was considered as statistically significant. Statistical analyses were performed using the statistical software environment r (version 3.5.2; R Foundation for Statistical Computing; http://www.R‐project.org).\n\nResults\nSurgery\nEarly postoperative surgical interventions were needed in four patients due to immediate postoperative swelling/hematoma and to cover skin defects. Other surgical procedures included resection of arteriovenous fistulas, scar correction, and interventions for improvement of hand function (Table 2). The esthetic outcome is shown in SDC1.\n\nTable 2 Secondary surgical interventions.\n\nSecondary surgical procedures\tPatient (time post Tx)\t\nDecompression of hematoma and tissue swelling\t3 (day 7), 5 (days 1, 5, 10, 13)\t\nTransplantation of skin autografts for wound closure\t1 (day 2), 3 (day 2)\t\nCoverage of a skin defect with a split‐thickness skin graft\t2 (day 3)\t\nResection of arteriovenous fistulas\t1 (6 months), 5 (3.5 years)\t\nSkin graft resection\t3 (1 year)\t\nCosmetic scar surgery, scar correction\t2 (2 years), 3 (4 years)\t\nArthroplasty MR II‐V dextra, and tenolysis extens\t5 (1.5 years)\t\nOpponensplasty (IV)\t3 (2 years)\t\nFinger amputation\t4 (7 years)\t\nTx, transplantation.\n\nJohn Wiley & Sons, LtdRejection and immunosuppression\nAll patients experienced acute rejections during their follow‐up. Detailed reports were published elsewhere [12, 13, 14, 16, 17, 18, 19, 26, 27]. Most often macroscopic skin lesions were indicative for rejection with or without tingling or burning sensations. Out of 43 rejection episodes, the majority were T‐cell mediated rejections (TCMR), 12 were classified as ABMR, one as B‐cell mediated rejection (BCMR), and one as chronic rejection (Fig. 1a, Table 3). Rejections were observed more frequently early after transplantation (Fig. 1b). ABMR was noticed first at 1.5 years. 2/5 patients developed serum DSA (anti‐HLA class II) and 2/5 anti‐HLA‐class I, as assessed by Luminex® 200™ (Table 3).\n\nFigure 1 Characteristics of rejection episodes. Characteristics of rejection overall (a,c) and over time (b,d) with regard to rejection type and rejection severity according to Banff 2007 guidelines, observed in patients 1–5 during a 6–20‐year follow‐up after hand or forearm transplantation. Antibody‐mediated rejection (ABMR), donor‐specific alloantibodies (DSA).\n\nTable 3 Immunologic complications and immunosuppression.\n\n\tOverall\tPatient 1\tPatient 2\tPatient 3\tPatient 4*\n\tPatient 5\t\nFollow‐up (year)\tMean 13\t20\t17\t14\t7\t6\t\nRejection episodes (n)\t43\t4\t16\t10\t10\t3\t\nTCMR (n)\t29 (67.44%)\t4\t12\t9\t1\t3\t\nBCMR (n)\t1 (2.33%)\t0\t0\t1\t0\t0\t\nABMR (n)\t12 (27.90%)\t0\t4\t0\t8\t0\t\nChronic rejection (n)\t1 (2.33%)\t0\t0\t0\t1\t0\t\nGraft loss\t1/9 hands\tNo\tNo\tNo\tYes (at 7 years)\tNo\t\nDevelopment of anti‐HLA class II\t3/5\tNo\tYes (donor‐specific, initially at 9 years)\tYes (not donor‐specific, initially at 6.5 years)\tYes (donor‐specific, initially at 1.5 years)\tNo\t\nDevelopment of anti‐HLA class I\t1/5\tNo\tYes (initially at 12 years)\tNo\tNo\tNo\t\nSkin changes\t2/5\tNo\tAbnormal skin color and texture, diminished hair growth (since 12 years)\tAbnormal skin color, texture, vascularization, and hair growth (since 7–9 years)\tNo\tNo\t\nNail changes\t2/5\tNo\tAbnormal nail growth (since 13 years)\tDiminished nail growth (since 7 years)\tNo\tNo\t\nEarly steroid‐sparing IS protocol\t1/5\tNo\tNo\tNo\tYes\tNo\t\nBelatacept treatment\t3/5\tNo\tTransient conversion (~13–16 years)\tTransient conversion (~9–12.5 years)\tAttempt (at 6 years, but failed)\tYes (start POD 100)\t\nCurrent IS\t\tSirolimus (4–6 ng/ml) prednisolone (5 mg/day)\tTacrolimus (10–12 ng/ml), mycopheolic acid 500 mg/day, prednisolone 10 mg/day\tTacrolimus (8 ng/ml), sirolimus (8 ng/ml), prednisolone 5 mg/day, protopic + advantan creme\t\tTacrolimus (8 ng/ml), belatacept (5 mg/kg/6 weeks)\t\nABMR, antibody‐mediated‐rejection; BCMR, B‐cell‐mediated rejection; DSA, donor‐specific antibodies; HLA, human leukocyte antigen; IS (∙), targeted trough levels; IS, immunosuppression; n, number; POD, postoperative day; TCMR, T‐cell‐mediated rejection.\n\n* Graft had to be amputated 7 years post‐transplantation.\n\nJohn Wiley & Sons, LtdBanff grading [21] of rejection in punch skin biopsies revealed 51.28% rejections as moderate (grade II, Fig. 1c,d). However, the histopathologic appearance of ABMR as indicated by a predominance of B‐cells coinciding with the presence of DSA was found to be rather heterogenous and varied with regard to localization, extent, and dynamics of the cell infiltrate (Fig. 2a–h). This makes it difficult to precisely classify such rejections using the Banff‐scheme 21, which currently lacks a classification for ABMR and chronic rejection. Immunohistochemistry in rejecting skin biopsies revealed a significantly increased proportion of CD3+ T‐cells after year 3 (67.57 ± 5.34 vs. 82.47 ± 1.78 vs. 81.08 ± 5.02, P < 0.001). The highest proportion of CD20+ B‐cells was observed at 4–10 years (8.40 ± 1.27, P = 0.012), while CD68+ macrophages were more dominant early after transplantation (15.48 ± 2.59, P = 0.022). No significant change in Foxp3+ T‐regulatory‐cells was found over time. Endothelial C4d expression significantly increased with time post‐transplant (P < 0.05, Fig. 2i,j).\n\nFigure 2 Histology and immunohistochemistry of rejection. Skin biopsies revealed a heterogeneous histopathologic appearance of ABMR (DSA+, a–h). During ABMR with high levels of DSAs observed in patient 2 at 14 years, Banff rejection grade III (a), infiltrating cells consisted of T‐cells (b), B‐cells (c), and macrophages (d), which were mainly located in the superficial dermis. ABMR, DSA+ in patient 4 at 2.5 years histopathologic revealed aggregates of cell infiltrates located perivascular in the deep dermis, while the superficial dermis was spared (e). These infiltrates were dominated by B‐cells (g) with few T‐cells (f), while endothelial C4d was negative (h). Analysis of immunohistochemical markers found in the skin during rejection early, late, and very late after transplantation (i,j). *P < 0.05, **P < 0.01, ***P < 0.001.\n\nThe unilateral transplant recipient (patient 4) developed DSA at 1.5 years and underwent multiple ABMRs with levels of DSA ranging between 8000 and 19 000 MFI (mean fluorescent intensity). Histopathology revealed sparse infiltrates in the superficial dermis without epidermal involvement, even in the presence of macroscopic changes. A B‐cell‐dominated infiltrate was organized in cell aggregates in some cases and mainly located perivascular in the mid‐dermis (Fig. 2e–h). Also, vascular changes consistent with vasculitis were observed. Overall, histopathologic changes were mild or even absent in this patient and did not correlate with rejection severity, including macroscopic skin changes, DSA and challenging rejection treatment. Development of skin ulcera/necrosis leads to amputation of the hand allograft at approximately 7 years (Fig. 3a–c). Histopathology showed severe graft vasculopathy by then, indicating chronic rejection (Fig. 3d–l).\n\nFigure 3 Graft loss in the unilateral hand transplant recipient (patient 4) due to chronic rejection at 7 years. History of amputation of dig. IV and skin changes one month before graft amputation (a–c). Histopathology of the amputated hand allograft at 7 years revealed severe skin necrosis (Banff grade IV) and cell infiltration (d). Myointimal hyperplasia and occlusion of the lumen (e) were observed in superficial dermal as well as deeply located large vessels, which stained highly positive for C4d (f). Further immunohistochemical analysis (g–k) revealed the perivascular cell infiltrate highly positive for CD4 (h) and HLA DR (k).\n\nIn all other cases, rejection had been successfully managed. Most often, rejection responded to a steroid bolus and transient increase of IS ± topical treatment. More aggressive rejections during the early postoperative period were treated with thymoglobulin and/or alemtuzumab. ABMR in general did not respond to conventional treatment (steroids + tacrolimus dose increase); however, a rapid effect of rituximab treatment was observed. Immunoadsorption had been applied successfully to treat ABMR at 14 years in patient 2. Unfortunately, none of these treatment strategies including plasmapheresis were able to prevent graft loss in patient 4.\n\nThe remaining patients are free of rejection (Banff 0 or 0‐I) and negative for DSA at this point. No histopathologic signs for chronic rejection (as per the description by Morelon et al. [28]) were observed in skin biopsies. However, two patients have developed skin and nail changes over time (Table 3), which may be indicative for an early stage of chronic rejection.\n\nInfectious complications and side effects\nAll patients experienced infections and metabolic side effects (Table 4). The majority of these complications evolved within the first and second postoperative year and are most likely attributable to high‐dose IS during the early postoperative period. In the long run, autoimmune and proliferative diseases were observed. Details on the specific therapy are published elsewhere [17, 18, 29, 30, 31. To keep calcineurin inhibitor (CNI)‐induced side effects low, reduction of tacrolimus trough levels and conversion from tacrolimus to mTOR‐inhibitors or to Belatacept was cautiously aimed for in all patients. No neurologic side effects caused by CNI were recorded in our cohort. Introduction of Belatacept led to a stabilization of creatinine plasma levels in our patients [5]. Patient 5 was transplanted a donor kidney 191 days after bilateral hand transplantation due to preexisting but undetected kidney disease that did not recover even after conversion to Belatacept [5]. Patient 4 developed a progressive CNI‐induced renal insufficiency/nephropathy at 3 years after unilateral hand transplantation. All attempts to convert his IS to the aforementioned substances failed and the hand allograft had to be amputated due to severe rejection at year seven. At 1 year after hand transplant removal, gastric cancer was diagnosed. Magnetic resonance and computed tomography scans revealed metastasis and peritoneal carcinosis at time of diagnosis. Chemotherapy with Leucovorin (200 ml/m2) and 5‐Fluorouracil (2600 mg/m2) was initiated but failed to significantly decelerate progression of the disease. The patient eventually succumbed to this disease. While gastric cancer is not typically associated with IS and cancer occurred after graft removal and cessation of IS, a relation between the intense and multi‐year IS and the cancer cannot be out ruled.\n\nTable 4 Side effects.\n\nSide effects\tPatient\t\nRecurrent CMV infection\t1, 2, 3\t\nHPV associated skin warts\t2, 5\t\nInvasive fungal infection with Alternaria\t2\t\nOral aphthous lesions\t2\t\nEpidermatitis/eczema (recipient skin)\t2\t\nCondyloma\t3\t\nMyocarditis\t3\t\nPangastritis\t3\t\nHypertension\t2, 3, 4, 5\t\nHyperlipidemia\t1, 3, 4\t\nDiabetes mellitus (noninsulin‐dependent)\t1\t\nHeadache\t2\t\nLeukocytopenia\t2\t\nRadius fracture (graft)\t1\t\nSubdural hematoma\t5\t\nBullous pemphigoid\t1\t\nNasolabial and frontal basal cell carcinoma\t1\t\nNasal squamous cell carcinoma (Keratoacanthoma)\t1\t\nAcute prerenal kidney failure due to gastroenteritis\t3\t\nCNI‐induced renal insufficiency/nephropathy\t4\t\nAcute kidney failure necessitating kidney transplantation\t5\t\nM‐TOR intolerance\t4\t\nLung emphysema\t4\t\nUrosepsis (E.faecium)\t5\t\nSepsis with multi‐organ failure due to influenza virus infection\t3\t\nGastric cancer\t4\t\nCMV, cytomegalovirus; CNI, calcineurin inhibitor; m‐TOR, mammalian target of rapamycin; HPV, human papilloma virus.\n\nJohn Wiley & Sons, LtdImaging\nAt the most recent follow‐up, radio‐morphological studies demonstrated intact osteosynthesis in all hands/forearms without signs of osteodestructive/proliferative alterations (SDC2 a–d). Angiography and computed tomography angiography revealed patent blood flow and consistent perfusion of tissues without irregularities (SDC2). Duplex ultrasound constantly indicated an increased flow resistance in the radial and ulnar artery of patients 1, 2, and 3 (RI ranging between 0.9 and 1), and fatty degeneration of the allograft forearm muscles in patient 2. Importantly, no vessel wall thickening as a signal for emerging vasculopathy was seen in any of the four patients. FMRI revealed typical activation in the motor and somatosensory cortex at 5 years after bilateral forearm transplantation. At 15 years, a broad activation in the respective areas was observed when stimulated by finger tapping (Fig. 4), comparable to healthy, nontransplanted individuals. This observation indicates fully reorganization of the motor and somatosensory cortex after limb transplantation.\n\nFigure 4 Functional magnetic resonance imaging (fMRI). fMRI was performed using a 1.5 Tesla magnetic resonance scanner and a head coil with eight arrays. Four consecutive fMRI measurements were performed with rest and motion paradigms including finger typing, softball compression, and fist clenching of both hands. 15 years after bilateral forearm transplantation motoric activation after finger tapping of the left (upper row) and right hand (lower row) appeared to be normal and was comparable to healthy, nontransplanted individuals. Activation of the primary motor and somatosensory cortex as well as the supplementary motor areas (SMA, a,b). In both hands, an adequate sensomotoric activation was achieved. Ipsilateral cerebellar activation after finger tapping (c).\n\nFunctional outcome\nHand function and sensitivity continuously improved during the first years in all patients (Fig. 5, SDC3). In hands transplanted at wrist level or above recovery of intrinsic muscle activity was observed at year 1, while the one hand transplanted at the metacarpal level regained intrinsic hand function not before year 2. Protective sensation was found in all patients within the first year. Specifically, patient 1 regained outstanding hand function, performing all activities of daily living (ADLs) [27]. Functional recovery after forearm transplantation (patient 2) was slower compared to distal hand transplantation, but eventually a satisfying functional outcome was achieved. The return of function is superior to what the patient had experienced with myoelectrical prostheses. An improvement in the performance of ADLs, the patient´s independence and satisfaction as assessed by DASH questionnaire, ARAT and HTSS was observed in all patients (Fig. 6).\n\nFigure 5 Functional outcomes and trends. Grip strength (a) and key pinch strength (b) evolution for the right (r) and the left (l) transplanted hand of patients 1–5 in kilograms (kg). Evolution of thumb opposition measured by the Kapandji Score for the right (r) and left (l) transplanted hand of patients 1–5 (c). Trends for functional parameters over time (d–g). Values were related to the 5‐years outcome for each patient.\n\nFigure 6 Functional outcomes. Disabilities of the arm, shoulder and hand (DASH) score evolution (a). Action research arm test (ARAT) evolution recorded for the right (r) and left (l) arm of patients 1–5 (b). Hand transplantation score system (HTSS) score evolution (c). Activities of daily living (ADL) presented by patient 1 (d), patient 2 (e), patient 3 (f), and patient 5 (g).\n\nIn the long run, intermittent improvement or deteriorations of hand function were observed (Fig. 5 + SDC3). A tendency toward an overall slow deterioration, especially late after transplantation, was found for grip strength, key pinch strength, and thumb opposition (Fig. 5d–f). No association of a concurrent decrease in function and rejection could be observed (Table 5). In fact, hand function remained stable also during rejection episodes (Fig. 7a). However, a negative impact of rejection on patients´ well‐being – according to the score indicative for presence of side effects due to intensified IS requiring pharmacological treatment ‐ and quality of life (QOL) was found (Table 5). QOL scores were significantly lower during rejection, when compared to QOL scores in the absence of rejection (Fig. 7b). Patient satisfaction significantly correlated with an overall acceptable upper limb function expressed by a high ARAT and HTSS and a low DASH, a flexible, movable index finger and good sensitivity, as indicated by a low s‐2PD (Table 5).\n\nTable 5 Correlation of functional and psychological parameter and scores with rejection and patient satisfaction.\n\n\tRejection\tPatient satisfaction\t\nCOR\t\nP\n\tAdj. P (FDR)\tCOR\t\nP\n\tAdj. P (FDR)\t\nGrip strength\t0.107\t0.288\t0.550\t0.183\t0.114\t0.156\t\nKey pinch strength\t0.094\t0.350\t0.550\t0.126\t0.279\t0.307\t\nThumb opposition*\n\t0.390\t\n2.1 × 10−5\n\t\n2.3 × 10−4\n\t0.124\t0.244\t0.298\t\nDASH\t−0.007\t0.946\t0.952\t−0.521\t\n1.4 × 10−6\n\t\n7.7 × 10−6\n\t\nARAT\t0.158\t0.152\t0.550\t0.587\t\n2.5 × 10−8\n\t\n2.8 × 10−7\n\t\nHTSS\t0.171\t0.221\t0.550\t0.510\t\n6.6 × 10−4\n\t\n2.3 × 10−3\n\t\nTAROM thumb\t0.011\t0.910\t0.952\t0.119\t0.308\t0.308\t\nTAROM index\t0.006\t0.952\t0.952\t0.375\t\n8.5 × 10−4\n\t\n2.3 × 10−3\n\t\ns‐2PD thumb\t−0.052\t0.610\t0.838\t−0.350\t\n2.3 × 10−3\n\t\n5.0 × 10−3\n\t\ns‐2PD middle\t−0.098\t0.339\t0.550\t−0.292\t\n0.011\n\t\n0.018\n\t\ns‐2PD little\t−0.101\t0.345\t0.550\t−0.323\t\n5.0 × 10−3\n\t\n9.1 × 10−3\n\t\nPatient satisfaction*\n\t−0.142\t0.219\t0.219\t\t\t\t\nWell‐being*\n\t−0.232\t\n0.039\n\t0.058\t\t\t\t\nQoL*\n\t−0.278\t\n0.015\n\t\n0.045\n\t\t\t\t\nAdj. P (FDR), adjusted P‐value based on the false discovery rate (FDR) according to the Benjamini–Hochberg method; COR, correlation coefficient (Spearman’s rank correlation rho or Kendall’s tau b); P, P‐value.\n\nSignificant P‐values (<0.05) are shown in bold.\n\n* For ordinal data Kendall’s tau b was used.\n\nJohn Wiley & Sons, LtdFigure 7 Functional outcome related to rejection. Functional parameters/scores (a) and psychological scores (b) in the absence and during rejection.\n\nElectrophysiological studies\nNerve conduction studies demonstrated motor reinnervation for the median and ulnar nerve in all patients. Motor action potentials steadily increased starting at year one until year five and remained stable thereafter with the exception of patient 4, where deterioration was timely related to repeated, severe rejection after year three (SDC4 a–e). Sensory reinnervation was observed later than motor reinnervation (SDC4 f–j). In general, amplitudes of compound motor and sensory action potentials remained lower when compared to healthy individuals.\n\nPsychological outcomes\nAlthough the patients had a different history of hand loss and showed diverse psychological conditions, all had one common aim: being “whole” again [23]. For evaluation of the first three patients, the standardized psychosocial evaluation and follow‐up protocol (iRT‐PSP) was not yet in place and psychosocial outcomes are descriptive. Table 6 summarizes the main psychosocial outcomes with respect to psychopathology, depression, anxiety, psychological well‐being, and QOL, gathered by recent post‐transplant follow‐up ratings.\n\nTable 6 Psychosocial outcomes of annual follow‐up screenings (iRT‐PSP protocol).\n\nPsychometric iRT‐PSP results\tPatient 1\tPatient 2\tPatient 3\tPatient 4*\n\tPatient 5\t\n\nBrief Symptom Inventory (BSI)\n*\nby Derogatis et al. [41]\t\n\t\nT‐values (cutoff score >65)\n\t\nHostility\t55A\n\t\n38BA\n\t\n38BA\n\t40A\n\t38A\n\t\nAnxiety\t38A\n\t48A\n\t\n38BA\n\t48A\n\t38A\n\t\nDepression\t41A\n\t41A\n\t41A\n\t43A\n\t41A\n\t\nParanoid ideation\t41A\n\t41A\n\t41A\n\t41A\n\t41A\n\t\nPhobic anxiety\t45A\n\t45A\n\t45A\n\t45A\n\t45A\n\t\nPsychoticism\t44A\n\t44A\n\t44A\n\t44A\n\t44A\n\t\nSomatization\t57A\n\t61A\n\t40A\n\t56A\n\t40A\n\t\nObsessive–compulsive\t43A\n\t\n35BA\n\t\n35BA\n\t\n36BA\n\t35A\n\t\nInterpersonal sensitivity\t48A\n\t40A\n\t40A\n\t41A\n\t40A\n\t\nPSDI positive symptom distress index\t48A\n\t55A\n\t\n26BA\n\t\n26BA\n\t\n26BA\n\t\nPST positive symptom total\t45A\n\t40A\n\t\n30BA\n\t40A\n\t\n20BA\n\t\nGSI global severity index\t44A\n\t44A\n\t\n31BA\n\t38A\n\t\n26BA\n\t\n\nPatient Health Questionnaire (PHQ) by Spitzer et al.\n[\n\n42]\n\n\t\n\t\nDepression & anxiety index\n\t\nPHQ‐9 depression scale\tNone‐minimal\tNone‐minimal\tNone‐minimal\tNone‐minimal\tNone‐minimal\t\nGAD‐7 anxiety scale\tNone‐minimal\tNone‐minimal\tNone‐minimal\tNone‐minimal\tNone‐minimal\t\n\nScales of psychological well‐being (PWB) by Ryff and Keyes [43]\t\n\t\nPsychological well‐being\n\t\nPWB total score\t89\t96\t90\t81\t79\t\n\nSF‐36 health survey by Ware et al. [44]\t\n\t\nT‐values (cutoff score >65)\n\t\nPhysical functioning\t40A\n\t50A\n\t53A\n\t58A\n\t\n33BA\n\t\nRole‐physical\t58A\n\t56A\n\t56A\n\t58A\n\t52A\n\t\nBodily pain\t51A\n\t55A\n\t45A\n\t51A\n\t55A\n\t\nGeneral health\t52A\n\t49A\n\t45A\n\t43A\n\t53A\n\t\nVitality\t49A\n\t\n66AA\n\t51A\n\t59A\n\t48A\n\t\nSocial functioning\t42A\n\t57A\n\t57A\n\t45A\n\t42A\n\t\nRole‐emotional\t54A\n\t54A\n\t54A\n\t54A\n\t53A\n\t\nMental health\t46A\n\t\n65AA\n\t56A\n\t64A\n\t43A\n\t\nSelection of psychometric instruments of the iRT‐PSP evaluation and follow‐up protocol. T‐values have been calculated to compare the iRT‐PSP results of evaluated patients with norm samples.\n\nSeverity index (compared to norm samples): BAbelow average; Aaverage; AAabove average.\n\n* Psychosocial outcomes of patient 4 have been collected before chronic graft rejection and amputation.\n\nJohn Wiley & Sons, LtdAll patients successfully assimilated the transplanted hand(s) into their body‐/self‐image and were able to develop a sense of “ownership”. They reported a high degree of satisfaction and improved confidence in appearance and social situation. No psychiatric disorders have been recorded in the post‐transplant course and all patients described average levels of psychological distress. Specifically, no severe depression and/or anxiety have been evaluated post‐transplantation. Patients unanimously observed improvements in QOL, psychological well‐being, and ADLs, as stated above. Multiple rejections and difficulties with rehabilitation caused psychological distress in the unilateral hand transplanted patient.\n\nDiscussion\nGood to excellent functional results with a high degree of patient satisfaction can be achieved after hand/ forearm transplantation, however, immunologic complications including acute and chronic rejection, and side effects burdened the postoperative courses to various degrees in our cohort and remain the main challenges. Adverse effects were manageable with specific therapy or interventions, except for the gastric cancer where the disease was advanced when diagnosed and progressed rapidly despite therapy. Even if the number of acute rejections decreased after the early postoperative phase in our patients, events do occur years after hand/forearm transplantation. In comparison to the first decade of our experience, an increased number of rejections concomitant to presence of DSA were observed early and late post‐transplantation. While patients 1 and 5 with uneventful follow‐ups were never positive for DSA, patients with more complicated immunologic courses developed DSA between 1.5 and 9 years. The relevance of DSA in the context of VCA remains poorly understood. In solid organ transplantation, DSA have been shown to exhibit a detrimental impact on risk of rejection and graft survival [32, 33. When the first VCA cases were performed 20 years ago, methods for DSA assessment were not as advanced and routine clinical use was not established in most centers. Our unilateral hand transplant recipient experienced multiple ABMR with high levels of DSA over a period of 4 years [5], resulting in chronic rejection and graft loss. In reference, the French group reported development of de‐novo DSA and several rejection episodes, resulting in partial graft loss of the first face allograft [7]. Based on our observations and the reports by others [34], we speculate that DSA and repetitive ABMR may result – or be the result of – a complicated immunologic course and indicative for the risk of developing vasculopathy and chronic rejection in VCA. Such patients should be evaluated at close intervals with particular attention to DSA levels and vascular changes [35]. We hypothesize, that fluctuations of trough levels of IS may have contributed to the challenging immunologic courses in our patients 2 and 4 and facilitated the repeat/chronic activation of the immune response with development of DSA. Patient nonadherence is often difficult to prove but correlates well with DSA development and graft loss in solid organ and VCA [9, 28, 36, 37, 38. Minimizing the overall level of IS to the level required to prevent rejection remains an important factor in VCA patients. However, according to our experience a slow and cautious adoption of IS over years may help to avoid development of DSA, ABMR, and possibly graft loss. Our observations are based on a relatively small number of patients, but these findings together with a systematic evaluation of the phenomenon of DSA and ABMR in VCA [34] supports the relevance for the immunologic course on graft survival.\n\nCurrently, diagnosis of rejection is based on histopathologic examination of a skin biopsy [20] using a 5‐graded classification system introduced in 2007 [21]. Severity of ABMR in our patients was difficult to classify per the existing Banff criteria since criteria for ABMR have not been formally publicized. In our cohort, cases classified as ABMR histopathologically showed a considerable number of B‐cells, which were most often organized in aggregates. The bulk of the infiltrate was located perivascular in the deep dermis, while the superficial dermis was often spared and the epidermis hardly ever involved. In some, but not all ABMR endothelial C4d and peripheral node addressin (PNAd)‐staining were detected. Vascular alterations have been observed in severe cases. As the number of reports on this specific type of rejection in VCA have increased over the past years [5, 7, 12, 39, an update of the existing Banff classification is urgently warranted. Our findings further fuel the need to perform deep skin tissue biopsies since the manifestations of rejection are most prominent in the deeper dermis during ABMR.\n\nOverall, the phenotype of the infiltrate during rejection significantly changed over the observation time‐period of 19 years. This phenomenon may be explained in part by differences in rejection severity. While six grade III rejections were observed early (until year 3), only one grade III and one grade IV rejection were recoded between years 4–10. The highest number of ABMRs was seen between years 4–10, which correlates with a significant increase in CD20+ B‐cells. Contrary to previous observations by our group [40], the amount of Foxp3+ cells during rejection was not increased at later time‐points. The increase in endothelial C4d expression during rejections between years 4–10 correlates with the high number of ABMR during this time‐period. However, a further significant increase of C4d‐staining during rejections after year 10 does not correlate with a higher number of ABMR, suggesting that this marker might not be specifically indicative for ABMR in VCA.\n\nTwo patients have developed macroscopic features suggestive for a mild stage of chronic rejection over the past years, including lichenoid skin changes, dyschromia, nail changes, and finger thinning, accompanied by recurrent pain. Both patients had also experienced ABMR and/or developed anti‐HLA antibodies, and showed a rather complicated immunologic follow‐up. While histopathologic skin or vascular changes as per ultrasound/computed tomography hinting on chronic rejection were not evident, a mild stage of chronic rejection cannot be ruled out and both patients are under close surveillance.\n\nInterestingly, regain of intrinsic musculature took longest in the very recent case with a transplantation level at the metacarpal level at the right side. This was surprising as this hand allograft revealed the lowest reinnervation distance of all. The exceptional long ischemia time (Table 1) may in part be accountable for this. While in general hand function remained relatively stable with intermittent fluctuations after year 5, a slow but remarkable trend toward deterioration of hand function, especially of the intrinsic musculature, was observed late after transplantation. However, it should be taken into account that a mild decrease of hand function may also be attributable to the advanced age of patient 1. Acute rejection did not show an immediate negative impact on hand function; however, a long‐term effect cannot be out ruled at this point. In the unilateral hand transplant recipient, a slight, but continuous decrease of all functional parameters was recorded three years before graft amputation, suggesting that repetitive rejections over years may negatively affect the functional outcome. Rather than a decrease of hand function, concurrent rejection negatively influenced patients´ well‐being and QOL, which may be explained by intensified IS, hospitalization and concern by then. Moreover, our data indicate that besides restoration of functionality regain of sensitivity probably is the most significant factor for patient satisfaction and happiness after hand transplantation.\n\nIndication and patient selection remain challenging due to the inherited health risks of the procedure. Successful outcome appears to be highly dependent on the motivation and reasonable expectations of the patients. Hence, patient selection and informed consent remain critical and have become the center of attention. We felt that the iRT‐PSP [23] helps with this process since it ensures a structured approach tailored to the specific criteria relevant in patients who suffer from limb loss and consider transplantation. Another important immediate goal in the field is the definition of endpoints for the assessment of the outcome. In solid organ transplantation, an established and robust primary endpoint is graft survival. In hand transplantation, however, graft survival alone may not be considered as a veritable primary endpoint since “survival” of a graft does not necessarily imply good function. Ultimately, hand transplantation is performed with the intention to improve a patients’ QOL. This would imply QOL‐measures as endpoints. The assessment of QOL, however, remains inconsistent and depending on the status prior to the intervention. The International Hand and Composite Tissue Allotransplantation Society (IRHCTA) score established in 2005 [2] was a commendable first step. While this tool considers the situation of hand amputation as a starting point and addresses not only functional but also psychological and patients’ subjective parameters on satisfaction, the design may make it relatively easy to provide very high scores and come short in effectively identifying less satisfactory outcomes. Value and significance, may vary within individuals, making it more difficult to objectively evaluate the outcome in a standardized fashion and define a certain level of success. An interdisciplinary consensus is warranted as the field is advancing.\n\nIn conclusion, complicated immunologic courses after hand transplantation may favor development of DSA and ABMR and eventually result in chronic rejection and graft loss. Aiming for a most stable immunologic situation with optimized and individually carefully adopted IS may be the key to prevent rejection, deterioration of graft function, and graft loss, and thereby guarantee good compliance and patient satisfaction.\n\nAuthorship\nTH: participated in performance of the study, data analysis, writing of the paper. FM: participated in performance of the study, writing of the paper. AW: participated in performance of the study. HH: participated in data analysis. MN: participated in study design, performance of the study, data analysis. VB: participated in performance of the study. JK: participated in performance of the study, data analysis, writing of the paper. BGZ: participated in data analysis. BZ: participated in data analysis. DW: participated in performance of the study. GP: participated in study design, performance of the study. WNL: participated in performance of the study, data analysis. RZ: participated in performance of the study. MG: participated in study design, performance of the study. RA: participated in performance of the study. GB: participated in study design, performance of the study. RM: participated in study design, performance of the study. DÖ: participated in study design, performance of the study. SS: participated in study design, performance of the study, writing of the paper.\n\nFunding\nThe authors have nothing to disclose.\n\nConflicts of interest\nThe authors have declared no conflicts of interest.\n\nSupporting information\n\nFigure S1. Aesthetic outcome after bilateral hand (patients 1, 3 and 5) and forearm (patient 2) transplantation at the most recent follow‐up.\n\n\nFigure S2. Computed tomography‐angiography with 3D‐reconstruction of graft vessels (a–d, pronation; h, supination) and conventional angiography (e–g) of patients 1, 2, 3 and 5 at the most recent follow‐up.\n\n\nFigure S3. Results of total active range of motion (TAROM, a–e) and static 2‐point discrimination (s‐2PD, f–j) recorded at the annual follow‐up are shown for patients 1–5 individually (blue arrow: T‐cell‐mediated rejection; red arrow: antibody‐mediated rejection; green arrow: B‐cell‐mediated rejection).\n\n\nFigure S4. Evolution of amplitudes of compound motor action potentials (CMAP, right column, a–e) and compound sensory action potentials (CSAP, left column, f–j) recorded from m. abductor pollicis brevis (APB, median nerve) and m. abductor digiti minimi (ADM, ulnar nerve) for the right (r) and left (l) hand allograft of patients 1–5. x‐axis: years post‐transplant.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nDubernard \nJM \n, \nOwen \nE \n, \nHerzberg \nG \n, et al\nHuman hand allograft: report on first 6 months\n. 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"fulltext_license": "CC BY-NC",
"issn_linking": "0934-0874",
"issue": "33(12)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "complications; donor-specific antibodies; hand and forearm transplantation; immunosuppression; rejection; vascularized composite allotransplantation",
"medline_ta": "Transpl Int",
"mesh_terms": "D005542:Forearm; D006084:Graft Rejection; D063987:Hand Transplantation; D006801:Humans; D011788:Quality of Life; D012189:Retrospective Studies",
"nlm_unique_id": "8908516",
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"pages": "1762-1778",
"pmc": null,
"pmid": "32970891",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term outcome after hand and forearm transplantation - a retrospective study.",
"title_normalized": "long term outcome after hand and forearm transplantation a retrospective study"
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{
"abstract": "A 50-year-old male visited the outpatient clinic and complained of fever, poor oral intake, and weight loss. A chest X-ray demonstrated streaky and fibrotic lesions in both lungs, and chest CT revealed multifocal peribronchial patchy ground-glass opacities with septated cystic lesions in both lungs. Cell counts in the bronchoalveolar lavage fluid revealed lymphocyte-dominant leukocytosis, and further analysis of lymphocyte subsets showed a predominance of cytotoxic T cells and few T helper cells. Video-assisted wedge resection of the left upper lobe was performed, and the histologic examination was indicative of a Pneumocystis jirovecii infection. Trimethoprim-sulfamethoxazole (TMP-SMX) was orally administered for 3 weeks; however, the patient complained of cough, and the pneumonia was aggravated in the follow-up chest X-ray and chest CT. Molecular studies demonstrated mutations at codons 55 and 57 of the dihydropteroate synthase (DHPS) gene, which is associated with the resistance to TMP-SMX. Clindamycin-primaquine was subsequently administered for 3 weeks replacing the TMP-SMX. A follow-up chest X-ray showed that the pneumonia was resolving, and the cough was also alleviated. A positive result of HIV immunoassay and elevated titer of HCV RNA indicated HIV infection as an underlying condition. This case highlights the importance of careful monitoring of patients with P. jirovecii pneumonia (PCP) during the course of treatment, and the molecular study of DHPS mutations. Additionally, altering the anti-PCP drug utilized as treatment must be considered when infection with drug-resistant P. jirovecii is suspected. To the best of our knowledge, this is the first case of TMP-SMX-resistant PCP described in Korea.",
"affiliations": "Division of Pulmonology and Allergy, Gachon University Gil Medical Center, Incheon 405-760, Korea.;Division of Infection, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 405-760, Korea.;Department of Radiology, Gachon University Gil Medical Center, Incheon 405-760, Korea.;Departement of Pathology, Gachon University Gil Medical Center, Incheon 405-760, Korea.;Division of Pulmonology and Allergy, Gachon University Gil Medical Center, Incheon 405-760, Korea.;Division of Pulmonology and Allergy, Gachon University Gil Medical Center, Incheon 405-760, Korea.;Division of Pulmonology and Allergy, Gachon University Gil Medical Center, Incheon 405-760, Korea.",
"authors": "Lee|Sang Min|SM|;Cho|Yong Kyun|YK|;Sung|Yon Mi|YM|;Chung|Dong Hae|DH|;Jeong|Sung Hwan|SH|;Park|Jeong-Woong|JW|;Lee|Sang Pyo|SP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014295:Trimethoprim; D013420:Sulfamethoxazole",
"country": "Korea (South)",
"delete": false,
"doi": "10.3347/kjp.2015.53.3.321",
"fulltext": "\n==== Front\nKorean J ParasitolKorean J. ParasitolKJPThe Korean Journal of Parasitology0023-40011738-0006The Korean Society for Parasitology and Tropical Medicine 2617482610.3347/kjp.2015.53.3.321kjp-53-3-321Case ReportA Case of Pneumonia Caused by Pneumocystis jirovecii Resistant to Trimethoprim-Sulfamethoxazole Lee Sang Min 1Cho Yong Kyun 2Sung Yon Mi 3Chung Dong Hae 4Jeong Sung Hwan 1Park Jeong-Woong 1Lee Sang Pyo 1*1 Division of Pulmonology and Allergy, Gachon University Gil Medical Center, Incheon 405-760, Korea2 Division of Infection, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon 405-760, Korea3 Department of Radiology, Gachon University Gil Medical Center, Incheon 405-760, Korea4 Departement of Pathology, Gachon University Gil Medical Center, Incheon 405-760, Korea* Corresponding author (allergy21@hotmail.com)6 2015 30 6 2015 53 3 321 327 20 11 2014 1 6 2015 2 6 2015 © 2015, Korean Society for Parasitology and Tropical Medicine2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.A 50-year-old male visited the outpatient clinic and complained of fever, poor oral intake, and weight loss. A chest X-ray demonstrated streaky and fibrotic lesions in both lungs, and chest CT revealed multifocal peribronchial patchy ground-glass opacities with septated cystic lesions in both lungs. Cell counts in the bronchoalveolar lavage fluid revealed lymphocyte-dominant leukocytosis, and further analysis of lymphocyte subsets showed a predominance of cytotoxic T cells and few T helper cells. Video-assisted wedge resection of the left upper lobe was performed, and the histologic examination was indicative of a Pneumocystis jirovecii infection. Trimethoprim-sulfamethoxazole (TMP-SMX) was orally administered for 3 weeks; however, the patient complained of cough, and the pneumonia was aggravated in the follow-up chest X-ray and chest CT. Molecular studies demonstrated mutations at codons 55 and 57 of the dihydropteroate synthase (DHPS) gene, which is associated with the resistance to TMP-SMX. Clindamycin-primaquine was subsequently administered for 3 weeks replacing the TMP-SMX. A follow-up chest X-ray showed that the pneumonia was resolving, and the cough was also alleviated. A positive result of HIV immunoassay and elevated titer of HCV RNA indicated HIV infection as an underlying condition. This case highlights the importance of careful monitoring of patients with P. jirovecii pneumonia (PCP) during the course of treatment, and the molecular study of DHPS mutations. Additionally, altering the anti-PCP drug utilized as treatment must be considered when infection with drug-resistant P. jirovecii is suspected. To the best of our knowledge, this is the first case of TMP-SMX-resistant PCP described in Korea.\n\nPneumocystis jiroveciitrimethoprimsulfamethoxazoledrug resistanceclindamycinprimaquine\n==== Body\nINTRODUCTION\nPneumocystis jirovecii is an opportunistic pathogen, and is a major cause of serious pneumonia in immunocompromised conditions, including congenital immunodeficiency, organ transplantation, or acquired immune deficiency syndrome (AIDS) [1]. The standard regimen of treatment or prophylaxis for pneumonia caused by P. jirovecii is cotrimoxazole which contains sulfamethoxazole (SMX) and trimethoprim (TMP) [2]. However, a few studies have reported therapeutic failure of the regimens used to treat pneumonia caused by P. jirovecii [3-10], and no reports occurred in Korea. Here, we describe a case in which TMP-SMX, in sufficient dose and duration, had failed to treat pneumonia caused by P. jirovecii which was then successfully treated with clindamycin-primaquine thereafter.\n\nCASE RECORD\nA 50-year-old male visited the outpatient clinic and complained of fever, poor oral intake, and weight loss (6 kg loss in 2 months). Routine laboratory tests and a chest X-ray were performed. Complete blood counts revealed mild leucopenia (WBC 3,720/μl), mild anemia (Hb 11.2 g/dl), and mild eosinophilia (830/μl), however, a normal platelet level (246,000/μ) was observed. Liver function tests showed elevated liver enzymes (AST 61 IU/L, ALT 74 IU/L, and GGT 215 IU/L), and serologic studies for hepatitis B virus, hepatitis C virus, human immunodeficiency virus (HIV), and syphilis were negative. A routine chest X-ray yielded streaky and fibrotic lesions in both lungs (Fig. 1A), which led to further evaluation using contrast chest computed tomography (CT). The chest CT revealed multifocal peribronchial patchy ground-glass opacities in both lungs with septated cystic lesions in the left upper lobe, and the right lower lobe (Fig. 2A, B).\n\nBronchoscopy was performed, but no endobronchial lesions were observed. Bronchoalveolar lavage (BAL) was performed in the right middle lobe. Cell counts in BAL revealed a lymphocyte-dominant leukocytosis (white cells 342/μl, neutrophils 9%, lymphocytes 37%, eosinophils 5%, and macrophages 49%). Further analysis of lymphocyte subsets showed a predominance of cytotoxic T cells (cytotoxic T cells 98.3%, T helper cells 1.7%, natural killer cells 3%, and B cells 0.1%). Cytologic studies, acid-fast bacillus stain, and PCR for tuberculosis and non-tuberculotic mycobacteria in the BAL fluid exhibited negative results. A tuberculin skin test and interferon-γ release assay (Quantiferon®; Carnegie, Victoria, Australia) were also negative. A video-assisted wedge resection of the left upper lobe was performed. Upon histological examination, hematoxylin and eosin (H&E) staining revealed eosinophilic frothy exudates in alveolar spaces accompanied by mild interstitial inflammation, and Grocott-Gomori’s methenamine silver (GMS) stains, performed during the histological examination, revealed many cystic- and trophic-form organisms (arrows) in the alveolar exudate, consistent with P. jirovecii infection (Fig. 3). Trimethoprim-sulfamethoxazole (TMP-SMX) was administered orally (2 double strength TMP-SMX tablets every 8 hr) [11]. The patient’s fever subsided within 3 days (from 38.5˚C to 37.0˚C), and the streaky and fibrotic lesions observed in both lungs on the chest X-ray were also markedly improved (Fig. 1B) after 12 days of TMP-SMX administration, which enabled the patient to be discharged.\n\nTMP-SMX treatment continued to be administrated for additional 17 days following the patient’s discharge from the hospital. However, the patient complained of cough again, and a follow-up chest X-ray showed aggravation of the streaky and fibrotic lesions in both lungs (Fig. 1C). The patient was readmitted to the hospital, and chest CT was rechecked. A follow-up chest CT revealed an aggravation of multifocal peribronchial ground-glass opacity and septated cystic lesions in both upper lungs, and a newly appeared consolidation in the left lower lobe (Fig. 2C, D). P. jirovecii was clinically suspected to be resistant to TMP-SMX, and molecular studies carried out using PCR with primers Dp15 (5´-TCTGAATTTTATAAAGCGCCTACAC-3´) and Dp800 (5´-ATTTCATAAACATCATGAACCCG-3´) demonstrated mutations at codons 55 and 57 of the dihydropteroate synthase (DHPS) gene as a previous report [12].\n\nPrimaquine (4 mg/kg/day intravenous once daily) and clindamycin (600 mg intravenous every 8 hr) were administrated for 3 weeks in place of the TMP-SMX. Consequently, the cough was resolved, and a follow-up chest X-ray showed improvement of the streaky and fibrotic lesions in both lungs (Fig. 1D). We strongly suspected that HIV infection was an underlying condition, and rechecked the HIV immunoassay, which was determined to be positive. Further evaluation of HIV infection was performed; the titer of HCV RNA was determined to be 110,000 copies/ml, and the number of T helper cells in the peripheral blood was only 3/μl. Antiviral treatment regimen targeting the HIV was initiated, including lopinavir (800 mg/day), ritonavir (200 mg/day), lamivudine (300 mg/day), and zidovudine (600 mg/day), and the patient was discharged.\n\nDICUSSION\nP. jirovecii pneumonia (PCP) should be strongly suspected in HIV-infected patients that have a CD4+ T cell count less than 200 cells/µl, 1-3-β-d-glucan levels greater than 80 pg/ml (if available), and signs and symptoms that are typical of the infection; especially dyspnea, cough, and diffuse, bilateral, interstitial, or alveolar infiltrates present on a chest X-ray or chest CT [13]. A confirmatory diagnosis of PCP requires the identification of cystic or trophic forms in appropriate specimens, both of which can be visualized using GMS, cresyl violet, Gram-Weigert, toluidine blue, Wright-Giemsa, and Diff-Quick staining. Pathologic confirmation is especially important when other infections or co-infections are suspected or need to be excluded [14-16].\n\nCotrimoxazole, namely TMP-SMX, is the most common drug used for prophylaxis and treatment of PCP, and has been utilized as an effective treatment option for many years [5]. In addition to TMP-SMX, TMP-dapsone or clindamycin-primaquine can be used as an alternative regimen. In patients that do not exhibit any improvement after 4 to 8 days of therapy, treatment failure must be considered. Randomized trials have demonstrated that these treatments exhibited a comparable effectiveness in treating PCP. A previously published multicenter study randomly assigned 181 patients with mild to moderate PCP to therapy with TMP-SMX, TMP-dapsone, or clindamycinprimaquine for 21 days [11], and no differences were observed in the therapeutic failure rate (approximately 5% at day 7, and 10% at day 21) among the treatment groups. Another randomized trial comparing TMP-SMX with TMP-dapsone in 60 PCP patients demonstrated no differences in the response to therapy; however, more TMP-SMX treated patients exhibited adverse reactions to the therapy [4].\n\nThe current case was not initially diagnosed as having HIV infection as an underlying condition. The patient complained of fever, poor oral intake, and weight loss, and multifocal, peribronchial patchy ground-glass opacities in both lungs with septated cystic lesions were observed in chest CT. Bronchoscopy performed with BAL did not yield a confirmative diagnosis, so we could not but carry out a video-assisted wedge resection of the left upper lobe. In histological examinations, GMS staining of the specimen showed many cystic and trophic forms, which finally led to the diagnosis of PCP. We retrospectively suspected the presence of HIV infection as an underlying condition, and reassessed the HIV immunoassay, which turned out to be positive, and the HIV RNA titer was determined to be 110,000 copies/ml. The initial negative and subsequent positive HIV immunoassay and a positive virologic test, led us to suspect that the patient was in the initial stages of HIV infection, since the approximate time from infection to a positive immunoassay and viral load test is 15 to 45 days and 5 to 15 days, respectively [17-19].\n\nTo treat the PCP, high-dose TMP-SMX was orally administered, and the patient’s symptoms and radiologic findings were markedly improved within several days. However, PCP was aggravated 1 month later despite continuing the medication. The PCP was suspected to be resistant to TMP-SMX, and molecular studies confirmed mutations at codons 55 and 57 of the DHPS gene that are known to be associated with sulfaresistance of P. jirovecii [20].\n\nIntravenous TMP-SMX, or pentamidine, is primarily recommended when oral TMP-SMX treatment failure is suspected, as demonstrated in a previous case report [6]. However, these 2 drugs were unavailable in our hospital, so primaquine and clindamycin were substituted for TMP-SMX, which resulted in an improvement of PCP.\n\nCotrimoxazole consists of TMP and SMX, and TMP seems to be inactive against pneumocystis [6]. Consequently, cotrimoxazole acts as sulfa monotherapy [5]. A common second-line agent is dapsone, which, like sulfamethoxazole, inhibits the enzyme DHPS [5,21]. These 2 DHPS inhibitors have been used as a prophylaxis or treatment for PCP in hundreds of thousands of patients over the past 2 decades, and the development of sulfa-resistant strains of P. jirovecii was inevitable [5]. Mutations in the P. jirovecii DHPS gene have been described in 2 case reports [6,22], and a small cohort study that contained 27 patients [23]. However, those studies did not demonstrate that the mutations caused the drug resistance, since human strains of P. jirovecii cannot be cultured in vitro [5]. Instead, Helwig-Larsen et al. [12] found an association between the occurrence of DHPS mutations and the failure of PCP treatment with sulfa drugs in a large study. More importantly, DHPS mutations were linked to a higher risk of death within 3 months of the diagnosis, most likely due to inadequate responses to therapy. In a Japanese study, DHPS mutations were identified at amino acid positions 55 and/or 57 in isolates from 6 (25.0%) of 24 patients with P. jirovecii pneumonia, and cotrimoxazole treatment failed more frequently in patients whose isolates had DHPS mutations than in those whose isolates had wild-type DHPS [24]. Zingale et al. [7] suggested that theses DHPS mutations were significantly more common in patients exposed to sulfa drugs than in those not exposed to sulfa drugs in their study of 70 bronchoalveolar lavage (BAL) specimens with positive PCR for P. jirovecii. These phenomena were also confirmed in a study by Nahimana et al. [8] who conducted BAL in 13 AIDS patients who had 2 separate episodes of pneumonia [8]. While P. jirovecii cannot be cultivated, subsequent in vitro studies used Saccharomyces cerevisiae and Escherichia coli to further elucidate the association between DHPS polymorphisms and sulfa resistance, and suggested that mutations in DHPS correlate with sulfa drug resistance [9,10,25-27]. In the current case report, mutations at codons 55 and 57 of the DHPS gene were identified. In addition to DHPS, a recent study demonstrated the association of dihydrofolate reductase (DHFR) variants and resistance to trimethoprim in clinical isolates of P. jirovecii [28].\n\nIn summary, TMP-SMX was orally administered with a sufficient dose and duration in our patient. However, treatment failure was eventually detected in a follow-up chest X-ray and chest CT, and molecular analysis suggested mutations at codons 55 and 57 of the DHPS gene, which has been shown to confer sulfa resistance to P. jirovecii. Primaquine and clindamycin were substituted for TMP-SMX, which finally improved the PCP. The current case report indicates that PCP patients must be carefully monitored during treatment, and molecular analysis of DHPS mutations should be performed. Additionally, appropriate changes of anti-PCP drugs should be considered when a drugresistant P. jirovecii infection is suspected. To our knowledge, this is the first case of TMP-SMX-resistant PCP reported in Korea.\n\nThe authors of this article have no financial or other issues that might lead to a conflict of interest.\n\nFig. 1. Initial chest X-ray and follow-up chest X-rays after the initiation of treatment for Pneumocystis jirovecii pneumonia (PCP). (A) Initial chest X-ray showed streaky and fibrotic lesions in both lungs. (B) In the follow-up chest X-ray performed 12 days after the initiation of TMP-SMX treatment, the lesions were markedly improved. (C) In a follow-up chest X-ray carried out 29 days after the initiation of TMP-SMX treatment, streaky and fibrotic lesions in both lungs were aggravated. (D) In the follow-up chest X-rays, performed 21 days after changing the anti-PCP therapy from TMP-SMX to primaquine-clindamycin, the lesions were improved again.\n\nFig. 2. Initial chest CT revealed multifocal, peribronchial patchy ground-glass opacities in both lungs with septated cystic lesions (arrow) in the left upper lobe (A), and the right lower lobe (B). A follow-up chest CT revealed the aggravation of multifocal, peribronchial ground-glass opacity, and septated cystic lesions (arrows) in both upper lungs (C), and the newly appeared consolidation (arrow) in the left lower lobe (D).\n\nFig. 3. Photomicrography of Pneumocystis jirovecii pneumonia. (A) Hematoxylin and eosin staining shows eosinophilic frothy exudates in alveolar spaces accompanied by mild interstitial inflammation (H&E, ×200). (B) Grocott-Gomori’s methenamine silver (GMS) stain visualized many cystic- and trophic-form organisms (arrows) in alveolar exudate, consistent with Pneumocystis jirovecii infection (GMS, ×400).\n==== Refs\nREFERENCES\n1 Sepkowitz KA Opportunistic infections in patients with and patients without acquired immunodeficiency syndrome Clin Infect Dis 2002 34 1098 1107 11914999 \n2 Benson CA Kaplan JE Masur H Pau A Holmes KK Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America MMWR Recomm Rep 2004 53 1 112 15841069 \n3 Patterson JH Lindsey IL Edwards ES Logan WD Jr Pneumocystis carinii pneumonia and altered host resistance: treatment of one patient with pentamidine isethionate Pediatrics 1966 38 388 397 4162452 \n4 Medina I Mills J Leoung G Hopewell PC Lee B Modin G Benowitz N Wofsy CB Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone N Engl J Med 1990 323 776 782 2392131 \n5 Meshnick SR Drug-resistant Pneumocystis carinii Lancet 1999 354 1318 1319 10533856 \n6 Mei Q Gurunathan S Masur H Kovacs JA Failure of co-trimoxazole in Pneumocystis carinii infection and mutations in dihydropteroate synthase gene Lancet 1998 351 1631 1632 9620722 \n7 Zingale A Carrera P Lazzarin A Scarpellini P Detection of Pneumocystis carinii and characterization of mutations associated with sulfa resistance in bronchoalveolar lavage samples from human immunodeficiency virus-infected subjects J Clin Microbiol 2003 41 2709 2712 12791912 \n8 Nahimana A Rabodonirina M Helweg-Larsen J Meneau I Francioli P Bille J Hauser PM Sulfa resistance and dihydropteroate synthase mutants in recurrent Pneumocystis carinii pneumonia Emerg Infect Dis 2003 9 864 867 12890330 \n9 Meneau I Sanglard D Bille J Hauser PM Pneumocystis jirovecii dihydropteroate synthase polymorphisms confer resistance to sulfadoxine and sulfanilamide in Saccharomyces cerevisiae Antimicrob Agents Chemother 2004 48 2610 2616 15215117 \n10 Iliades P Meshnick SR Macreadie IG Dihydropteroate synthase mutations in Pneumocystis jirovecii can affect sulfamethoxazole resistance in a Saccharomyces cerevisiae model Antimicrob Agents Chemother 2004 48 2617 2623 15215118 \n11 Safrin S Finkelstein DM Feinberg J Frame P Simpson G Wu A Cheung T Soeiro R Hojczyk P Black JR Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine Ann Intern Med 1996 124 792 802 8610948 \n12 Helweg-Larsen J Benfield TL Eugen-Olsen J Lundgren JD Lundgren B Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P. carinii pneumonia Lancet 1999 354 1347 1351 10533864 \n13 Tasaka S Tokuda H Recent advances in the diagnosis of Pneumocystis jirovecii pneumonia in HIV-infected adults Expert Opin Med Diagn 2013 7 85 97 23530845 \n14 Kim HW Kim MG Woo YS Boo CS Jo SK Kim HK Jo WY Lee KG Kim HO Oh CR Kim JH A case of Pneumocystis jirovecii pneumonia following CMV duodenitis in a kidney transplant patient Korean J Nephrol 2008 27 631 637 \n15 Jung JY Rhee KH Koo DH Park IN Shim TS Pneumocystis jirovecii pneumonia mimicking miliary tuberculosis in a kidney transplanted patient Tubercul Respir Dis 2009 67 127 130 \n16 Kim TY Nam WJ Kim SM Shin JH Lee KE Kim SH Oh DJ Yu SH Pneumonia caused by fungus, Pneumocystis jirovecii and cytomegalovirus coinfection in patient with renal transplantation: a case report J Korean Soc Transplant 2009 23 161 165 \n17 Branson BM Stekler JD Detection of acute HIV infection: we can't close the window J Infect Dis 2012 205 521 524 22207652 \n18 Owen SM Testing for acute HIV infection: implications for treatment as prevention Curr Opin HIV AIDS 2012 7 125 130 22314506 \n19 Cohen MS Gay CL Busch MP Hecht FM The detection of acute HIV infection J Infect Dis 2010 202 suppl 2 S270 S277 20846033 \n20 Tyagi AK Mirdha BR Guleria R Mohan A Luthra K Singh UB Study of dihydropteroate synthase (DHPS) gene mutations among isolates of Pneumocystis jirovecii Indian J Med Res 2008 128 734 739 19246797 \n21 Castro M Treatment and prophylaxis of Pneumocystis carinii pneumonia Semin Respir Infect 1998 13 296 303 9872626 \n22 Lane BR Ast JC Hossler PA Mindell DP Bartlett MS Smith JW Meshnick SR Dihydropteroate synthase polymorphisms in Pneumocystis carinii J Infect Dis 1997 175 482 485 9203679 \n23 Kazanjian P Locke AB Hossler PA Lane BR Bartlett MS Smith JW Cannon M Meshnick SR Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients AIDS 1998 12 873 878 9631140 \n24 Takahashi T Hosoya N Endo T Nakamura T Sakashita H Kimura K Ohnishi K Nakamura Y Iwamoto A Relationship between mutations in dihydropteroate synthase of Pneumocystis carinii f. sp. hominis isolates in Japan and resistance to sulfonamide therapy J Clin Microbiol 2000 38 3161 3164 10970350 \n25 Iliades P Meshnick SR Macreadie IG Mutations in the Pneumocystis jirovecii DHPS gene confer cross-resistance to sulfa drugs Antimicrob Agents Chemother 2005 49 741 748 15673759 \n26 Iliades P Meshnick SR Macreadie IG Analysis of Pneumocystis jirovecii DHPS alleles implicated in sulfamethoxazole resistance using an Escherichia coli model system Microb Drug Resist 2005 11 1 8 15770087 \n27 Moukhlis R Boyer J Lacube P Bolognini J Roux P Hennequin C Linking Pneumocystis jirovecii sulfamethoxazole resistance to the alleles of the DHPS gene using functional complementation in Saccharomyces cerevisiae Clin Microbiol Infect 2010 16 501 507 19673964 \n28 Queener SF Cody V Pace J Torkelson P Gangjee A Trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of Pneumocystis jirovecii Antimicrob Agents Chemother 2013 57 4990 4998 23896474\n\n",
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"keywords": "Pneumocystis jirovecii; clindamycin; drug resistance; primaquine; sulfamethoxazole; trimethoprim",
"medline_ta": "Korean J Parasitol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D024881:Drug Resistance, Bacterial; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011014:Pneumonia; D011859:Radiography; D013420:Sulfamethoxazole; D014295:Trimethoprim",
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"title": "A Case of Pneumonia Caused by Pneumocystis jirovecii Resistant to Trimethoprim-Sulfamethoxazole.",
"title_normalized": "a case of pneumonia caused by pneumocystis jirovecii resistant to trimethoprim sulfamethoxazole"
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"abstract": "BACKGROUND\nElderly patients with acute leukemia have high mutation frequency and are often accompanied by various underlying diseases, so treatment is difficult and mortality is high.\n\n\nMETHODS\nWe report an elderly acute myeloid leukemia patient with a complex karyotype who received a reduced dose of decitabine in induction chemotherapy due to a combination of severe heart disease.\n\n\nRESULTS\nAfter a course of induction chemotherapy, the patient achieved complete cytogenetic remission. Cardiac function did not deteriorate during or after chemotherapy.\n\n\nCONCLUSIONS\nDose-reduced decitabine alone can be effective and safe in the induction chemotherapy for elderly AML patients with complex karyotype.",
"affiliations": null,
"authors": "Sun|Yingying|Y|;Wu|Chengcheng|C|;Liu|Chunyan|C|;Shao|Zonghong|Z|",
"chemical_list": "D003561:Cytarabine; D000077209:Decitabine; D001374:Azacitidine",
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"title": "Dose-Reduced Decitabine Might Bring Benefits for Elderly AML Patients with Complex Karyotype: a Case Report.",
"title_normalized": "dose reduced decitabine might bring benefits for elderly aml patients with complex karyotype a case report"
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{
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{
"abstract": "This case series discusses 3 patients with long-standing eczematous or psoriasiform dermatitis, demonstrated by multiple biopsies. Following off-label treatment with dupilumab, all 3 patients had clinical expansion of disease, with histopathologic features consistent with cutaneous T-cell lymphoma (CTCL) on subsequent biopsy. We postulate that this expansion likely was secondary to an exacerbation of extant CTCL following exposure to dupilumab. A proposed mechanism of promotion of CTCL is based on the functional increase in IL-13 available for binding at the upregulated IL-13 receptor (IL-13R) α2 site on cells, following blockade of the α1 receptor with dupilumab. This progression merits further investigation.",
"affiliations": "Department of Dermatology, Penn State Milton S. Hershey Medical Center, USA.;Department of Dermatology, Penn State Milton S. Hershey Medical Center, USA.;Keystone Dermatology and Center for Skin Surgery, Altoona, Pennsylvania, USA.;Department of Dermatology, University of North Carolina, Chapel Hill, USA.",
"authors": "Hollins|L Claire|LC|;Wirth|Paul|P|;Fulchiero|Gregory J|GJ|;Foulke|Galen T|GT|",
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"country": "United States",
"delete": false,
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"title": "Long-standing dermatitis treated with dupilumab with subsequent progression to cutaneous T-cell lymphoma.",
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{
"abstract": "BACKGROUND\nModern pharmacological reperfusion in ST segment elevation acute myocardial infarction means the application of fibrin specific thrombolytics combined with modern antiplatelets therapy--dual antiplateles therapy, acetylsalicylic acid and clopidogrel, and enoxaparin. The contribution of each agent has been widely examined in large clinical studies, but not sufficiently has been known about the effects of a combined approach, where the early angiography and percutaneous coronary intervention is added during hospitalization, if necessary.\n\n\nOBJECTIVE\nThe aim of the paper is to compare the effects of streptokinase and alteplase, together with the standard modern adjuvant antiplatelets and anticoagulation therapy (aspirin, clopidogrel, enoxaparin) in patients with ST segment elevation acute myocardial infarction, on electrocardiographic and angiographic signs of the achieved myocardial reperfusion.\n\n\nMETHODS\nThe prospective study included 127 patients with the first ST segment elevation acute myocardial infarction who were treated with a fibrinolytic agent in the first 6 hours from the chest pain onset. The examined group included 40 patients on the alteplase reperfusion therapy, while the control 87 patients were on the streptokinase therapy. All the patients received the same adjuvant therapy and all were examined by coronary angiography on the 3rd to 10th day of hospitalization. Reperfusion effects were estimated on the basis of the following: ST segment resolution at 60, 90 and 120 minutes, the appearance of reperfusion arrhythmias at the electrocardiogram, percentage of residual stenosis at the \"culprit\" artery, TIMI coronary flow at the \"culprit\" artery and the appearance of new major adverse coronary events in the 6-month-follow-up period.\n\n\nRESULTS\nBy analysing the resolution of the sum of ST segment elevation in infarction leading 60 minutes after the beginning of the medication application, we received a statistically significantly higher resolution of ST segment in the group of patients who received alteplase (p < 0.05). 60 minutes after the application of thrombolytics, 64% of patients at streptokinase showed the absence of ST segment resolution (<30%), and 32% of patients at alteplase (p < 0.0001). Reperfusion arrhythmias as the sign of successful myocardial reperfusion were present in 62.5% of patients at alteplase and in 57.4% of patients at streptokinase, but the difference is not statistically significant.There was no statistically significant difference in the degree of residual stenosis at the,culprit\" artery in the compared groups of patients. TIMI 3 flow was achieved in 75% of patients at alteplase and in 38% of patients at streptokinase (p < 0.0001). There was no statistically significant difference in the frequency of major adverse coronary events in the 6-month-follow-up period after acute myocardial infarction.\n\n\nCONCLUSIONS\nAlteplase with modern adjuvant therapy of ST segment elevation acute myocardial infarction shows the earlier achievement of coronary perfusion as well as better coronary flow compared to streptokinase. There is no statistically significant difference in the frequency of reperfusion arrhythmias, degree of residual stenosis at the\"culprit\"artery and the frequency of new coronary events in the 6-month-follow-up period after acute myocardial infarction.",
"affiliations": null,
"authors": "Tomasević|Miloje|M|;Kostić|Tomislav|T|;Apostolović|Svetlana|S|;Perisić|Zoran|Z|;Djordjević-Radojković|Danjela|D|;Koraćević|Goran|G|;Salinger-Martinović|Sonja|S|",
"chemical_list": "D005343:Fibrinolytic Agents; D013300:Streptokinase; D010959:Tissue Plasminogen Activator",
"country": "Serbia",
"delete": false,
"doi": "10.2298/sarh0810481t",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0370-8179",
"issue": "136(9-10)",
"journal": "Srpski arhiv za celokupno lekarstvo",
"keywords": null,
"medline_ta": "Srp Arh Celok Lek",
"mesh_terms": "D000328:Adult; D000368:Aged; D017023:Coronary Angiography; D004562:Electrocardiography; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D015425:Myocardial Reperfusion; D013300:Streptokinase; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "0027440",
"other_id": null,
"pages": "481-7",
"pmc": null,
"pmid": "19069338",
"pubdate": "2008",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparative effect of streptokinase and alteplase on electrocardiogram and angiogram signs of myocardial reperfusion in ST segment elevation acute myocardial infarction.",
"title_normalized": "comparative effect of streptokinase and alteplase on electrocardiogram and angiogram signs of myocardial reperfusion in st segment elevation acute myocardial infarction"
} | [
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{
"abstract": "This case report describes the remarkable recovery of a patient with very long-standing, medically intractable and disabling, lower-limb, complex regional pain syndrome type II following the resection, crushing, and relocation of sensory nerves.",
"affiliations": "Department of Medicine, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA Anesthesia Research Unit, McGill University, Montreal, Quebec, Canada Department of Anesthesia, University of Calgary, Alberta, Canada.",
"authors": "Watson|Peter C N|PCN|;Mackinnon|Susan E|SE|;Dostrovsky|Jonathan O|JO|;Bennett|Gary J|GJ|;Farran|Peter R|PR|;Carlson|Torie|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.pain.2014.01.025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0304-3959",
"issue": "155(6)",
"journal": "Pain",
"keywords": "Causalgia; Complex regional pain syndrome; Surgical treatment",
"medline_ta": "Pain",
"mesh_terms": "D002422:Causalgia; D005260:Female; D006801:Humans; D009409:Nerve Crush; D019635:Neurosurgical Procedures; D055815:Young Adult",
"nlm_unique_id": "7508686",
"other_id": null,
"pages": "1168-1173",
"pmc": null,
"pmid": "24502845",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nerve resection, crush and re-location relieve complex regional pain syndrome type II: a case report.",
"title_normalized": "nerve resection crush and re location relieve complex regional pain syndrome type ii a case report"
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"literaturereference": "Watson CPN, Mackinnon SE, Dostrovsky JO, Bennett GJ, Farran RP, Carlson T. Nerve resection, crush and re-location relieve complex regional pain syndrome type II: A case report. Pain. 2014;155:1186-1173",
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"reactionmeddrapt": "Immune thrombocytopenia",
"reactionmeddraversionpt": "25.0",
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},
{
"reactionmeddrapt": "Withdrawal syndrome",
"reactionmeddraversionpt": "25.0",
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},
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},
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"reactionmeddraversionpt": "25.0",
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"literaturereference": "Watson CPN, Mackinnon SE, Dostrovsky JO, Bennett GJ, Farran RP, Carlson T.. Nerve resection, crush and re-location relieve complex regional pain syndrome type II: A case report. Pain. 2014;155(6):1-6",
"literaturereference_normalized": "nerve resection crush and re location relieve complex regional pain syndrome type ii a case report",
"qualification": "1",
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},
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] |
{
"abstract": "Trastuzumab improves outcomes in patients with ERBB2-positive (formerly HER2) breast cancer but is associated with treatment-induced cardiotoxicity, most commonly manifest by an asymptomatic decline in left ventricular ejection fraction (LVEF). Little is known to date regarding the long-term effects of treatment-induced cardiotoxicity on cardiopulmonary function in patients who survive trastuzumab-treated breast cancer.\n\n\n\nTo determine whether treatment-induced cardiotoxicity recovers or is associated with long-term cardiopulmonary dysfunction in survivors of ERBB2-positive breast cancer.\n\n\n\nThis cross-sectional case-control study enrolled patients with nonmetastatic ERBB2-positive breast cancer after completion of trastuzumab-based therapy (median, 7.0 [interquartile range (IQR), 6.2-8.7] years after therapy) who met 1 of 2 criteria: (1) cardiotoxicity (TOX group) developed during trastuzumab treatment (ie, asymptomatic decrease of LVEF≥10% from baseline to <55% [n = 22]) or (2) no evidence of cardiotoxicity during trastuzumab treatment (NOTOX group [n = 20]). Patients were treated at the Memorial Sloan Kettering Cancer Center. Fifteen healthy control participants (HC group) were also enrolled for comparison purposes. All groups were frequency matched by age strata (<55, 55-64, and ≥65 years). Data were collected from September 9, 2016, to August 10, 2018, and analyzed from November 20, 2018, to August 12, 2019.\n\n\n\nSpeckle-tracking echocardiography and maximal cardiopulmonary exercise testing were performed to measure indices of left ventricular function (including LVEF and global longitudinal strain [GLS]) and peak oxygen consumption (peak VO2).\n\n\n\nA total of 57 participants (median age, 60.8 [IQR, 52.7-65.7] years) were included in the analysis. Overall, 38 of 42 patients with breast cancer (90%) were treated with anthracyclines before trastuzumab. Resting mean (SD) LVEF was significantly lower in the TOX group (56.9% [5.2%]) compared with the NOTOX (62.4% [4.0%]) and HC (65.3% [2.9%]) groups; similar results were found for GLS (TOX group, -17.8% [2.2%]; NOTOX group, -19.8% [2.2%]; HC group, -21.3% [1.8%]) (P < .001). Mean peak VO2 in the TOX group (22.9 [4.4] mL/kg/min) was 15% lower compared with the NOTOX group (27.0 [5.3] mL/kg/min; P = .03) and 25% lower compared with the HC group (30.5 [3.4] mL/ kg/min; P < .001). In patients with breast cancer, GLS was significantly associated with peak VO2 (β coefficient, -0.75; 95% CI, -1.32 to -0.18).\n\n\n\nTreatment-induced cardiotoxicity appears to be associated with long-term marked impairment of cardiopulmonary function and may contribute to increased risk of late-occurring cardiovascular disease in survivors of ERBB2-positive breast cancer.",
"affiliations": "Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Duke Cancer Institute, Durham, North Carolina.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Yu|Anthony F|AF|;Flynn|Jessica R|JR|;Moskowitz|Chaya S|CS|;Scott|Jessica M|JM|;Oeffinger|Kevin C|KC|;Dang|Chau T|CT|;Liu|Jennifer E|JE|;Jones|Lee W|LW|;Steingart|Richard M|RM|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1001/jamacardio.2019.5586",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "5(3)",
"journal": "JAMA cardiology",
"keywords": null,
"medline_ta": "JAMA Cardiol",
"mesh_terms": "D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D001943:Breast Neoplasms; D066126:Cardiotoxicity; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004452:Echocardiography; D005080:Exercise Test; D005260:Female; D006801:Humans; D008875:Middle Aged; D010101:Oxygen Consumption; D018719:Receptor, ErbB-2; D013318:Stroke Volume; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left",
"nlm_unique_id": "101676033",
"other_id": null,
"pages": "309-317",
"pmc": null,
"pmid": "31939997",
"pubdate": "2020-03-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "30819377;22300778;25257632;16376782;23871490;22987084;30543812;25172399;27881567;6744546;29894274;23158536;21991949;23562088;23764185;22112290;26942202;26417058;25113839;19476640;30384883;31433450;24837860;17962609;16977706;26116691;30632311;22614980;25552469;12524257;16030088;30826225;29072977;16400678;16818906;16908934;24390149;27329778",
"title": "Long-term Cardiopulmonary Consequences of Treatment-Induced Cardiotoxicity in Survivors of ERBB2-Positive Breast Cancer.",
"title_normalized": "long term cardiopulmonary consequences of treatment induced cardiotoxicity in survivors of erbb2 positive breast cancer"
} | [
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}
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"literaturereference": "YU AF, FLYNN JR, MOSKOWITZ CS, SCOTT JM, OEFFINGER KC, DANG CT, ET AL. LONG-TERM CARDIOPULMONARY CONSEQUENCES OF TREATMENT-INDUCED CARDIOTOXICITY IN SURVIVORS OF ERBB2-POSITIVE BREAST CANCER. JAMA-CARDIOL 2020?5(3):309-317.",
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},
{
"reactionmeddrapt": "Atrial fibrillation",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
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{
"abstract": "Pityriasis rubra pilaris (PRP) is a rare chronic inflammatory papulosquamous dermatosis affecting both adults and children. Six subtypes of PRP have been described. Recently, the management of PRP with biologic immunosuppressive agents regularly used in psoriasis has been supported by several case reports and series. Ustekinumab is an anti-IL12/23 IgG1 kappa human monoclonal antibody. It has been approved for the treatment of Crohn's disease, plaque psoriasis, psoriatic arthritis and ulcerative colitis. It has also been reported to be effective as an off-label treatment for PRP. Current data are equivocal regarding infectious disease risk with ustekinumab administration. We describe a case of meningococcal and HSV-2 infection of the central nervous system in a patient being treated with ustekinumab for PRP.\nThe administration of biologic immunosuppressive agents can result in severe life-threatening infections.Research is required on the infection potential of ustekinumab.Physicians should be aware of the possibility of infectious disease when prescribing biologic agents.Vaccination is essential in immunosuppressed adults.",
"affiliations": "Second Propaedeutic Department of Internal Medicine and Research Institute, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece.;Second Propaedeutic Department of Internal Medicine and Research Institute, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece.;Second Propaedeutic Department of Internal Medicine and Research Institute, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece.;Second Propaedeutic Department of Internal Medicine and Research Institute, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece.;Second Propaedeutic Department of Internal Medicine and Research Institute, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece.;Second Propaedeutic Department of Internal Medicine and Research Institute, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Kalogeropoulos|Charalampos I|CI|;Papathanasiou|Konstantinos A|KA|;Tsagkaraki|Ismini|I|;Giannopoulos|Georgios|G|;Bamias|Aristotelis|A|;Boutati|Eleni I|EI|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_001615",
"fulltext": "\n==== Front\nEur J Case Rep Intern Med\nEuropean Journal of Case Reports in Internal Medicine\n2284-2594 SMC Media Srl \n\n10.12890/2020_001615\n1615-1-13609-1-10-20200520\nArticles\nA Case of Meningococcal and HSV-2 Meningitis in a Patient Being Treated with Ustekinumab for Pityriasis Rubra Pilaris\nKalogeropoulos Charalampos I Papathanasiou Konstantinos A Tsagkaraki Ismini Giannopoulos Georgios Bamias Aristotelis Boutati Eleni I Second Propaedeutic Department of Internal Medicine and Research Institute, University General Hospital Attikon, National and Kapodistrian University of Athens, Athens, Greece\n2020 \n22 5 2020 \n7 8 00161504 3 2020 11 3 2020 © EFIM 20202020This article is licensed under a Commons Attribution Non-Commercial 4.0 LicensePityriasis rubra pilaris (PRP) is a rare chronic inflammatory papulosquamous dermatosis affecting both adults and children. Six subtypes of PRP have been described. Recently, the management of PRP with biologic immunosuppressive agents regularly used in psoriasis has been supported by several case reports and series. Ustekinumab is an anti-IL12/23 IgG1 kappa human monoclonal antibody. It has been approved for the treatment of Crohn’s disease, plaque psoriasis, psoriatic arthritis and ulcerative colitis. It has also been reported to be effective as an off-label treatment for PRP. Current data are equivocal regarding infectious disease risk with ustekinumab administration. We describe a case of meningococcal and HSV-2 infection of the central nervous system in a patient being treated with ustekinumab for PRP.\n\nLEARNING POINTS\nThe administration of biologic immunosuppressive agents can result in severe life-threatening infections.\n\nResearch is required on the infection potential of ustekinumab.\n\nPhysicians should be aware of the possibility of infectious disease when prescribing biologic agents.\n\nVaccination is essential in immunosuppressed adults.\n\nPityriasis rubra pilaris (PRP)ustekinumabmeningococcal meningitis\n==== Body\nHOSPITAL GRAND ROUNDS\nUniversity General Hospital Attikon, by Editorial Board Member Eleni Boutati\n\nTThe University General Hospital «Attikon», Athens, Greece, is a tertiary University teaching hospital. It was founded in 2002 and first patients admitted in November 2003. Nowadays it has a capacity of 677 beds, with 22 University Clinics, and with over 2500 employees and 500 staff physicians representing more than 60 specialties and subspecialties. It is the only General University Hospital in Athens. The hospital is managed by the Health National System of Greece and all Clinics, Units and Laboratories are coordinated by the School of Medicine of the National and Kapodistrian University of Athens. Its main mission is to provide secondary and tertiary care to the citizens, to support the operation of University Clinics and Special Units, to train medical students, doctors, and other health care professionals, as well as to promote research development in the health sector.\n\nINTRODUCTION\nPityriasis rubra pilaris (PRP) refers to a group of rare skin conditions found in both adults and children and characterized by chronic inflammatory papulosquamous dermatosis. Six subtypes of PRP have been described. Follicular palmoplantar hyperkeratosis and peachy coral plaques affecting the head, trunk and limbs are common to all subtypes. PRP can occasionally progress to a generalized erythroderma, with ‘islands of sparing’, which are areas of unaffected skin considered the hallmark of this disease. Its aetiopathogenesis is still uncertain, but current evidence suggests a multifactorial origin. The vast majority of cases are sporadic, although familial autosomal dominant and recessive patterns of inheritance have been suggested [1]. Treating PRP is a clinical challenge since some cases are self-limiting and do not require treatment, while others are unresponsive to any treatment combination. This management complexity together with the disease’s rarity may partly explain the lack of standard treatment guidelines. Most dermatologists support combination therapies with administration of systemic agents and topical therapy. Topical agents for symptomatic treatment include emollients, keratolytic agents (such as urea), topical corticosteroids, tazarotene and topical calcineurin inhibitors. Oral retinoids are the first-line option for systemic treatment. Methotrexate and UV-light therapy (phototherapy) in combination with retinoids, as well as cyclosporin A have also been used. However, the risk of adverse effects with combination therapy is higher than with monotherapy. Recently, several case reports and series have supported the use of biologic immunosuppressive agents, including TNF-alpha inhibitors (infliximab, etanercept) as well as ustekinumab and secukinumab, in PRP patients unresponsive to conventional treatment [1, 2].\n\nUstekinumab is an anti-IL12/23 IgG1 kappa human monoclonal antibody. It has been approved for the treatment of moderately to severely active Crohn’s disease, plaque psoriasis, psoriatic arthritis, and recently ulcerative colitis [3]. It has been reported to be effective in PRP as an off-label treatment given the fact that treatment options are limited [4–7]. Common side effects of ustekinumab include injection site reactions, flu-like symptoms, headache, fatigue, diarrhoea, skin rash and itching [3]. It has been postulated that, as a biologic treatment, it can increase the chance of serious infections (including tuberculosis, and bacterial, viral and fungal infections), skin cancer, reversible posterior leukoencephalopathy syndrome (RPLS) and hypersensitivity reactions. An analysis of 2014 PSOLAR data (an observational study of 12,093 patients with psoriasis) identified no increased risk of malignancy, major adverse cardiovascular events, serious infection or mortality with ustekinumab [8].\n\nWe report a case of meningococcal and HSV-2 infection of the central nervous system (CNS) in a patient being treated with ustekinumab for PRP. To the best of our knowledge, there are only two other reported cases of CNS infection in patients treated with ustekinumab [9, 10].\n\nCASE DESCRIPTION\nAn intubated 60-year-old man was urgently transferred by air from a rural hospital to our emergency department as a possible case of CNS infection necessitating intensive care treatment in a higher-level tertiary hospital. The patient’s history showed acute onset of fever up to 38.5°C accompanied by rigor, neck stiffness, vomiting and confusion lasting 3 days. He had initially presented to the emergency department of a rural hospital, where he underwent basic laboratory evaluation. An emergent computed tomography (CT) brain scan did not demonstrate any abnormal findings. The patient was considered for a lumbar puncture due to marked nuchal rigidity. Since the blood tests revealed a mild increase in INR and the rural hospital lacked neurosurgical facilities, cerebrospinal fluid (CSF) examination was temporarily postponed and the patient was administered an intravenous dose of ceftriaxone within the first hour of medical contact. The patient’s mental status rapidly deteriorated and it was decided to intubate him for airway protection. The patient was then admitted to our hospital a few hours after intubation. The patient had a 10-year history of PRP, a bilateral saphenectomy 10 years previously for venous insufficiency of the lower extremities, and frequent episodes of herpes simplex virus infections (herpes labialis) since childhood. He quit smoking several years ago and drinks alcohol only on rare social occasions. The patient’s PRP was initially managed with acitretin and topical steroids. After 6 years of treatment and because of repeated skin lesion relapses, the patient’s dermatologist decided to escalate treatment with the addition of subcutaneous injections of ustekinumab 45 mg at week 0 and week 4 and every 12 weeks thereafter. The patient had regular medical check-ups every 6 months, with no abnormal findings in the most recent laboratory work-up (Table 1) 2 months previously.\n\nAdditionally, pre-treatment tests for latent mycobacterium tuberculosis infection, viral hepatitis (HBV, HCV) and human immunodeficiency virus (HIV) were all negative. The patient had received his last injection of ustekinumab 40 days previously and was not on any additional medication.\n\nAt presentation to our hospital, the patient was intubated, under mechanical ventilation and haemodynamically stable. The clinical examination revealed mild nuchal rigidity, with no rash or signs of increased intracranial pressure. His pupils were of equal and normal size, and reactive to light. The rest of the examination was unremarkable. A repeat CT of the brain showed no changes compared with the baseline imaging obtained a few hours previously. Due to high clinical suspicion of CNS infection and apparent immunosuppression, the patient was given empiric broad-spectrum antibiotics, adding intravenous ampicillin/sulbactam, vancomycin and acyclovir to ceftriaxone. The admission electrocardiogram showed a normal sinus rhythm with 1:1 atrioventricular conduction, while a supine chest x-ray showed the tracheal tube in the correct place with no signs of lung infiltrates or cardiac silhouette abnormalities. The admission arterial blood gas analysis (on FiO2 100%, respiratory rate 16/min, tidal volume 500 ml and positive end-expiratory pressure 5 cm H2O) showed pH 7.42, pCO2 40.6 mmHg, pO2 350 mmHg, HCO3 26 mmol/l, lactic acid 1.2 mmol/l, and SO2 100%. As part of our hospital protocol, blood tests were repeated and revealed an increase in white blood cell count and in C-reactive protein (CRP), as well as a normocytic normochromic anaemia and thrombocytopenia. INR was 0.96 (Table 2). The patient was transferred to our hospital’s intensive care unit (ICU), where a lumbar puncture was performed. CSF examination revealed 5.440/mm3 cells with polymorphonuclear predominance, low glucose 18 mg/dl (blood glucose was 120 mg/dl) and high protein levels (477 mg/dl) (Table 3). Gram stain revealed gram-negative diplococci, while PCR examination identified both Neisseria meningitidis serogroup B and HSV-2. During his stay in the ICU, the patient presented persistent euvolemic hyponatremia that was attributed to inappropriate secretion of antidiuretic hormone (SIADH) due to the CNS infection.\n\nThe patient progressively improved over the following days, displaying normalization of inflammatory markers and hyponatremia. After 5 days of intensive care treatment, the patient was successfully weaned from the endotracheal tube and transferred to our internal medicine ward for further management. At that point, he was haemodynamically stable and afebrile. Apart from slight confusion, the patient’s progress was initially uncomplicated while he was on ceftriaxone and acyclovir. However, on day 4 of his stay in our ward, he started to exhibit spiking fevers up to 38.5°C. Over the following 3 days he displayed abnormally elevating liver function tests (transferase enzymes) in combination with persistent fever but no new signs or symptoms. After infectious specialist team consultation and negative blood and urine cultures, we decided to stop intravenous antibiotics. Two days later, the patient became afebrile and his liver function tests returned to normal, suggesting the fever was caused by drugs. Thorough imaging analysis was requested (CT of the brain, chest and abdomen) but results were unremarkable. After 3 weeks of hospitalization, the patient was discharged ambulatory, afebrile and restored back to his previous excellent health. Our recommendation to his treating dermatologist was to halt ustekinumab for PRP. The patient was strongly advised to get vaccinated with pneumococcal (PCV-13, PPSV-23) and inactivated influenza vaccines as well as with meningococcal group B and groups A, C, W135 and Y vaccines. Follow-up in the patient’s local hospital 1 month later showed an unremarkable clinical examination and normal blood tests.\n\nDISCUSSION\nN. meningitidis and herpes simplex type 2 are common causes of CNS infection in adults. N. meningitidis, a gram-negative diplococcus and obligate human pathogen, normally colonizes the nasopharynx and is typically found in 10% of asymptomatic carriers. In Europe and the USA, serogroup B is the main type causing meningococcal disease. Patients with meningococcal meningitis usually present with acute onset of severe headache, fever, nausea, vomiting, photophobia and a stiff neck as well as lethargy, altered mental status or prolonged fever, especially the elderly. Another common manifestation is a diffuse petechial rash especially on the trunk and lower extremities. Risk factors predisposing to meningococcal disease include congenital complement deficiencies or dysfunctional properdin, asplenia (anatomical or functional), HIV infection and smoking or concurrent viral infections of the upper respiratory tract [11]. Although it is thought ustekinumab may be implicated in some cases of serious infection [12], there are still conflicting arguments concerning the potential of biologic agents like ustekinumab to increase this risk [13]. According to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Infections in Compromised Hosts (ESGICH) Consensus, ustekinumab should be considered to pose a low risk for infections, as most infections are limited to the upper respiratory tract and only a few cases of opportunistic infections or TB reactivation have been reported, as shown in reports from four psoriasis trials where patients were exposed to ustekinumab for up to 3 years [14]. Note that our patient had been exposed ustekinumab for 4 consecutive years.\n\nThere are only two other reported cases of ustekinumab associated with CNS infection [9, 10], and no reports of meningococcal meningitis or combined viral–bacterial meningitis in patients treated with this biologic agent.\n\nThe quality of evidence-based medicine presented in case reports may be low, but they can still teach us valuable everyday clinical practice lessons. Specifically, our previously healthy patient was exposed to an immunosuppressive agent associated with a low risk of infection but which eventually endangered his life by impairing the efficiency of his immune system. The patient may have had genetic predisposing factors, especially since genome-wide association studies have identified single nucleotide polymorphisms that render carriers prone to bacterial meningitis and cold sores, among other common infections [15]. We believe that, until the ability of novel biologic agents to trigger infections has been elucidated, clinicians should be vigilant when prescribing such medications. We also stress the importance of vaccination and strongly recommend the vaccination status of any patient starting on biologic agents should be meticulously revised well in advance of medication commencement so their immune system can be improved.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nTable 1 Normal blood test results 20 days before the patient’s last ustekinumab injection\n\nParameter (blood)\tResults\tNormal range\t\nLeucocytes (K/μl)\t7.62\t4.00–10.00\t\nPlatelets (K/μl)\t188\t150.0–400.0\t\nHaemoglobin (g/dl)\t13.5\t13.5–18.0\t\nHaematocrit (%)\t40.8\t40.0–54.0\t\nCRP (mg/dl)\t0.1\t<0.5\t\nCreatinine (mg/dl)\t0.8\t0.6–1.3\t\nUrea (mg/dl)\t34\t10–50\t\nSGOT (U/l)\t18\t<37\t\nSGPT (U/l)\t16\t<41\t\nγ-GT (U/l)\t16\t0–16\t\nALP (U/l)\t70\t40–129\t\nLDH (U/l)\t164\t135–225\t\nAnti-HIV I, II\tNegative\tNegative\t\nHBsAg (IU)\tNegative, 0.4\tNegative <0.9\t\nAnti-HCV (IU)\tNegative, 0.1\tNegative <0.9\t\nTable 2 Blood test results in our emergency department\n\nParameter (blood)\tResults\tNormal range\t\nLeucocytes (K/μl)\t11.14\t4.00–11.00\t\nNeutrophils (%)\t86.9\t40.0–75.0\t\nPlatelets (K/μl)\t75\t150.0–400.0\t\nHaemoglobin (g/dl)\t11.0\t13.5–17.5\t\nHaematocrit (%)\t31.4\t41.0–53.0\t\nMCV (fl)\t84.9\t76.0–96.0\t\nMCHC (g/dl)\t35.0\t30.0–36.0\t\nCRP (mg/dl)\t441.0\t0–6.0\t\nCreatinine (mg/dl)\t0.5\t0.7–1.2\t\nUrea (mg/dl)\t46.6\t16.6–48.5\t\nAST/SGOT (U/l)\t14\t<40\t\nALT/SGPT (U/l)\t13\t<41\t\nγ-GT (U/l)\t24\t8.0–61.0\t\nALP (U/l)\t53\t40–129\t\nPT (sec)\t10.86\t10.0–13.00\t\nINR\t0.96\t0.90–1.20\t\nAPTT (sec)\t34.82\t24.00–39.00\t\nFibrogen (mg/dl)\t988.5\t200.0–400.0\t\nNa (mmol/l)\t135\t136–146\t\nK (mmol/l)\t4.1\t3.5–5.1\t\nCa (mg/dl)\t8.3\t8.6–10.3\t\nLDH (U/l)\t411\t135–225\t\nCK (U/l)\t102\t39–308\t\nTroponin (pg/ml)\t8.4\t<14\t\nTable 3 CSF examination results\n\nParameter (CSF)\tResults\t\nNumber of cells (/mm3)\t5.440\t\nPolymorphonuclear neutrophils (%)\t90\t\nNumber of RBC (/mm3)\t960\t\nColour\tLight yellow\t\nAppearance\tSlightly cloudy\t\nTotal protein (mg/dl)\t477.0\t\nAlbumin (mg/dl)\t138.20\t\nGlucose (mg/dl)\t18\t\nLDH (U/l)\t95\t\nGram strain\tGram-negative diplococcus\t\nPCR (film array)\tNeisseria meningitidis serogroup B(+)\nHerpes simplex virus 2 (+)\n==== Refs\nREFERENCES\n1 Klein A Landthaler M Karrer S Pityriasis rubra pilaris: a review of diagnosis and treatment Am J Clin Dermatol 2010 11 3 157 170 20184391 \n2 Kromer C Sabat R Celis D Mössner R Systemic therapies of pityriasis rubra pilaris: a systematic review J Dtsch Dermatol Ges 2019 17 3 243 259 \n3 emc STELARA 45 mg and 90 mg, solution for injection (vials) and solution for injection in prefilled syringe Summary of product characteristics Available from: https://www.medicines.org.uk/emc/medicine/32569 Accessed 26 March 2020 \n4 Wohlrab J Kreft B Treatment of pityriasis rubra pilaris with ustekinumab Br J Dermatol 2010 163 3 655 656 20491761 \n5 Chowdhary M Davila U Cohen DJ Ustekinumab as an alternative treatment option for chronic pityriasis rubra pilaris Case Rep Dermatol 2015 7 1 46 50 25969677 \n6 Napolitano M Lembo L Fania L Abeni D Didona D Didona B Ustekinumab treatment of pityriasis rubra pilaris: a report of five cases J Dermatol 2018 45 2 202 206 29080273 \n7 Aragón-Miguel R Prieto-Barrios M Calleja-Algarra A Velasco-Tamariz V Andres-Lencin JJ Ortiz-Romero P Refractory pityriasis rubra pilaris with good response after treatment with ustekinumab J Dtsch Dermatol Ges 2018 16 8 1022 1025 \n8 Papp K Gottlieb AB Naldi L Pariser D Ho V Goyal K Safety surveillance for ustekinumab and other psoriasis treatments from the Psoriasis Longitudinal Assessment and Registry (PSOLAR) J Drugs Dermatol 2015 14 7 706 714 26151787 \n9 Stöllberger C Finsterer J Varicella zoster virus meningitis under ustekinumab because of plaque psoriasis J Dermatol 2017 44 6 703 705 28150333 \n10 Van Den Tooren HK Bharambe V Silver N Michael BD Herpes simplex virus encephalitis in a patient receiving ustekinumab associated with extensive cerebral edema and brainshift successfully treated by immunosuppression with dexamethasone BMJ Case Rep 2019 12 8 \n11 Mount HR Boyle SD Aseptic and bacterial meningitis: evaluation, treatment, and prevention Am Fam Physician 2017 96 5 314 322 28925647 \n12 Janssen Biotech, Inc STELARA® (ustekinumab). Highlights of prescribing information Available from http://www.stelarahcp.com/pdf/PrescribingInformation.pdf Accessed 20 February 2020. \n13 Sehgal VN Pandhi D Khurana A Biologics in dermatology: adverse effects Int J Dermatol 2015 54 12 1442 1460 26147909 \n14 Winthrop KL Mariette X Silva JT Benamu E Calabrese LH Dumusc A ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors) Clin Microbiol Infect 2018 24 S21 40 29447987 \n15 Tian C Hromatka BS Kiefer AK Eriksson N Noble SM Tung JY Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections Nat Commun 2017 8 1 599 28928442\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2284-2594",
"issue": "7(8)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Pityriasis rubra pilaris (PRP); meningococcal meningitis; ustekinumab",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
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"other_id": null,
"pages": "001615",
"pmc": null,
"pmid": "32789127",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "28925647;25969677;20491761;29447987;28150333;26151787;29080273;29947473;30520557;31413050;26147909;20184391;28928442",
"title": "A Case of Meningococcal and HSV-2 Meningitis in a Patient Being Treated with Ustekinumab for Pityriasis Rubra Pilaris.",
"title_normalized": "a case of meningococcal and hsv 2 meningitis in a patient being treated with ustekinumab for pityriasis rubra pilaris"
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"literaturereference": "THHFVZ2ZV+YBOAK/UBTEXM5BDCMUC1CTKHKBHIPIXU1XHTACDE1FLEAJH+BAISTS D, TSAGKARAKI I, GIANNOPOULOS G, BAMIAS A, BOUTATI E, PAPATHANASIOU K. A CASE OF MENINGOCOCCAL AND HSV?2 MENINGITIS IN A PATIENT BEING TREATED WITH USTEKINUMAB FOR PITYRIASIS RUBRA PILARIS. EUR J CASE REP INTERN MED.",
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{
"abstract": "There is a preclinical rationale for inhibiting angiogenesis in mesothelioma. We aimed to assess the efficacy and safety of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated malignant pleural mesothelioma.\n\n\n\nRAMES was a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial done at 26 hospitals in Italy. Eligible patients were aged 18 years or older, had Eastern Cooperative Oncology Group performance status 0-2, and histologically proven malignant pleural mesothelioma progressing during or after first-line treatment with pemetrexed plus platinum. Patients were randomly assigned (1:1) to receive intravenous gemcitabine 1000 mg/m2 on days 1 and 8 every 3 weeks plus either intravenous placebo (gemcitabine plus placebo group) or ramucirumab 10 mg/kg (gemcitabine plus ramucirumab group) on day 1 every 3 weeks, until tumour progression or unacceptable toxicity. Central randomisation was done according to a minimisation algorithm method, associated with a random element using the following stratification factors: ECOG performance status, age, histology, and first-line time-to-progression. The primary endpoint was overall survival, measured from the date of randomisation to the date of death from any cause. Efficacy analyses were assessed in all patients who had been correctly randomised and received their allocated treatment, and safety analyses were assessed in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03560973, and with EudraCT, 2016-001132-36.\n\n\n\nBetween Dec 22, 2016, and July 30, 2018, of 165 patients enrolled 161 were correctly assigned and received either gemcitabine plus placebo (n=81) or gemcitabine plus ramucirumab (n=80). At database lock (March 8, 2020), with a median follow-up of 21·9 months (IQR 17·7-28·5), overall survival was longer in the ramucirumab group (HR 0·71, 70% CI 0·59-0·85; p=0·028). Median overall survival was 13·8 months (70% CI 12·7-14·4) in the gemcitabine plus ramucirumab group and 7·5 months (6·9-8·9) in the gemcitabine plus placebo group. Grade 3-4 treatment-related adverse events were reported in 35 (44%) of 80 patients in the gemcitabine plus ramucirumab group and 24 (30%) of 81 in the gemcitabine plus placebo group. The most common treatment-related grade 3-4 adverse events were neutropenia (16 [20%] for gemcitabine plus ramucirumab vs ten [12%] for gemcitabine plus placebo) and hypertension (five [6%] vs none). Treatment-related serious adverse events were reported in five (6%) in the gemcitabine plus ramucirumab group and in four (5%) patients in the gemcitabine plus placebo group; the most common was thromboembolism (three [4%] for gemcitabine plus ramucirumab vs two [2%] for gemcitabine plus placebo). There were no treatment-related deaths.\n\n\n\nRamucirumab plus gemcitabine significantly improved overall survival after first-line standard chemotherapy, with a favourable safety profile. This combination could be a new option in this setting.\n\n\n\nEli Lilly Italy.\n\n\n\nFor the Italian translation of the abstract see Supplementary Materials section.",
"affiliations": "Medical Oncology Unit, Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Oncology, IRCCS Humanitas Research Hospital, Milan, Italy. Electronic address: paolo.zucali@hunimed.eu.;Medical Oncology Unit, Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Mesothelioma Unit, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy; Infrastruttura Ricerca Formazione e Innovazione, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padua, Italy.;Thoracic Oncology Unit, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy.;Medical Oncology Unit, AOU Policlinico Vittorio Emanuele, Catania, Italy.;Medical Oncology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore, Milan, Italy; Medical Oncology Unit, University of Insubria, Varese, Italy.;Medical Oncology Unit, IRCCS Istituto Nazionale Tumori Regina Elena, Rome, Italy.;Thoracic Oncology Division, Istituto Europeo di Oncologia IRCCS, Milan, Italy.;Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy.;Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy; Department of Oncology, ASST Cremona, Cremona, Italy.;Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy; Department of Oncology, Ospedale San Paolo, Milan, Italy.;Department of Oncology, IRCCS Humanitas Research Hospital, Milan, Italy.;Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Oncology, IRCCS Humanitas Research Hospital, Milan, Italy.;Medical Oncology Unit, Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Medical Oncology Unit, Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Infrastruttura Ricerca Formazione e Innovazione, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.;Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padua, Italy.;Medical Oncology Unit, Clinical Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.;Department of Oncology, Cliniche Humanitas Gavazzeni, Bergamo, Italy.",
"authors": "Pinto|Carmine|C|;Zucali|Paolo Andrea|PA|;Pagano|Maria|M|;Grosso|Federica|F|;Pasello|Giulia|G|;Garassino|Marina Chiara|MC|;Tiseo|Marcello|M|;Soto Parra|Hector|H|;Grossi|Francesco|F|;Cappuzzo|Federico|F|;de Marinis|Filippo|F|;Pedrazzoli|Paolo|P|;Bonomi|Maria|M|;Gianoncelli|Letizia|L|;Perrino|Matteo|M|;Santoro|Armando|A|;Zanelli|Francesca|F|;Bonelli|Candida|C|;Maconi|Antonio|A|;Frega|Stefano|S|;Gervasi|Erika|E|;Boni|Luca|L|;Ceresoli|Giovanni Luca|GL|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; C056507:gemcitabine; C543333:ramucirumab",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(21)00404-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "22(10)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D010997:Pleural Neoplasms; D000077982:Progression-Free Survival; D013997:Time Factors",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1438-1447",
"pmc": null,
"pmid": "34499874",
"pubdate": "2021-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial.",
"title_normalized": "gemcitabine with or without ramucirumab as second line treatment for malignant pleural mesothelioma rames a randomised double blind placebo controlled phase 2 trial"
} | [
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}
],
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"reaction": [
{
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},
{
"reactionmeddrapt": "Product use in unapproved indication",
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}
],
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},
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"literaturereference": "Pinto C, Zucali PA, Pagano M, Grosso, F, Pasello G, Garassino MC et al.. Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial.. LANCET ONCOL. 2021;22(10):1438-1447",
"literaturereference_normalized": "gemcitabine with or without ramucirumab as second line treatment for malignant pleural mesothelioma rames a randomised double blind placebo controlled phase 2 trial",
"qualification": "3",
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},
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},
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},
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}
] |
{
"abstract": "Rhabdomyolysis, if severe, can lead to acute kidney injury (AKI). Myoglobin is an iron and oxygen-binding protein that is freely filtered by the glomerulus. Precipitation of myoglobin in the nephrons' distal parts is responsible for tubular damage with AKI as a consequence. Extracorporeal clearance of myoglobin is conventionally attempted by the use of continuous renal replacement therapy (CRRT) with high cut-off dialysis membranes to limit the extent of the damage. We describe a case of a 56-year-old man with traumatic crush injury and a persistent source of muscle ischaemia unresponsive to high dose CRRT with EMiC-2 filter. Due to therapy failure, he was subsequently treated with the addition of a haemoadsorber (CytoSorb®) to the circuit. This reduced myoglobin and creatine kinase levels successfully despite ongoing tissue ischaemia. However, CytoSorb® was not enough to maintain microcirculatory perfusion, resulting in the eventual demise of the patient due to severity of the injury. Our report indicates that myoglobin was efficiently removed with CytoSorb® following exchange with the conventional high cut-off filter in continuous venovenous haemodialysis in severe traumatic rhabdomyolysis.",
"affiliations": "Department of Intensive Care, Erasmus Medical Centre, University Medical Center, Rotterdam, The Netherlands, olcaydilken@gmail.com.;Department of Intensive Care, Erasmus Medical Centre, University Medical Center, Rotterdam, The Netherlands.;Department of Intensive Care, Erasmus Medical Centre, University Medical Center, Rotterdam, The Netherlands.;Department of Intensive Care, Erasmus Medical Centre, University Medical Center, Rotterdam, The Netherlands.;Department of Intensive Care, Erasmus Medical Centre, University Medical Center, Rotterdam, The Netherlands.;Department of Intensive Care, Erasmus Medical Centre, University Medical Center, Rotterdam, The Netherlands.",
"authors": "Dilken|Olcay|O|;Ince|Can|C|;van der Hoven|Ben|B|;Thijsse|Sjoerd|S|;Ormskerk|Patricia|P|;de Geus|Hilde R H|HRH|",
"chemical_list": "D015415:Biomarkers; D009211:Myoglobin; D003402:Creatine Kinase",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000505899",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-5068",
"issue": "49(6)",
"journal": "Blood purification",
"keywords": "CytoSorb; Microcirculation; Myoglobin; Renal failure; Shock",
"medline_ta": "Blood Purif",
"mesh_terms": "D015415:Biomarkers; D003402:Creatine Kinase; D006440:Hemofiltration; D006801:Humans; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009211:Myoglobin; D012206:Rhabdomyolysis; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "8402040",
"other_id": null,
"pages": "743-747",
"pmc": null,
"pmid": "32114569",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Successful Reduction of Creatine Kinase and Myoglobin Levels in Severe Rhabdomyolysis Using Extracorporeal Blood Purification (CytoSorb®).",
"title_normalized": "successful reduction of creatine kinase and myoglobin levels in severe rhabdomyolysis using extracorporeal blood purification cytosorb"
} | [
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"activesubstancename": "NOREPINEPHRINE"
},
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"medicinalproduct": "NORADRENALINE /00127501/"
},
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}
],
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"reaction": [
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"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "DILKEN O, INCE C, VAN DER HOVEN B, THIJSSE S, ORMSKERK P, DE GEUS HRH. SUCCESSFUL REDUCTION OF CREATINE KINASE AND MYOGLOBIN LEVELS IN SEVERE RHABDOMYOLYSIS USING EXTRACORPOREAL BLOOD PURIFICATION (CYTOSORB). BLOOD?PURIF 2020?49(6):743?747.",
"literaturereference_normalized": "successful reduction of creatine kinase and myoglobin levels in severe rhabdomyolysis using extracorporeal blood purification cytosorb",
"qualification": "3",
"reportercountry": "NL"
},
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"receiptdate": "20210813",
"receivedate": "20210813",
"receiver": {
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"receivertype": "6"
},
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"sendertype": "2"
},
"serious": 1,
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20211014"
}
] |
{
"abstract": "The authors present the case of a 38-year-old man with schizophrenia and with severe insomnia, who attempted suicide twice during oral drug therapy with risperidone. The patient slept barely 2 or 3 h per night, and he frequently took half days off from work due to excessive daytime sleepiness. As a maladaptive behavior to insomnia, he progressively spent more time lying in bed without sleeping, and he repeatedly thought about his memories, which were reconstructed from his hallucinations. His relatives and friends frequently noticed that his memories were not correct. Consequently, the patient did not trust his memory, and he began to think that the hallucinations controlled his life. During his insomniac state, he did not take antipsychotic drugs regularly because of his irregular meal schedule due to his excessive daytime sleepiness. The authors started cognitive behavioral therapy for insomnia (CBT-i) with aripiprazole long acting injection (LAI). CBT-i is needed to be tailored to the patient's specific problems, as this case showed that the patient maladaptively use chlorpromazine as a painkiller, and he exercised in the middle of the night because he believed he can fall asleep soon after the exercise. During his CBT-i course, he learned how to evaluate and control his sleep. The patient, who originally wanted to be short sleeper, began to understand that adequate amounts of sleep would contribute to his quality of life. He finally stopped taking chlorpromazine and benzodiazepine as sleeping drugs while taking suvorexant 20 mg. Through CBT-i, he came to understand that poor sleep worsened his hallucinations, and consequently made his life miserable. He understood that good sleep eased his hallucinations, ameliorated his daytime sleepiness and improved his concentration during working hours. Thus, he was able to improve his self-esteem and self-efficacy by controlling his sleep. In this case report, the authors suggest that CBT-i can be an effective therapy for schizophrenia patients with insomnia to the same extent of other psychiatric and non-psychiatric patients.",
"affiliations": "Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.;Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, Japan.",
"authors": "Izuhara|Muneto|M|;Matsuda|Hiroyuki|H|;Saito|Ami|A|;Hayashida|Maiko|M|;Miura|Syoko|S|;Oh-Nishi|Arata|A|;Azis|Ilhamuddin Abdul|IA|;Abdullah|Rostia Arianna|RA|;Tsuchie|Keiko|K|;Araki|Tomoko|T|;Ryousuke|Arauchi|A|;Kanayama|Misako|M|;Hashioka|Sadayuki|S|;Wake|Rei|R|;Miyaoka|Tsuyoshi|T|;Horiguchi|Jun|J|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fpsyt.2018.00260",
"fulltext": "\n==== Front\nFront PsychiatryFront PsychiatryFront. PsychiatryFrontiers in Psychiatry1664-0640Frontiers Media S.A. 10.3389/fpsyt.2018.00260PsychiatryCase ReportCognitive Behavioral Therapy for Insomnia as Adjunctive Therapy to Antipsychotics in Schizophrenia: A Case Report Izuhara Muneto *Matsuda Hiroyuki Saito Ami Hayashida Maiko Miura Syoko Oh-Nishi Arata Azis Ilhamuddin Abdul Abdullah Rostia Arianna Tsuchie Keiko Araki Tomoko Ryousuke Arauchi Kanayama Misako Hashioka Sadayuki Wake Rei Miyaoka Tsuyoshi Horiguchi Jun Department of Psychiatry, Faculty of Medicine, Shimane University, Izumo, JapanEdited by: Lino Nobili, Ospedale Niguarda Ca' Granda, Italy\n\nReviewed by: Armando D'Agostino, Università degli Studi di Milano, Italy; Anna Castelnovo, San Paolo Hospital, Italy\n\n*Correspondence: Muneto Izuhara izuhara@med.shimane-u.ac.jpThis article was submitted to Sleep and Chronobiology, a section of the journal Frontiers in Psychiatry\n\n12 6 2018 2018 9 26019 1 2018 25 5 2018 Copyright © 2018 Izuhara, Matsuda, Saito, Hayashida, Miura, Oh-Nishi, Azis, Abdullah, Tsuchie, Araki, Ryousuke, Kanayama, Hashioka, Wake, Miyaoka and Horiguchi.2018Izuhara, Matsuda, Saito, Hayashida, Miura, Oh-Nishi, Azis, Abdullah, Tsuchie, Araki, Ryousuke, Kanayama, Hashioka, Wake, Miyaoka and HoriguchiThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The authors present the case of a 38-year-old man with schizophrenia and with severe insomnia, who attempted suicide twice during oral drug therapy with risperidone. The patient slept barely 2 or 3 h per night, and he frequently took half days off from work due to excessive daytime sleepiness. As a maladaptive behavior to insomnia, he progressively spent more time lying in bed without sleeping, and he repeatedly thought about his memories, which were reconstructed from his hallucinations. His relatives and friends frequently noticed that his memories were not correct. Consequently, the patient did not trust his memory, and he began to think that the hallucinations controlled his life. During his insomniac state, he did not take antipsychotic drugs regularly because of his irregular meal schedule due to his excessive daytime sleepiness. The authors started cognitive behavioral therapy for insomnia (CBT-i) with aripiprazole long acting injection (LAI). CBT-i is needed to be tailored to the patient's specific problems, as this case showed that the patient maladaptively use chlorpromazine as a painkiller, and he exercised in the middle of the night because he believed he can fall asleep soon after the exercise. During his CBT-i course, he learned how to evaluate and control his sleep. The patient, who originally wanted to be short sleeper, began to understand that adequate amounts of sleep would contribute to his quality of life. He finally stopped taking chlorpromazine and benzodiazepine as sleeping drugs while taking suvorexant 20 mg. Through CBT-i, he came to understand that poor sleep worsened his hallucinations, and consequently made his life miserable. He understood that good sleep eased his hallucinations, ameliorated his daytime sleepiness and improved his concentration during working hours. Thus, he was able to improve his self-esteem and self-efficacy by controlling his sleep. In this case report, the authors suggest that CBT-i can be an effective therapy for schizophrenia patients with insomnia to the same extent of other psychiatric and non-psychiatric patients.\n\nschizophreniainsomniacognitive behavioral therapylong acting injectable antipsychotic(LAI)cognitive behavioral therapy for insomnia(CBT-i)\n==== Body\nBackground\nSleep disturbance occurs in up to 80% of patients with schizophrenia (1–3) in the prodromal phase or precedes psychotic exacerbation (4). Patients with schizophrenia have various sleep abnormalities such as increased sleep onset, decreased total sleep time, more waking time after sleep onset, decreased sleep efficacy, reduced slow wave sleep, reductions in latency and duration of rapid eye movement (REM) sleep (5, 6). Furthermore, due to circadian rhythm misalignment ranging from phase-advance/delay to non-24 h periods in sleep-wake cycles, highly irregular and fragmented sleep epochs are also common in schizophrenic patients (7, 8). These sleep and circadian disturbances are also observed early or in the prodromal stages of psychosis (9, 10). Poor sleep and a disturbed circadian rhythm cause cognitive dysfunction, low treatment adherence, poor family relationships, and poor self-efficacy, and there is an increasing awareness of the importance of sleep to mental health (11–13). Cognitive behavioral therapy for insomnia (CBT-i) is a promising technique to improve not only sleep abnormalities but also a patient's self-esteem because patients have to think about and discover their own problems during the CBT-i course (14). This procedure makes patients feel like they are participating in their own therapy, compared to just answering questions asked by and taking medications prescribed by physicians (15). Nevertheless, monotherapy of sleep medication or CBT-i fails to improve patients' psychotic symptoms (16–18). Meanwhile, long-acting injection (LAI) of antipsychotic drugs is available and these drugs have produced improvements in psychiatric symptoms and reduced relapses and the rate of hospitalization (19–23). In this report, the authors present a case in which CBT-i was effective in the treatment of a schizophrenic patient with severe insomnia who had twice attempted suicide. The authors believe that this case suggests that schizophrenia patients can benefit from CBT-i, as other psychiatric and non-psychiatric patients do.\n\nCase presentation\nA 38-year-old man with schizophrenia presented after his second suicide attempt through an overdose with 48 tablets of burotizolam, 42 tablets of haloxazolam and 14 tablets of levomepromazine. The patient's childhood and adolescent development was normal. He was a good student and an active soccer player in high school. His social skills were standard, and he had no family history of mental illness. When he was 23 years old and a fourth year university student, he became convinced that he was being observed and he withdrew from social activities. His parents brought him to a psychiatric hospital, and he was diagnosed with schizophrenia according to DSM-IV-TR (24). The prescribed medication worked well and he was able to graduate from university at 27 years old. After graduating, he worked part time in a convenience store or at a nursery for several years. He then started to work at a distribution business under a handicapped employment program. His father committed suicide 3 years before he first presented at our hospital and a friend also died from a sickness. Because his auditory hallucinations repeatedly told him that he was responsible for their deaths, he could not stop blaming himself for their passing, in spite of his mother and brother telling him that he was not responsible. He was pessimistic about his future partly because he was able to earn only a meager income. In order to increase his income, he started a second part-time job at a supermarket in addition to his distribution job. He slept less and felt the accumulation of fatigue. He started to stockpile sleeping medications and he eventually took 76 tablets of brotizolam and 30 tablets of eszopiclone. The next morning his mother found him unconscious and called an ambulance. His mother brought his empty medicine containers to the hospital. At his first presentation, his physical examinations and vital signs were normal. He appeared to be very sleepy, but he managed to speak. The emergency department doctor ordered a blood test, a chest x-ray, an electrocardiogram test, a urine toxicology test, and a computed tomography brain scan. All results were within normal range, except a positive result for benzodiazepine in his urine and a slightly elevated white blood cell count (10.92 × 103/μL). The emergency doctor enlisted a psychiatric doctor to evaluate his mental state. The patient claimed that his auditory hallucinations sounded like someone was booing in addition to radio sounds from a distance. He also claimed he was being tracked by the police. He admitted suicidal ideation and reported that he was sad because he could not die. Because his depressive symptoms occurred 4 weeks prior to his first admission, the authors carefully excluded the possibility of schizoaffective disorder and depressive disorders or bipolar disorder. However, the patient did not show manic symptom or markedly diminished interest, and his depressive thoughts seemed to ease shortly after his admission. Obviously, his mood episodes have been present for a minority of the total duration of the active and residual phases of illness; however, his memory changing delusion and auditory hallucination remains continuously. Furthermore, he showed negative symptom that he had withdrew from social activity except working. The authors diagnosed schizophrenia according to DSM 5 (25). His decreased ability to discriminate between his thought and true memories as mentioned previously suggests the presence of disturbance of the self which also supports this diagnosis (26). The authors prescribed risperidone 6 mg, brotizolam 0.25 mg, and eszopiclone 2 mg. Soon after the treatment started, he became calm and claimed his suicidal ideation disappeared. However, during the patient's second hospitalization, 6 months later, he admitted that he had lied. He wanted to go home quickly so he pretended to be healthy. He subsequently obtained a distribution job contract for the coming season by himself and he was supposed to be followed by a nearby clinic as a condition of his hospital discharge. He started his distribution job but he could not work regularly. Again, he wanted to earn more money so he started attending lectures to get a healthcare worker license. Consequently, his sleep time was reduced and he started to feel life was troublesome once again. He subsequently overdosed as mentioned previously. The next morning, his mother brought him to the emergency department again. She had no idea when he attempted to commit suicide but she last saw him the previous night at 10 p.m. His mother brought his empty medicine containers. His vital signs were normal, and he managed to speak. The emergency doctor conducted a blood test, a chest x-ray and a computed tomography brain scan. All the results were normal, except an elevated white blood cell count (12.16 × 103/μL), creatine kinase (429 U/L), and chloride (109 mmol/L). His mother brought with her more than 100 risperidone tablets. It became obvious that he had not taken his pills regularly. The authors thought his adherence worsened during his psychotic period and started a long acting injectable antipsychotic (LAI). Because the patient worked regularly, the authors choose an injection given once in a 4-week period. Furthermore, because several studies showed it made significant improvements in the quality of life (22), the authors chose aripiprazole LAI at 400 mg. The authors also prescribed 20 mg of suvorexant per day and gradually discontinued brotizolam 0.25 mg and flunitrazepam 2 mg because the authors were concerned about a possible third suicide attempt while using benzodiazepine. Because both of the patient's admissions were associated with poor sleep, the authors examined the patient by polysomnography (PSG) and a multiple sleep latency test (MSLT) to exclude comorbid diseases such as sleep apnea syndrome or restless legs syndrome. As shown in Figure 1, he woke frequently during his sleep (25.6 times per hour on average as shown in Figure 1A) and he lived with excessive daytime sleepiness (he fell asleep within 2 min; on four out of five trials during the MSLT, as shown in Figure 1B). His Apnea-Hypopnea Index (AHI) was slightly elevated (5.1 times/hour), and respiratory events were not associated with significant desaturations (the minimum SpO2 was 95%). His BMI was 19.8. Malocclusion or tonsil swelling was not observed. Figure 2 shows the patient's sleep log. The patient did not show sleep phase advance or delay. The patient's Pittsburgh Sleep Quality Index (PSQI) score was 13, while over 5 points on the PSQI represents insomnia (27). Two months after his second admission, he was discharged while being prescribed suvorexant 20 mg, and chlorpromazine 25 mg per day in addition to aripiprazole LAI 400 mg per month. His Brief Psychiatric Rating Scale (BPRS) (28) dropped form 48 at admission to 42 at discharge. Six months after his second admission, the authors and the patient started CBT-i according to the CBT-i therapeutic manual (29). The authors also referred to the four causes cited by Chiu et al. (30): (a) beliefs that sleep problems cannot be changed; (b) trauma and adversity; (c) lifestyle choices and lack of motivation; (d) medication side effects and the 12 problems cited by Waite et al. (31): (a) Poor sleep environment; (b) Lack of daytime activity; (c) Lack of evening activity; (d) Disrupted circadian rhythm; (e) Sleep as an escape from distressing experiences; (f) Fear of bed; (g) Nightmares; (h) Night-time awakenings; (i) Sleep disrupted by voices/paranoia; (j) Worry; (k) Neuroleptic medication side effects; and (l) Reducing hypnotics. Our CBT-i consisted of eight sessions with each session ranging from 30 to 45 min. The first two sessions were educational sessions that attempted to find disturbances such as a misunderstanding of sleep hygiene or an inadequate sleep environment. In the other six sessions the authors and the patient tried to find other targets to tackle. For instance, the patient tried eating a carbohydrate (banana) before sleep, stopped checking his watch, warmed his body before going to bed, turned off small lights in his room, changed his routine of taking a bath before eating dinner to prevent him from taking a nap after dinner, bought a blackout curtain and an air conditioner. He also tried to wake up early in order to exercise in the morning instead of doing in the middle of the night because he believed he can fall asleep soon after the exercise. The whole course of sleep and psychological tendencies are shown in Figure 3. The patient's BPRS dropped to 24 and his PSQI dropped to 8. His sleep time increased steadily however, at his sixth session, he claimed that he could not sleep at night and he felt a strong sense of sleepiness during the day. His mental health care team consisted of two physician groups; with one group treating his psychiatric symptoms and the other group (the authors) treating his sleep abnormality. The first physician group increased the patient's chlorpromazine from 25 to 37.5 mg. The authors, as the second physician group treating the patient's sleep abnormality, discussed reducing the patient's chlorpromazine with the first physician group because the authors believed that his sleep troubles were not caused by a difficulty in falling asleep but by the dosage of chlorpromazine being too high for the patient's current ability to fall asleep which was gradually being strengthened by CBT-i. At the seventh session, the authors encountered another misunderstanding of the patient in which the authors believed the patient's headaches were being caused by a lack of sleep, while the patient used chlorpromazine as a painkiller. The authors prescribed acetaminophen 400 mg as a painkiller, and stopped the administration of chlorpromazine. At the eighth session, the patient claimed that he had almost no trouble sleeping except when he forgets to take suvorexant.\n\nFigure 1 (A) Polysomnography (PSG) results show slightly elevated Apnea-Hypopnea Index (AHI; 5.1 times/hour) and severe night awakening (25.6 times/hour). Minimum SpO2 (95%) was not severely decreased. Stage 1 Non REM sleep was slightly increased and REM sleep slightly decreased. Stage 3 sleep and sleep efficacy were normal. (B) A multiple sleep latency test (MSLT) shows excessive daytime sleepiness. He slept within 2 min four times out of five. Narcolepsy was excluded because no sleep onset REM (SoREM) was observed. (C) Sleep structure shows he woke a lot at the beginning of his sleep and woke an astonishing number of times. He took chlorpromazine 12.5 mg three times at 22:10, 0:15, and 2:45. No snoring of no periodic limb movement was observed.\n\nFigure 2 Sleep log: ■ represents sleep, □ represents drowsiness, and ▲ represents taking a sleeping pill. Sleep time, including drowsiness, steadily increased from 5 to 7 h. No sleep phase advance/delay was observed.\n\nFigure 3 Case treatment and clinical course. The patient's total sleep time increased from 5 to 7 h per day and his insomnia and psychotic symptoms decreased steadily. He could stop using chlorpromazine as a sedative. Psychiatric symptoms were evaluated by BPRS and sleep disturbance was evaluated by PSQI. BPRS dropped from 48 to 24. PSQI dropped from 13 to 8. CBT-i, Cognitive Behavioral Therapy for insomnia; BPRS, The Brief Psychiatric Rating Scale; PSQI, Pittsburgh Sleep Quality Index.\n\nDiscussion\nAs this case showed, schizophrenic patients can benefit from CBT-i. In addition to preventing a recurrence, the patient could stop taking chlorpromazine and benzodiazepine as soporifics while continuing with suvorexant 20 mg. The authors want to emphasize the possibility of using the CBT-i therapy to avoid the polypharmacy caused by severe sleep/circadian disturbance with schizophrenia. Our case with schizophrenia exhibited illogical attitudes toward sleep. CBT-i might be time-consuming, but it is an effective procedure to correct a patient's misunderstandings that might delay recovery. In limitation, the authors cannot exclude the possibility of LAI alone preventing a recurrence, but CBT-i might also strengthen the stability of the prevention from recurrence through enforcing the patient's feelings of self-efficacy by controlling his own life.\n\nRecovery is hard to define (32) because it defines the well-being of each individual patient. LAI treatment improved remission rates from ~42 to 64% and decreased relapse rates from 42 to 9.3% compared with oral antipsychotics (33). However, remission does not mean recovery. It means the patient does not meet diagnostic criteria, but it does not indicate the patient's well-being or recovery. Schizophrenic patients prefer CBT-i therapy to drug therapy because this choice empowers them by allowing them to take responsibility for their own recovery (15).\n\nInsomnia and delusions affected our patient's life. In the state of insomnia, he suffered from delusions repeatedly; therefore, he could not maintain his level of concentration during his work. In his view, sleepiness and hallucinations controlled his life. CBT-i worked very well, partially because LAI eased the patient's hallucinations and delusions and this change made his sleep problems more easily treatable.\n\nDuring the courses of CBT-i treatment, the authors and the patient focused mainly on the four causes cited by Chiu et al. (30), and the 12 problems cited by Waite et al. (31). For instance, as Chiu's fourth cause, the medication side effects were evident as the source of the true problem of sleep disturbance in the sixth session, and the authors and the patient could therefore agree to stop chlorpromazine. Furthermore, this discontinuation of regular use of chlorpromazine also made the authors noticed that the patient's maladaptive use of antipsychotic drugs as painkiller. Consequently, the patient could stop the use of chlorpromazine completely. Based on Waite's first problem involving a poor sleep environment, the patient bought a new blackout curtain and an air conditioner. Waite's third problem involving a lack of evening activity led us to change the patient's routine around dinner, and thus prevent napping after eating. These kinds of time consuming, persistent efforts improved not only his sleep quality but also his self-esteem.\n\nConcluding remarks\nLike this patient, schizophrenia patients can benefit from CBT-i, as other psychiatric and non-psychiatric patients do. This means that having a psychotic diagnosis is not a criterion for exclusion from CBT-i. This approach, in combination with pharmacological treatment, may offer psychotic patients an additional advantage in terms of sleep quality and overall quality of life, when compared to anti-psychotic drug treatment alone. During the CBT-i course, the patient's sleep stabilized. Furthermore, if CBT-i is properly tailored to the patient, physicians and patients will benefit from finding cognitive distortions or maladaptive behaviors, as this case showed that the authors managed to reduce the use of antipsychotics through correcting the fallacious use of antipsychotic drugs as a painkiller. The authors cannot determine the ratio of the contributions of CBT-i and LAI, but the authors believe that CBT-i was needed to stabilize psychiatric symptoms through strengthening the patient's sleep and self-efficacy. The authors suggest that physicians and patients consider the possibility that schizophrenia with severe sleep disturbance can be ameliorated through this treatment of the sleep disturbance. This case report is a demonstration of the efficacy of the combination of CBT-i and anti-psychotic drugs in schizophrenia with a comorbid insomnia disorder.\n\nEthics statement\nThis case study was carried out in accordance with the recommendations of the Ethical Committee of Shimane University Faculty of Medicine with written informed consent from the subject. The subject gave written informed consent in accordance with the Declaration of Helsinki. Written informed consent was also obtained from the patient for the publication of this case report.\n\nAuthor contributions\nMI, HM, MH, SM, TM: substantial contributions to the conception or design of the work; MI, AS, IA, RA, KT, TA, AO-N, RAA, and MK: acquisition, analysis, or interpretation of data for the work; MI, HM, SH, RW, TM, and JH: drafting the work or revising it critically for important intellectual content; MI, HM, AS, MH, SM, AO-N, IA, RA, KT, TA, RAA, MK, SH, RW, TM, and JH: final approval of the version to be published.\n\nConflict of interest statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Haynes PL Parthasarathy S Kersh B Bootzin RR . Examination of insomnia and insomnia treatment in psychiatric inpatients . Int J Ment Health Nurs. (2011 ) 20 :130 –6 . 10.1111/j.1447-0349.2010.00711.x 21371228 \n2. 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BMC Psychiatry (2015 ) 15 :285 . 10.1186/s12888-015-0678-4 26573691 \n33. Stevens GL Dawson G Zummo J . Clinical benefits and impact of early use of long-acting injectable antipsychotics for schizophrenia . Early Interv Psychiatry (2016 ) 10 :365 –77 . 10.1111/eip.12278 26403538\n\n",
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"issn_linking": "1664-0640",
"issue": "9()",
"journal": "Frontiers in psychiatry",
"keywords": "cognitive behavioral therapy; cognitive behavioral therapy for insomnia(CBT-i); insomnia; long acting injectable antipsychotic(LAI); schizophrenia",
"medline_ta": "Front Psychiatry",
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"pmid": "29946274",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
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"title": "Cognitive Behavioral Therapy for Insomnia as Adjunctive Therapy to Antipsychotics in Schizophrenia: A Case Report.",
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{
"abstract": "Pneumomediastinum is a rare complication of substance use, likely due to a Valsalva maneuver after drug inhalation. There are no previously documented associations between pneumomediastinum and opioid use. A 30-year-old man with a history of recent heroin and fentanyl inhalation presented to the emergency department in respiratory distress requiring intubation. His course was complicated by pneumomediastinum which subsequently developed tension physiology. He required emergent surgical decompression with a \"blowhole incision\" to his anterior chest. Although a rare complication of polysubstance use, pneumomediastinum can progress to tension physiology, requiring prompt diagnosis and management.",
"affiliations": "Department of Emergency Medicine, University of California San Diego, San Diego, CA, USA. Electronic address: rnene@ucsd.edu.;Department of Emergency Medicine, University of California San Diego, San Diego, CA, USA.;Department of Surgery, Division of Cardiovascular and Thoracic Surgery, University of California San Diego, San Diego, California, USA.;Department of Surgery, Division of Cardiovascular and Thoracic Surgery, University of California San Diego, San Diego, California, USA.;Department of Surgery, Division of Cardiovascular and Thoracic Surgery, University of California San Diego, San Diego, California, USA.;Department of Surgery, Division of Cardiovascular and Thoracic Surgery, University of California San Diego, San Diego, California, USA.;Department of Emergency Medicine, University of California San Diego, San Diego, CA, USA.;Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of California San Diego, San Diego, CA, USA.",
"authors": "Nene|Rahul V|RV|;Hryniewicki|Adam T|AT|;Roderick|Elizabeth|E|;Chicotka|Scott|S|;Vazquez|Moises Hernandez|MH|;Thistlewaite|Patricia A|PA|;Coffey|Christanne|C|;Odish|Mazen F|MF|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.ajem.2021.09.008",
"fulltext": "\n==== Front\n8309942\n1286\nAm J Emerg Med\nAm J Emerg Med\nThe American journal of emergency medicine\n0735-6757\n1532-8171\n\n34556391\n10.1016/j.ajem.2021.09.008\nnihpa1768896\nArticle\nCase report: Tension pneumomediastinum from opioid inhalation\nNene Rahul V. MD PhD a*\nHryniewicki Adam T. MD a\nRoderick Elizabeth MD b\nChicotka Scott MD b\nVazquez Moises Hernandez MD b\nThistlewaite Patricia A. MD, PhD b\nCoffey Christanne MD a\nOdish Mazen F. MD c\na Department of Emergency Medicine, University of California San Diego, San Diego, CA, USA\nb Department of Surgery, Division of Cardiovascular and Thoracic Surgery, University of California San Diego, San Diego, California, USA\nc Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of California San Diego, San Diego, CA, USA\nAuthor contributions\n\nRVN drafted the manuscript with assistance from ATH, ER, SC, MHV, PAT, CC, and MFO. All authors reviewed and assisted with revisions of the final manuscript. RVN takes responsibility for the manuscript as a whole.\n\n* Corresponding author. rnene@ucsd.edu (R.V. Nene).\n7 1 2022\n3 2022\n04 9 2021\n01 3 2022\n53 281.e5281.e8\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/).\nPneumomediastinum is a rare complication of substance use, likely due to a Valsalva maneuver after drug inhalation. There are no previously documented associations between pneumomediastinum and opioid use. A 30-year-old man with a history of recent heroin and fentanyl inhalation presented to the emergency department in respiratory distress requiring intubation. His course was complicated by pneumomediastinum which subsequently developed tension physiology. He required emergent surgical decompression with a “blowhole incision” to his anterior chest. Although a rare complication of polysubstance use, pneumomediastinum can progress to tension physiology, requiring prompt diagnosis and management.\n==== Body\npmc1. Introduction\n\nEmergency department visits related to substance use disorder are becoming increasingly common [1], and emergency physicians should be prepared for the myriad ways these patients can present. Spontaneous pneumomediastinum (SPM) is a rare complication of substance use, and patients typically present with chest pain, shortness of breath, sore throat, and neck pain [2]. SPM usually has a benign course and self-resolves without intervention. However, rarely, SPM can progress to tension physiology, especially in patients requiring positive pressure ventilation. We present a case of tension pneumomediastinum associated with opioid inhalation and describe the medical and surgical management of such cases.\n\n2. Case report\n\nA 30-year-old incarcerated man with a history of polysubstance abuse presented with shortness of breath. He admitted to smoking fentanyl and heroin a few hours prior to arrival. His symptoms began the morning of presentation, including fatigue, malaise, and nausea. On arrival, the patient was afebrile, with a blood pressure of 105/97 mmHg, heart rate of 120 beats per minute, respiratory rate of 36 per minute, and initial oxygen saturation of 81% on room air, with improvement to 98% on 15 l nonrebreather facemask. He was toxic appearing. Bilateral rhonchi and crepitus along the anterior chest wall were noted on initial lung exam. The rest of his physical exam was unremarkable.\n\nChest x-ray was notable for pneumomediastinum with no evidence of pneumothorax (Fig. 1). The patient’s mental status and respiratory status worsened, requiring emergent intubation. Enhanced computed tomography (CT) scan of the chest confirmed extensive pneumomediastinum (Fig. 2). Thirty minutes later, the patient became more unstable and required vasopressor support, concerning for developing tension physiology. Repeat exam now showed the chest wall crepitus expanded to cover his entire anterior chest wall, neck, and lower face. The cardiothoracic surgery service was consulted for emergent surgical decompression of his pneumomediastinum, and a “blowhole incision” was performed at bedside. A 4-cm incision was made below the right clavicle and the incision depth was carried to the pectoralis major fascia, but did not enter muscle. A vacuum-assisted wound device (Wound vac: 3 M-KCI, San Antonio, TX) was placed within the defect, covered with an occlusive dressing, and suction begun at −125 mmHg (Fig. 3). His crepitus resolved over the next several hours, with x-ray resolution of his pneumomediastinum after 2 days. The patient was discharged on hospital day 21 neurologically intact.\n\n3. Discussion\n\n3.1. Pathophysiology\n\nPulmonary barotrauma is defined as alveolar damage secondary to positive pressure within the bronchial tree, leading to the accumulation of air in extra-alveolar areas, with the most common clinical manifestations being pneumothorax, pneumomediastinum, and subcutaneous emphysema [3]. In our case, we suspect that glottic closure immediately following deep inspiration from inhaled drug use created high positive pressure within the tracheobronchial tree, leading to alveolar rupture and tracking of air into the mediastinum, a phenomenon called the Macklin effect [4].\n\nInhalation or insufflation of multiple substances have been identified as risk factors in the development of SPM, including cocaine, marijuana, 3,4-Methyl enedioxy methamphetamine (MDMA), and nitrous oxide [5–8]. Case reports on SPM associated with methamphetamine, ketamine, mephedrone, hookah, and vaping have also been reported [9–12]. To our knowledge there are no previous case reports of heroin or other opioid inhalation or insufflation leading to SPM.\n\n3.2. Medical management\n\nSPM is typically a benign disease requiring only conservative management, including observation, bedrest, analgesics, and cough suppressants [2]. There is insufficient evidence to recommend the routine use of prophylactic antibiotics or administration of 100% oxygen. However, patients with pneumomediastinum receiving mechanical ventilation are at risk for further worsening barotrauma. Ventilator settings should be titrated to minimize respiratory rate, plateau pressure, and peak inspiratory pressures. This can be accomplished by reducing positive end-expiratory pressure (PEEP) and tidal volume (TV). For patients with persistent pneumomediastinum, extracorporeal membrane oxygenation (ECMO) may provide additional support [13,14].\n\n3.3. Surgical management\n\nSevere pneumomediastinum may result in tension physiology similar to cardiac tamponade. The increase in mediastinal pressure compromises venous return to the heart, leading to cardiovascular collapse [15]. This rare complication has no well-established treatment modality, however multiple surgical approaches have been historically described, such as decompressive sternotomy [16] and chest tube placement directly within the mediastinum [17]. Our cardiothoracic surgeons chose a less invasive procedure, utilizing a modified “blowhole incision” with negative pressure wound therapy (NPWT), which was also effective at resolving the patient’s extensive subcutaneous emphysema (Figs. 3 and 4). Although the incision does not directly violate the mediastinum, the connection between the tissue planes and the application of the NPWT is effective in draining the mediastinal air [18].\n\n4. Why should an emergency physician be aware of this?\n\nPatients with polysubstance abuse frequently visit emergency departments and can present with various vague complaints. Emergency physicians should be aware of the association between drug ingestion and thoracic barotrauma, as well as its management. In severe cases requiring intubation, emergency physicians should understand initial ventilator management strategies. They should also be aware that pneumomediastinum can progress to tension physiology, requiring emergent decompression.\n\nFinancial support\n\nMazen Odish is currently receiving a grant (T32GM121318) from National Institutes of General Medical Sciences, National Institute of Health.\n\nFig. 1. Chest x-rays during hospitalization. A. Initial chest x-ray at presentation, demonstrating air within the mediastinum (arrow). B. Chest x-ray post intubation, 3 h after arrival. C. X-ray during tension physiology, demonstrating extensive subcutaneous air (star), 4 h after arrival. D. X-ray following blowhole incision and resolution of pneumomediastinum and subcutaneous air, hospital day 3.\n\nFig. 2. Enhanced computed tomography during hospitalization demonstrating pneumomediastinum, extensive subcutaneous emphysema, and eventual resolution. A: coronal section, hospital day 1. B: transverse section, hospital day 1. C: coronal section, hospital day 4, D: transverse section, hospital day 4. Arrows: mediastinal air. Star: lung consolidation, likely from a combination of atelectasis, aspiration and pneumonia.\n\nFig. 3. Application of negative pressure wound therapy. A: A 4 cm incision is made on the anterior chest below the clavicle. B: Blunt dissection is carried down to maximize egress of the subcutaneous emphysema. C: Black wound vacuum sponge is placed in the wound bed. D: Negative suction pump is connected.\n\nFig. 4. Blowhole Incision on Anterior Chest with a Negative Pressure Wound Vacuum. Chest tattoo blurred for patient confidentiality.\n\nConflicts of interest\n\nNone.\n==== Refs\nReferences\n\n[1] QuickStats. Number of emergency department visits for substance abuse or dependence per 10,000 persons aged ≥18 years, by age group — United States, 2008–2009 and 2016–2017. MMWR Morb Mortal Wkly Rep. Dec. 2019;68 (50 ): 1171. 10.15585/mmwr.mm6850a7.31856150\n[2] Takada K , Management of spontaneous pneumomediastinum based on clinical experience of 25 cases. Respir Med. Sep. 2008;102 (9 ):1329–34. 10.1016/j.rmed.2008.03.023.18585025\n[3] Gotway MB , Thoracic complications of illicit drug use: an organ system approach. RadioGraphics. Oct. 2002;22 (suppl_1 ):S119–35. 10.1148/radiographics.22.suppl_1.g02oc01s119.12376606\n[4] Macklin CC . Transport of air along sheaths of pulmonic blood vessels from alveoli to mediastinum. Arch Intern Med. Nov. 1939;64 (5 ):913. 10.1001/archinte.1939.00190050019003.\n[5] Costeira De FS , Vieira F , Gomes FM , Leite C . Pneumomediastinum and subcutaneous emphysema: complication of cocaine use. BMJ Case Rep. Oct. 2019;12 (10 ). 10.1136/bcr-2019-229205.\n[6] Weiss ZF , Gore S , Foderaro A . Pneumomediastinum in marijuana users: a retrospective review of 14 cases. BMJ Open Respir Res. 2019;6 (1 ):e000391. 10.1136/bmjresp-2018-000391.\n[7] Obiechina NE , Jayakumar A , Khan Y , Bass J . Bilateral pneumothorax, surgical emphysema and pneumomediastinum in a young male patient following MDMA intake. BMJ Case Rep. Apr. 2018;2018. 10.1136/bcr-2017-223103.\n[8] Tavare AN , Li D , Hare SS , Creer DD . Pneumomediastinum and pneumorrhachis from recreational nitrous oxide inhalation: no laughing matter. Thorax. 2018;73 (2 ): 195–6. 10.1136/thoraxjnl-2017-210291.28743767\n[9] Chen G-A , Yang C-C . Late diagnosis of methamphetamine inhalation related pneumothorax, pneumomediastinum and diffuse subcutaneous emphysema: a case report. J Acute Med. Mar. 2018;8 (1 ):30–3. 10.6705/j.jacme.201803_8(1).0005.32995199\n[10] Williams J , Hsu E , Flamer-Caldera A , Ferrabolli YJ . The special K constellation, a rare presentation of ketamine use: a case report. Cureus. May 2019;11 (5 ):e4766. 10.7759/cureus.4766.31363447\n[11] Graham R , Bowen N , Singh J . Mephedrone inhalation causes pneumomediastinum. BMJ Case Rep. Mar. 2014;2014. 10.1136/bcr-2014-203704.\n[12] Alaska YA . Spontaneous pneumomediastinum secondary to hookah smoking. Am J Case Rep. May 2019;20 :651–4. 10.12659/AJCR.915118.31056536\n[13] Daoud O , Extracorporeal membrane oxygenation in 5 patients with bronchial fistula with severe acute lung injury. Ann Thorac Surg. Jul. 2011;92 (1 ):327–30. 10.1016/j.athoracsur.2011.01.060.21718865\n[14] Odish MF , Treatment of bronchopleural and alveolopleural fistulas in acute respiratory distress syndrome with extracorporeal membrane oxygenation, a case series and literature review. Crit Care Explor. May 2021;3 (5 ):e0393. 10.1097/CCE.0000000000000393.34036268\n[15] Beg MH , Reyazuddin , Ansari MM . Traumatic tension pneumomediastinum mimicking cardiac tamponade. Thorax. Jul. 1988;43 (7 ):576–7. 10.1136/thx.43.7.576.3212757\n[16] Jennings S , Peeceeyen S , Horton M . Tension pneumomediastinum after blunt chest trauma. ANZ J Surg. Jan. 2015;85 (1–2 ):90–1. 10.1111/ans.12378.24172602\n[17] Campisi A , Poletti V , Ciarrocchi AP , Salvi M , Stella F . Tension pneumomediastinum in patients with COVID-19. Thorax. Dec. 2020;75 (12 ):1130–1. 10.1136/thoraxjnl-2020-215012.32747475\n[18] Son BS , Lee S , Cho WH , Hwang JJ , Kim KD , Kim DH . Modified blowhole skin incision using negative pressure wound therapy in the treatment of ventilator-related severe subcutaneous emphysema. Interact Cardiovasc Thorac Surg. Dec. 2014;19 (6 ):904–7. 10.1093/icvts/ivu287.25164135\n\n",
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"affiliations": "Department of Cardiology, Mt. Sinai Medical Center/Bronx VA, Bronx, New York, USA.",
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"title": "Intracoronary abciximab use in patients undergoing PCI at a community hospital: a single operator experience.",
"title_normalized": "intracoronary abciximab use in patients undergoing pci at a community hospital a single operator experience"
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"abstract": "Thrombotic microangiopathy (TMA) is a rare but severe complication of tumors and their chemotherapeutic treatment. We report on two patients with chemotherapy-induced TMA who were successfully treated with a short course of the terminal complement inhibitor eculizumab. Both patients quickly achieved remission of microangiopathic hemolytic anemia and recovery of renal function. After withdrawal of eculizumab, remission was stable over an observation period of 47 months and 15 months, respectively. Our data show that eculizumab is effective in treating chemotherapy-induced TMA. Discontinuation of eculizumab is feasible once the complement-activating condition is controlled and the trigger is eliminated. Additional studies need to determine the optimal duration of complement-directed therapies and validate effective monitoring strategies after discontinuation of such therapy.",
"affiliations": "Section of Nephrology, University Hospital, Ulm.;Section of Nephrology, University Hospital, Ulm.;Section of Nephrology, University Hospital, Ulm.;Section of Nephrology, University Hospital, Ulm.;Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, and University Hospital Ulm.;Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, and University Hospital Ulm.;Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany.;Section of Nephrology, University Hospital, Ulm.;Section of Nephrology, University Hospital, Ulm.",
"authors": "Schulte-Kemna|Lena|L|;Reister|Barbara|B|;Bettac|Lucas|L|;Ludwig|Ulla|U|;Fürst|Daniel|D|;Mytilineos|Joannis|J|;Bergmann|Carsten|C|;van Erp|Rene|R|;Schröppel|Bernd|B|",
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"doi": "10.5414/CNCS109836",
"fulltext": "\n==== Front\nClin Nephrol Case Stud\nDustri\nClinical Nephrology. Case Studies\n2196-5293 Dustri-Verlag Dr. Karl Feistle \n\n10.5414/CNCS109836\nCase Report\nNephrology!--Bitte Füllen-->\nEculizumab in chemotherapy-induced thrombotic microangiopathy \nSchulte-Kemna Lena 1 Reister Barbara 1 Bettac Lucas 1 Ludwig Ulla 1 Fürst Daniel 23 Mytilineos Joannis 23 Bergmann Carsten 4 van Erp Rene 1 Schröppel Bernd 1 1 Section of Nephrology, University Hospital, Ulm, \n2 Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, and University Hospital Ulm, \n3 Institute of Transfusion Medicine, University of Ulm, and \n4 Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany\nCorrespondence to Bernd Schröppel, MD Section of Nephrology, University Hospital, 89070 Ulm, Germany bernd.schroeppel@uniklinik-ulm.de\n2020 \n17 4 2020 \n8 25 32\n2 4 2019 28 2 2020 © Dustri-Verlag Dr. K. Feistle2020 This is an open-access article distributed under the terms of the Creative\nCommons Attribution License, which permits unrestricted use, distribution, and\nreproduction in any medium, provided the original work is properly cited.Thrombotic microangiopathy (TMA) is a rare but severe complication of tumors and their chemotherapeutic treatment. We report on two patients with chemotherapy-induced TMA who were successfully treated with a short course of the terminal complement inhibitor eculizumab. Both patients quickly achieved remission of microangiopathic hemolytic anemia and recovery of renal function. After withdrawal of eculizumab, remission was stable over an observation period of 47 months and 15 months, respectively. Our data show that eculizumab is effective in treating chemotherapy-induced TMA. Discontinuation of eculizumab is feasible once the complement-activating condition is controlled and the trigger is eliminated. Additional studies need to determine the optimal duration of complement-directed therapies and validate effective monitoring strategies after discontinuation of such therapy. \n\nthrombotic microangiopathycomplementeculizumabchemotherapyremissionaHUS\n==== Body\nIntroduction \nThrombotic microangiopathy (TMA) encompasses a group of disorders presenting with microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and ischemic organ damage, most frequently of the kidneys and the central nervous system [1, 2]. \n\nAtypical hemolytic uremic syndrome (aHUS) is a complement-mediated TMA caused by dysregulation of the alternative complement pathway. At least 50% of patients have an underlying inherited or acquired complement abnormality, exacerbated by complement-activating conditions, like infections, drugs, pregnancy, or cancer [3, 4]. \n\nDrug-induced TMA has been reported with antineoplastic agents including gemcitabine, docetaxel, and doxorubicin [5, 6, 7]. Direct cytotoxic and immune-mediated endothelial damage have been proposed as underlying pathologies [5]. While immune-mediated damage generally shows acute onset within 2 – 3 weeks of drug exposure, the clinical manifestation of cytotoxic damage is either acute or slowly progressive with cumulative dose-dependent toxicity [5, 8, 9]. Distinguishing cancer-related TMA as a consequence of cancer itself from cases of chemotherapy-induced TMA can be challenging. However, metastatic disease is more common in cancer-related TMA, whereas in chemotherapy-induced TMA, little or no active malignancy is detectable [10]. While discontinuation of the offending drug and supportive care are the primary treatment options in drug-induced TMA, in some cases this intervention is unable to limit the already dysregulated complement activity and requires therapeutic complement inhibition. \n\nEculizumab, approved as therapy for aHUS in 2011, is a humanized monoclonal antibody that binds to the complement component C5, preventing its cleavage into C5a and ultimately the formation of the membrane attack complex (SC5b-9) [11]. \n\nWhile the contributory role of complement dysregulation in drug-induced TMA is increasingly acknowledged, data on the efficacy of eculizumab, the duration of such therapy, and the incidence and type of detected complement abnormalities are sparse. \n\nHere, we report on two patients with chemotherapy-induced TMA, who were successfully managed with temporary eculizumab therapy and remained relapse free for a follow-up of 47 and 15 months, respectively. \n\nCase reports \nPatient 1 \nA 52-year-old woman admitted with acute onset of altered mental status, bloody diarrhea, and anuric acute kidney injury. Six months prior to admission, chemotherapy with docetaxel, doxorubicin, and cyclophosphamide was started for invasive ductal breast cancer. The last dose of chemotherapy was administered 3 days before symptoms started. Admission laboratory showed serum creatinine of 480 µmol/L, Coombs-negative hemolytic anemia with schistocytes on peripheral blood smear and thrombocytopenia of 64/µL. Lactate dehydrogenase (LDH) was 1,658 IU/mL and haptoglobin < 0.10 g/L. Coagulation tests were within the normal range, international normalized ratio (INR) 1.3 and partial thromboplastin time (PTT) 35 seconds, ruling out disseminated intravascular coagulation. Shiga toxin producing E. coli associated hemolytic uremic syndrome (STEC-HUS) was excluded by negative stool cultures for Shiga toxin-producing E. coli strains. Stool cultures for shigella, salmonella, campylobacter, and yersiania as well as PCR for Clostridium difficile were negative. Thrombotic thrombocytopenic purpura (TTP) was excluded by ADAMTS13 activity of 37% of control values. No ADAMTS13 antibodies were detected. \n\nShortly after admission, she developed seizures with respiratory failure requiring intubation. With the diagnosis of TMA, therapeutic plasma exchanges (TPE) were started. Daily TPE over 12 days and steroid therapy showed no effect on clinical symptoms and hemolysis. She had persistent seizures and required renal replacement therapy. Eculizumab was eventually initiated 20 days after admission. Immediately after the first dose of eculizumab, we observed a rapid and dramatic improvement of neurological symptoms. Renal replacement therapy could be discontinued 2 weeks later. Eculizumab was administered 6 times over a period of 5 weeks (Figure 1A). Breast-conserving surgery was performed 7 weeks after termination of eculizumab, followed by radiation therapy. During 47 months of follow-up, renal function continued to improve (eGFR 68 mL/min), and no relapse of TMA has occurred (Figure 1A) (Table 2). \n\nNext-generation sequencing identified a homozygous polymorphism in complement factor H (CFH) gene (synonymous variant c.1419 G>A, p.Ala473Ala). CFH autoantibodies were not detected. \n\nPatient 2 \nA 57-year-old woman admitted with hypertensive urgency, progressive decline of renal function, and MAHA. She was diagnosed with pancreatic cancer 30 months prior to admission and since then treated with gemcitabine and Nab-paclitaxel. Chemotherapy had been discontinued 6 weeks earlier when a decline in renal function, hemolytic anemia, and mild thrombocytopenia (130/µL) was first noted. \n\nAdmission laboratory showed serum creatinine of 363 µmol/L (eGFR 11 mL/min), Coombs negative hemolytic anemia with schistocytes on peripheral blood smear, and thrombocytopenia of 108/µL. LDH was 760 IU/mL, haptoglobin < 0.10 g/L, and coagulation tests were within the normal range (INR 1, PTT 31 seconds). Stool cultures were negative for Shiga toxin-producing E. coli, and ADAMTS13 activity was 61% of control values. Urinalysis showed proteinuria with a protein/creatinine ratio of 0.8 g/g. Several plasma infusions were given without improvement of hemolysis or renal function. The patient received eculizumab 7 days after admission, followed by prompt resolution of hemolysis and improvement of renal function. Eculizumab was discontinued after a total of 8 doses over a period of 10 weeks. During 15 months of follow-up, renal function remained stable (eGFR 36 mL/min), and no relapse of TMA occurred (Figure 1B) (Table 2). The patient died of pancreatic cancer 18 months after initial hospital admission. \n\nNext-generation sequencing identified a heterozygous polymorphism in CFH gene (synonymous variant c.1419 G>A, p.Ala473 Ala). \n\nDiscussion \nWe report on two patients with chemotherapy-induced TMA, persistent after discontinuation of the culprit drug and TPE/plasma infusion. In both patients, the clinical response to therapy with eculizumab was prompt and remission stable after cessation of treatment. Treatment with eculizumab was well tolerated, and no adverse events were reported. \n\nDue to limited clinical experience, the optimal strategy for treatment of chemotherapy-induced TMA, especially the role of eculizumab, is not yet clear. Discontinuation of the offending drug and supportive care are the primary treatment options. Due to the long turnaround time for us to receive the results of the ADAMTS13 activity plasma infusions (case #2) and therapeutic plasma exchange (case #1) was initially used. \n\nIn agreement with others we found that TPE/plasma infusion was not effective in patients with chemotherapy-induced TMA [12, 13, 14, 15, 16, 17, 18]. \n\nPatient 1 presented, among other symptoms, with bloody diarrhea. However, the presence of diarrhea is not sufficient to exclude other forms of TMA as ~ 30 – 40% of aHUS and TTP cases involve gastrointestinal symptoms, including bloody diarrhea [19, 20]. \n\nGenetic mutations leading to dysregulation of the alternative complement pathway or autoantibodies against complement regulatory proteins are identified in ~ 50% of aHUS patients [4]. However, genetic variants in complement regulatory proteins are also detected in patients with secondary, e.g., chemotherapy-induced, TMA [3]. In such patients, the underlying dysregulation of the alternative complement system may be unmasked by the applied drug, acting as a complement-activating trigger. Given the incomplete penetrance of the genetic defects, complement-activating conditions play an important role for the development of TMA [3, 21, 22]. \n\nIn most patients with TMA, a complement-activating trigger can be identified, and in 28% of patients with an activating trigger, a genetic risk mutation can be found [3]. \n\nThe largest group of aHUS-associated mutations occurs in the CFH gene, and more than 60% of these mutations are clustered within the C-terminal recognition region [23, 24, 25]. CFH is a central regulator of the alternative pathway of complement by acting as a cofactor to factor I in the breakdown and inactivation of C3b [26]. \n\nIn both of our patients, we identified a polymorphism in the CFH gene (c.1419 G>A). This variant has a high allele frequency in the general population, and its isolated occurrence seems not to be associated with an increased aHUS risk [27]. \n\nThe mechanism of gemcitabine-related TMA appears to be dose-related with a reported incidence of 1%. Both immune-mediated and cytotoxic injury have been proposed as underlying pathophysiology [12, 28]. Cytotoxic damage is the assumed mechanism in the few described cases of doxorubicin- and docetaxel-related TMA [5, 6, 29]. \n\nTo date, several cases of the use of eculizumab in chemotherapy-induced TMA have been reported, most of them regarding gemcitabine (summarized in Table 1). Before the availability of eculizumab, a case series reported ~ 29 patients with suspected gemcitabine-related TMA. Despite discontinuation of gemcitabine, 7 (24%) patients progressed to end-stage renal disease (ESRD), and 3 (10%) patients developed chronic renal failure [30]. These reports and our observation support induction therapy with eculizumab in cases of persisting TMA. \n\nEculizumab is approved for lifelong therapy of aHUS. However, the possible side effects, especially the risk of meningococcal infection, the inconvenience of a bi-monthly application, and the significant costs have prompted interest in alternative dosing schedules and complete discontinuation. A recent review analyzed data from unpublished cases, published case reports, clinical trials, and the Global aHUS Registry regarding patient outcomes after eculizumab discontinuation [31]. Of the case reports, a subsequent TMA manifestation was observed in 31% (16/52) of patients after eculizumab discontinuation. Data from five clinical trials documented a relapse in 20% (12/61) of patients after cessation of therapy with eculizumab with a median follow-up of 24 weeks. Terminal renal failure occurred in 5% (3/61) of the patients. Of note, relapse risk was independent of an identified genetic mutation, high-risk polymorphism, or autoantibody status. Data from the Global aHUS Registry found a relapse in 16% (12/76) of patients. In the cases described above, disease recurrence was unpredictable in both timing and severity [31]. \n\nThe French aHUS Registry described a relapse rate after eculizumab discontinuation in 31% (12/38) of the patients [32]. The risk of recurrence was higher in the presence of complement gene variants. The highest risk was associated with CFH variants, whereas no relapse was seen in patients without identified mutations or negative CFH autoantibodies. In case of relapse, early reinstitution (≤ 48 hours) of eculizumab resulted in rapid hematologic remission and a return of serum creatinine to baseline level [32]. \n\nWhile current evidence suggests a relapse rate after eculizumab discontinuation of ~ 30%, there is little available clinical data for estimating the risk of relapse in chemotherapy-induced TMA [29]. \n\nIn 2017, the KDIGO controversies conference published recommendations for best treatment strategies in aHUS. No evidence was currently seen to support lifelong therapy in all aHUS patients. The consensus suggested that eculizumab withdrawal could be considered on an individual and risk-stratified basis after a minimum treatment duration of 6 – 12 months to ensure recovery of endothelial damage [33]. Important risk factors for TMA relapses constitute an identified genetic mutation, former TMA episodes, or concomitant permanent or likely recurrent complement-activating condition. Close monitoring of renal function and hematological parameters after eculizumab withdrawal is mandatory; however, there are no evidence-based data about the reliability of a specific parameter and the optimal frequency of testing [33]. \n\nIn summary, our report supports the role of complement-directed therapy with eculizumab as an effective therapeutic option in the management of refractory chemotherapy-induced TMA. In our opinion, eculizumab discontinuation is feasible in carefully selected patients after permanent removal of the complement-activating condition. Further studies are needed to elucidate the role of genetic variants in complement-regulatory proteins in chemotherapy-induced TMA and to define parameters predictive of complement activation and likely TMA recurrence. Until then, the decision to withdraw eculizumab has to be made on an individual basis. \n\nFunding \nNone. \n\nConflict of interest \nB.S.: Consultant/Speaker Honoraria from Alexion, Amgen, Novartis, Astellas, Boehringer Ingelheim, Vifor Pharma, Astra-Zeneka, Janssen. Grants from Alexion, Sanofi, Pfizer. \n\nC.B. is an employee of Limbach and holds a part-time faculty appointment at the University of Freiburg. His research lab receives support from the Deutsche Forschungsgemeinschaft (DFG) DFG BE 3910/8-1 and DFG BE 3910/9-1, the Collaborative Research Center (SFB) KIDGEM 1140 and from the Federal Ministry of Education and Research (BMBF, 01GM1903I and 01GM1903G). He received speaker honoraria from Alexion and PTC Therapeutics. \n\nThe other authors do not have a conflict of interest. \n\nFigure 1. A: Case 1, induction therapy with 6 doses of eculizumab. Serum creatinine and thrombocytes from admission to last follow-up (week 211). Breast-conserving surgery was performed 7 weeks after withdrawal of eculizumab, followed by radiation therapy 3 months later. TPE = therapeutic plasma exchange; CVVHD = continuous veno-venous hemodialysis; HD = hemodialysis. B: Case 2, induction therapy with 8 doses of eculizumab. Serum creatinine and thrombocytes from admission to last-follow up (week 42). FFP = fresh frozen plasma.\n\nTable 1. Studies of chemotherapy-induced thrombotic microangiopathy treated with eculizumab. \nPatients \n(n)\tDrug\tPrevious therapy\tDoses of eculizumab (range) / duration of treatment\tMedian follow-up (range)\tImproved renal outcome\tGenetic analysis\tReference\t\n1\tGemcitabine\tDW + TPE + Steroids + RTX\t4 / 3 weeks\t17.5 weeks\tYes\tNT\tStarck [34] 2014\t\n1\tMitomycin C\tDW + TPE\t8 / 3 months\t18 months\tYes\tNT\tFaguer [35] 2013\t\n1\tCisplatin\tDW\tNot reported / 4 months\tNot reported\tYes, relapse 2 months after stop of eculizumab\tCD46 mutation\tGilbert [36] 2013\t\n4\tGemcitabine\tDW + TPE in 1 patient \nDW + steroids in 1 patient \nDW in 2 patients\t6.25 (5 – 8) / not reported\tNot reported\tYes\tNT\tAl-Ustwani [37] 2014\t\n1\tGemcitabine\tDW + TPE\t4 / not reported\t11 weeks\tNo\tND\tTsai [38] 2014\t\n1\tGemcitabine\tDW + Steroids\t6 / 7 weeks\t3 months\tNo\tNT\tKarkowsky [39] 2015\t\n1\tGemcitabine\tDW + TPE\t7 / 10 weeks\tNot reported\tYes\tNT\tRogier [16] 2016\t\n1\tGemcitabine\tDW + TPE\t7 / 8 weeks\t3 months\tYes\tNT\tLopez [40] 2017\t\n8\tGemcitabine\tDW\t4.5 (3 – 22) / not reported\tNot reported\tYes\tNT\tGrall [41] 2016\t\n7\tGemcitabine \nDasatinib \nBevacizumab \nBleomycin\tDW \nDW + TPE (2 patients)\tNot reported / 14 weeks \n(2 – 24 weeks), 1 ongoing\tNot reported\tYes\tNT\tWeitz/Deloughery [42] 2018\t\n2\tGemcitabine \nCarfilzomib\tDW + TPE\tNot reported\t42.5 weeks (33-52)\tYes\tNT\tGosain [43] 2017\t\n1\tGemcitabine\tDW + TPE\t20 / 9 months\t17 months\tYes\tNT\tKrishnappa [44] 2018\t\nDW = offending drug withdrawn; TPE = therapeutic plasma exchange; RTX = rituximab; NT = not tested; ND = not detected.\n\n\n\n\n\nTable 2. Summary case report 1 and 2. \nCase\tAge/ Gender\tCAC\tOrgan involvement/ Presentation\tGenetic\tEculizumab duration/doses\tCreatinine (µmol/L) at the end of eculizumab\tCreatinine (µmol/L) at last follow-up\tRelapse\tFollow-up (months)\t\n1\t52 y/F\tDocetaxel Doxorubicin\tKidney/acute \nCNS/acute \nLungs/acute\tCFH polymorphism synonymous variant \nc.1419 G>A, p.Ala4773 Ala\t5 weeks/6\t120\t83\tNo\t47\t\n2\t57 y/F\tGemcitabine\tKidney/chronic \nSevere hypertension\tCFH polymorphism \nSynonymous variant \nc.1419 G>A \np.Ala473 Ala\t10 weeks/8\t154\t140\tNo\t15\t\nCAC = complement activating condition; CNS = central nervous system; CFH = complement factor H.\n==== Refs\nReferences\n1 \nGeorge JN \nNester CM \nSyndromes of thrombotic microangiopathy.\n\nN Engl J Med .\n2014 ;\n371 :\n654 –666\n.\n25119611 \n2 \nMoake JL \nThrombotic microangiopathies.\n\nN Engl J Med .\n2002 ;\n347 :\n589 –600\n.\n12192020 \n3 \nNoris M \nCaprioli J \nBresin E \nMossali C \nPianetti G \nGamba S \nDaina E \nFenili C \nCastelletti F \nSorosina A \nPiras R \nDonadelli R \nMaranta R \nvan der Meer I \nConway EM \nZipfel PF \nGoodship TH \nRemuzzi G \nRelative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.\n\nClin J Am Soc Nephrol .\n2010 ;\n5 :\n1844 –1859\n.\n20595690 \n4 \nCampistol JM \nArias M \nAriceta G \nBlasco M \nEspinosa L \nEspinosa M \nGrinyó JM \nMacía M \nMendizábal S \nPraga M \nRomán E \nTorra R \nValdés F \nVilalta R \nRodríguez de Córdoba S \nAn update for atypical haemolytic uraemic syndrome: diagnosis and treatment. 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"fulltext_license": "CC BY",
"issn_linking": "2196-5293",
"issue": "8()",
"journal": "Clinical nephrology. Case studies",
"keywords": "aHUS; chemotherapy; complement; eculizumab; remission; thrombotic microangiopathy",
"medline_ta": "Clin Nephrol Case Stud",
"mesh_terms": null,
"nlm_unique_id": "101638685",
"other_id": null,
"pages": "25-32",
"pmc": null,
"pmid": "32318323",
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"abstract": "Intralesional mitomycin C after direct visual internal urethrotomy for recurrent urethral stricture disease in patients suboptimal for open urethroplasty is an established option. We report a case of urethro-cavernosal-spongiosal fistula after intralesional mitomycin C into an area of previous dorsal inlay urethroplasty. The patient presented with pus draining from the urethral meatus ten days after treatment. Sterile abscesses developed within the corporal and spongious bodies, draining freely into the urethra. Complete spontaneous healing followed short-term transurethral catheterization and antibiotic prophylaxis.",
"affiliations": "Medical University Innsbruck, Department of Urology, 35 Anich Street, 6020, Innsbruck, Austria.;Medical University Innsbruck, Department of Urology, 35 Anich Street, 6020, Innsbruck, Austria.;Medical University Innsbruck, Department of Urology, 35 Anich Street, 6020, Innsbruck, Austria.;Medical University Innsbruck, Department of Urology, 35 Anich Street, 6020, Innsbruck, Austria.;Medical University Innsbruck, Department of Urology, 35 Anich Street, 6020, Innsbruck, Austria.;Medical University Innsbruck, Department of Urology, 35 Anich Street, 6020, Innsbruck, Austria.",
"authors": "Rehder|Peter|P|;Pedrini|Marco|M|;Jelisejevas|Lukas Andrius|LA|;Gulacsi|Alexandra|A|;Horninger|Wolfgang|W|;Stuehmeier|Jannik|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2020.101281",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30169-8\n10.1016/j.eucr.2020.101281\n101281\nEndourology\nUrethro-cavernosal-spongiosal fistula after intralesional mitomycin C for recurrent urethral stricture disease\nRehder Peter peter.rehder@i-med.ac.at∗1 Pedrini Marco Jelisejevas Lukas Andrius Gulacsi Alexandra Horninger Wolfgang Stuehmeier Jannik 1 Medical University Innsbruck, Department of Urology, 35 Anich Street, 6020, Innsbruck, Austria\n∗ Corresponding author. peter.rehder@i-med.ac.at1 Peter Rehder and Jannik Stuehmeier are equally contributing first authors.\n\n\n25 5 2020 \n11 2020 \n25 5 2020 \n33 10128117 5 2020 21 5 2020 24 5 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Intralesional mitomycin C after direct visual internal urethrotomy for recurrent urethral stricture disease in patients suboptimal for open urethroplasty is an established option. We report a case of urethro-cavernosal-spongiosal fistula after intralesional mitomycin C into an area of previous dorsal inlay urethroplasty. The patient presented with pus draining from the urethral meatus ten days after treatment. Sterile abscesses developed within the corporal and spongious bodies, draining freely into the urethra. Complete spontaneous healing followed short-term transurethral catheterization and antibiotic prophylaxis.\n\nKeywords\nMitomycin CUrethro-cavernosal fistulaUrethral strictureComplication\n==== Body\nIntroduction\nMultimorbid patients with urethral stricture disease are challenging to manage. Patients that suffer from vascular incidents often end up with proximal bulbar strictures. Some of these are related to prolonged transurethral catheterization during intensive care, others suffer from relative hypoperfusion of the bulbar urethra during episodes of hypotension. The bulbar urethra has a dual blood supply, proximal from the bulbar urethral arteries, and distal via the dorsal penile arteries via the glans to the urethra. The search for non-operative solutions to treat recurrent stricture disease is ongoing. Mitomycin C (MMC) is an antibiotic isolated from Streptomyces caespitosus with antiproliferative properties. A study involving intraurethral mitomycin C in an experimental setting in rats, low dosages caused less fibrosis and higher dosages were toxic.1 Topical application of MMC inhibits fibroblast proliferation thus producing less type I collagen to limit scar formation. Intralesional MMC has shown potential to treat recurrent bladder neck contractures.2 We report about the development of an urethro-cavernosal-spongiosal fistula after transurethral intralesional MMC injection for the treatment of recurrent bulbo-penile stricture disease in a multimorbid patient.\n\nCase presentation\nIn 2011, a 66-year-old patient presented to the urology outpatient clinic with a weak urinary stream and incontinence after an open retropubic radical prostatectomy five years ago. Comorbidities are psoriasis vulgaris, obesity, hypertension and cardiovascular disease having suffered from a myocardial infarction 2001, and degenerative lumbar vertebral problems. The uroflow rate was 3,3ml/s with more than 50% residual of the bladder capacity of 650ml. The retrograde urethrogram demonstrated a tight proximal bulbar urethral stricture. Urethroscopy showed the stricture and multiple intraurethral calcifications. A dorsal inlay urethroplasty with a 3 × 5cm free thinned-out inner foreskin flap corrected the stricture (Fig. 1). At this stage, there were no clinical signs of lichen sclerosis. A transobturator retroluminal male sling treated the urinary incontinence. All went well for five years when the patient presented again in 2016 with a weak urinary stream. On clinical examination, he had meatal stenosis with signs of lichen sclerosis. Careful urethroscopy showed a tight urethral stricture just distal to the dorsal inlay foreskin patch. The meatal stenosis was dilated, and an internal urethrotomy done for the proximal penile urethral stricture. Intralesional mitomycin C was given at a concentration of 0,4mg/ml for a total of 1,6mg (Fig. 2). The patient was without symptoms for a whole year. In 2017, the same procedure was repeated. Six months after the second internal urethrotomy and intralesional MMC, the proximal urethral stricture recurred including narrowing of the distal urethra up to the meatus. The cardiovascular status of the patient deteriorated and a third dilatation and direct visual internal urethrotomy (DVIU) with intralesional MMC performed. One week after removal of the transurethral catheter, which remained for five days after surgery, the patient complained of pus draining from the urethra. Urine cultures remained negative. Micturition cystourethrography (MCUG) demonstrated contrast solution entering into the corpora spongiosum and cavernosum at the site of the dorsal inlay. Penile sonography and CT scan confirmed the urethro-cavernosal-spongiosal fistula (Fig. 3). Gentle manual pressure onto the base of penile shaft drained the abscess quite effectively. The patient was otherwise asymptomatic. A 16 French transurethral catheter drained the bladder for 1 week and ciprofloxacin 500mg twice daily given for 10 days. Follow-up MCUG and penile sonography confirmed resolution of the fistula. Later in 2018, the lichen sclerosis of the penile urethra worsened for which the patient receives regular urethral dilations. The cardiovascular status of the patient precludes surgery because of the high risk for general anaesthesia.Fig. 1 A and B) Urethral stricture with extensive intraurethral calcifications as seen on urethroscopy with a guidewire in position.\n\nC) Short tight proximal bulbar urethral stricture as seen on retrograde urethrography.\n\nD) Post-surgery result after dorsal inlay urethroplasty with arrows indicating the length of the patch during micturition cystourethrography (MCUG).\n\nFig. 1Fig. 2 A) Endoscopic view of recurrent urethral stricture at distal end of inlay urethroplasty.\n\nB) Retrograde urethrography showing recurrent urethral stricture at distal end of inlay urethroplasty.\n\nC) Intralesional mitomycin C given after direct visual internal urethrotomy. Arrow indicates the proximal healed dorsal inlay graft.\n\nD) Calibre difference on MCUG indirectly indicating distal urethral lichen sclerosis.\n\nFig. 2Fig. 3 A) MCUG showing extravasation into corporal and spongious bodies indicating presence of urethro-cavernosal-spongiosal fistula ten days after intralesional mitomycin C in the area of the previous dorsal inlay urethroplasty.\n\nB) Liquefaction of tissues within both spongious and corporal bodies indicated with arrows on contrast CT scan.\n\nC) Urethroscopy showing intact urothelium six weeks after healing.\n\nD) MCUG six weeks after spontaneous healing of fistula without any signs of extravasation.\n\nFig. 3\n\nDiscussion\nIn 2007, the effects of treatment with mitomycin C in anterior urethral stricture recurrence after internal urethrotomy were published. There was a fair amount of controversy concerning the dosage and application to be intraluminal, intralesional or suburothelial, whether it should be repeated and if how often.3 Evidence suggests it to be useful in patients who are suboptimal candidates for open reconstruction. Lichen sclerosis poses an altogether different problem for which MMC is not recommended.4 We know that intravesical MMC given after transurethral resection of bladder tumour with extravasation has led to serious fistula formation.5 In our case, intralesional injection of MMC involved the area of the previous dorsal inlay in the proximal bulbar urethra. This possibly predisposed the patient to develop the urethro-cavernosal-spongiosal fistula. As all microbiotic cultures remained negative, and the pus drained freely, spontaneous recovery was uneventful. The DVIU might also cause a fistula, but as there was no bleeding during or after the procedure, and the delayed presentation of the urethral discharge makes it highly likely that the mitomycin C lead to formation of the fistula.\n\nConclusion\nUrethro-cavernosal-spongiosal fistula after transurethral intralesional mitomycin C for recurrent urethral stricture disease is a potentially very serious complication. Spontaneous recovery in this multimorbid patient was fortunate. MMC for the therapy in urethral stricture disease still needs further intensive investigation. The use should be limited for individualized cases in competent hands, preferably at centres of expertise in controlled studies. Finding ways to treat recurrent urethral stricture disease in patients with many comorbidities would save these patients from living with transurethral or suprapubic catheters. Intralesional MMC after dorsal inlay urethroplasty is contraindicated.\n\nDeclarations of interest\nNo author has conflicts of interest for this paper.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nPatient data anonymized and patient's consent obtained for publication.\n==== Refs\nReferences\n1 Ayyildiz A. Nuhoglu B. Gulerkaya B. Effect of intraurethral Mitomycin-C on healing and fibrosis in rats with experimentally induced urethral stricture Int J Urol : Off. J. Jpn. Urol. Assoc. 11 12 2004 1122 1126 \n2 Vanni A.J. Zinman L.N. Buckley J.C. Radial urethrotomy and intralesional mitomycin C for the management of recurrent bladder neck contractures J Urol 186 1 2011 156 160 21575962 \n3 Mazdak H. Meshki I. Ghassami F. Effect of mitomycin C on anterior urethral stricture recurrence after internal urethrotomy Eur Urol 51 4 2007 1089 1092 discussion 92 17157434 \n4 Farrell M.R. Lawrenz C.W. Levine L.A. Internal urethrotomy with intralesional mitomycin C: an effective option for endoscopic management of recurrent bulbar and bulbomembranous urethral strictures Urology 110 2017 223 227 28735714 \n5 Dangle P.P. Wang W.P. Pohar K.S. Vesicoenteric, vesicovaginal, vesicocutaneous fistula -an unusual complication with intravesical mitomycin Can J Urol 15 5 2008 4269 4272 18814818\n\n",
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"abstract": "A triple-negative breast cancer patient had no hereditary BRCA1, BRCA2, or TP53 risk variants. After exhaustion of standard treatments, she underwent experimental treatments and whole-exome sequencing of tumor, blood, and a metastasis. Well-tolerated experimental bortezomib monotherapy was administered for a progression-free period of 11 mo. After progression, treatments were changed and the exome data were evaluated, expanded with RNA and exome sequencing of a late-stage metastasis. In the final stage, eribulin alone and in combination with anthracyclines were administered. While suffering from grade 3 adverse events, skin metastases progressed. She lived 51 mo after initial diagnosis.Toxicity from anthracyclines and cisplatin may have been due to associated germline variants CBR3 C4Y and V224M and GSTP1 I105V, respectively. Somatic mutations predicted or reported as pathogenic were detected in 38 genes in tumor tissues. All tumor samples harbored the heterozygous TP53 Y220C variant, known to destabilize p53 and down-regulate p53-mediated apoptosis. The success of bortezomib may be explained by the previously reported up-regulation of caspase-mediated apoptosis, which is p53-independent. Phylogenetic analysis of blood, primary tumor, and two metastases inferred an ancestral tumor cell with 12 expressed tumor mutations from which all three tumors may have evolved.Although our first urgent analysis could only include 40 genes, postmortem analysis uncovered the aggressiveness and suggested experimental therapies including 16 actionable targets, partly validated by immunohistochemistry. Exome and transcriptome analyses yielded comprehensive therapy-relevant information and should be considered for patients at first diagnosis.",
"affiliations": "Department of Molecular and Experimental Medicine, Avera Cancer Institute, La Jolla, California 92037, USA.;Department of Molecular and Experimental Medicine, Avera Cancer Institute, La Jolla, California 92037, USA.;Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.;Department of Medicine A, Hematology and Oncology, University Hospital Muenster, D-48149 Muenster, Germany.;Department of Medicine A, Hematology and Oncology, University Hospital Muenster, D-48149 Muenster, Germany.;Department of Medicine A, Hematology and Oncology, University Hospital Muenster, D-48149 Muenster, Germany.;Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, D-48149 Muenster, Germany.;Institute of Pathology Mannheim, University Hospital Mannheim, D-68167 Mannheim, Germany.;Department of Medicine IV, Hematology and Oncology, University Hospital of Halle (Saale), D-06120 Halle, Germany.;Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schleswig-Holstein, D-24105 Kiel, Germany.;Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schleswig-Holstein, D-24105 Kiel, Germany.;Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA.;Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schleswig-Holstein, D-24105 Kiel, Germany.;Department of Pediatric Haematology and Oncology, Hannover Medical School, D-30625 Hannover, Germany.;Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schleswig-Holstein, D-24105 Kiel, Germany.",
"authors": "Meißner|Tobias|T|;Mark|Adam|A|;Williams|Casey|C|;Berdel|Wolfgang E|WE|;Wiebe|Stephanie|S|;Kerkhoff|Andrea|A|;Wardelmann|Eva|E|;Gaiser|Timo|T|;Müller-Tidow|Carsten|C|;Rosenstiel|Philip|P|;Arnold|Norbert|N|;Leyland-Jones|Brian|B|;Franke|Andre|A|;Stanulla|Martin|M|;Forster|Michael|M|",
"chemical_list": "D016159:Tumor Suppressor Protein p53; D000069286:Bortezomib; D000429:Alcohol Oxidoreductases; C531130:CBR3 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi",
"country": "United States",
"delete": false,
"doi": "10.1101/mcs.a001677",
"fulltext": "\n==== Front\nCold Spring Harb Mol Case StudCold Spring Harb Mol Case StudcshmcscshmcscshmcsCold Spring Harbor Molecular Case Studies2373-2873Cold Spring Harbor Laboratory Press 2867969110.1101/mcs.a001677MeibnerMCS001677Research ReportMetastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events TNBC TP53-mutated patientTNBC TP53-mutated patientMeißner Tobias 1Mark Adam 1Williams Casey 2Berdel Wolfgang E. 3Wiebe Stephanie 3Kerkhoff Andrea 3Wardelmann Eva 4Gaiser Timo 5Müller-Tidow Carsten 610Rosenstiel Philip 7Arnold Norbert 78Leyland-Jones Brian 2Franke Andre 7Stanulla Martin 9Forster Michael 71 Department of Molecular and Experimental Medicine, Avera Cancer Institute, La Jolla, California 92037, USA;2 Department of Molecular and Experimental Medicine, Avera Cancer Institute, Sioux Falls, South Dakota 57105, USA;3 Department of Medicine A, Hematology and Oncology, University Hospital Muenster, D-48149 Muenster, Germany;4 Gerhard-Domagk-Institute of Pathology, University Hospital Muenster, D-48149 Muenster, Germany;5 Institute of Pathology Mannheim, University Hospital Mannheim, D-68167 Mannheim, Germany;6 Department of Medicine IV, Hematology and Oncology, University Hospital of Halle (Saale), D-06120 Halle, Germany;7 Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schleswig-Holstein, D-24105 Kiel, Germany;8 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Christian-Albrechts-University of Kiel, D-24105 Kiel, Germany;9 Department of Pediatric Haematology and Oncology, Hannover Medical School, D-30625 Hannover, Germany10 Present address: Department of Internal Medicine V, Hematology Oncology and Rheumatology, Heidelberg University Hospital, D-69120 Heidelberg, Germany\n\nCorresponding author: m.forster@ikmb.uni-kiel.de7 2017 3 4 a0016771 1 2017 24 4 2017 © 2017 Meißner et al.; Published by Cold Spring Harbor Laboratory Press2017This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.A triple-negative breast cancer patient had no hereditary BRCA1, BRCA2, or TP53 risk variants. After exhaustion of standard treatments, she underwent experimental treatments and whole-exome sequencing of tumor, blood, and a metastasis. Well-tolerated experimental bortezomib monotherapy was administered for a progression-free period of 11 mo. After progression, treatments were changed and the exome data were evaluated, expanded with RNA and exome sequencing of a late-stage metastasis. In the final stage, eribulin alone and in combination with anthracyclines were administered. While suffering from grade 3 adverse events, skin metastases progressed. She lived 51 mo after initial diagnosis.\n\nToxicity from anthracyclines and cisplatin may have been due to associated germline variants CBR3 C4Y and V224M and GSTP1 I105V, respectively. Somatic mutations predicted or reported as pathogenic were detected in 38 genes in tumor tissues. All tumor samples harbored the heterozygous TP53 Y220C variant, known to destabilize p53 and down-regulate p53-mediated apoptosis. The success of bortezomib may be explained by the previously reported up-regulation of caspase-mediated apoptosis, which is p53-independent. Phylogenetic analysis of blood, primary tumor, and two metastases inferred an ancestral tumor cell with 12 expressed tumor mutations from which all three tumors may have evolved.\n\nAlthough our first urgent analysis could only include 40 genes, postmortem analysis uncovered the aggressiveness and suggested experimental therapies including 16 actionable targets, partly validated by immunohistochemistry. Exome and transcriptome analyses yielded comprehensive therapy-relevant information and should be considered for patients at first diagnosis.\n\nductal carcinoma in situmultifocal breast carcinomaGerman Federal Ministry of Education and Research01ZX1306Cluster of Excellence “Inflammation at Interfaces”305564\n==== Body\nINTRODUCTION\nAbout one in five breast cancer patients test negative for the estrogen, progesterone, and Her2 receptors in their tumor tissues. The diagnosis of triple-negative breast cancer (TNBC) is associated with a higher recurrence rate and a less favorable prognosis than receptor-positive breast cancer. About 10% of younger patients with TNBC have a germline BRCA1 risk variant for contralateral breast cancer and ovarian cancer (Robertson et al. 2012). Breast cancer patients with a familial history of cancer or who are young are increasingly being offered genetic counseling and testing for germline risk variants in BRCA1, BRCA2, TP53, and other genes. Patients with germline BRCA risk variants are then offered bilateral mastectomy. Patients without germline TP53 risk variants may be offered adjuvant radiotherapy, whereas germline TP53 risk variant carriers may be at an increased risk for radiation induced secondary cancers. In addition to germline testing, breast cancer tissue testing is increasingly being proposed to match approved cancer drugs with the patient's individual somatic mutations or gene expression profile (Vasan et al. 2014; Meißner et al. 2015).\n\nAfter the initial diagnosis, the now deceased TNBC patient was tested for BRCA1, BRCA2, and TP53 germline risk variants when she underwent standard treatments. After segmentectomy, relapse, bilateral mastectomy, and completing the last line of standard treatments, the patient decided to undergo additional experimental off-label therapy. Her treatments, which included bortezomib, eribulin, and pembrolizumab, are summarized in Figure 1. Whole-exome sequencing was performed on peripheral blood (PB), primary tumor (PT), and a metastasis (MK), after standard treatments failed. Whole-exome sequencing was chosen to allow the analysis of ∼90% of all genomic protein coding regions, giving a much more complete scientific and potential clinical data yield than gene panel testing. Two years later, RNA and whole-exome sequencing were performed on a fine needle aspirate of a metastasis (MF) taken at the final stage of the disease. Detailed somatic mutation analysis was performed but interpretation could not be completed until postmortem. The mutational signatures (Fig. 2) were associated with defective DNA mismatch repair, which nowadays would probably trigger immunotherapy (Le et al. 2015).\n\nFigure 1. Patient history. Time line in months summarizing surgical procedures, diagnoses, drug treatments, adverse events, and molecular findings. Previously reported associations with gene variants/mutations are shown in red, and associations with gene expression are shown in green. Time line colors and boxes are yellow for germline, red for ancestral tumor cell, blue for mv2 (see Fig. 3), brown for primary tumor, lilac for first metasis (MK), gray for final metasis (MF), and orange for unsampled terminal tumor clones. Gene names are in italics, up-regulation is shown by an arrow, PSM members PSMB1 and PSMB5 of the proteasome family. tox, toxicity; mets, metastases; p53mut, mutated p53.\n\nFigure 2. Somatic signatures. Pie charts showing the weights of each Catalogue of Somatic Mutations in Cancer (COSMIC) somatic signature assigned for the samples primary tumor (A), MK (B), and MF (C). Signature 1: aging (i.e., the result of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine). Signature 3: found in breast, ovarian, and pancreatic cancers. It is associated with failure of DNA double-strand break repair by homologous recombination. It is strongly associated with germline and somatic BRCA1 and BRCA2 mutations in breast, pancreatic, and ovarian cancers. In pancreatic cancer, responders to platinum therapy usually exhibit Signature 3 mutations. Signature 5: found in all cancer types and most cancer samples. Etiology is unknown. Signature 6: associated with defective DNA mismatch repair and found in microsatellite unstable tumors. Signature 7: likely due to ultraviolet light exposure. Signature 12: usually contributes a small percentage (<20%) of the mutations observed in a liver cancer sample. Signature 15: associated with defective DNA mismatch repair. Signature 26: believed to be associated with defective DNA mismatch repair. Signature 29: has been observed only in gingivo-buccal oral squamous cell carcinoma, pattern of C>A mutations due to tobacco chewing.\n\nThe mutations furthermore allowed us to infer tumor evolution and an ancestral tumor cell (Fig. 3), which may have been of interest for treatment decisions, for diagnostic surveillance, and for the patient's own interest in understanding her disease. We analyzed germline pharmacogenomic variants in the exome data and found mutations associated with adverse drug toxicities from which the patient suffered. However, PharmGKB evidence levels for many of these drug–variant combinations are currently low. In summary, our aims were to find out (a) whether gene expression or somatic mutations may explain the efficacy of bortezomib in this patient, or her bone and soft tissue metastases, which were not detected early using CT and bone scintigraphy imaging, and (b) whether certain variants may explain her adverse reactions to anthracyclines, capecitabine, and cisplatin. Finally, we also discuss hypothetical treatment options arising from the completed analysis results.\n\nFigure 3. Tumor evolution phylogeny, ancestral tumor cell and mutation-matched drug associations. The phylogenetic network shows that all three tumor nodes branch from the inferred ancestral tumor cell node mv1, which is characterized by 12 somatically mutated genes including TP53, NOTCH3, and ADAM17. The gene names on the links are the differences between a pair of nodes, harboring a rare/novel mutation predicted or known as disease-causing. Bold names indicate genes previously reported for breast cancer/TNBC. Amino acid changes are shown in Human Genome Variation Society (HGVS) nomenclature, followed by functional consequences: (U) unknown; (L) loss of function; (N) unknown but possibly neutral. A star indicates that the mutated allele was detected in the RNA-seq of the final metastasis, and two stars indicate nonsense-mediated decay of the stopgain-mutated allele. TP53 harbors a known pathogenic mutation that is expressed. The primary tumor and first metastasis each harbor 3 additional somatically mutated genes including shared GABRA5, and the final metastasis shows 21 additional somatically mutated genes. Potentially favorable drugs are associated to the mutated genes with an arrow, and potentially unfavorable drugs with a “stop” arrow. Drugs that were administrated to the patient are not in parentheses; hypothetical drugs that target the known TP53 mutation with at least some human in vivo evidence that were not administered are in parentheses. (1) Stands for hypothetical drugs that are discussed in the Discussion. The patient's polymorphisms in the shown germline genes are associated with adverse toxicity and lower response.\n\nRESULTS\nClinical Presentation\nPrimary Tumor: Diagnosis and Treatment\nA 55-yr-old female of central European ancestry presented with breast cancer of the left mamma. Figure 1 summarizes her patient history, course of treatments, adverse events, and associated molecular findings. She had a previous history of pollinosis and of surgeries for appendicitis, tonsillitis, a cyst at the left thyroid gland, and varicosis. Her primary tumor was a poorly differentiated invasive ductal breast carcinoma in the left lower quadrant with distinct lymphangiosis carcinomatosa. Immunohistochemical (IHC) staining of tumor tissue for the estrogen, progesterone, and Her2 receptors was negative. In a blood test, no pathogenic germline risk variants were detected in BRCA1, BRCA2, or TP53. Surgical treatment consisted of segmentectomy of the left mamma after sonographic marking, sentinel node biopsy, and axillary lymphonodectomy. Surgery was followed by dose escalating dose-dense sequential adjuvant chemotherapy (Citron et al. 2003; Citron 2008) with 4× concurrent epirubicin and cyclophosphamide (EC) every 2 wk followed by paclitaxel, a microtubule-targeting agent, every 2 wk. In months 5 and 6, postoperative radiotherapy was performed on the left breast with a dose of 50.4 Gy and a boost to 61.2 Gy onto the tumor region in the lower left quadrant. Radiotherapy was furthermore applied to the ipsilateral supraclavicular and axillary lymph drainage region with a dose of 50.4 Gy.\n\nFirst Recurrence: Diagnosis and Treatment\nIn month 17, no signs of metastases were visible using computed tomography (CT) imaging. In month 18, we diagnosed a local recurrence on the left side, a secondary tumor in the operation scar region, and another tumor at 3 o'clock. Mastectomy was performed on the left breast and also—at the patient's decision—on the contralateral breast. Axillary dissection by the surgeon and histology by the pathologist showed histologically poorly differentiated invasive ductal mamma carcinoma and associated ductal carcinoma in situ (12 mm) with a high core malignancy score. Bone scintigraphy showed no signs of skeletal metastases. From months 18 to 20, three cycles of chemotherapy with cisplatin and ifosfamide were applied and then stopped because of complications (hyponatremia, genital abscess, superinfected mamma) and grade 3 adverse events (protracted nausea/emesis, hematological toxicity, polyneuropathy). From months 23 to 39, adjuvant therapy with bortezomib was applied in 14-d intervals.\n\nSecond Recurrence: Diagnosis\nIn month 36 the first clinical signs of local recurrence occurred. In month 39, an extensive local recurrence was diagnosed with diffuse lymphangiosis carcinomatosa and soft tissue infiltration in the left thoracic aperture, the left thoracic wall, and the shoulder girdle muscles, with infiltration into the truncus inferior of the left plexus brachialis. The patient suffered from paresis of the left shoulder. Multifocal locoregional soft tissue metastases were found prepectorally on the right side, mediastinally, along the left arteria thoracica interna, paraaortic in the abdomen, and interaortocavic immediately below the diaphragm. Bone metastases were seen in the marrow of the right proximal femur. Magnetic resonance imaging (MRI) indicated the possibility of pulmonal metastasis, and differential diagnosis came up with lymphonodular metastasis.\n\nPalliative Chemotherapy\nPalliative chemotherapy was applied using a combination of capecitabine and bevacizumab (antibody targeting VEGF) from months 39 to 43 with partial response and grade 2 and 3 hand–foot syndrome as subjectively tolerable adverse events. General system-wide and local progression occurred very suddenly in month 43, and the therapy was changed to vinorelbin monotherapy, a microtubule targeting agent. In month 46, CA15-3 increased considerably and local progression was seen, therefore the therapy was switched to gemcitabine. In month 47, rapid progression, pain, and swelling occurred. A skin metastasis biopsy was taken for IHC and next-generation sequencing analyses, and the therapy was changed to eribulin, a microtubule-targeting agent, leading to a clear response. In the course of month 48, progression occurred. Therefore, in month 49, therapy was changed to a combination of eribulin with pegylated doxorubicin, with grade 3–4 stomatitis as adverse events. Hospitalization then became necessary. Although differential diagnosis was not clear at this point, as to whether adverse events or tumor progression were the cause for the patient's deterioration, the doses of eribulin and pegylated doxorubicin were reduced. Pembrolizumab then was finally applied according to the patients’ wish. The patient died 6 d later as a result of cancer progression at 51 mo after first diagnosis.\n\nGenomic Analysis\nNext-Generation Sequencing\nSequencing statistics for whole-exome sequencing (WES) and RNA sequencing of the final metastasis sample are listed in Table 1. For samples PB, PT, and MK, a variant call format (VCF) file was available only, hence sequencing statistics were not available to us.\n\nTable 1. Next-generation sequencing statistics for sample MF (WES and RNA-seq)\n\n\tMF WES\tRNA-seq 50 ng\tRNA-seq 100 ng\t\nTotal reads\t41,389,563\t110,576,133\t81,360,029\t\nMapped reads\t99.15%\t97.42%\t97.64%\t\nDuplicated reads\t39.3%\t70.8%\t70.8%\t\nOn target ratea\t77.6%\t93.2%\t91.7%\t\nMean coveragea\t122×\tNot applicable\tNot applicable\t\nMF, final metastasis; WES, whole-exome sequencing.\n\naMapping statistics are based on TruSeq Exome regions and computed using Qualimap without the duplicated reads.\n\nSomatic Signatures\nMutational processes can be characterized by unique combinations of mutation types in the form of mutational signatures. We analyzed somatic mutations from the primary tumor sample and the two metastatic samples for mutational signatures based on a set of 30 signatures identified and hosted at Catalogue of Somatic Mutations in Cancer (COSMIC). We detected a total of 9/30 signatures (Signatures 1, 3, 5, 6, 7, 12, 15, 26, 29) among the three samples. Signatures 1, 3, and 12 were detected in all three samples. PT and MK shared signatures 1, 3, 7, 12, and 15, with signature 26 in addition being present in PT. Compared with PT and MK, MF did not have signatures 7, 15, and 26, but signatures 5, 6, and 29 were present (Fig. 2).\n\nPharmacogenomic Germline Variants\nRelevant germline variants were detected in CBR3, CYBA, CYP1B1, ERCC2, GSTP1, and SOD2, which are associated with toxicity or response to anthracyclines, cyclophosphamide, and cisplatin. These variants and the evidence levels as curated by PharmGKB (Whirl-Carrillo et al. 2012) are shown in Table 2.\n\nTable 2. Pharmacogenomic germline variants associated with toxicity and/or effectiveness\n\nGene\tGenomic coordinates (hg19)\tHGVS cDNA\tHGVS protein\tVariant type\tPharmGKB evidence level\tdbSNP\tGenotype\tComments\t\nCBR3\tChr 21: 37518706\tNM_001236: c.730G>A\tp.V244M\tMissense\t2B\trs1056892\thet\tHigher doxorubicin cardiotox.\t\nCBR3\tChr 21: 37507501\tNM_001236: c.11G>A\tp.C4Y\tMissense\t3\trs8133052\thet\tDoxorub. neutropenia, cardiotox.\t\nCYBA\tChr 16: 88713236\tNM_000101: c.214T>C\tp.Y72H\tMissense\t3\trs4673\thom\tLower acute doxorub. cardiotox.\t\nCYP1B1\tChr 2: 38298203\tNM_000104: c.1294G>C\tp.V432L\tMissense\t3\trs1056836\thet\tLess effective dose-intense paclitaxel\t\nDPYD\tChr 1: 98348885\tNM_000110: c.85C>T\tp.R29C\tMissense\t3\trs1801265\thom\tDecreased 5-FU tox risk\t\nERCC2\tChr 19: 45867259\tNM_001130867: c.862G>A\tp.D288N\tMissense\t3\trs1799793\thom\tLower cisplatin response\t\nGSTP1\tChr 11: 67352689\tNM_000852: c.313A>G\tp.I105V\tMissense\t2A\trs1695\thet\tIncreased cisplatin tox risk\t\nSOD2\tChr 6: 160113872\tNM_000636: c.47T>C\tp.V16A\tMissense\t2B\trs4880\thet\tLess effective cyclophosphamide, lower tox\t\nPharmGKB evidence levels: 2A, moderate evidence and variant in Very Important Pharmacogene; 2B, moderate evidence; 3, unreplicated or conflicting evidence.\n\nHGVS, Human Genome Variation Society; dbSNP, Database for Short Genetic Variations; het, heterozygous; hom, homozygous.\n\nTumor Evolution Phylogeny and Ancestral Tumor Cell Clone\nWe constructed a phylogenetic network from somatic mutations in the primary tumor, the first metastasis, and the final metastasis, using the peripheral blood sample as the germline node in the network. The somatic mutations that we focused on are shown in Figure 3. No homozygous mutation was seen among these somatic mutations. All included somatic mutations were either unknown or occur with a low allele frequency in the general population. Six of these mutations are known to occur in cancer patients (i.e., the TP53, HCFC1, ADD3, IL17RD, PIK3C2G, ROCK1 mutations) and all remaining mutations were predicted to be damaging by two prediction tools, MutationTaster (Schwarz et al. 2014) and Combined Annotation-Dependent Depletion (CADD) (Kircher et al. 2014). The network shows that all three tumor samples evolved from a common precursor tumor clone with 12 somatic mutations shared in all three tumor samples (Fig. 3). Of note, this precursor clone includes somatic missense mutations in TP53, HCFC1, ADAM17, and ITPR2, which are detailed in Table 3. The primary tumor additionally includes missense mutations in GABRA (shared with the first metastasis, Table 3), CHAD, and others (Table 3). The first metastasis (month 18) includes missense mutations in DKGZ and ADD3 (Table 3), and the final metastasis (month 47) harbors 18 additional missense mutations and also three stopgain mutations, in FXR1, PCDHGB4, and ROCK1 (Table 3).\n\nTable 3. Somatic rare pathogenic or predicted damaging mutations, which are discussed in the Results or Discussion\n\nGene\tGenomic coordinates (hg19)\tHGVS cDNA\tHGVS protein\tVariant type\tPredicted effect\tdbSNP, COSMIC\tGenotype\tComments\t\nShared mutations in all tumor samples\t\nADAM17\tChr 2: 9633900\tNM_003183: c.1969G>A\tp.D657N\tMissense\tD/34\t\thet\tRNA. TNBC, BrCa progression\t\nCCDC14\tChr 3: 123680145\tNM_022757: c.20G>C\tp.R7P\tMissense\tD/16\t\thet\tRNA. Centriole duplication\t\nHCFC1\tChr X: 153224834\tNM_005334: c.1553C>T\tp.S518F\tMissense\tD/25\t\thet\tRNA. BrCa driver, BRCA1 pathway\t\nITPR2\tChr 12: 26835564\tNM_002223: c.1191G>T\tp.W397C\tMissense\tD/21\t\thet\tRNA. BrCa\t\nNFRKB\tChr 11: 129758492\tNM_006165: c.373C>G\tp.R125G\tMissense\tD/17\t\thet\tRNA. Candidate oncogene\t\nNOTCH3\tChr 19: 15272207\tNM_000435: c.6232C>T\tp.R2078W\tMissense\tD/17\t\thet\tNeural development, BrCa\t\nRTN4\tChr 2: 55254481\tNM_020532: c.754C>G\tp.L252V\tMissense\tD/15\t\thet\tCell adhesion, migration, metastasis, and apoptosis\t\nSYBU\tChr 8: 110588198\tNM_001099746: c.572G>C\tp.R191P\tMissense\tD/21\t\thet\tRNA. Microtubule and neural associated\t\nTHRAP3\tChr 1: 36748223\tNM_005119: c.59C>T\tp.S20L\tMissense\tD/28\t\thet\tRNA. Cancer growth, damage response\t\nTP53\tChr 17: 7578190\tNM_000546: c.659A>G\tp.Y220C\tMissense\tD/22\trs121912666 COSM10758\thet\tRNA. Pathogenic. Germline in Li–Fraumeni, somatic\t\nTRPM6\tChr 9: 77390891\tNM_001177310: c.3296C>T\tp.P1099L\tMissense\tD/21\t\thet\tBrCa, magnesium homeostasis\t\nZNF384\tChr 12: 6781631\tNM_001135734: c.979G>A\tp.A327T\tMissense\tD/21\t\thet\tRNA. Fusions with TAF15 or EP300 in ALL\t\nShared mutations in primary tumor and first metastasis\t\nGABRA5\tChr 15: 27185116\tNM_000810: c.769A>T\tp.I257F\tMissense\tD/23\t\thet\tGABA inhibits BrCa cell migration\t\nPrivate mutations in primary tumor\t\nTCF3\tChr 19: 1619388\tNM_001136139: c.1253T>C\tp.L418P\tMissense\tD/17\t\thet\tNot a mutational driver in BrCa\t\nXXYLT1\tChr 3: 194991727\tNM_152531: c.61C>T\tp.R21C\tMissense\tD/24\t\thet\tNOTCH pathway\t\nPrivate mutations in first metastasis\t\nADD3\tChr 10: 111890220\tNM_001121: c.1708G>A\tp.E570K\tMissense\tD/33\tCOSM914716\thet\tEndometrial carcinoma\t\nDGKZ\tChr 11: 46354955\tNM_201532: c.130G>T\tp.E44X\tStopgain\tD/37\t\thet\tInduces cell-cycle arrest, is target of p53\t\nPrivate mutations in final metastasis\t\nFXR1\tChr 3: 180688068\tNM_001013438: c.1525C>T\tp.R509X\tStopgain\tA/36\t\thet\tRNA. Activation of cyclin-dependent kinase inhibitors, p53\t\nHMGCR\tChr 5: 74655244\tNM_001130996: c.2161A>T\tp.S721C\tMissense\tD/24\t\thet\tRNA. BrCa, dereg. lipogenesis ass. with mut. p53\t\nIL17RD\tChr 3: 57132008\tNM_017563: c.1723C>T\tp.R575W\tMissense\tD/16\tCOSM249014\thet\tRNA. BrCa. epithelial to mesenchymal transformation, migration/invas.\t\nIQGAP1\tChr 15: 90999512\tNM_003870: c.1741G>A\tp.D581N\tMissense\tD/20\t\thet\tRNA. BrCa. Cell invasiveness\t\nPCDHGB4\tChr 5: 140767815\tNM_003736: c.364G>T\tp.E122X\tStopgain\tA/34\t\thet\tNonsense-mediated decay. BrCa.\t\nPIK3C2G\tChr 12: 18552594\tNM_004570: c.2005C>T\tp.L669F\tMissense\tD/19\trs61754413\thet\tGene implicated in cancer development\t\nROCK1\tChr 18: 18535139\tNM_005406: c.3580A>T\tp.K1194X\tStopgain\tA/50\t\thet\tRNA. Malignant ascites in gastric cancer\t\nSLC15A1\tChr 13: 99339879\tNM_005073: c.1783G>A\tp.E595K\tMissense\tD/35\t\thet\tRNA. Overexpressed in some cancers. Substrate transport.\t\nHGVS, Human Genome Variation Society; dbSNP, Database for Short Genetic Variations; COSMIC, Catalogue of Somatic Mutations in Cancer; RNA, somatic mutation also detected in RNA-seq of final metastasis; TNBC, gene associated with triple-negative breast cancer; BrCa, gene associated with breast cancer; ALL, gene associated with acute lymphoblastic leukemia; het, heterozygous; hom, homozygous. Predicted effect from MutationTaster is disease-causing (D) or disease-causing-automatic (A), and from Combined Annotation-Dependent Depletion (CADD) is the Phred-like C score.\n\nRecurrent Somatic Nonsynonymous Mutations in All Three Tumor Tissue Samples\nThe somatic TP53 mutation p.Y220C (or p.Y61C, p.Y88C, or p.Y181C, depending on transcript variant; Database for Short Genetic Variations [dbSNP] ID rs121912666) (Table 3), was heterozygous in each tumor sample, with an allele frequency of ∼0.5 (between 0.36 and 0.58). It is a known somatic mutation in COSMIC in at least 37 breast cancer tissue samples (at time of writing), and also in ovary, esophagus, upper aerodigestive tract, and lung cancers. In ClinVar, the mutation has not previously been reported as a somatic tumor tissue mutation but has been reported as a pathogenic germline Li–Fraumeni syndrome variant. The mutation p.Y220C is localized in the core domain of p53 and by introducing a surface crevice it leads to accelerated denaturing of the protein at body temperature (Boeckler et al. 2008). The HCFC1 p.S518F mutation has been reported in a melanoma patient (Hugo et al. 2016) (patient 13). The remaining recurrent somatic mutations in all three tumor samples are not yet reported, to our knowledge. For SYBU the G>A and G>T mutations have been reported in COSMIC but not the patient's c.572G>C mutation. All somatic mutations were clearly detected in the RNA-seq data of the final metastasis, except for NOTCH3, TRPM6, and RTN4, with only one mutated RNA read each. For NOTCH3 and TRPM6, the wild-type expression was halved compared with the in-house healthy controls.\n\nRecurrent Somatic Nonsynonymous Mutation in Primary Tumor and First Metastasis\nThe GABRA5 mutation (Table 3) has not been reported to our knowledge and its functional consequences are unknown.\n\nPrivate Somatic Nonsynonymous Mutations in Primary Tumor\nThe mutations in TCF3 and XXYLT1 (Table 3) are novel to our knowledge.\n\nPrivate Somatic Nonsynonymous Mutations in First Metastasis\nThe stop mutation DGKZ p.E44* (Table 3) is novel to our knowledge. The missense mutation ADD3 p.E570K is reported in COSMIC to be seen in three The Cancer Genome Atlas (TCGA) endometrial carcinoma samples (http://cancer.sanger.ac.uk/cosmic/mutation/overview?id=914716). ADD3 p.E570K is predicted as tolerated by Alamut Visual (AlignGVD class C0, SIFT tolerated) but as disease-causing by MutationTaster and CADD.\n\nPrivate Somatic Nonsynonymous Mutations in Final Metastasis\nOf the 21 private mutations, all three stopgain mutations (ROCK1 p.K1194*, FXR1 p.R509*, PCDHGB4 p.E122*) are expressed on the RNA level and are predicted to be the most damaging (Table 3). The ROCK1 p.K1194* mutation lies in the first exon, knocking out all protein-binding regions of this allele, and has been reported in a lung cancer cell line (Sosonkina et al. 2014). The PCDHGB4 p.E122* mutation also lies in the first exon, within the cadherin protein domain. The mutation in FXR1 lies in exon 16 near the protein-binding region. Thirteen of the 18 private missense mutations were found expressed on the RNA level: ADRBK2, AGAP1, CEBPZ, CNTN3, DBNL, FBP2, HMGCR, IL17RD, IQGAP1, KLHL28, METTL4, SLC15A1, and WDR37 (Supplemental Table 1). IL17RD p.R575W has been reported as a somatic mutation in pancreatic cancer (Wu et al. 2011). The SLC15A1 (aka HPEPT1) p.E595K mutation has been reported as a loss-of-function mutation (Xu et al. 2009). The following genes or their somatically mutated alleles were not detected as expressed: CPXM2, DUSP26, KCNG2, LPPR4, PIK3C2G, and PCDHGB4. CPXM2 p.G50R was imputed as a germline variant for a noncancer patient (A Kainz, pers. comm.).\n\nDifferential Gene Expression\nWe analyzed differential gene expression by comparing the patient's expression data (two replicates) from the final metastasis sample against a set of 11 normal breast tissue controls. Of note, 9810/19,301 genes (51%) were significantly differentially expressed between the patient's tumor samples and the controls (Supplemental Table 2). A total of 4591 genes were up-regulated and 5219 genes were down-regulated. Of these genes, 4851 had a greater than twofold (log2) and 1536 a greater than fourfold (log2) difference in expression level. The 10 most up- and down-regulated genes are presented in Supplemental Table 3. Among the differentially expressed genes, 410 could be assigned as “breast cancer–relevant” based on a list of 433 breast cancer–relevant genes generated using GLAD4U webservice. The 10 most up- and down-regulated breast cancer relevant genes as defined by this method are presented in Supplemental Table 4. KEGG Pathway enrichment analysis on the differentially expressed, breast cancer–relevant genes revealed 31 KEGG pathways showing significant enrichment with those genes (Supplemental Table 5).\n\nDrug–Gene Interaction\nQuerying the Drug–Gene Interaction Database (DGIdb; http://dgidb.genome.wustl.edu/) (Griffith et al. 2013) for drug–gene interactions using differential up-regulated genes (log2 FC > 1) revealed a candidate list of 60 compounds across 16 genes (Table 4). With respect to the applied anthracyclines (epirubicin, doxorubicin), microtubule inhibitors (paclitaxel, vinorelbine, and eribulin), and bortezomib: TOP2A, members of the microtubule gene family, and members of the proteasome gene family and were up-regulated 29-fold, 3.6-fold, and 5.6-fold, respectively (Supplemental Table 2).\n\nTable 4. Overexpressed breast cancer relevant genes associated with clinical compounds\n\nSymbol\tEntrez\tLog2FC\tClinically actionable compound(s)\t\nRAD51\t5888\t5\tAmuvatinib\t\nTOP2A\t7153\t4.9\tDaunorubicin, Doxorubicin, Epirubicin, Idarubicin, Dexrazoxane, Lucanthone, Amsacrine, Mitoxantrone, Teniposide\t\nAURKB\t9212\t4.5\tDanusertib, Tozasertib, AT9283, GSK1070916, PF-03814735, Barasertib, SNS-314, ML8237\t\nAURKA\t6790\t4.3\tPF-03814735, Alisertib, SNS-314, AT9283, ENMD-2076, Danusertib, Tozasertib, ML8237\t\nCHEK1\t1111\t3.6\tRabusertib, SCH900776, AZD7762\t\nCHEK2\t11200\t2.0\tAZD7762\t\nNOTCH1\t4851\t2.0\tRO4929097, γ-Secretase\t\nPARP1\t142\t1.9\tVeliparib, Olaparib, Rucaparib\t\nPIK3R2\t5296\t1.9\tApitolisib, Pilaralisib, GSK2636771, Pictilisib, PI-103, Gedatolisib, SF1126, Sophoretin, Omipalisib\t\nRRM1\t6240\t1.8\tFludarabine, Gemcitabine, Hydroxyurea, Cladribine\t\nSYK\t6850\t1.7\tFostamatinib\t\nCDK4\t1019\t1.6\tPalbociclib, Abemaciclib, Ribociclib, Alvocidib\t\nAKT1\t207\t1.5\tMK2206, Ipatasertib, Perifosine, AZD5363\t\nMAP2K1\t5604\t1.4\tTAK-733, RO4987655, Pimasertib, Refametinib, AZD8330, Trametinib, Selumetinib, GDC-0623, Cobimetinib\t\nALK\t238\t1.3\tBrigatinib, Crizotinib, Ganetespib, Ensartinib, ASP3026\t\nERBB3\t2065\t1.1\tAV-203, GE-huMab-HER3, Patritumab, Seribantumab, LMJ716, REGN1400, H4B-121Ab, MM-111, Duligotuzumab, Istiratumab, GSK2849330, KTN3379, Osimertinib\t\nSources: MyCancerGenomeClinicalTrial, TALC, DrugBank, MyCancerGenome, CancerCommons (aggregated by DGIdb)—initial results returned from DGIdb have been manually revised and curated.\n\nBold indicates Federal Drug Administration (FDA)-approved drugs (on-label as well as off-label); all other drugs are preclinical or in clinical trials. Names ending in ib (small molecule inhibitor) or ab (antibody) indicate gene (or mutation) specificity.\n\nLog2FC, log2 of fold change.\n\nImmunohistochemical Staining\nTo validate the RNA-seq overexpression findings for sample MF in the absence of matched normal tissue from the same patient, we used antibody staining on the same tissue sample. We used antibodies that were available and properly established in our pathology laboratories. Figure 4 shows that CDK4 transcript up-regulation (threefold) and MKI67 up-regulation (13-fold) is clearly validated by IHC. ALK staining was negative, although RNA-seq analysis revealed a 2.4-fold up-regulation of transcript levels. Androgen receptor staining was weakly positive in 20% of lesional cells although RNA-seq indicated strong down-regulation in the patient's metastasis sample compared with the control samples.\n\nFigure 4. CDK4-immunohistochemical staining of final skin metastasis. Histopathological findings. (A) Islands of tumor cells are identified within the dermis (hematoxylin and eosin, 100×). (B) High Ki-67 proliferation index marks the nuclei of many neoplastic cells. This independently validates the 13-fold RNA-seq overexpression that was averaged over the final metastasis tissue sample (400×). (C) Tumor cell nuclei stain weakly but distinctly for CDK4, independently validating the threefold averaged RNA-seq overexpression (400×). (D) Isotype negative control with no detectable staining (400×).\n\nDISCUSSION\nIn this case study, we aimed to identify potential targeted drugs using an exome- and transcriptome-based molecular profile of the patient's tumor and metastases. We also examined whether the molecular profile may explain the response or nonresponse to the administered drugs, the adverse events to some of the drugs, and the high aggressiveness seen in this individual TNBC case. To rapidly inform of potential targeted drugs, we scanned the existing whole-exome results for novel and known drug-associated somatic tumor tissue mutations in only those genes that are listed in https://www.mycancergenome.org/ and some commercial cancer panels, as well as in TP53, BRCA1, BRCA2. This first scan only found a single mutation—that is, the heterozygous damaging somatic mutation in TP53 in both tumor samples but not the germline sample. Our later in-depth analyses confirmed the TP53 mutation to be drug- and disease-relevant in the context of the complete set of somatic mutations in the tumor samples. To inform of potential further targeted treatments (Table 4), we also sequenced the whole transcriptome from the final metastasis sample, scanned for overexpressed genes by comparing the patient's sample with a set of healthy breast tissue controls, and validated the overexpressed genes on the protein level using available antibody stains. Metastatic tumor nodes accumulate a significant number of mutations that should be considered for treatment and that were not present in the primary tumor. For this reason, we analyzed the complete whole-exome data of the primary tumor and the two metastatic samples, classified each tumor sample using the COSMIC somatic signatures, and performed extensive database and literature research for the identified somatic tumor tissue mutations that were predicted as damaging. Because more than one tumor sample was available, we were able to see the shared mutations in each tumor sample that could be addressed with the same treatment, which serves to narrow down the lengthy list of potential treatments.\n\nSomatic Signatures\nSomatic signatures from the Sanger Center's COSMIC website (http://cancer.sanger.ac.uk/cosmic/signatures) allow a quick classification based on lists of somatic tumor tissue mutations that may otherwise be difficult to interpret, and may provide a first answer for patients who ask how and why their tumor started. Figure 2 shows that the earlier tumors PT and MK are associated with aging and ultraviolet light exposure (∼25%–30% Signature 1 and ∼10% Signature 7) and failure of DNA damage repair (∼20%–25% Signature 3—BRCA1/2-related, and ∼15%–25% Signature 15). For PT, there is also ∼10% Signature 26, which is associated with defective DNA mismatch repair. The causes of Signature 12 (∼10%–20%) are unknown, probably because it is usually seen in liver metastases, which may arise from a wide range of primary tumors. For MF the main signature is DNA damage repair failure (∼40% Signature 3 and ∼15% Signature 6), aging (∼10% Signature 1), and relatively uninformative remaining signature contributions (∼10% unknown, ∼10% Signature 29—gingivo-buccal oral squamous cell carcinoma, ∼10% Signature 12—liver cancer, ∼10% Signature 5—found in most cancers with unknown etiology).\n\nTumor Evolution Phylogeny\nThe concept of applying phylogenetic methods to analyze tumor evolution is not new (Shibata 2012; Murtaza et al. 2015). Having established the tumor evolution phylogeny, it is tempting to estimate the timespan for the ancestral tumor cell to evolve into the primary tumor. This may give an indication of the time window for early detection of the expanding tumor cell population. A stringent estimation method including error bounds is given in Saillard et al. (2000), which assumes a star-like phylogeny and a linear mutation rate. In cancer cells, the mutation rate depends on the number of mutations and the genes that are mutated (Loeb and Loeb 2000). Our patient's tumor evolution phylogeny is nearly star-like, but with only three tumor samples it is too sparse for applying the stringent estimation method. Therefore, we compared the discovery times and branch lengths of the final metastasis and the primary tumor with each other, and taking the mutation rate to be identical for both branches, we estimated that there was a time window of possibly only 6 mo for earlier detection of the primary tumor in our patient.\n\nSomatic Mutations in the Inferred Ancestral Tumor Cell and Detected in All Three Tumor Samples\nTP53 p.Y220C\nThe heterozygous pathogenic somatic tumor tissue mutation rs121912666 in TP53 is probably not the single driver mutation, because it is reported in ClinVar as a pathogenic germline variant for Li–Fraumeni cases, meaning that affected patients can live disease free for years or decades. The 12 predicted damaging somatic tumor tissue mutations in the trunk of our phylogenetic tumor evolution tree (Fig. 3) also strongly suggest that the viable ancestral tumor cell required multiple damaging mutations that may include several or all of these 12 mutations or the nine mutations detected to be highly expressed in the RNA-seq. However, p53 is a key apoptosis protein. On the functional level, this specific p.Y220C mutation does not affect the binding regions but leads to protein destabilization and much more rapid denaturing than wild-type p53 (Boeckler et al. 2008). On the frequency level, the p.Y220C mutation is reported as the ninth most frequent p53 mutation, affecting approximately 75,000 new cancer patients worldwide every year (Boeckler et al. 2008). Specifically, the p.Y220C mutation (aka p.Y88C) has been reported as a heterozygous somatic driver mutation in a Chinese breast cancer patient (Song et al. 2015). In our patient, the mutated TP53 allele was expressed in 90% of all transcripts in the final metastasis that we biopsied. The p53-mediated apoptosis pathway may therefore have been impaired significantly in her tumor cells.\n\nIt can hence be argued that the success of 11 mo of progression-free survival under bortezomib (proteasome inhibitor) experimental treatment was due to p53-independent apoptosis. Bortezomib was selected by the treating clinician as off-label therapy because of a published role of proteasome inhibitors in TNBC as determined by short interfering RNA (siRNA) screens (Petrocca et al. 2013). The course of disease suggests but does not prove transient therapeutic activity. Bortezomib has previously been reported to up-regulate CASP3, CASP8, and CASP9 (Saha et al. 2010), and down-regulate BCL2 (Goktas et al. 2010). Significant up-regulation of some proteasome transcripts underlined this possible activity of bortezomib in the TNBC patient. The TP53 mutation also suggested use of BCL2 inhibition (venetoclax); however, the RNA-seq data were inconclusive because of low coverage in BCL2. Impaired p53 has been associated with doxorubicin resistance (Dunkern et al. 2003). To overcome the resistance, an in vitro experiment successfully combined doxorubicin with a PARP inhibitor (Muñoz-Gámez et al. 2005). APR-246 (aka PRIMA-1), the first drug in clinical trials that directly targets mutant p53 is currently in a Phase 1b/II clinical trial (PiSSARO, ClinicalTrials.gov ID NCT02098343). APR-246 showed strong synergies with cisplatin in p.Y220C-mutated cancer cell lines (Mohell et al. 2015), and also with olaparib in p53-mutated non-small-cell lung cancer cell lines (Deben et al. 2016). Further compounds such as PK7088 that specifically target the p.Y220C induced crevice are in preclinical development (Joerger and Fersht 2010; Liu et al. 2013).\n\nADAM17 p.D657N and NOTCH3 p.R2078W\nThe enzyme encoded by ADAM17, also known as tumor necrosis factor-α-converting enzyme (TACE) sheds the extracellular domain of various receptors such as heparin-binding EGF, transforming growth factor-α (TGFA), amphiregulin (AREG), neuregulin (NRG), epiregulin (EREG), and β-cellulin (BTC) (Meng et al. 2016) from the cell membrane leading to an activation of downstream signaling pathways with significance in triple-negative breast cancer cells (Caiazza et al. 2015). NOTCH3 is a reported breast cancer driver gene where inactivating mutations or deletions in the PEST domain activate the Notch pathway (Wang et al. 2015). For breast cancer, the known somatic mutations form a cluster in the PEST region of our patient's p.R2078G mutation (https://www.intogen.org/search?gene=NOTCH3&cancer=BRCA). NOTCH3 expression was nearly undetectable in our RNA-seq data of the tumor tissue. At the Avera Cancer Institute, we see ADAM17 and Notch aberrations quite often in TNBC (B Leyland-Jones, pers. comm.). γ-Secretase inhibitors are under development for this pathway (Olsauskas-Kuprys et al. 2013; Wang et al. 2015).\n\nThe Remaining Shared Somatic Mutations and Their Potential Co-Driver Roles\nThe HCFC1 gene is reported as a major downstream effector of BRCA1-associated protein 1 (Kamburov et al. 2015) and as a breast cancer driver gene (The Cancer Genome Atlas Network 2012). The HCFC1 mutation ties in with somatic signature 3, which is reported for BRCA1- or BRCA2-associated failure of DNA double-strand break repair. ITPR2 is associated with estradiol-induced breast cancer; ITPR2 inhibitors include caffeine and the experimental compounds 2-APB and xestospongin C (XeC) (Szatkowski et al. 2010). NFRKB modulates NFKB1 and is being evaluated as a candidate oncogene (Bueno et al. 2010). THRAP3 has been associated with prostate cancer growth (Ino et al. 2016) and DNA damage response (Beli et al. 2012). ZNF384 fusions with TAF15 or EP300 are associated with acute lymphoblastic leukemia (Ping et al. 2015; Kim et al. 2016). Together, these seven genes and their expressed mutated alleles appear to be a plausible driver mutation combination required for a viable ancestral tumor cell. The SYBU mutation also appears to be relevant because its expression is detected in MF, despite being so far known only to be expressed in nerve cells. SYBU encodes syntabulin, which is a microtubule-associated protein that mediates transport of vesicles to neuronal processes (Su et al. 2004; Ying et al. 2012). TRPM6 is involved in magnesium homeostasis and epithelial magnesium transport, and somatic mutations clustering in the same region have been reported in Chinese breast cancer patients (Zhang et al. 2015). The role of magnesium in cancer development is much debated (Trapani et al. 2016), and it seems to vary depending on stage such as carcinogenesis, primary tumor growth, and metastasis formation (V Trapani, pers. comm.). RTN4 is associated with cell adhesion, migration, metastasis, and apoptosis in various cancers (Chi et al. 2015; Xue et al. 2015). Mutated alleles of TRPM6 and RTN4 were nearly undetectable in our RNA-seq data of the tumor tissue.\n\nPerhaps Actionable Somatic Nonsynonymous Mutations That Do Not Appear in All Three Tumor Samples\nWe identified 26 mutations that were predicted damaging and that were not shared in all three tumor samples. The therapeutical and functional consequences of these mutations are currently not known, therefore any inferences are speculative. However, it is striking that nearly all of the mutated genes are known to be associated with TNBC, breast cancer, other cancers, invasion, metastasis, proliferation, relapse, and so on. A full discussion of all 26 genes is beyond the scope of this section, but interested readers can refer to the Supplemental Material for a short comment on the relevance of each gene. We now briefly discuss potential targets found to be mutated in the patient, for which inexpensive repurposed drugs and an expensive leukemia treatment could be considered.\n\nPrimary Tumor and First Metastasis\nRegarding mutated GABRA5 in the primary tumor (PT) and the first metastasis (MK), the wild-type gene encodes a receptor for its ligand GABA, which inhibits norepinephrine-induced migration of breast and colon carcinoma cells (Entschladen et al. 2004). Lorazepam, an approved GABA agonist often used to treat anxiety disorders in cancer patients, may have a potential use as an anti-metastatic drug (Entschladen et al. 2004). The nonspecific β-blocker propranolol inhibits norepinephrine-induced migration of breast cancer cells and increases the cytotoxicity of natural killer cells, reducing distant metastases and improving 10-yr survival significantly from 70% to 90% (Powe et al. 2010). In nonrandomized comparisons of treated versus untreated ovarian cancer cohorts—characterized by mutated p53 in most patients—propranolol cohorts showed increased median overall survival (Watkins et al. 2015).\n\nPrimary Tumor\nRegarding mutated TCF3 in the primary tumor, the wild-type gene encodes a key transcription factor for lymphopoiesis (Fischer et al. 2015), and a successful therapy protocol exists for the TCF3-PBX1 acute lymphoblastic leukemia subtype.\n\nFinal Metastasis\nRegarding the mutated genes HMGCR and IQGAP1 in the final metastasis (MF): HMGCR encodes the rate-limiting enzyme in the mevalonite pathway. Pharmacologic inhibition of HMGCR with statins is reported to inhibit breast cancer cell growth in vitro (Pampalakis et al. 2015), reduce the risk and/or severity of breast cancer (Clendening et al. 2010), exhibit antimetastatic and antitumorigenic effects in ovarian cancer (Stine et al. 2016), and show anticancer effects in gastric cells (Chushi et al. 2016). IQGAP1 was associated with breast cancer cell invasion (Alemayehu et al. 2013), and its protein was reported as one of two binding targets of disulfuram (an anti–alcohol addiction drug), as a suggested TNBC combination treatment with doxorubicin (Alemayehu et al. 2013).\n\nWhole-Transcriptome Sequencing\nWhole-transcriptome sequencing of tumor RNA is of immense value to inform of overexpressed target genes and fusions in addition to the targets that can be identified by DNA-based mutation analysis alone. Furthermore, the functional effect of a tumor mutation can sometimes be tracked by looking at the expression of genes downstream from the mutated gene. For example, a FLT3 mutation of “unknown significance” in combination with overexpression of the downstream RNA transcripts for RAS, RAF, and MEK would be hypothesized as an activating FLT3 mutation; therapeutic consequences would be consideration of FLT3 inhibitors quizartinib or sorafinib, or downstream MEK inhibitors trametinib or cobimetinib. (The FLT3 mutation was a low-confidence mutation in this case study, which turned out to be an artefact.) Lastly, mutations that are not seen in RNA may be of secondary interest as probably being passenger mutations, whereas mutations detected in DNA can be considered validated if also seen in RNA.\n\nIn this case study we compared the RNA-seq data from the final metastasis sample against in-house healthy controls to obtain gene expression profiles. We saw an up-regulation of breast cancer relevant genes, many of which have been reported to be associated with proliferation, tumor progression, poor prognosis, or resistance to therapy. A small selection will be discussed here, and the interested reader is referred to Supplemental Data for a discussion of further genes. The significance of the TP53 mutation that was detected in the exomes ties in with the expression-based gene set enrichment analysis that ranks the p53 signaling pathway on rank 2 (Supplemental Table 5). On the single-gene level, overexpression of survivin (BIRC5) supports the anti-apoptosis theme. Survivin overexpression has been shown to inhibit apoptosis, promote mitosis, and to facilitate angiogenesis (Lv et al. 2010). It has further been linked to drug/radiation resistance (Lv et al. 2010) as well as being associated with poor prognosis (Tanaka et al. 2000; Span et al. 2004). Survivin has been established as a specific cancer cell target for preclinical immunotherapeutics (Bertino et al. 2013). Overexpression of homeodomain transcription factor HOXB13 has been shown to correlate with tamoxifen resistance in ER-positive breast cancer (Shah et al. 2013). HOXB13 is used as a biomarker within the breast cancer index (BCI) (Sgroi et al. 2013; Sgroi and Brufsky 2016). Cyclin E1 (CCNE1) is a well characterized oncogene. Overexpression in breast cancer is associated with proliferation and poor prognosis (Caldon and Musgrove 2010). At the Avera Cancer Institute, we frequently observe aberrations in CCNE1 in TNBC and ovarian tumors (B Leyland-Jones, pers. comm.). CDK2 inhibitors are in clinical trials to target CCNE1 amplification. CCNE1 overexpression is in agreement with the highly significant cell-cycle pathway that the gene set enrichment analysis placed on rank 3 (Supplemental Table 5). The RAD51 overexpression ties in with the highly significant homologous recombination pathway in the gene set enrichment analysis (rank 6) and with the Somatic Signature 3 (Fig. 1, Homologous recombination failure in breast and other cancers). At the Avera Cancer Institute, we would consider a poly ADP ribose polymerase (PARP) inhibitor or a platinum-based therapy. RAD51 overexpression was also reported to increase during breast cancer progression and metastasis and to promote the development of distant metastasis in TNBC (Wiegmans et al. 2014).\n\nDown-regulation of the progesterone receptor (PGR) (Purdie et al. 2014) and of GSTM1 (S Willis, unpubl.) are prognostically bad (Supplemental Table 4). Topoisomerase II α (TOP2A) overexpression, independent from amplification, is highly associated with cell proliferation and aggressive tumor subtypes (Romero et al. 2011). TOP2A was up-regulated 29-fold, providing an expression-based rationale for therapeutic attempts with epirubicin and doxorubicin, but in the patient's case neither drug worked and she suffered from grade 3–4 stomatitis. The tubulin β chain (TUBB) expression was up-regulated 3.3-fold. The patient received paclitaxel, vinorelbin, and eribulin, which target tubulin β chain according to DrugBank (www.drugbank.ca). Although paclitaxel was applied within the Citron protocol, and vinorelbin and eribulin appeared to halt progression temporarily, their efficacy was disappointing compared with a Belgian trial (Aftimos et al. 2016) and not obvious compared with bortezomib. PSMB5 and PSMB1 were up-regulated 5.6-fold and threefold, respectively. These members of the proteasome gene family are inhibited by bortezomib (www.drugbank.ca), showing that not necessarily the highest up-regulated genes need be prioritized for a relatively long period of progression-free survival. A typical combination therapy to enhance the response to bortezomib in multiple myeloma is to add dexamethasone or to combine bortezomib, dexamethasone, and the histone deacetylase (HDAC) inhibitor panobinostat (which would have addressed the up to sevenfold up-regulated HDAC gene family members).\n\nHypothetical Surveillance of Treatment Response Using cfDNA Panels\nIn the terminal stage, the standard blood biomarker CA15-3 was stable, but skin metastases showed a completely different picture of rapid disease progression. The longitudinal detection at different treatment time points of somatic mutations in cell-free DNA (cfDNA) from blood plasma was first introduced on a large scale in the United States in 2014. In Germany, these longitudinal tests are not reimbursed by the public health insurers and are little known. The surveillance of the TP53 mutation, which would have been detected by any current cfDNA gene panel, possibly could have been more accurate than CA15-3 (Dawson et al. 2013; Heidary et al. 2014; Olsson et al. 2015). To gain information on actionable mutations, a broad cfDNA panel is needed. cfDNA next-generation sequencing (NGS) tests may pay for themselves by guiding drug choice and saving costs by detecting the lack of drug response at an early stage of treatment.\n\nConclusion\nThis was a first pilot for our ongoing multicenter collaboration to synergize our efforts and investigate methods to improve patient testing and the selection of therapies. This case study demonstrates that molecular profiling, if performed fast and early in the course of disease, can inform on potential targets and drugs, with the proviso that it alone cannot always reliably predict whether a drug will work: specifically, the patient's very high TOP2A expression level was an unsuitable biomarker for the selection of the anthracyclines that the patient received. Likewise, the RRM2 and TYMS overexpression do not appear suitable biomarkers for the indication of gemcitabine. However, the moderate TUBB overexpression tied in with the moderate and short-lived successes of vinorelbin and eribulin. The TYMS overexpression tied in with the moderate capecitabine response. The molecular case for possible bortezomib activity was plausible on the TP53 mutation level and the proteasome overexpression level. However, facing the multitude of genetic information and their potential link to pharmacologically actionable target patterns, from a clinical perspective it will be a major task to build relevance-based algorithms for interventions. Furthermore, every NGS-guided choice of targeted drugs has to be prospectively compared with clinical choice of therapy regimen delineated from several generations of controlled trials to place them correctly into our therapeutic armamentarium. In view of the tremendous amount of information that can be extracted from NGS and needs to be researched, validated, and summarized, timely whole-exome and transcriptome diagnostics should be considered at an early point in time, when the first line of treatment begins and when healthy reference tissue is still available. We suggest that mutated TP53 does not need to be seen as unrelated to treatments or as a desolate prognosis, but that many p53-independent treatments already exist that may be considered.\n\nMETHODS\nDNA library preparation and exome capture were executed using the Kapa Hyper Plus Library Prep Kit and the SeqCap EZ MedExome Target Enrichment Kit (Roche). Paired-end whole-exome sequencing was performed on the Illumina NextSeq 500 platform, with 150-bp reads. Alignment was done with Burrows–Wheeler alignment (BWA)-MEM against the human reference hg19 (Li and Durbin 2009). DNA alignments were processed according to GATK best practices steps (McKenna et al. 2010). GATK HaplotypeCaller version 3.3-0 and VarScan version 2.3.9 (Koboldt et al. 2012) were used to call variants. ANNOVAR was used to annotate the union of the two call sets (Wang et al. 2010). The phylogenetic network was constructed with Network 5.0.0.0 (Fluxus). Somatic signatures in the primary tumor and the metastatic samples were inferred using the deconstructSigs method (Rosenthal et al. 2016).\n\nRNA library preparation and targeted capture of libraries with exome baits were performed with the Illumina TruSeq RNA Access kit on two RNA aliquots as technical replicates. Paired-end RNA sequencing was performed on the Illumina NextSeq 500 platform with 76-bp reads. Mapping of RNA reads against the human reference hg19 and generation of gene counts were done using STAR (Dobin et al. 2013). RNA-seq count data were processed and differential expression analysis was performed using the DESeq2 Bioconductor package (Anders and Huber 2010), comparing the two patient tumor samples against a set of 11 in-house generated breast tissue controls. KEGG gene set enrichment analysis on differentially expressed and breast cancer relevant genes was performed using the g:ProfileR Bioconductor package (https://cran.r-project.org/web/packages/g.ProfileR/index.html). Drug–gene interactions for up-regulated genes were retrieved from the DGIdb database (Griffith et al. 2013).\n\nA detailed description of samples, NGS, and data analysis methods is available in the Supplemental Methods.\n\nADDITIONAL INFORMATION\nData Deposition and Access\nSomatic variants were reported to COSMIC under COSP identifier COSP42774 (Supplemental Table 6). Raw sequence data were submitted to the NCBI Sequence Read Archive under SRA BioProject ID PRJNA358250, BioSample IDs SAMN06168104, SAMN06168105, and SAMN06168106.\n\nEthics Statement\nThe patient provided written and verbal consent for the research, publication, and sharing of her data. This case study was approved by the ethics board of the University Hospital of Schleswig-Holstein under reference number D 433/17.\n\nAcknowledgments\nWe thank the patient for her medical data, samples, and cooperation. We thank Brandon Young, Amanda Andrews, Cayce Conolly, Dorina Ölsner, and Melanie Vollstedt for technical assistance and Peter Forster, Go Ito, Alexander Kainz, Klaus Pantel, Pradip De, and Valentina Trappani for valuable discussions.\n\nAuthor Contributions\nT.M. and M.F. designed research, analyzed the data, and wrote the manuscript. C.M.-T. organized sequencing of peripheral blood, primary tumor, and first metastasis. A.M. performed data analysis and helped to write the manuscript. E.W. and T.G. performed immunohistochemical staining and analysis. C.W. and B.L.-J. helped to interpret results and write the manuscript, especially the discussion of hypothetical treatment options. N.A., P.R., and A.F. helped to write the manuscript. M.S. relayed medical information from the patient, helped to design research, organize the study, analyze the data, interpret results, and write the manuscript. W.E.B., S.W., and A.K. treated the patient and helped to write the manuscript. All authors read and approved the final manuscript.\n\nFunding\nW.E.B.’s laboratory is supported by Deutsche Forschungsgemeinschaft (DFG EXC 1003 cells in motion cluster of excellence). The Institute of Clinical Molecular Biology is supported by the German Federal Ministry of Education and Research (BMBF) as part of the e:Med framework (“sysINFLAME”, grant 01ZX1306), the Cluster of Excellence “Inflammation at Interfaces” (ExC 306), SysMedIBD EU FP7 under grant agreement no. 305564 and DEEP IHEC (TP2.3 and 5.2, BMBF).\n\nCompeting Interest Statement\nM.F. cofounded Fluxus Technology Ltd (free Network 5.0.0.0 software).\n\nSupplementary Material\nSupplemental Material\n [Supplemental material is available for this article.]\n==== Refs\nREFERENCES\nAftimos P , Polastro L , Ameye L , Jungels C , Vakili J , Paesmans M , van den Eerenbeemt J , Buttice A , Gombos A , de Valeriola D , \n2016 \nResults of the Belgian expanded access program of eribulin in the treatment of metastatic breast cancer closely mirror those of the pivotal phase III trial . 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Bioinformatics \n25 : 1754 –1760 .19451168 \nLiu X , Wilcken R , Joerger AC , Chuckowree IS , Amin J , Spencer J , Fersht AR . 2013 \nSmall molecule induced reactivation of mutant p53 in cancer cells . Nucleic Acids Res \n41 : 6034 –6044 .23630318 \nLoeb KR , Loeb LA . 2000 \nSignificance of multiple mutations in cancer . Carcinogenesis \n21 : 379 –385 .10688858 \nLv Y-G , Yu F , Yao Q , Chen J-H , Wang L . 2010 \nThe role of survivin in diagnosis, prognosis and treatment of breast cancer . J Thorac Dis \n2 : 100 –110 .22263027 \nMcKenna A , Hanna M , Banks E , Sivachenko A , Cibulskis K , Kernytsky A , Garimella K , Altshuler D , Gabriel S , Daly M , DePristo MA . 2010 \nThe Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data . Genome Res \n20 : 1297 –1303 .20644199 \nMeißner T , Fisch KM , Gioia L , Su AI . 2015 \nOncoRep: an n-of-1 reporting tool to support genome-guided treatment for breast cancer patients using RNA-sequencing . BMC Med Genomics \n8 : 24 .25989980 \nMeng X , Hu B , Hossain MM , Chen G , Sun Y , Zhang X . 2016 \nADAM17-siRNA inhibits MCF-7 breast cancer through EGFR-PI3K-AKT activation . Int J Oncol \n49 : 682 –690 .27221510 \nMohell N , Alfredsson J , Fransson Å , Uustalu M , Byström S , Gullbo J , Hallberg A , Bykov VJN , Björklund U , Wiman KG . 2015 \nAPR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells . Cell Death Dis \n6 : e1794 .26086967 \nMuñoz-Gámez JA , Martín-Oliva D , Aguilar-Quesada R , Cañuelo A , Nuñez MI , Valenzuela MT , Ruiz de Almodóvar JM , De Murcia G , Oliver FJ . 2005 \nPARP inhibition sensitizes p53-deficient breast cancer cells to doxorubicin-induced apoptosis . Biochem J \n386 : 119 –125 .15456408 \nMurtaza M , Dawson S-J , Pogrebniak K , Rueda OM , Provenzano E , Grant J , Chin S-F , Tsui DWY , Marass F , Gale D , \n2015 \nMultifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer . Nat Commun \n6 : 8760 .26530965 \nOlsauskas-Kuprys R , Zlobin A , Osipo C . 2013 \nγ-Secretase inhibitors of Notch signaling . Onco Targets Ther \n6 : 943 –955 .23901284 \nOlsson E , Winter C , George A , Chen Y , Howlin J , Tang MH , Dahlgren M , Schulz R , Grabau D , van Westen D , \n2015 \nSerial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease . EMBO Mol Med \n7 : 1034 –1047 .25987569 \nPampalakis G , Politi AL , Papanastasiou A , Sotiropoulou G . 2015 \nDistinct cholesterogenic and lipidogenic gene expression patterns in ovarian cancer—a new pool of biomarkers . Genes Cancer \n6 : 472 –479 .26807200 \nPetrocca F , Altschuler G , Tan SM , Mendillo ML , Yan H , Jerry DJ , Kung AL , Hide W , Ince TA , Lieberman J . 2013 \nA genome-wide siRNA screen identifies proteasome addiction as a vulnerability of basal-like triple-negative breast cancer cells . 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Br J Cancer \n110 : 565 –572 .24300977 \nRobertson L , Hanson H , Seal S , Warren-Perry M , Hughes D , Howell I , Turnbull C , Houlston R , Shanley S , Butler S , \n2012 \nBRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years . Br J Cancer \n106 : 1234 –1238 .22333603 \nRomero A , Martín M , Cheang MCU , López García-Asenjo JA , Oliva B , He X , de la Hoya M , García Sáenz JÁ , Arroyo Fernández M , Díaz Rubio E , \n2011 \nAssessment of Topoisomerase II α status in breast cancer by quantitative PCR, gene expression microarrays, immunohistochemistry, and fluorescence in situ hybridization . Am J Pathol \n178 : 1453 –1460 .21435434 \nRosenthal R , McGranahan N , Herrero J , Taylor BS , Swanton C . 2016 \ndeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution . 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J Clin Oncol \n34 : 3941 –3942 .\nSgroi DC , Sestak I , Cuzick J , Zhang Y , Schnabel CA , Schroeder B , Erlander MG , Dunbier A , Sidhu K , Lopez-Knowles E , \n2013 \nPrediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: A prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population . Lancet Oncol \n14 : 1067 –1076 .24035531 \nShah N , Jin K , Cruz LA , Park S , Sadik H , Cho S , Goswami CP , Nakshatri H , Gupta R , Chang HY , \n2013 \nHOXB13 mediates tamoxifen resistance and invasiveness in human breast cancer by suppressing ERα and inducing IL-6 expression . Cancer Res \n73 : 5449 –5458 .23832664 \nShibata D . 2012 \nCancer. Heterogeneity and tumor history . Science \n336 : 304 –305 .22517848 \nSong F , Li X , Song F , Zhao Y , Li H , Zheng H , Gao Z , Wang J , Zhang W , Chen K . 2015 \nComparative genomic analysis reveals bilateral breast cancers are genetically independent . Oncotarget \n6 : 31820 –31829 .26378809 \nSosonkina N , Hong S-K , Starenki D , Park J-I . 2014 \nKinome sequencing reveals RET G691S polymorphism in human neuroendocrine lung cancer cell lines . Genes Genomics \n36 : 829 –841 .25530832 \nSpan PN , Sweep FCGJ , Wiegerinck ETG , Tjan-Heijnen VCG , Manders P , Beex LVAM , De Kok JB . 2004 \nSurvivin is an independent prognostic marker for risk stratification of breast cancer patients . Clin Chem \n50 : 1986 –1993 .15364883 \nStine JE , Guo H , Sheng X , Han X , Schointuch MN , Gilliam TP , Gehrig PA , Zhou C , Bae-Jump VL . 2016 \nThe HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer . Oncotarget \n7 : 946 –960 .26503475 \nSu Q , Cai Q , Gerwin C , Smith CL , Sheng Z-H . 2004 \nSyntabulin is a microtubule-associated protein implicated in syntaxin transport in neurons . Nat Cell Biol \n6 : 941 –953 .15459722 \nSzatkowski C , Parys JB , Ouadid-Ahidouch H , Matifat F . 2010 \nInositol 1,4,5-trisphosphate-induced Ca2+ signalling is involved in estradiol-induced breast cancer epithelial cell growth . Mol Cancer \n9 : 156 .20565939 \nTanaka K , Iwamoto S , Gon G , Nohara T , Iwamoto M , Tanigawa N . 2000 \nExpression of survivin and its relationship to loss of apoptosis in breast carcinomas . Clin Cancer Res \n6 : 127 –134 .10656440 \nThe Cancer Genome Atlas Network . 2012 \nComprehensive molecular portraits of human breast tumours . Nature \n490 : 61 –70 .23000897 \nTrapani V , Luongo F , Arduini D , Wolf FI . 2016 \nMagnesium modulates doxorubicin activity through drug lysosomal sequestration and trafficking . Chem Res Toxicol \n29 : 317 –322 .26918850 \nVasan N , Yelensky R , Wang K , Moulder S , Dzimitrowicz H , Avritscher R , Wang B , Wu Y , Cronin MT , Palmer G , \n2014 \nA targeted next-generation sequencing assay detects a high frequency of therapeutically targetable alterations in primary and metastatic breast cancers: implications for clinical practice . Oncologist \n19 : 453 –458 .24710307 \nWang K , Li M , Hakonarson H . 2010 \nANNOVAR: functional annotation of genetic variants from high-throughput sequencing data . Nucleic Acids Res \n38 : e164 .20601685 \nWang K , Zhang Q , Li D , Ching K , Zhang C , Zheng X , Ozeck M , Shi S , Li X , Wang H , \n2015 \nPEST domain mutations in Notch receptors comprise an oncogenic driver segment in triple-negative breast cancer sensitive to a γ-secretase inhibitor . Clin Cancer Res \n21 : 1487 –1496 .25564152 \nWatkins JL , Thaker PH , Nick AM , Ramondetta LM , Kumar S , Urbauer DL , Matsuo K , Squires KC , Coleman RL , Lutgendorf SK , \n2015 \nClinical impact of selective and nonselective β-blockers on survival in patients with ovarian cancer . Cancer \n121 : 3444 –3451 .26301456 \nWhirl-Carrillo M , McDonagh EM , Hebert JM , Gong L , Sangkuhl K , Thorn CF , Altman RB , Klein TE . 2012 \nPharmacogenomics knowledge for personalized medicine . Clin Pharmacol Ther \n92 : 414 –417 .22992668 \nWiegmans AP , Al-Ejeh F , Chee N , Yap P-Y , Gorski JJ , Da Silva L , Bolderson E , Chenevix-Trench G , Anderson R , Simpson PT , \n2014 \nRad51 supports triple negative breast cancer metastasis . Oncotarget \n5 : 3261 –3272 .24811120 \nWu J , Jiao Y , Dal Molin M , Maitra A , de Wilde RF , Wood LD , Eshleman JR , Goggins MG , Wolfgang CL , Canto MI , \n2011 \nWhole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways . Proc Natl Acad Sci \n108 : 21188 –21193 .22158988 \nXu L , Haworth IS , Kulkarni AA , Bolger MB , Davies DL . 2009 \nMutagenesis and cysteine scanning of transmembrane domain 10 of the human dipeptide transporter . Pharm Res \n26 : 2358 –2366 .19685173 \nXue H , Wang Z , Chen J , Yang Z , Tang J . 2015 \nKnockdown of reticulon 4C by lentivirus inhibits human colorectal cancer cell growth . Mol Med Rep \n12 : 2063 –2067 .25847052 \nYing Y , Li L , Cao W , Yan D , Zeng Q , Kong X , Lu L , Yan M , Xu X , Qu J , \n2012 \nThe microtubule associated protein syntabulin is required for glucose-stimulated and cAMP-potentiated insulin secretion . FEBS Lett \n586 : 3674 –3680 .22975310 \nZhang Y , Cai Q , Shu X-O , Gao Y-T , Li C , Zheng W , Long J . 2015 \nWhole-exome sequencing identifies novel somatic mutations in Chinese breast cancer patients . J Mol Genet Med \n9 : 183 .26870154\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2373-2873",
"issue": "3(4)",
"journal": "Cold Spring Harbor molecular case studies",
"keywords": "ductal carcinoma in situ; multifocal breast carcinoma",
"medline_ta": "Cold Spring Harb Mol Case Stud",
"mesh_terms": "D000429:Alcohol Oxidoreductases; D000069286:Bortezomib; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D051549:Glutathione S-Transferase pi; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010802:Phylogeny; D064726:Triple Negative Breast Neoplasms; D016159:Tumor Suppressor Protein p53; D000073359:Whole Exome Sequencing",
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"title": "Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events.",
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{
"abstract": "Tumor lysis syndrome is uncommon in solid tumors but with the use of immunotherapy (checkpoint inhibitors) their incidence is increasing. Physicians need to take adequate precautions while treating patients with immunotherapy. The findings of our case report will help improve our current understanding of tumor lysis syndrome specially in solid tumors and will help in developing multidisciplinary treatment and prophylaxis strategies for this uncommon, but potentially fatal complication.",
"affiliations": "Internal Medicine Morehouse School of Medicine Grady Memorial Hospital Atlanta Georgia.;Hematology-Oncology Morehouse School of Medicine Grady Memorial Hospital Atlanta Georgia.;Internal Medicine Morehouse School of Medicine Grady Memorial Hospital Atlanta Georgia.;Internal Medicine Morehouse School of Medicine Grady Memorial Hospital Atlanta Georgia.;Internal Medicine Morehouse School of Medicine Grady Memorial Hospital Atlanta Georgia.",
"authors": "Shah|Manan|M|https://orcid.org/0000-0002-2304-1468;Jain|Sanjay|S|;Abe|Temidayo|T|https://orcid.org/0000-0001-8371-2000;Surapaneni|Phani Keerthi|PK|;Bhatia|Kapil|K|",
"chemical_list": null,
"country": "England",
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"doi": "10.1002/ccr3.2737",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2737\nCCR32737\nCase Report\nCase Reports\nPembrolizumab‐axitinib‐induced tumor lysis syndrome in a patient with metastatic renal cancer\nSHAH et al.Shah Manan https://orcid.org/0000-0002-2304-1468\n1\nmshah@msm.edu Jain Sanjay \n2\n Abe Temidayo https://orcid.org/0000-0001-8371-2000\n1\n Surapaneni Phani Keerthi \n1\n Bhatia Kapil \n1\n \n1 \nInternal Medicine\nMorehouse School of Medicine\nGrady Memorial Hospital\nAtlanta\nGeorgia\n\n\n2 \nHematology‐Oncology\nMorehouse School of Medicine\nGrady Memorial Hospital\nAtlanta\nGeorgia\n\n* Correspondence\n\nManan Shah, Department of Internal Medicine, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310.\n\nEmail: mshah@msm.edu\n\n15 2 2020 \n4 2020 \n8 4 10.1002/ccr3.v8.4704 708\n23 10 2019 09 1 2020 24 1 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nTumor lysis syndrome is uncommon in solid tumors but with the use of immunotherapy (checkpoint inhibitors) their incidence is increasing. Physicians need to take adequate precautions while treating patients with immunotherapy. The findings of our case report will help improve our current understanding of tumor lysis syndrome specially in solid tumors and will help in developing multidisciplinary treatment and prophylaxis strategies for this uncommon, but potentially fatal complication.\n\nTumor lysis syndrome is uncommon in solid tumors but with the use of immunotherapy (checkpoint inhibitors) their incidence is increasing. Physicians need to take adequate precautions while treating patients with immunotherapy. The findings of our case report will help improve our current understanding of tumor lysis syndrome specially in solid tumors and will help in developing multidisciplinary treatment and prophylaxis strategies for this uncommon, but potentially fatal complication.\n\n\n\nimmunotherapypembrolizumabprophylaxistumor lysis syndrome source-schema-version-number2.0cover-dateApril 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.9 mode:remove_FC converted:08.04.2020\n\n\nShah \nM \n, \nJain \nS \n, \nAbe \nT \n, \nSurapaneni \nPK \n, \nBhatia \nK \n. Pembrolizumab‐axitinib‐induced tumor lysis syndrome in a patient with metastatic renal cancer\n. Clin Case Rep . 2020 ;8 :704 –708\n. 10.1002/ccr3.2737\n==== Body\n1 INTRODUCTION\nTumor lysis syndrome is an oncological emergency, which occurs as a result of breakdown of tumor cells after initiation of therapy leading to hyperkalemia, hyperuricemia, and release of cytokines in the body causing alterations in the normal cellular milieu.1, 2 More than half of the cases of tumor lysis are associated with hematological malignancies. However in the era of modern immunotherapy specially with tyrosine kinase inhibitors, their incidence is increasing.3, 4 Cairo and Bishop classification has been used to diagnose tumor lysis syndrome, which includes clinical and laboratory definitions.5 Laboratory Tumor lysis syndrome is defined as two or more of the following—uric acid above 8 mg/dL or 25% above base line, phosphate above 4 mg/dL or 25% above baseline and calcium below 7 mg/dL. Clinical tumor lysis syndrome is defined as the above plus one or more including seizure, raised creatinine, cardiac arrhythmias, or sudden death. Overall mortality can be as high as 79%.\n\n2 CASE SUMMARY\nA 37‐year‐old woman with a past medical history of hypertension, biopsy‐confirmed metastatic (Figure 1) clear cell renal carcinoma (metastasis to lung and liver), started on pembrolizumab‐axitinib (200/5 mg) 8 days ago presents from the outpatient cancer center complaining of fatigue and palpitations. On presentation, vital signs were blood pressure 98/70 mm Hg, pulse 118 bpm, respiratory rate 22, and temperature 98.6 F. Physical examination was significant for a nonobese female in acute distress, tachycardic with mild abdominal tenderness. Laboratory findings revealed potassium of 6.5 mg/dL, uric acid of 11.2 mg/dL, serum calcium of 8.8 mg/dL and serum creatinine of 1.5 mg/dL. Prechemotherapy laboratories were potassium 4.2 mg/dL, uric acid of 6.3 mg/dL, and calcium of 10 mg/dL (Table 1). EKG revealed sinus tachycardia with peaked T waves, and chest X‐ray was normal. The patient was admitted to the intensive care unit due to concern for tumor lysis syndrome. She was started on intravenous fluids, calcium gluconate, allopurinol, and insulin drip for hyperkalemia.\n\nFigure 1 CT images showing lung metastasis (blue arrows), pleural‐based metastatic nodule (green arrow), large liver metastasis (red arrows), and a large approximately 10 × 9 cm left renal mass (black arrows)\n\nTable 1 Depicting laboratories before and after initiation of treatment\n\n \t \tOn day of admission\tBefore treatment\t\nPotassium‐serum\tLatest ref range: 3.4‐5.1 meq/L\t6.5 (HH)\t4.2\t\nChloride‐serum\tLatest ref range: 101‐111 meq/L\t96 (L)\t100\t\nCO2 content‐serum\tLatest ref range: 22‐32 mmol/L\t29\t28\t\nAnion gap\tLatest ref range: 1‐13 mmol/L\t12\t10\t\nGlucose\tLatest ref range: 70‐125 mg/dL\t90\t85\t\nUrea nitrogen‐serum\tLatest ref range: 8‐22 mg/dL\t51 (H)\t23\t\nCreatinine\tLatest ref range: 0.7‐1.2 mg/dL\t1.5 (H)\t0.9\t\nGlomerular filtration rate\tLatest ref range: >60 mL/min/1.73 mE2\t>60\t>60\t\nOsmo, calculated\tLatest ref range: 275‐300 mOsm/kg\t287\t295\t\nProtein, total‐serum\tLatest ref range: 6.0‐8.3 g/dL\t8.4 (H)\t6.6\t\nAlbumin, BCG‐serum\tLatest ref range: 3.5‐5.0 g/dL\t3.9\t4.0\t\nCalcium, albumin adjusted\tLatest ref range: 8.9‐10.3 mg/dL\t8.8\t10\t\nCalcium, total serum\tLatest ref range: 8.9‐10.3 mg/dL\t8.8\t \t\nBilirubin, total‐serum\tLatest ref range: 0.3‐1.6 mg/dL\t1.6\t1.5\t\nBilirubin, direct‐serum\tLatest ref range: ≤0.5 mg/dL\t0.5\t0.5\t\nAST (SGOT)\tLatest ref range: 10‐42 U/L\t40\t38\t\nALT (SGPT)\tLatest ref range: 17‐63 IU/L\t74 (H)\t60\t\nAlkaline phosphatase serum\tLatest ref range: 38‐126 IU/L\t506 (H)\t347\t\nUric acid\tLatest ref range F‐3.4‐70 mg/dL\t11\t6.3\t\nJohn Wiley & Sons, LtdOn the second day of admission, uric acid was 7.0 mg/dL, potassium 5.2 mg/dL, and creatinine at 1.5 mg/dL. She became short of breath and hypoxic. Oxygen saturation decreased to 86% on room air, and respiratory rate was 26 bpm. Follow‐up chest X‐ray revealed a diffuse infiltrate in the lungs concerning for acute respiratory distress syndrome (ARDS) and CT scan to rule out pulmonary embolism was negative. She was subsequently intubated and stabilized on mechanical ventilatory support.\n\nBy day 3, her laboratory findings revealed normal sodium, potassium, and uric acid levels. Her creatinine level was around 1.7 mg/dL. However, she continued to require high ventilatory support, developed a sudden cardiac arrest, and subsequently passed away. The cause of her death was attributed to ARDS.\n\n3 DISCUSSION\nWe describe a patient with metastatic renal cell carcinoma started on pembrolizumab‐axitinib‐based therapy who developed tumor lysis syndrome within 8 days of initiation of therapy. To our knowledge, this is one of the fewer descriptions of this combination causing tumor lysis syndrome. Pembrolizumab is a anti‐PD‐1 drug, and axitinib is a tyrosine kinase inhibitor affecting VEGF receptors 1,2, and 3. It is believed that check point inhibitors like pembrolizumab lead to activation of T‐cell‐mediated cytokines destruction of tumor cells, thereby causing all the parametric changes.6, 7\n\n\nPembrolizumab‐Axitinib has been recently approved by FDA as the first‐line treatment for advanced and metastatic renal cell carcinoma. Approval was based on the Keystone‐426 trial, a randomized, multicentric trial. The trial demonstrated a statistically significant improvement in overall survival in patients treated with the above combination versus those treated with sunitinib.8 Pembrolizumab has also been used in metastatic cervical, endometrial, squamous cell lung cancer, and melanomas.9 The major adverse reactions associated with pembrolizumab include peripheral edema, fatigue, headaches, hypokalemia, hypoglycemia, hypomagnesemia, and diarrhea.9, 10\n\n\nTumor lysis syndrome is an oncological emergency that is caused by massive lysis of tumor cells with release of potassium and phosphate into the systemic circulation. Although there is general consensus that tumor lysis syndrome represents a set of metabolic complications that arise from treatment of rapidly proliferating neoplasm, there have been few attempts to specifically define them. Cairo Bishop definition, proposed in 2004, has been widely used for defining tumor lysis syndrome. It also includes a grading system to identify the severity of tumor lysis syndrome.11\n\n\nCairo Bishop Definition includes two major categories which includes the following:\nLaboratory tumor lysis syndrome—Defined as any two or more abnormal serum values of the parameters mentioned below within 3 days before or 7 days after institution of chemotherapy (Table 2).\n\nClinical tumor lysis syndrome—Defined as laboratory tumor lysis syndrome plus one or more of the following that was not directly or probably attributable to a therapeutic agent: increased serum creatinine, cardiac arrhythmias/sudden death, or a seizure.\n\n\n\n\nTable 2 Cairo Bishop definition with laboratory parameters\n\n \tValue\tChange from baseline\t\nUric acid\t>8 mg/dL\t>25% from baseline\t\nPotassium\t>6 meq/dL\t>25% from baseline\t\nPhosphorus\t>4.5 mg/dL\t>25% from baseline\t\nCalcium\t>7 mg/dL\t>25% from baseline\t\nJohn Wiley & Sons, LtdRisk factors that need to be taken into consideration while identifying tumor lysis syndrome include—chemosensitivity of the tumor, burden of the disease which includes size more than 10 cm, bone marrow involvement and pretreatment hyperuricemia and hyperphosphatemia. An expert panel identified prophylaxis recommendations based on tumor lysis syndrome risk mentioned in detail (Table 3).11 Low‐risk patients can be managed with aggressive intravenous hydration with or without allopurinol, while rasburicase is recommended for high‐risk patients.\n\nTable 3 Table showing tumor lysis syndrome risk categories for prophylaxis\n\nLow risk\tIntermediate risk\tHigh risk\t\nMost solid tumors\tNeuroblastoma, germ cell tumor, small cell lung cancer\tBurkitt's leukemia\t\nMultiple myeloma\tPlasma cell leukemia\tAcute myeloid leukemia with a WBC count >100 × 109/L\t\nChronic myeloid leukemia\tAcute myeloid leukemia with a WBC count of 25‐100 × 109/L\tAcute lymphoblastic leukemia with a WBC count >100 × 109/L\t\nChronic lymphoid leukemia\tAdult T cell leukemia/Lymphoma\tStage III and IV lymphomas\t\n\nAdult intermediate\n\n\nNon‐Hodgkin's lymphoma with normal HDL\n\n\n\tAcute lymphoblastic leukemia with WBC count <100 × 109/L\tRenal dysfunction\t\n \t \tPreexisting hyperuricemia and hyperphosphatemia\t\nJohn Wiley & Sons, LtdHematological malignancies are most frequently associated with tumor lysis syndrome. In a systemic review of 387 adult patients showed that Acute leukemias which includes Acute myeloblastic leukemia and Acute Lymphocytic leukemia constituted 27 and 19 percent of patients who were at risk or who developed tumor lysis syndrome.12 Solid tumors were present in <1%.12 Solid tumors associated with tumor lysis syndrome mainly include small cell lung carcinoma, germ cell tumors, medulloblastoma, neuroblastoma, and urothelial tumors.12 In a recent systematic review of tumor lysis syndrome in solid malignancies, GU cancer was present in approximately 7% of the cases, all the reported cases received chemotherapy.Overall mortality rate was around 70%.13 To improve our understanding, we reviewed cases of tumor lysis syndrome in patients with renal cell cancer receiving immunotherapy (Table 4), the mean age was 64 years, tumor lysis syndrome was seen between 2‐14 days of treatment. The most striking feature of this review was that all the cases including our case had fatal consequences, thereby showing a mortality rate of 100%.7\n\n\nTable 4 Case reports depicting tumor lysis syndrome due to checkpoint inhibitors in renal tumors\n\nAuthor\tAge\tGender\tCancer\tLiver metastasis\tDrug\tTime to tumor lysis syndrome\tRasburicase\tOutcome\t\nBrunnhoelzl and Wang 10\n\t77\tF\tRenal urothelial\tYes\tAtezolizumab\tDay 14\tNo\tDeath\t\nHerbst et al14\n\t70\tN/A\tRenal urothelial\tN/A\tAtezolizumab\tN/A\tN/A\tN/A\t\nSater HA et al15\n\t74\tM\tRenal cell carcinoma\tNo\tNivolumab\tDay 2\tN/A\tDeath\t\nOur case report\t37\tF\tRenal cell carcinoma\tYes\tPembrolizumab\tDay 8\tNo\tDeath\t\nJohn Wiley & Sons, LtdDespite the above preventive measures, 3%‐5% of the patients will develop tumor lysis syndrome, which include laboratory and/or clinical evidence of tumor lysis syndrome as defined by Cairo Bishop classification.13\n\n\nDifferentials that need to be considered or that can mimic tumor lysis syndrome include renal failure secondary to nephrotoxic drugs or acute tubular necrosis, medications like thiazides causing hyperuricemia, ACE inhibitors, and potassium‐sparing diuretics (spironolactone) causing hyperkalemia.\n\nUnlike tumor lysis syndrome in hematological malignancies its cause in solid tumors is not well understood. The pattern of tumor lysis syndrome in solid tumors is variable. This may explain why the mortality associated with tumor lysis tumor is higher than in hematological malignancies.12, 13\n\n\nThe findings of our case report will help improve our current understanding of tumor lysis syndrome specially in solid tumors and will help in developing multidisciplinary treatment and prophylaxis strategies for this uncommon, but potentially fatal complication. The importance of being cautious while dealing with newer immunotherapy agents has been reiterated with this case report.\n\n4 CONCLUSION\nOur case is unique and possibly the first description of pembrolizumab causing tumor lysis syndrome. In addition to this, tumor lysis syndrome in solid tumors is uncommon, but with the increasing use of immunotherapy combinations physicians should pay attention to rising rates of tumor lysis syndrome in solid tumors which have potentially fatal consequences.\n\nCONFLICT OF INTEREST\nNone.\n\n\nAUTHOR\nCONTRIBUTION\n\nMS and SJ: was involved in the conception and design of the work, data collection, drafting of the manuscript, critical revision of the manuscript, and final approval of the version to be published; TA, PS, and KB: reviewed literature and helped in revisions of the manuscript.\n==== Refs\nREFERENCES\n1 \n\nWilson \nFP \n, \nBerns \nJS \n. Onco‐nephrology: tumor lysis syndrome\n. Clin J Am Soc Nephrol . 2012 ;7 :1730 ‐1739\n.22879434 \n2 \n\nCairo \nMS \n, \nBishop \nM \n. Tumour lysis syndrome: new therapeutic strategies and classification\n. Br J Haematol . 2004 ;127 (1 ):3 ‐11\n. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15384972\n15384972 \n3 \n\nDavidson \nMB \n, \nThakkar \nS \n, \nHix \nJK \n, \nBhandarkar \nND \n, \nWong \nA \n, \nSchreiber \nMJ \n. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome\n. Am J Med . 2004 ;116 (8 ):546 ‐554\n.15063817 \n4 \n\nJoshita \nS \n, \nYoshizawa \nK \n, \nSano \nK \n, et al. A patient with advanced hepatocellular carcinoma treated with sorafenib tosylate showed massive tumor lysis with avoidance of tumor lysis syndrome\n. Intern Med . 2010 ;49 (11 ):991 ‐994\n. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20519814\n20519814 \n5 \n\nLaurent \nS \n, \nQueirolo \nP \n, \nBoero \nS \n, et al. The engagement of CTLA4 on primary melanoma cell lines induces antibody dependent cellular cytotoxicity and TNF‐α production\n. J Transl Med . 2013 ;11 :108 .23634660 \n6 \n\nBoyerinas \nB \n, \nJochems \nC \n, \nFantini \nM \n, et al. Antibody‐dependent cellular cytotoxicity activity of a novel AntiPD‐L1 antibody avelumab (MSB0010718C) on human tumor cells\n. Cancer Immunol Res . 2015 ;3 (10 ):1148 ‐1157\n.26014098 \n7 \n\nCordrey \nEO \n and \nWang \nJ \n. Tumor lysis syndrome associated with immune checkpoint blockade in solid tumors\n. Japanese J Cancer Oncol Res . 2018 ;1 (1 ):1005 .\n8 \n\nRini \nBI \n, \nPlimack \nER \n, \nStus \nV \n, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal‐cell carcinoma\n. N Engl J Med . 2019 ;380 :1116 ‐1127\n. 10.1056/NEJMoa1816714 \n30779529 \n9 \nLexicomp Inc \n. \nPembrolizumab Drug Information and Update . Copyright 1978‐2020 Lexicomp Inc .\n10 \n\nBrunnhoelzl \nD \n, \nWang \nJ \n. Acute tumor lysis syndrome after anti-pd-1 immunotherapy nivolumab for metastatic melanoma\n. J Mol Oncol Res . 2017 ;1 :5 –6\n.\n11 \n\nCairo \nMS \n, \nCoiffier \nB \n, \nReiter \nA \n. Recommendations for the evaluation of risk and prophylaxis of tumor lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus\n. Br J Haematol . 2010 ;149 :578 .20331465 \n12 \n\nCoiffier \nB \n, \nAltman \nA \n, \nPui \nCH \n, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence‐based review\n. J Clin Oncol \n2008 ;26 :2767 . Copyright ©2008 American Society of Clinical Oncology.18509186 \n13 \n\nMirrakhimov \nAE \n, \nAli Alaa \nM \n, \nKhan \nM \n, \nBarbaryan \nA \n. Tumor lysis syndrome in solid tumors: an up to date review of the literature\n. Rare Tumors . 2014 ;6 (2 ):5389 .25002953 \n14 \n\nHerbst \nRS \n, \nSoria \nJC \n, \nKowanetz \nM \n, et al. Predictive correlates of response to the anti‐PD‐L1 antibody MPDL3280A in cancer patients\n. Nature . 2014 ;515 (7528 ):563 ‐567\n.25428504 \n15 \n\nSater \nHA \n, \nPatel \nRM \n, \nSullivan \nBT \n, \nParikh \nJ \n. A Case report of inflammatory syndrome presenting as tumor lysis syndrome after single dose of nivolumab\n. J Cancer Prev Curr Res . 2017 ;8 (2 ):00271 .\n\n",
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"abstract": "Bilateral femoral neuropathy is an uncommon complication of various surgical and nonsurgical procedures, such as pelvic/abdominal surgery or vaginal delivery. Case Report. We report a case of a 41-year-old male who was found unresponsive against the wall in a \"lithotomy-type\" position with both knees flexed at approximately 90 degrees and both hips flexed and externally rotated at approximately 90 and 60 degrees, respectively, 24-48 hours after a drug overdose (combination of dihydrocodeine, paracetamol, diazepam, and amitriptyline). During his recovery, he complained of severe bilateral proximal lower limb weakness and bilateral distal lower limb pain and allodynia. His symptoms were initially attributed to critical illness myopathy/neuropathy (CIMN). However, thorough clinical and neurophysiological evaluation revealed that his symptoms were due to severe bilateral femoral neuropathies.\nTo our knowledge, this is the first reported case of bilateral femoral nerve palsy due to prolonged posturing in a \"lithotomy-type\" position in the context of a drug overdose.",
"affiliations": "Neurophysiology Department, Sunderland Royal Hospital, South Tyneside & Sunderland NHS Foundation Trust, Sunderland, UK.;Neurology Department, Sunderland Royal Hospital, South Tyneside & Sunderland NHS Foundation Trust, Sunderland, UK.;Second Department of Psychiatry, University General Hospital \"Attikon\", School of Medicine, Athens, Greece.;Second Department of Psychiatry, University General Hospital \"Attikon\", School of Medicine, Athens, Greece.;First Department of Urology, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki, Greece.;Neurology Department, Sunderland Royal Hospital, South Tyneside & Sunderland NHS Foundation Trust, Sunderland, UK.",
"authors": "Tsiptsios|D|D|https://orcid.org/0000-0002-1601-8788;Daud|D|D|;Tsamakis|K|K|;Rizos|E|E|;Anastadiadis|A|A|;Cassidy|A|A|",
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"fulltext": "\n==== Front\nCase Rep Neurol Med\nCase Rep Neurol Med\nCRINM\nCase Reports in Neurological Medicine\n2090-6668 2090-6676 Hindawi \n\n10.1155/2020/2352850\nCase Report\nBilateral Femoral Neuropathy: A Rare Complication of Drug Overdose due to Prolonged Posturing in Lithotomy Position\nhttps://orcid.org/0000-0002-1601-8788Tsiptsios D. tsiptsios.dimitrios@yahoo.gr\n1\n Daud D. \n2\n Tsamakis K. \n3\n Rizos E. \n3\n Anastadiadis A. \n4\n Cassidy A. \n2\n \n1Neurophysiology Department, Sunderland Royal Hospital, South Tyneside & Sunderland NHS Foundation Trust, Sunderland, UK\n\n2Neurology Department, Sunderland Royal Hospital, South Tyneside & Sunderland NHS Foundation Trust, Sunderland, UK\n\n3Second Department of Psychiatry, University General Hospital “Attikon”, School of Medicine, Athens, Greece\n\n4First Department of Urology, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki, Greece\nAcademic Editor: Norman S. Litofsky\n\n\n2020 \n10 3 2020 \n2020 235285028 10 2019 5 2 2020 22 2 2020 Copyright © 2020 D. Tsiptsios 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.Background\n Bilateral femoral neuropathy is an uncommon complication of various surgical and nonsurgical procedures, such as pelvic/abdominal surgery or vaginal delivery. Case Report. We report a case of a 41-year-old male who was found unresponsive against the wall in a “lithotomy-type” position with both knees flexed at approximately 90 degrees and both hips flexed and externally rotated at approximately 90 and 60 degrees, respectively, 24–48 hours after a drug overdose (combination of dihydrocodeine, paracetamol, diazepam, and amitriptyline). During his recovery, he complained of severe bilateral proximal lower limb weakness and bilateral distal lower limb pain and allodynia. His symptoms were initially attributed to critical illness myopathy/neuropathy (CIMN). However, thorough clinical and neurophysiological evaluation revealed that his symptoms were due to severe bilateral femoral neuropathies. \n\nConclusions\n To our knowledge, this is the first reported case of bilateral femoral nerve palsy due to prolonged posturing in a “lithotomy-type” position in the context of a drug overdose.\n==== Body\n1. Introduction\nBilateral femoral neuropathy is an uncommon complication of various surgical and nonsurgical procedures, such as pelvic/abdominal surgery or vaginal delivery, but rarely encountered in other scenarios or circumstances.\n\n2. Case Presentation\nWe report the case of a 41-year-old male who was referred to our Neurophysiological Department with a suspected diagnosis of critical illness myopathy/neuropathy (CIMN) after he exhibited marked bilateral quadriceps muscle wasting with distal lower limb pain and allodynia following his recovery from coma due to a drug overdose.\n\nProminent fibrillations and positive sharp waves were EMGraphically recorded from the vastus medialis and vastus lateralis muscles bilaterally. Moreover, no motor unit action potentials (MUAPs) could be recruited from the aforementioned muscles. In the Intensive Care Unit (ICU) setting, such findings are usually encountered in cases of very severe critical illness myopathy.\n\nHowever, tibial and peroneal motor nerve conduction studies and sural and superficial peroneal sensory nerve conduction studies were within normal limits bilaterally (Table 1). These findings were not suggestive of a large fibre peripheral neuropathy and led to a review of the clinical diagnosis of CIMN, and additional neurophysiological testing was undertaken. The findings on clinical examination were also hard to reconcile with a diagnosis of CIMN as, while the quadriceps muscles were severely wasted bilaterally, all other muscles including iliopsoas and hip adductors exhibited 5/5 motor strength. Moreover, the sensory loss was focal, with numbness and hypoesthesia over the anteromedial thighs and medial lower legs bilaterally. In addition, while the knee jerks were absent, the ankle jerks were present bilaterally.\n\nAdditional neurophysiological testing revealed that saphenous sensory nerve action potentials were absent bilaterally. Otherwise, EMG findings from iliopsoas and adductor longus muscles were unremarkable bilaterally (Table 1).\n\nThus, the clinical and neurophysiological findings were consistent with severe bilateral femoral neuropathies at the level of the inguinal region. It has to be stated that, while prominent abnormal spontaneous activity and unrecordable MUAPs from both quadriceps muscles are potentially suggestive of a severe underlying critical illness myopathy, it is important to realise that such EMGraphic findings can be seen in cases of severe underlying neuropathies, as in our case.\n\nDue to the fact that a pelvic CT scan was unremarkable, with no evidence of an underlying hematoma or iliopsoas muscle swelling, and creatine phosphokinase value was within normal limits, thus excluding rhabdomyolysis and crush syndrome that could explain the patient's symptoms, his clinical history was reviewed. Interestingly, his mother had found him unresponsive 24–48 hours after a drug overdose (according to paramedics, empty packets of dihydrocodeine, paracetamol, diazepam, and amitriptyline were found around him) against the wall in a “lithotomy-type” position with both knees flexed at approximately 90 degrees and both hips flexed and externally rotated at approximately 90 and 60 degrees, respectively. This prolonged posturing seems to have resulted in severe bilateral femoral nerve palsies due to excessive nerve stretching and/or pressure under the inguinal ligament.\n\n3. Discussion\nUnilateral femoral neuropathy is an uncommon mononeuropathy and is usually caused by compression in the pelvis or inguinal region. Typical causes in the pelvis include compression by an iliacus or retroperitoneal hematoma, by a retractor blade during pelvic surgery, or by a pelvic mass. Typical causes in the inguinal region include compression by the inguinal ligament during the lithotomy position and by an inguinal hematoma or by other inguinal masses [1].\n\nBilateral simultaneous femoral neuropathy is even more uncommon. It is typically seen as a complication of either pelvic or abdominal surgery or vaginal delivery. In such instances, the proposed mechanisms of nerve injury are as follows:Stretching and/or prolonged compression of the nerve caused by the self-retaining retractors that can directly compress the nerve against the pelvic sidewall\n\nCompression of the iliac vessels causing direct ischemia of the nerve\n\nProlonged compression of the femoral nerves under the inguinal ligament, or\n\nExcessive stretching due to excessive abduction and external rotation of the hips during lithotomy positioning [2–6]\n\n\n\nIn addition to the above iatrogenic causes, there are reports of rare cases of bilateral femoral nerve compression and ischemia due to iliopsoas hematomas [7–10] and iliopsoas swelling secondary to rhabdomyolysis [11, 12]. There are also individual reports of bilateral femoral neuropathy due to vasculitis in the context of disseminated intravascular coagulopathy [13] and due to blunt force trauma [14].\n\nA single case of bilateral femoral neuropathy after drug overdose has also been reported [15]. On this occasion, a female had sat down on a chair with her legs stuck under a desk before then losing consciousness and falling backwards without any support for her head or arms. This prolonged hyperlordotic position resulted in a presumed stretch-induced ischemia of the nerve at the level of the iliopsoas groove.\n\nOur case differs from the aforementioned in that our patient was found unresponsive in a different position, i.e., with both knees flexed at approximately 90 degrees and both hips flexed at approximately 90 degrees and externally rotated at approximately 60 degrees. Thus, to our knowledge, this is the first reported case of bilateral simultaneous femoral neuropathy due to prolonged posturing in a “lithotomy-type” position in the context of a drug overdose. The presumed mechanism of nerve injury is excessive nerve stretching and/or pressure under the inguinal ligament. More specifically, profound muscle relaxation due to lack of protective reflexes and muscle tone in the context of drug overdose might have resulted in excessive bilateral external hip rotation >45 degrees in a “lithotomy-type” position that also encompassed bilateral knee and hip flexion at approximately 90 degrees each. This position causes both femoral nerves to enter the thigh acutely angulated and twisted beneath the tough and inelastic inguinal ligament, leading to microvascular and/or local mechanical nerve injury. In case this position is kept for more than 4 hours, it may lead to permanent bilateral femoral nerve damage [6].\n\nThis case illustrates the importance of taking a thorough collateral history in those presenting with weakness following an admission to the ICU. A thorough neurological evaluation should always precede neurophysiological testing, as not all cases of acute or subacute lower limb weakness and sensory loss in this setting are due to CIMN. As we have described, rare neurological entities such as bilateral femoral neuropathies can also be encountered.\n\nAcknowledgments\nThe author would like to thank the patient and the family.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nTable 1 Neurophysiological findings.\n\nSensory nerve conduction studies\t\nNerve and site\tOnset latency\tPeak latency\tAmplitude\tSegment\tLatency difference\tDistance\tConduction velocity\t\n\n\n\t\nPeroneal R\t\nAnkle\t2.0 ms\t2.6 ms\t15 µV\tDorsum of foot-ankle\t2.0 ms\t100 mm\t49 m/s\t\nPeroneal L\t\nAnkle\t2.1 ms\t2.9 ms\t12 µV\tDorsum of foot-ankle\t2.1 ms\t95 mm\t45 m/s\t\nSural R\t\nLower leg\t1.7 ms\t2.6 ms\t12 µV\tAnkle-lower leg\t1.7 ms\t95 mm\t55 m/s\t\nSural L\t\nLower leg\t1.7 ms\t2.6 ms\t12 µV\tAnkle-lower leg\t1.7 ms\t95 mm\t55 m/s\t\nSaphenous R\t\n \tNo recording\tLower leg-ankle\t \t \t \t\nSaphenous L\t\n \tNo recording\tLower leg-ankle\t \t \t \t\n\n\n\t\nMotor nerve conduction studies\t\nNerve and site\tLatency\tAmplitude\tSegment\tLatency difference\tDistance\tConduction velocity\tF-latency\t\n\n\n\t\nPeroneal R\t\nAnkle\t5.9 ms\t2.7 mV\tExtensor digitorum brevis-ankle\t5.9 ms\tmm\tm/s\t \t\nFibula (head)\t13.0 ms\t1.9 mV\tAnkle-fibula (head)\t7.1 ms\t320 mm\t45 m/s\t \t\nTibial R\t\nAnkle\t4.1 ms\t20.0 mV\tAbductor hallucis-ankle\t4.1 ms\tmm\tm/s\t53.9 msec\t\nTibial L\t\nAnkle\t3.9 ms\t20.7 mV\tAbductor hallucis-ankle\t3.9 ms\tmm\tm/s\t53.3 msec\t\n\n\n\t\nElectromyography\t\n \tSpontaneous activity\tMUAPs\tActivation\tRecruitment\t\n \tFibrillations\tPSWs\tAmplitude\tDuration\tPhases\t \t \t\n\n\n\t\nRight vastus lateralis\t+3\t+3\tNo MUAPs could be recruited\t\nRight vastus medialis\t+3\t+3\tNo MUAPs could be recruited\t\nLeft vastus lateralis\t+3\t+3\tNo MUAPs could be recruited\t\nLeft vastus medialis\t+3\t+3\tNo MUAPs could be recruited\t\nRight iliopsoas\t0\t0\tN\tN\tN\tN\tN\t\nLeft iliopsoas\t0\t0\tN\tN\tN\tN\tN\t\nRight adductor longus\t0\t0\tN\tN\tN\tN\tN\t\nLeft adductor longus\t0\t0\tN\tN\tN\tN\tN\t\nPSWs, positive sharp waves; MUAPs, motor unit action potentials; N, normal.\n==== Refs\n1 Katirji B. Kaminksi H. Ruff R. L. Compressive and entrapment neuropathies of the lower extremity Neuromuscular Disorders in Clinical Practice 2014 2nd Berlin, Germany Springer 933 937 \n2 Bono V. La Bella V. Spataro R. Bilateral iatrogenic femoral neuropathy Journal of Clinical Neurology 2015 11 4 398 399 10.3988/jcn.2015.11.4.398 2-s2.0-84942748991 26256661 \n3 Vanrell J. A. Balasch J. Bilateral femoral neuropathy after microsurgical reversal of tubal sterilization: case report and analysis of contributing factors Human Reproduction 1987 2 4 345 347 10.1093/oxfordjournals.humrep.a136547 2-s2.0-0023627980 3624433 \n4 Choi S.-P. Oh B.-M. Ahn W. Bilateral femoral neuropathy after vaginal delivery-a case report Korean Journal of Anesthesiology 2009 57 2 228 232 10.4097/kjae.2009.57.2.228 30625863 \n5 Warner M. A. Warner D. O. Harper C. M. Schroeder D. R. Maxson P. M. Lower extremity neuropathies associated with lithotomy positions Anesthesiology 2000 93 4 938 942 10.1097/00000542-200010000-00010 2-s2.0-0033775815 11020742 \n6 Hsieh L.-F. Liaw E.-S. Cheng H.-Y. Hong C.-Z. Bilateral femoral neuropathy after vaginal hysterectomy Archives of Physical Medicine and Rehabilitation 1998 79 8 1018 1021 10.1016/s0003-9993(98)90104-6 2-s2.0-0031821995 9710179 \n7 Macauley P. Soni P. Akkad I. Bilateral femoral neuropathy following psoas muscle hematomas caused by enoxaparin therapy American Journal of Case Reports 2017 18 937 940 10.12659/ajcr.904975 2-s2.0-85029641694 28848224 \n8 Podger H. Kent M. Femoral nerve palsy associated with bilateral spontaneous iliopsoas haematomas: a complication of venous thromboembolism therapy Age and Ageing 2016 45 1 175 176 10.1093/ageing/afv176 2-s2.0-84964607413 26764404 \n9 Lamdhade S. Dashti R. Thussu A. Alroughani R. A young male presented with acute inguinal pain, bilateral quadriceps weakness and hyperesthesia of anterior thighs post-thrombolysis for acute myocardial infarction Annals of Saudi Medicine 2014 34 3 265 266 10.5144/0256-4947.2014.265b 25266191 \n10 Puéchal X. Lioté F. Kuntz D. Bilateral femoral neuropathy caused by iliacus hematomas during anticoagulation after cardiac catheterization American Heart Journal 1992 123 1 262 263 10.1016/0002-8703(92)90788-w 2-s2.0-0026558353 1309622 \n11 Ng Y. Li H. Chan C. Bilateral femoral nerve compression and compartment syndrome resulting from influenza A-induced rhabdomyolysis: a case report Journal of Orthopaedic Surgery 2008 16 1 117 121 10.1177/230949900801600128 18453675 \n12 Nicolle M. Doherty T. Algahtani H. Bilateral femoral neuropathy complicating rhabdomyolysis and acute renal failure Journal of Clinical Neuromuscular Disease 2005 6 4 153 156 10.1097/01.cnd.0000158995.49007.d6 2-s2.0-20844432504 19078767 \n13 Cheok C. Y. Merican A. Ng W. M. Bilateral femoral neuropathy associated with disseminated intravascular coagulopathy: a case report Medical Journal of Malaysia 2006 61 97 99 \n14 D’Amelio L. F. Musser D. J. Rhodes M. Bilateral femoral nerve neuropathy following blunt trauma Journal of Neurosurgery 1990 73 4 630 632 10.3171/jns.1990.73.4.0630 2-s2.0-0025003041 2204692 \n15 Mathis S. Boisguéheneuc F. d. Godenèche G. Ansquer S. Neau J.-P. Bilateral femoral neuropathy after massive toxic ingestion in a suicide attempt The Neurologist 2012 18 2 70 72 10.1097/nrl.0b013e318247b9bf 2-s2.0-84858142410 22367832\n\n",
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"medicinalproduct": "DIHYDROCODEINE"
},
{
"actiondrug": "5",
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},
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"medicinalproduct": "PARACETAMOL"
}
],
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"patientonsetage": "41",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Neuropathy peripheral",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Coma",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TSIPTSIOS D, DAUD D, TSAMAKIS K, RIZOS E, ANASTADIADIS A, CASSIDY A. BILATERAL FEMORAL NEUROPATHY: A RARE COMPLICATION OF DRUG OVERDOSE DUE TO PROLONGED POSTURING IN LITHOTOMY POSITION. CASE REPORTS IN NEUROLOGICAL MEDICINE. 2020 MAR 10?1-4. DOI:10.1155/2020/2352850",
"literaturereference_normalized": "bilateral femoral neuropathy a rare complication of drug overdose due to prolonged posturing in lithotomy position",
"qualification": "1",
"reportercountry": "GB"
},
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"receiptdate": "20200515",
"receivedate": "20200424",
"receiver": {
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
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"transmissiondate": "20200714"
}
] |
{
"abstract": "About 20% of MM patients have T2DM. We assessed the impact of T2DM/pre-T2DM on MM progression and OS. We collected retrospective data of newly diagnosed MM patients in Maccabi health services, Israel, between 2012 and 2016. The study included 503 MM patients, median age 67.2 years (IQR: 33.5-91.2). Median follow-up was 32 months (IQR 19.4-47). T2DM and pre-T2DM were recorded in 24.1% and 51% patients, respectively. Median TT2T and OS in the cohort were 17.5 months (95% confidence interval (CI) 15-20) and unreached, respectively. T2DM patients had shorter TT2T (HR = 1.31, 95%CI 1.0-1.72, p=.047), particularly transplanted patients; 20.2 vs. 40 months (HR = 2.09, 95%CI 1.18-3.71, p=.012). In a multivariable model, T2DM had a borderline significant risk of all-cause mortality, adjusted HR 1.38 (p=.09). Pre-diabetes had no impact on TT2T or OS. T2DM predicted a shorter TT2T, particularly in transplanted patients, and tended to be associated with shorter survival.",
"affiliations": "Hematology Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Maccabitech Institute for Research & Innovation, Maccabi Healthcare Services, Tel Aviv, Israel.;Hematology Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Hematology Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Maccabitech Institute for Research & Innovation, Maccabi Healthcare Services, Tel Aviv, Israel.",
"authors": "Avivi|Irit|I|;Yekutiel|Naama|N|;Cohen|Inbar|I|0000-0003-3980-3305;Cohen|Yael C|YC|0000-0002-9061-7287;Chodick|Gabriel|G|;Weil|Clara|C|0000-0002-0174-7208",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2021.1933474",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "62(11)",
"journal": "Leukemia & lymphoma",
"keywords": "Myeloma; diabetes; pre-diabetes",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000368:Aged; D015331:Cohort Studies; D004334:Drug Administration Schedule; D006801:Humans; D009101:Multiple Myeloma; D011236:Prediabetic State; D012189:Retrospective Studies",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2785-2792",
"pmc": null,
"pmid": "34098831",
"pubdate": "2021-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Diabetes, but not pre-diabetes, is associated with shorter time to second-line therapy and worse outcomes in patients with multiple myeloma.",
"title_normalized": "diabetes but not pre diabetes is associated with shorter time to second line therapy and worse outcomes in patients with multiple myeloma"
} | [
{
"companynumb": "IL-AMGEN-ISRSP2021189851",
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{
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"activesubstance": {
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"drugindication": "Plasma cell myeloma",
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"medicinalproduct": "VELCADE"
},
{
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{
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"medicinalproduct": "CYCLOPHOSPHAMIDE"
},
{
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},
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"drugindication": "Plasma cell myeloma",
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"medicinalproduct": "MELPHALAN"
}
],
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"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Cohen, I. Diabetes, but not pre-diabetes, is associated with shorter time to second-line therapy and worse outcomes in patients with multiple myeloma. LEUKEMIA + LYMPHOMA. 2021;62 (11):2785-2792",
"literaturereference_normalized": "diabetes but not pre diabetes is associated with shorter time to second line therapy and worse outcomes in patients with multiple myeloma",
"qualification": "3",
"reportercountry": "IL"
},
"primarysourcecountry": "IL",
"receiptdate": "20211207",
"receivedate": "20211207",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20154611,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 1,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene and occur almost absolutely in carcinomas arising in non-smokers. Crizotinib, the first inhibitor of anaplastic lymphoma kinase (ALK), ROS1 and c-Met receptor kinase, has been used in the treatment of ALK-positive non-small cell lung cancer. Side effects of crizotinib mostly consist of grade 1-2 gastrointestinal events (nausea, vomiting, diarrhea and constipation), grade 1-2 edema and fatigue; grade 1 visual disorders, rare cases of elevated liver enzymes and pneumonitis. We are presenting a case of adenocarcinoma of lung, who progressed on first-line chemotherapy and received crizotinib as second line therapy for 9 months. Patient has very good partial response to crizotinib and had some side effects of crizotinib like nausea, vomiting, diarrhea, fatigue, asthenia and anorexia, asymptomatic transaminitis in the first 2 to 3 weeks of therapy and managed symptomatically. But after 9 months, he developed sudden onset left sided vision loss. On fundoscopic examination he was found to have \"cherry red spot\" and fundus flourescein angiography revealed central retinal artery occlusion (CRAO). After 15 days of vision loss patient developed pleural effusion, and pleural fluid cytology was positive for malignant cells. Visual symptoms are very well known in the literature as side effects of crizotinib, but CRAO is not yet been documented. As this patient is not having any prothrombotic state like diabetes, hypertension, atherosclerosis, hyperhomocysteinemia or any genetic disorders except malignancy. Hypercoagulability disorders are known to be commonly associated with a variety of cancer types including lung cancer. This appears to be a sign of early crizotinib resistance in this patient because there was no history of prior hypercoagulable state. To the best of our knowledge this is the first case report in the world literature, as CRAO presenting as a sign of crizotinib resistance in an adenocarcinoma of lung patient who was on crizotinib.",
"affiliations": "Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.;Department of Medical and Pediatric Oncology, GCRI, Ahmedabad, Gujarat, India.",
"authors": "Madabhavi|Irappa|I|;Patel|Apurva|A|;Anand|Asha|A|;Panchal|Harsha|H|;Parikh|Sonia|S|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D006493:Heparin; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
"country": "England",
"delete": false,
"doi": "10.1111/crj.12550",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-6981",
"issue": "12(2)",
"journal": "The clinical respiratory journal",
"keywords": "CRAO; Crizotinib; adenocarcinoma; lung; non-small cell lung cancer; resistance; visual symptoms",
"medline_ta": "Clin Respir J",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000077547:Crizotinib; D004417:Dyspnea; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D006493:Heparin; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D035583:Rare Diseases; D020794:Receptor Protein-Tyrosine Kinases; D015356:Retinal Artery Occlusion; D018570:Risk Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "101315570",
"other_id": null,
"pages": "806-810",
"pmc": null,
"pmid": "27606884",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Central retinal artery occlusion, an early sign of crizotinib resistance in an alk positive adenocarcinoma of lung: A rare case report.",
"title_normalized": "central retinal artery occlusion an early sign of crizotinib resistance in an alk positive adenocarcinoma of lung a rare case report"
} | [
{
"companynumb": "IN-CIPLA LTD.-2018IN12049",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "LUNG ADENOCARCINOMA",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "PEMETREXED."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "077383",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "LUNG ADENOCARCINOMA",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CARBOPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MADABHAVI I, PATEL A, ANAND A, PANCHAL H, PARIKH S.. CENTRAL RETINAL ARTERY OCCLUSION, AN EARLY SIGN OF CRIZOTINIB RESISTANCE IN AN ALK POSITIVE ADENOCARCINOMA OF LUNG: A RARE CASE REPORT. 1 TO 18",
"literaturereference_normalized": "central retinal artery occlusion an early sign of crizotinib resistance in an alk positive adenocarcinoma of lung a rare case report",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20180322",
"receivedate": "20180322",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14667871,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "BACKGROUND\nDespite the failure of 2 randomized controlled trials assessing the utility of bypass for steno-occlusive cerebrovascular disease, a specific subset of patients with progressive and/or refractory symptoms may benefit from cerebral revascularization. This study assessed the efficacy and outcomes of bypass surgery for progressive and/or refractory steno-occlusive cerebrovascular disease.\n\n\nMETHODS\nA retrospective database review was performed to identify patients who underwent bypass for progressive and/or refractory steno-occlusive disease of the internal carotid artery or middle cerebral artery over a 4-year period (July 2014-July 2018). Surgical and clinical outcomes were recorded.\n\n\nRESULTS\nSeventeen patients (average age 62 ± 11 years) underwent extracranial-intracranial bypass for refractory and/or progressive steno-occlusive disease of the internal carotid artery or middle cerebral artery. Thirteen patients presented with stroke, 3 presented with recurrent transient ischemic attacks, and 1 presented with progressive hemiparesis. All patients had preoperative perfusion imaging deficits. Average temporary clip time was 35 ± 8 minutes. An interposition graft was used in 7 patients. There was 3 ischemic and 3 hemorrhagic perioperative strokes (35%); all were minor or related to anticoagulation. Over an average of 10 ± 10 months of follow-up, there were no ischemic strokes in the bypass-dependent territories. Of 17 patients, 16 (78%) achieved a Glasgow Outcome Scale score ≥4, and 13 (85%) achieved a modified Rankin Scale score ≤2.\n\n\nCONCLUSIONS\nBypass for steno-occlusive disease of the anterior intracranial circulation is a potentially effective treatment for patients with progressive and/or refractory ischemic symptoms, although the complication rate is significant. Optimal patient selection criteria and timing of surgery remain open questions.",
"affiliations": "Department of Neurological Surgery, University of California San Diego, San Diego, California, USA.;Department of Neurological Surgery, University of California San Diego, San Diego, California, USA.;Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.;Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.;Neurorestoration Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. Electronic address: jonathan.russin@med.usc.edu.",
"authors": "Steinberg|Jeffrey A|JA|;Rennert|Robert C|RC|;Ravina|Kristine|K|;Strickland|Ben A|BA|;Russin|Jonathan J|JJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.09.102",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "133()",
"journal": "World neurosurgery",
"keywords": "Cerebral bypass; Revascularization; Steno-occlusive ischemia; Stroke",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D000368:Aged; D016893:Carotid Stenosis; D002548:Cerebral Revascularization; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "e609-e618",
"pmc": null,
"pmid": "31563694",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rescue Cerebral Revascularization in Patients with Progressive Steno-Occlusive Ischemia of the Anterior Intracranial Circulation.",
"title_normalized": "rescue cerebral revascularization in patients with progressive steno occlusive ischemia of the anterior intracranial circulation"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-007330",
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"literaturereference": "STEINBERG JA, RENNERT RC, RAVINA K, STRICKLAND BA, RUSSIN JJ. RESCUE CEREBRAL REVASCULARIZATION IN PATIENTS WITH PROGRESSIVE STENO-OCCLUSIVE ISCHEMIA OF THE ANTERIOR INTRACRANIAL CIRCULATION. WORLD NEUROSURGERY. 2020?133:E609-18",
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] |
{
"abstract": "This FranceCoag network study assessed 33 patients with congenital factor XIII (FXIII) deficiency presenting FXIII levels <10 iu/dl. Diagnosis was based on abnormal bleeding in 29 patients, a positive family history in 2, recurrent miscarriages in 1 and was fortuitous in 1. Eighteen patients (62·1%) presented life-threatening umbilical or intracranial haemorrhages (ICH). Seven of the 15 patients who experienced ICH were diagnosed but untreated, including 3 with secondary neurological sequelae. All pregnancies without prophylaxis (26/26) led to miscarriages versus 3/16 with prophylaxis. In patients exhibiting FXIII levels <10 iu/dl, prophylaxis could be discussed at diagnosis and at pregnancy. Further controlled prospective studies are needed.",
"affiliations": "Hospices Civils de Lyon - Unite d'Hemostase Clinique, Hôpital Cardiologique Louis Pradel, Lyon, France.;Hospices Civils de Lyon - Unite d'Hemostase Clinique, Hôpital Cardiologique Louis Pradel, Lyon, France.;AP-HM, FranceCoag, Marseille, France.;AP-HM, FranceCoag, Marseille, France.;Hemophilia Care Center, Rouen University Hospital, Rouen, France.;Haemophilia Treatment Centre, Strasbourg University Regional Hospital, Strasbourg, France.;Haemophilia Treatment Centre, APHP, Hospital Necker, Paris, France.;Haematology and Transfusion, CHU Lille, Hospital Necker, Lille, France.;Haemophilia Treatment Centre, University Hospital of Toulouse, Toulouse, France.;Haematology and Transfusion, CHU Lille, Hospital Necker, Lille, France.;AP-HM, FranceCoag, Marseille, France.;Hospices Civils de Lyon - Unite d'Hemostase Clinique, Hôpital Cardiologique Louis Pradel, Lyon, France.",
"authors": "Bouttefroy|Séverine|S|0000-0002-6739-9488;Meunier|Sandrine|S|0000-0002-5319-1969;Milien|Vanessa|V|;Boucekine|Mohamed|M|0000-0002-6129-4386;Chamouni|Pierre|P|0000-0001-6269-2098;Desprez|Dominique|D|;Harroche|Annie|A|0000-0003-1567-0878;Hochart|Audrey|A|0000-0001-6592-0455;Thiercelin-Legrand|Marie Françoise|MF|;Wibaut|Bénédicte|B|;Chambost|Hervé|H|;Rugeri|Lucia|L|0000-0002-3103-1737;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.16133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "188(2)",
"journal": "British journal of haematology",
"keywords": "epidemiology; factor XIII; prophylaxis; rare bleeding disorder; registry",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D015331:Cohort Studies; D005177:Factor XIII Deficiency; D005260:Female; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "317-320",
"pmc": null,
"pmid": "31414482",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Congenital factor XIII deficiency: comprehensive overview of the FranceCoag cohort.",
"title_normalized": "congenital factor xiii deficiency comprehensive overview of the francecoag cohort"
} | [
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},
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],
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{
"reactionmeddrapt": "Death neonatal",
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},
{
"reactionmeddrapt": "Maternal exposure during pregnancy",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
},
{
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}
],
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"medicinalproduct": "FIBROGAMMIN P"
},
{
"actiondrug": "6",
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},
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},
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"medicinalproduct": "FIBROGAMMIN P"
},
{
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},
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"drugdosagetext": "42 UNK",
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"medicinalproduct": "FIBROGAMMIN P"
}
],
"patientagegroup": "2",
"patientonsetage": "19",
"patientonsetageunit": "802",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective for unapproved indication",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Factor XIII Inhibition",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BOUTTEFROY S, MEUNIER S, MILIEN V, BOUCEKINE M, CHAMOUNI P, DESPREZ D, ET AL.. CONGENITAL FACTOR XIII DEFICIENCY: COMPREHENSIVE OVERVIEW OF THE FRANCECOAG COHORT. BRITISH JOURNAL OF HAEMATOLOGY. 2019",
"literaturereference_normalized": "congenital factor xiii deficiency comprehensive overview of the francecoag cohort",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20191118",
"receivedate": "20191118",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 17042116,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200122"
}
] |
{
"abstract": "BACKGROUND\nTakotsubo syndrome (TS) may be triggered by numerous physical stress factors including exogenous Norepinephrine administration. The aim of this study is to report on the clinical features and outcome of serotonin-norepinephrine reuptake inhibitor (SNRI)-, selective NRI (S-NRI)-, and exogenously administered norepinephrine-induced TS in a largest possible cohort of published cases.\n\n\nMETHODS\nA computer assisted search of the electronic data base Pubmed was performed from 1990 to August 2016. All cases deemed to have SNRI-, S-NRI-, and norepinephrine-induced TS were retrieved.\n\n\nRESULTS\nTwenty two cases of SNRI-, S-NRI-, and norepinephrine-induced TS were retrieved from the literature. At presentation, the 22 patients with TS were 11 to 82years of age (mean age 49.9±20years). Seventeen of 21 (81%) of the patients were women. The most common presenting symptom was chest pain, which occurred in 59% of cases. The TS localization pattern was apical in 68%, mid-ventricular in 13.6%, basal in 13.6% and global in 4.5% of cases. Complications occurred in 7 of 22 (32%) with more complications in exogenously administered norepinephrine-induced TS (4 of 6, 66.7%) than SNRI-, and S-NRI-induced TS (3 of 16, 18, 8%) (p=0.054). All 4 male patients in the study developed complications. One patient (exogenous norepinephrine-induced TS) died during hospitalization.\n\n\nCONCLUSIONS\nThe SNRI-, and S-NRI-induced TS have clinical features, complications and course comparable to that of all-TS population cohorts, whereas the exogenously administered norepinephrine-induced TS has a more dramatic clinical presentation and complication rates, which resembles that of exogenously administered epinephrine-induced TS.",
"affiliations": "Karolinska Institute at Karolinska University Hospital, Department of Cardiology, Sweden. Electronic address: shams.younis-hassan@karolinska.se.",
"authors": "Y-Hassan|Shams|S|",
"chemical_list": "D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D009638:Norepinephrine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijcard.2016.12.184",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-5273",
"issue": "231()",
"journal": "International journal of cardiology",
"keywords": "Affective disorders; Catecholamines; Norepinephrine; Selective norepinephrine reuptake inhibitor; Serotonin norepinephrine reuptake inhibitor; Takotsubo",
"medline_ta": "Int J Cardiol",
"mesh_terms": "D004333:Drug Administration Routes; D006801:Humans; D009638:Norepinephrine; D010506:Periodicals as Topic; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "228-233",
"pmc": null,
"pmid": "28073659",
"pubdate": "2017-03-15",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Serotonin norepinephrine re-uptake inhibitor (SNRI)-, selective norepinephrine reuptake inhibitor (S-NRI)-, and exogenously administered norepinephrine-induced takotsubo syndrome: Analysis of published cases.",
"title_normalized": "serotonin norepinephrine re uptake inhibitor snri selective norepinephrine reuptake inhibitor s nri and exogenously administered norepinephrine induced takotsubo syndrome analysis of published cases"
} | [
{
"companynumb": "SE-ALEMBIC PHARMACUETICALS LIMITED-2017SCAL000245",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "078932",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "300 MG, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DEPRESSION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "300",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VENLAFAXINE HYDROCHLORIDE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Stress cardiomyopathy",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Y-HASSAN S. SEROTONIN NOREPINEPHRINE RE-UPTAKE INHIBITOR (SNRI)-, SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITOR (S-NRI)-, AND EXOGENOUSLY ADMINISTERED NOREPINEPHRINE-INDUCED TAKOTSUBO SYNDROME: ANALYSIS OF PUBLISHED CASES. INTERNATIONAL JOURNAL OF CARDIOLOGY. 2017;231:228-233",
"literaturereference_normalized": "serotonin norepinephrine re uptake inhibitor snri selective norepinephrine reuptake inhibitor s nri and exogenously administered norepinephrine induced takotsubo syndrome analysis of published cases",
"qualification": "3",
"reportercountry": "SE"
},
"primarysourcecountry": "SE",
"receiptdate": "20170321",
"receivedate": "20170321",
"receiver": {
"receiverorganization": "FDA",
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},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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{
"abstract": "Eosinophilia is uncommon in early rheumatoid arthritis (RA). The most frequent causes of hypereosinophilia during RA treatment are atopic eczema, allergy, helminth infection, haematological malignancy and drug-associated complications. The pathogenesis of this abnormality associated with anti-cytokine therapy is still unknown. We report the case of a young woman with RA and eosinophilia accompanied by systemic symptoms such as dyspnoea, fluid retention and eosinophilic vasculitis. An interesting observation was the persistence of eosinophilia during treatment with various biologics and its normalization after switching to the Janus kinase inhibitor baricitinib.",
"affiliations": "1st Department of Internal Medicine, Faculty of Medicine, Comenius University in Bratislava and University Hospital Bratislava, Staré Mesto, Mickiewiczova 13, 813 69, Bratislava, Slovakia. e.stenova@hotmail.com.;Department of Rheumatology, Saint Michael's Hospital, Bratislava, Slovakia.;Institute of Pathological Anatomy, Faculty of Medicine, Comenius University in Bratislava and University Hospital Bratislava, Bratislava, Slovakia.;1st Department of Internal Medicine, Faculty of Medicine, Comenius University in Bratislava and University Hospital Bratislava, Staré Mesto, Mickiewiczova 13, 813 69, Bratislava, Slovakia.",
"authors": "Šteňová|Emőke|E|https://orcid.org/0000-0001-6595-2959;Tarabčáková|Lenka|L|;Babál|Pavel|P|;Kašperová|Stela|S|",
"chemical_list": "D016207:Cytokines; D000075242:Janus Kinase Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-020-05134-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "39(11)",
"journal": "Clinical rheumatology",
"keywords": "Anti-cytokine therapy; Baricitinib; Eosinophilia; Rheumatoid arthritis; Vasculitis",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D016207:Cytokines; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome; D000075242:Janus Kinase Inhibitors",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "3507-3510",
"pmc": null,
"pmid": "32495227",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "6405032",
"title": "Hypereosinophilic syndrome-a rare adverse event of anti-cytokine treatment in rheumatoid arthritis resolved after Janus kinase inhibitor therapy.",
"title_normalized": "hypereosinophilic syndrome a rare adverse event of anti cytokine treatment in rheumatoid arthritis resolved after janus kinase inhibitor therapy"
} | [
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}
},
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] |
{
"abstract": "Animal and human studies have suggested the potential of mesenchymal stromal cells (MSCs) to treat systemic lupus erythematosus (SLE). Here, we present the results of compassionate MSC treatments for three SLE patients to provide the proof of concept for a randomized and controlled clinical trial. Three patients of different ethnicities who suffer from chronic SLE, and who presented with class IV active proliferative nephritis confirmed by biopsy, were treated with allogeneic MSCs from healthy donors. Ninety million cells were infused intravenously into each patient during high and very high activity disease flare-ups and follow-up was continued for 9 months. Multi-organic affectation was quantified by the SLE disease activity index (SLEDAI), and indicators of lupus nephritis activity, such as proteinuria, as well as lymphocyte and monocyte antigens and anti-HLA antibodies were measured at 1, 3, 6, and 9 months after treatment. Proteinuria levels improved dramatically during the 1st month after treatment and the ameliorations were sustained throughout the follow-up period. SLEDAI scores revealed early, durable, and substantial remissions that were complete for two patients and partial for the third patient and that permitted medication doses to be reduced 50-90%. These favourable outcomes support completion of the randomized and controlled MSC trial for SLE.",
"affiliations": "1 Autoimmune Diseases Unit, Department of Internal Medicine, Clinic University Hospital, Valladolid, Spain.;1 Autoimmune Diseases Unit, Department of Internal Medicine, Clinic University Hospital, Valladolid, Spain.;2 Institute for Molecular Biology and Genetics (IBGM), University of Valladolid and Spanish National Council, Valladolid, Spain.;2 Institute for Molecular Biology and Genetics (IBGM), University of Valladolid and Spanish National Council, Valladolid, Spain.",
"authors": "Barbado|J|J|;Tabera|S|S|;Sánchez|A|A|;García-Sancho|J|J|",
"chemical_list": "D003404:Creatinine",
"country": "England",
"delete": false,
"doi": "10.1177/0961203318804922",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "27(13)",
"journal": "Lupus",
"keywords": "Systemic lupus erythematosus (SLE); cell therapy; mesenchymal stromal cells; nephritis; stem cells",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D057176:Compassionate Use Trials; D003404:Creatinine; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008181:Lupus Nephritis; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D008875:Middle Aged; D000075082:Proof of Concept Study; D011507:Proteinuria; D012720:Severity of Illness Index; D013030:Spain; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "2161-2165",
"pmc": null,
"pmid": "30290717",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis.",
"title_normalized": "therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis"
} | [
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},
{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
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"drugdosagetext": "CUMULATIVE DOSE OF 35100 MG",
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"drugindication": "SYSTEMIC LUPUS ERYTHEMATOSUS",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Systemic lupus erythematosus",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BARBADO J, TABERA S, SANCHEZ A, GARCIA-SANCHO J.. THERAPEUTIC POTENTIAL OF ALLOGENEIC MESENCHYMAL STROMAL CELLS TRANSPLANTATION FOR LUPUS NEPHRITIS.. LUPUS. 2018?27 (13):2161-5",
"literaturereference_normalized": "therapeutic potential of allogeneic mesenchymal stromal cells transplantation for lupus nephritis",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20190502",
"receivedate": "20190502",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16264713,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "OBJECTIVE\ncytomegalovirus (CMV) infection is one of the most common complications in transplant patients, which can lead to multiple organ failure. The 80-90% of patients are cured with intravenous treatment standard (ganciclovir), or its oral prodrug (valganciclovir). In case there is no answer, we have alternatively another antiviral, foscarnet. A small number of patients do not respond to this, having a bad prognosis. The aim is to describe the case of a double lung transplant for cystic fibrosis, and recurrent CMV infection in which the use of leflunomide gets lower and even reach undetectable viral load.\n\n\nMETHODS\nwoman, 22 year old, double lung transplant for cystic fibrosis in March 2014. The CMV serology performed was positive in the donor and negative in the recipient. Controls viral load during prophylaxis with valganciclovir were negative in the receiver until the 6th month after transplantation, at which viral load was detected in controls (2 090 IU/ml). The patient was admitted to our hospital to receive intravenous treatment with ganciclovir, after one month with intravenous therapy viral load persisted positive (42 400 IU/ml). One study of resistance showed that was resistant to ganciclovir, so began treatment with intravenous foscarnet. This drug achieved negativizar viral load, so the treatment was discontinued, continuing with fortnightly controls viral load. After two months without treatment, viral load increased to 13 665 IU/ml, why was requested to Pharmacy Service the off-label use of leflunomide, with the intention that use oral therapy, instead of intravenous therapy. The patient was treated with valganciclovir until have the authorization of use of leflunomide, although unanswered, since in March 2015, at the start of leflunomide treatment the patient had a viral load of 17 344 IU/ml. The initial regimen was 100 mg of leflunomide daily for the first five days, followed by 20 mg every 12 hours. After fifteen days of treatment viral load had fallen to 531 IU/ml, becoming undetectable in one month. After four months of treatment the patient remains with undetectable viral load without having any adverse effect associated with it.\n\n\nCONCLUSIONS\nour case is an example where the use of leflunomide in CMV infection resistant to other therapies is an effective and convenient alternative for patients because it keeps undetectable viral load with an oral therapy without having to enter the hospital for intravenous treatment.",
"affiliations": "Servicio de Farmacia. Hospital Universitario 12 de Octubre.. isa_gv@hotmail.com.;Servicio de Farmacia. Hospital Universitario 12 de Octubre.. daniele.alioto@salud.madrid.org.;Servicio de Farmacia. Hospital Universitario 12 de Octubre.. olga.serrano@salud.madrid.org.;Servicio de Farmacia. Hospital Universitario 12 de Octubre.. josemiguel.ferrari@salud.madrid.org.",
"authors": "Gómez Valbuena|Isabel|I|;Alioto|Daniel|D|;Serrano Garrote|Olga|O|;Ferrari Piquero|Jose Miguel|JM|",
"chemical_list": "D000998:Antiviral Agents; D007555:Isoxazoles; D000077339:Leflunomide",
"country": "Spain",
"delete": false,
"doi": "10.7399/fh.2016.40.1.10161",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1130-6343",
"issue": "40(1)",
"journal": "Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria",
"keywords": null,
"medline_ta": "Farm Hosp",
"mesh_terms": "D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D024882:Drug Resistance, Viral; D005260:Female; D006801:Humans; D007555:Isoxazoles; D000077339:Leflunomide; D056687:Off-Label Use; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "9440679",
"other_id": null,
"pages": "52-4",
"pmc": null,
"pmid": "26882834",
"pubdate": "2016-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of leflunomide in a cytomegalovirus infection resistant: a report of a case.",
"title_normalized": "use of leflunomide in a cytomegalovirus infection resistant a report of a case"
} | [
{
"companynumb": "ES-BAUSCH-BL-2016-014067",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GANCICLOVIR"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "022211",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": null,
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"drugindication": "CYTOMEGALOVIRUS INFECTION",
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"medicinalproduct": "GANCICLOVIR."
}
],
"patientagegroup": null,
"patientonsetage": "22",
"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Viral load increased",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GOMEZ VALBUENA I, ALIOTO D, PABLOS-BRAVO S, LZARO-CEBAS A, FERNANDEZ-REDONDO D, NIEVES-SEDANO M, SERRANO-GARROTE O, FERRARI-POQUERO J. USE OF LEFLUNOMIDE IN A CYTOMEGALOVIRUS INFECTION RESISTANT: A REPORT OF A CASE. INTERNATIONAL JOURNAL OF CLINICAL PHARMACY. 2016;38:6:583-584.",
"literaturereference_normalized": "use of leflunomide in a cytomegalovirus infection resistant a report of a case",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20160621",
"receivedate": "20160621",
"receiver": {
"receiverorganization": "FDA",
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},
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"sender": {
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},
"serious": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160815"
}
] |
{
"abstract": "A 56-year-old man diagnosed with multiple myeloma was treated with CBD (cyclophosphamide, bortezomib, and dexamethasone; DEX), which was discontinued because of bortezomib-associated adverse events. Thereafter, he was treated with Ld (lenalidomide; LEN+DEX) followed by high-dose chemotherapy with autologous stem cell rescue, resulting in a complete response. Ld as maintenance therapy was discontinued because of immune thrombocytopenia, resulting in disease progression. Although treatment was switched to Pd (pomalidomide+DEX), DLd (daratumumab+LEN+DEX), and IRd (ixazomib+LEN+DEX); the patient's M protein level continued to increase and the extramedullary disease expanded despite radiotherapy. He was treated with E-Ld (elotuzumab+LEN+DEX) after 3 cycles of short VAD (vincristine, doxorubicin, and DEX). The extramedullary disease disappeared after 8 cycles of E-Ld. To the best of our knowledge, this is the first report showing the effectiveness of E-Ld treatment for extramedullary disease of a heavily treated patient for multiple myeloma. We believe that the clinical course of this patient provides useful insights about the antimyeloma mechanism of elotuzumab.",
"affiliations": "Department of Hematology and Oncology, Mie University Graduate School of Medicine.;Department of Hematology and Oncology, Mie University Graduate School of Medicine.;Department of Hematology and Oncology, Mie University Graduate School of Medicine.;Department of Hematology and Oncology, Mie University Graduate School of Medicine.;Department of Hematology and Oncology, Mie University Graduate School of Medicine.;Department of Hematology and Oncology, Mie University Graduate School of Medicine.;Department of Hematology and Oncology, Mie University Graduate School of Medicine.",
"authors": "Kashima|Emiko|E|;Fujieda|Atsushi|A|;Nato|Yuma|Y|;Ino|Kazuko|K|;Tawara|Isao|I|;Masuya|Masahiro|M|;Katayama|Naoyuki|N|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C546027:elotuzumab; D003907:Dexamethasone; D000077269:Lenalidomide",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.61.223",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "61(3)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Elotuzumab; Extramedullary disease; Late-phase; Multiple myeloma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D003907:Dexamethasone; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "223-227",
"pmc": null,
"pmid": "32224581",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment with a combination of elotuzumab, lenalidomide and dexamethasone of extramedullary disease in a patient with refractory multiple myeloma.",
"title_normalized": "successful treatment with a combination of elotuzumab lenalidomide and dexamethasone of extramedullary disease in a patient with refractory multiple myeloma"
} | [
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"companynumb": "JP-CELGENEUS-JPN-20200409631",
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"literaturereference": "KASHIMA E, FUJIEDA A, NATO Y, INO K, TAWARA I, MASUYA M, ET AL.. SUCCESSFUL TREATMENT WITH A COMBINATION OF ELOTUZUMAB, LENALIDOMIDE AND DEXAMETHASONE OF EXTRAMEDULLARY DISEASE IN A PATIENT WITH REFRACTORY MULTIPLE MYELOMA. THE JAPANESE JOURNAL OF HEMATOLOGY. 2020?61(3):223?7",
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"abstract": "OBJECTIVE\nWe compared the response to antipsychotic treatment between patients with and without tardive dyskinesia (TD) and examined the course of TD.\n\n\nMETHODS\nThis analysis compared 200 patients with DSM-IV-defined schizophrenia and TD and 997 patients without TD, all of whom were randomly assigned to receive one of 4 second-generation antipsychotics. The primary clinical outcome measure was time to all-cause treatment discontinuation, and the primary measure for evaluating the course of TD was change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to compare treatment discontinuation between groups. Changes in Positive and Negative Syndrome Scale (PANSS) and neurocognitive scores were compared using mixed models and analysis of variance. Treatment differences between drugs in AIMS scores and all-cause discontinuation were examined for those with TD at baseline. Percentages of patients meeting criteria for TD postbaseline or showing changes in AIMS scores were evaluated with χ(2) tests. Data were collected from January 2001 to December 2004.\n\n\nRESULTS\nTime to treatment discontinuation for any cause was not significantly different between the TD and non-TD groups (χ(2)(1) = 0.11, P = .743). Changes in PANSS scores were not significantly different (F(1,974) = 0.82, P = .366), but patients with TD showed less improvement in neurocognitive scores (F(1,359) = 6.53, P = .011). Among patients with TD, there were no significant differences between drugs in the decline in AIMS scores (F(3,151) = 0.32, P = .811); 55% met criteria for TD at 2 consecutive visits postbaseline, 76% met criteria for TD at some or all postbaseline visits, 24% did not meet criteria for TD at any subsequent visit, 32% showed a ≥ 50% decrease in AIMS score, and 7% showed a ≥ 50% increase in AIMS score.\n\n\nCONCLUSIONS\nSchizophrenia patients with and without TD were similar in time to discontinuation of treatment for any cause and improvement in psychopathology, but differed in neurocognitive response. There were no significant differences between treatments in the course of TD, with most patients showing either persistence of or fluctuation in observable symptoms.\n\n\nBACKGROUND\nclinicaltrials.gov Identifier: NCT00014001.",
"affiliations": "Department of Psychiatry, Veterans Affairs Medical Center and University of Pennsylvania School of Medicine, Philadelphia, USA. caroff@va.gov",
"authors": "Caroff|Stanley N|SN|;Davis|Vicki G|VG|;Miller|Del D|DD|;Davis|Sonia M|SM|;Rosenheck|Robert A|RA|;McEvoy|Joseph P|JP|;Campbell|E Cabrina|EC|;Saltz|Bruce L|BL|;Riggio|Silvana|S|;Chakos|Miranda H|MH|;Swartz|Marvin S|MS|;Keefe|Richard S E|RS|;Stroup|T Scott|TS|;Lieberman|Jeffrey A|JA|;|||",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D010879:Piperazines; D013844:Thiazoles; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; C092292:ziprasidone; D010546:Perphenazine; D018967:Risperidone; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.4088/JCP.09m05793yel",
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"issn_linking": "0160-6689",
"issue": "72(3)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D016009:Chi-Square Distribution; D003987:Dibenzothiazepines; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders; D000077152:Olanzapine; D010546:Perphenazine; D010879:Piperazines; D016016:Proportional Hazards Models; D011569:Psychiatric Status Rating Scales; D000069348:Quetiapine Fumarate; D018967:Risperidone; D012559:Schizophrenia; D012720:Severity of Illness Index; D013844:Thiazoles; D016896:Treatment Outcome",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "295-303",
"pmc": null,
"pmid": "20816031",
"pubdate": "2011-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "16172203;2863873;1675900;16317315;6626865;18583442;16532448;6133298;18827289;7910437;8098030;7961550;17548746;16641947;14992963;3153511;1678663;17766765;19570929;16187770;19192441;3220967;11274325;1375801;7840862;415329;4917967;16171976;15380859;2873613;5570997;3616518;12411269;15163258;12088164;19142099;2574607;8822534;6121550;9771818;14645311;9365997;7537286;18055180;19545976;17329466;17707251;6131655;8099483",
"title": "Treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia.",
"title_normalized": "treatment outcomes of patients with tardive dyskinesia and chronic schizophrenia"
} | [
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"literaturereference": "CAROFF SN, DAVIS VG, MILLER DD, DAVIS SM, ROSENHECK RA, MCEVOY JP, ET AL. TREATMENT OUTCOMES OF PATIENTS WITH TARDIVE DYSKINESIA AND CHRONIC SCHIZOPHRENIA. JOURNAL OF CLINICAL PSYCHIATRY 2011;72 (3):295-303.",
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{
"abstract": "Acute generalized exanthematous pustulosis (AGEP) is a rare cutaneous rash characterized by widespread sterile nonfollicular pustules. Cefepime is a fourth generation cephalosporin, used to treat severe infections. A 67-year-old man was admitted with acute gastroenterocolitis. On the seventh day, the patient developed a nosocomial pneumonia and cefepime was initiated. On the fourth day of cephalosporin treatment, he presented with a maculopapular, pruritic eruption affecting the face, neck, abdomen and limbs. One day later he developed disseminated pustular lesions and his temperature was 37°C. Laboratory analysis evidenced leukocytosis and skin biopsy showed subcorneal pustule, edema in the papillary dermis, perivascular inflammatory infiltrate consisting of neutrophils, leukocytoclasia and red cell extravasation in the epidermis. Cefepime was suspended and within 4 days the non-follicular pustules cleared following a desquamation. AGEP is a disease attributed to a variety of causes, but in 90% of the cases it is due to an adverse drug reaction. Antibiotics are implicated in 80% of these cases, mostly penicillins and macrolides. There are few cases associated with cephalosporins. It is very important to consider AGEP in cases of acute pustular rashes and drugs should be investigated as causative agents.",
"affiliations": "Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.",
"authors": "Botelho|L F F|LF|;Picosse|F R|FR|;Padilha|M H|MH|;Michalany|N|N|;Góis|A|A|;Porro|A M|AM|",
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"fulltext": "\n==== Front\nCase Rep DermatolCDECase Reports in Dermatology1662-6567S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 2110319210.1159/000314474cde0002-0082Published: June 2010Acute Generalized Exanthematous Pustulosis Induced by Cefepime: A Case Report Botelho L.F.F. a*Picosse F.R. aPadilha M.H. aMichalany N. bGóis A. cPorro A.M. aaDepartment of Dermatology, Federal University of São Paulo, São Paulo, BrazilbDepartment of Anatomopathology, Federal University of São Paulo, São Paulo, BrazilcDepartment of Emergency Medicine, Federal University of São Paulo, São Paulo, Brazil*Luciane F.F. Botelho, MD, Dermatology Department, Federal University of São PauloRua Borges Lagoa, 933/44, São Paulo, SP 04038-032 (Brazil), Tel. +55 11 3476 6963, E-Mail lucianebotelho@hotmail.comMay-Aug 2010 01 6 2010 01 6 2010 2 2 82 87 Copyright © 2010 by S. Karger AG, Basel2010This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Acute generalized exanthematous pustulosis (AGEP) is a rare cutaneous rash characterized by widespread sterile nonfollicular pustules. Cefepime is a fourth generation cephalosporin, used to treat severe infections. A 67-year-old man was admitted with acute gastroenterocolitis. On the seventh day, the patient developed a nosocomial pneumonia and cefepime was initiated. On the fourth day of cephalosporin treatment, he presented with a maculopapular, pruritic eruption affecting the face, neck, abdomen and limbs. One day later he developed disseminated pustular lesions and his temperature was 37°C. Laboratory analysis evidenced leukocytosis and skin biopsy showed subcorneal pustule, edema in the papillary dermis, perivascular inflammatory infiltrate consisting of neutrophils, leukocytoclasia and red cell extravasation in the epidermis. Cefepime was suspended and within 4 days the non-follicular pustules cleared following a desquamation. AGEP is a disease attributed to a variety of causes, but in 90% of the cases it is due to an adverse drug reaction. Antibiotics are implicated in 80% of these cases, mostly penicillins and macrolides. There are few cases associated with cephalosporins. It is very important to consider AGEP in cases of acute pustular rashes and drugs should be investigated as causative agents.\n\nKey Words\nAcute generalized exanthematous pustulosisDrug eruptionCefepime\n==== Body\nIntroduction\nAcute generalized exanthematous pustulosis (AGEP) is a rare acute reaction that is drug-induced in 90% of the cases [1], characterized by a widespread, sterile pustular rash. Pustules resolve spontaneously within a few days.\n\nCefepime is a fourth generation cephalosporin antibiotic used to treat febrile neutropenia, severe infections related to the urinary tract, skin, nosocomial pneumonia, brain abscess, and intra-abdominal and septic lateral/cavernous sinus thrombosis [2].\n\nCase Report\nA 67-year-old man with renal failure who had been on dialysis during the last 2 years and with an 8-year history of cardiac insufficiency was admitted to the hospital complaining of 6 days of diarrhea. He was hypotensive and dehydrated at admission. The patient was taken to the semi-intensive care unit and treated with ciprofloxacin. As a consequence, his diarrhea resolved on the sixth day after admission. His long-term medications had not been changed and consisted of acetylsalicylic acid, furosemide, captopril, carvedilol and clonazepam. On the seventh day, the patient became dyspneic and his chest radiograph showed a left lower lobe opacity. Treatment for nosocomial pneumonia was promptly initiated with cefepime (1 g/day). Five days later, he presented with a pruritic, erythematous, maculopapular eruption affecting the abdomen, neck and skin folds. One day later, he developed disseminated pustular lesions (fig. 1) and his temperature was 37°C. Laboratory exams evidenced C-reactive protein 136 mg/l, white blood cells 14,700 cells/μl (normal 3,500–10,500 cells/μl) with 11,995 cells/μl neutrophils (normal 1,700–8,000 cells/μl). Histology showed a toxic pustuloderma with spongiform subcorneal pustules, edema in the papillary dermis and perivascular inflammatory infiltrate consisting of neutrophils (fig. 2). Leukocytoclasis and red cell extravasation in the epidermis were present. After withdrawal of cefepime and introduction of imipenem, the disseminated skin nonfollicular pustules cleared within 4 days following a desquamation. The patient denied previous adverse reaction to other drugs and no personal or family history of psoriasis was evident. He was discharged from the hospital on day 19 after admission.\n\nDiscussion\nAGEP is a disease characterized by the rapid onset of many sterile, nonfollicular pustules usually arising on an edematous erythema and frequently accompanied by leukocytosis and fever. Skin symptoms usually arise rapidly after an insult and resolve spontaneously (within a few days). AGEP often starts predominantly in intertriginous areas or on the face, spreading rapidly to the trunk and lower limbs. The mean duration of the pustules is 9.7 days, and an annular desquamation typically follows for a few days. Complications are rare [1, 3]. The AGEP validation score of the EuroSCAR study group has been used to establish the diagnosis [4]. A score between 8 and 12 for AGEP is a definitive diagnosis (table 1). The case score was 11, according to the validation score of the EuroSCAR study group (table 2).\n\nThe main differential diagnosis of AGEP is pustular psoriasis. Because the pustules clinically and histologically resemble the lesions of pustular psoriasis and because in a number of reports patients had a history of plaque psoriasis, some authors assume that AGEP is nothing more than an acute exacerbation of psoriasis caused by a variety of exogenous triggers. However, many studies strongly suggest that AGEP is not associated with psoriasis [1, 5].\n\nUp to now AGEP has been attributed to a variety of causes such as viral infections [6,7,8,9,10], Chlamydia pneumoniae infection [11] or hypersensitivity to mercury [12], but the skin reaction is primarily an adverse response to drugs. Antibiotics, other than cefepime, have been implicated as the causative agents in 80% of individuals [13]. In this group, the disease is usually caused by penicillins or macrolides [14, 15]. The present case of AGEP has well defined criteria, and because correct diagnosis generally leads to spontaneous resolution once the causative drug is withdrawn, clinicians should keep the possibility of this cutaneous drug reaction in mind.\n\nFig. 1 Pustular lesions affecting the neck.\n\nFig. 2 Histology showed a toxic pustuloderma with spongiform subcorneal pustule and perivascular inflammatory infiltrate consisting of neutrophils.\n\nTable 1 AGEP validation score of EuroSCAR study group\n\nVariable\tScore\tVariable\t0Score\t\nMorphology\t\tCourse\t\t\nPustules\t\tMucosal involvement\t\t\n Typical∗\t+2\t Yes\t−2\t\n Compatible∗∗\t+1\t No\t0\t\n Insufficient∗∗∗\t+0\tAcute onset (<10 d)\t\t\nErythema\t\t Yes\t0\t\n Typical\t+2\t No\t−2\t\n Compatible\t+1\tResolution <15 days\t\t\n Insufficient\t+0\t Yes\t0\t\nDistribution/pattern\t\t No\t−4\t\n Typical\t+2\tFever >38.75°C\t\t\n Compatible\t+1\t Yes\t+1\t\n Insufficient\t+0\t No\t0\t\nPostpustular desquamation\t\tPolymorphonuclear neutrophils >7,000/mm3\t\t\n Yes\t+1\t Yes\t+1\t\n No/insufficient\t+0\t No\t0\t\n\t\tHistology\t\t\n\t\tOther disease\t−10\t\n\t\tNot representative/no histology\t0\t\n\t\tExocytosis of PMN\t+1\t\n\t\tSubcorneal and/or intraepidermal non-spongiform or NOS pustule(s) with papillary edema or subcorneal and/or intraepidermal spongiform or NOS pustule(s) without papillary edema\t+2\t\n\t\tSpongiform subcorneal and/or intraepidermal pustule(s) with papillary edema\t+3\t\nNOS = not otherwise specified.\n\nInterpretation: =0: no AGEP; 1–4: possible; 5–7: probable; 8–12: definite.\n\n∗ Typical: typical morphology.\n\n∗∗ Compatible: not typical, but not strongly suggestive of other disease.\n\n∗∗∗ Insufficient: lesions cannot be judged.\n\nTable 2 Patient AGEP score, according to EuroSCAR study group\n\nVariable\tScore\t\nMorphology\t\t\nPustules\t\t\n Typical\t+2\t\nErythema\t\t\n Typical\t+2\t\nDistribution/pattern\t\t\n Typical\t+2\t\nPostpustular desquamation\t\t\n Yes\t+1\t\n\t\nCourse\t\t\nMucosal involvement\t\t\n No\t+0\t\nAcute onset (<10 days)\t\t\n Yes\t+0\t\nResolution <15 days\t\t\n Yes\t+0\t\nFever >38.75°C\t\t\n No\t+0\t\nPolymorphonuclear neutrophils >7,000/mm3\t\t\n Yes\t+1\t\n\t\nHistology\t\t\nSpongiform subcorneal and/or intraepidermal pustule(s) with papillary edema\t+3\n==== Refs\nReferences\n1 Sidoroff A Dunant A Viboud C Halevy S Bavinck JN Naldi L Mockenhaupt M Fagot JP Roujeau JC Risk factors for acute generalized exanthematous pustulosis (AGEP) – results of a multinational case-control study (EuroSCAR) Br J Dermatol 2007 157 989 996 17854366 \n2 Barradell LB Bryson HM Cefepime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use Drugs 1994 47 471 505 7514976 \n3 Beylot C Doutre MS Beylot-Barry M Acute generalized exanthematous pustulosis Semin Cutan Med Surg 1996 15 244 249 9069592 \n4 Sidoroff A Halevy S Bavinck JN Vaillant L Roujeau JC Acute generalized exanthematous pustulosis (AGEP) – a clinical reaction pattern J Cutan Pathol 2001 28 113 119 11168761 \n5 Spencer JM Silvers DN Grossman ME Pustular eruption after drug exposure: is it pustular psoriasis or a pustular drug eruption? Br J Dermatol 1994 130 514 519 8186121 \n6 Ofuji S Yamamoto O Acute generalized exanthematous pustulosis associated with a human parvovirus B19 infection J Dermatol 2007 34 121 123 17239150 \n7 Rouchouse B Bonnefoy M Pallot B Acute generalized exanthematous pustular dermatitis and viral infection Dermatologica 1986 173 180 184 3533666 \n8 Feio AB Apetato M Costa MM Acute generalized exanthematous pustulosis due to Coxsackie B4 virus (in Portuguese) Acta Med Port 1997 10 487 491 9341042 \n9 Haro-Gabaldon V Sanchez-Sanchez-Vizcaino J Ruiz-Avila P Acute generalized exanthematous pustulosis with cytomegalovirus infection Int J Dermatol 1996 35 735 737 8891829 \n10 Naides SJ Piette W Veach LA Human parvovirus B19-induced vesiculopustular skin eruption Am J Med 1988 84 968 972 2834947 \n11 Manzano S Guggisberg D Hammann C Acute generalized exanthematous pustulosis: first case associated with a Chlamydia pneumoniae infection (in French) Arch Pediatr 2006 13 1230 1232 16919427 \n12 Lerch M Bircher AJ Systemically induced allergic exanthem from mercury Contact Derm 2004 50 349 353 15274725 \n13 Roujeau JC Bioulac-Sage P Bourseau C Acute generalized exanthematous pustulosis. Analysis of 63 cases Arch Dermatol 1991 127 1333 1338 1832534 \n14 Manders SM Heymann WR Acute generalized exanthemic pustulosis Cutis 1994 54 194 196 7813242 \n15 Trevisi P Patrizi A Neri I Farina P Toxic pustuloderma associated with azithromycin Clin Exp Dermatol 1994 19 280 281 8033402\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "2(2)",
"journal": "Case reports in dermatology",
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"medline_ta": "Case Rep Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101517685",
"other_id": null,
"pages": "82-87",
"pmc": null,
"pmid": "21103192",
"pubdate": "2010-06-01",
"publication_types": "D002363:Case Reports",
"references": "9341042;17854366;7813242;1832534;9069592;17239150;8186121;8033402;2834947;3533666;16919427;7514976;8891829;11168761;15274725",
"title": "Acute Generalized Exanthematous Pustulosis Induced by Cefepime: A Case Report.",
"title_normalized": "acute generalized exanthematous pustulosis induced by cefepime a case report"
} | [
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}
],
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},
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"literaturereference": "BOTELHO LF, ET AL. ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS INDUCED BY CEFEPIME: A CASE REPORT. CASE REP DERMATOL. 2010 JUN 1?2(2):82- 87.",
"literaturereference_normalized": "acute generalized exanthematous pustulosis induced by cefepime a case report",
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},
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},
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},
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{
"abstract": "BACKGROUND\nEfavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI) is used globally as first-line antiretroviral therapy (ART) in combination with a dual nucleoside backbone in adults and children from 3 years of age. Up to 40% of adults taking efavirenz report central nervous system (CNS) adverse effects, and the rates of discontinuation of efavirenz-based treatment are higher than other first-line regimens. Data on efavirenz discontinuation are more limited for children and adolescents.\n\n\nOBJECTIVE\nIn this study, we aimed to describe our single-centre paediatric experience of efavirenz.\n\n\nMETHODS\nRetrospective case-note audit of children and adolescents with perinatally acquired HIV who ever received efavirenz.\n\n\nRESULTS\nFrom 1998 and 2014, 51 children and adolescents aged ≤ 18 years received efavirenz-based treatment. Median age at efavirenz initiation was 9.4 years (interquartile range [IQR] 7-13). More than half (30/51; 59%) subsequently switched off efavirenz-15 (29%) following virological failure with NNRTI-associated resistance mutations, and 16 (30%) after reporting adverse effects. Of those who experienced adverse effects, one-fifth (19.6%) described CNS adverse effects, including sleep disturbance, reduced concentration, headaches, mood change and psychosis. Four children (three males) developed gynaecomastia, two developed hypercholesterolaemia, and one child developed Stevens-Johnson syndrome. Comparison between those reporting side effects and the rest of the cohort showed no difference in age, sex, initial CD4 cell count, viral suppression, length of efavirenz-based treatment, weight, or efavirenz dose per kilogram. Median time to switch was 25 months (IQR 10-71) in those who experienced side effects and 22 months (IQR 12-50) for virological failure. One individual experienced both virological failure and adverse effects.\n\n\nCONCLUSIONS\nAlmost two-thirds of this paediatric cohort switched from efavirenz-based treatment to an alternative regimen, due in equal proportions to both virological failure and toxicity. The majority of side effects involved the CNS. First-line regimens with improved tolerability and a higher genetic barrier to resistance should be the preferred option for children.",
"affiliations": "The Family Clinic, Imperial College Healthcare NHS Trust, St Mary's Hospital, Praed Street, London, UK. elke.wynberg@stcatz.ox.ac.uk.;The Family Clinic, Imperial College Healthcare NHS Trust, St Mary's Hospital, Praed Street, London, UK.;The Family Clinic, Imperial College Healthcare NHS Trust, St Mary's Hospital, Praed Street, London, UK.;The Family Clinic, Imperial College Healthcare NHS Trust, St Mary's Hospital, Praed Street, London, UK.;The Family Clinic, Imperial College Healthcare NHS Trust, St Mary's Hospital, Praed Street, London, UK.",
"authors": "Wynberg|Elke|E|http://orcid.org/0000-0003-1945-1613;Williams|Eleri|E|;Tudor-Williams|Gareth|G|;Lyall|Hermione|H|;Foster|Caroline|C|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-017-0605-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1173-2563",
"issue": "38(3)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000293:Adolescent; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D001835:Body Weight; D018791:CD4 Lymphocyte Count; D002648:Child; D003521:Cyclopropanes; D057915:Drug Substitution; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors; D017211:Treatment Failure; D019562:Viral Load",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "231-238",
"pmc": null,
"pmid": "29181714",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "27385585;25649230;23343913;23427878;14727217;27599655;28192529;14502007;16778736;10860894;28505015;26394902;21857286;25174636;24845154;25389551;26407716;24979445;16763529;19732176;23719350;25808896;27879556;26739573;16433869;26831894",
"title": "Discontinuation of Efavirenz in Paediatric Patients: Why do Children Switch?",
"title_normalized": "discontinuation of efavirenz in paediatric patients why do children switch"
} | [
{
"companynumb": "GB-MYLANLABS-2017M1083674",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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{
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"activesubstancename": "LAMIVUDINE"
},
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"medicinalproduct": "LAMIVUDINE."
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{
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},
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],
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"reaction": [
{
"reactionmeddrapt": "Gynaecomastia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Disturbance in attention",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "21.1",
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},
{
"reactionmeddrapt": "Sleep disorder",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Enuresis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Virologic failure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Headache",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mood altered",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypercholesterolaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Psychotic disorder",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stevens-Johnson syndrome",
"reactionmeddraversionpt": "21.1",
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "WYNBERG E, WILLIAMS E, TUDOR-WILLIAMS G, LYALL H, FOSTER C.. DISCONTINUATION OF EFAVIRENZ IN PAEDIATRIC PATIENTS: WHY DO CHILDREN SWITCH?. CLIN DRUG INVESTIG.. 2018?38 (3):231-8",
"literaturereference_normalized": "discontinuation of efavirenz in paediatric patients why do children switch",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20181218",
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"serious": 1,
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"seriousnessother": 1,
"transmissiondate": "20190204"
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"medicinalproduct": "ZIDOVUDINE."
}
],
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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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"reactionoutcome": "6"
},
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"reactionmeddrapt": "Fatigue",
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}
],
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},
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},
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},
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}
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"summary": null
},
"primarysource": {
"literaturereference": "WYNBERG E, WILLIAMS E, TUDOR-WILLIAMS G, LYALL H, FOSTER C. DISCONTINUATION OF EFAVIRENZ IN PAEDIATRIC PATIENTS: WHY DO CHILDREN SWITCH?. CLINICAL DRUG INVESTIGATION. 2017;1 TO 12",
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"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20171215",
"receivedate": "20171215",
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"safetyreportid": 14288583,
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
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}
] |
{
"abstract": "Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC.\n\n\n\nEligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD.\n\n\n\nDuring 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort.\n\n\n\nAdjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively.",
"affiliations": "Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital. Electronic address: Jennifer_bellon@dfci.harvard.edu.;Department of Data Science, Dana-Farber Cancer Institute.;Department of Medical Oncology, Dana-Farber Cancer Institute.;Department of Radiation Oncology, Massachusetts General Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital.;Department of Medical Oncology, Dana-Farber Cancer Institute.;Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts.;Department of Medical Oncology, Dana-Farber Cancer Institute.;Department of Medical Oncology, Dana-Farber Cancer Institute.",
"authors": "Bellon|Jennifer R|JR|;Chen|Yu-Hui|YH|;Rees|Rebecca|R|;Taghian|Alphonse G|AG|;Wong|Julia S|JS|;Punglia|Rinaa S|RS|;Shiloh|Ron Y|RY|;Warren|Laura E G|LEG|;Krishnan|Monica S|MS|;Phillips|John|J|;Pretz|Jennifer|J|;Jimenez|Rachel|R|;Macausland|Stephanie|S|;Pashtan|Itai|I|;Andrews|Chelsea|C|;Isakoff|Steven J|SJ|;Winer|Eric P|EP|;Tolaney|Sara M|SM|",
"chemical_list": "D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2021.03.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "111(1)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000328:Adult; D000368:Aged; D002945:Cisplatin; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008408:Mastectomy; D015412:Mastectomy, Segmental; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011446:Prospective Studies; D064726:Triple Negative Breast Neoplasms; D055815:Young Adult",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "45-52",
"pmc": null,
"pmid": "33713742",
"pubdate": "2021-09-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A Phase 1 Dose-Escalation Trial of Radiation Therapy and Concurrent Cisplatin for Stage II and III Triple-Negative Breast Cancer.",
"title_normalized": "a phase 1 dose escalation trial of radiation therapy and concurrent cisplatin for stage ii and iii triple negative breast cancer"
} | [
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}
],
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},
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"literaturereference": "Bellon JR, Chen Y-H, Rees R, Taghian AG, Wong JS, Punglia RS, et al. A Phase 1 Dose-Escalation Trial of Radiation Therapy and Concurrent Cisplatin for Stage II and III Triple-Negative Breast Cancer. Int-J-Radiat-Oncol-Biol-Phys 2021;111(1):45-52.",
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},
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"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "Bellon JR, Chen Y-H, Rees R, Taghian AG, Wong JS, Punglia RS, et al. A Phase 1 Dose-Escalation Trial of Radiation Therapy and Concurrent Cisplatin for Stage II and III Triple-Negative Breast Cancer. Int-J-Radiat-Oncol-Biol-Phys 2021;111(1):45-52.",
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"qualification": "1",
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},
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},
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},
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] |
{
"abstract": "BACKGROUND\nEpilepsy of infancy with migrating focal seizures (EIMFS) is one of the early-onset epileptic encephalopathies resistant to antiepileptic drugs, therefore carrying an extremely poor neurodevelopmental outcome. KCNT1, encoding for a sodium-activated potassium channel (KCa4.1 channel), has recently been reported as the major gene responsible for EIMFS. Since gain of function is the only type of mutation identified in patients with EIMFS, quinidine, a partial antagonist of KCa4.1 channel, is considered as a potential candidate for targeted treatment of EIMFS. However, treatment results reported so far vary from seizure-free state to no response, and cardiac side effect remains a challenge for dose titration and long-term treatment.\n\n\nMETHODS\nOur case was an infant diagnosed with EIMFS with confirmed mutation in KCNT1 gene. Quinidine therapy was started as early as 9 months old. Within the first month of treatment, the number of seizures reduced to about one third. However, seizure-free state was not obtained and his neuropsychological development remained severely delayed. After 16 months of treatment, quinidine had to be discontinued because of cardiac side effects. At 27 months of age, however, his seizures suddenly stopped and he remained seizure-free for five days. This coincided with the prescription of tipepidine, a commonly used antitussive, administered for his persistent cough. Reduction in seizure frequency was also observed with dextromethorphan, another conventional antitussive drug. Although the relation between these treatments and his symptom improvement is a matter of elucidation, there is a possibility that these nonnarcotic antitussive drugs might play a role in the treatment of EIFMS.",
"affiliations": "Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan.;Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan. Electronic address: shiraken@hotmail.co.jp.;Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan.;Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan.;Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan.;Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.;Department of Neurosurgery, National Center of Neurology and Psychiatry, Tokyo, Japan.;Department of Human Genetics, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.;Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.;College of Nursing and Nutrition, Shukutoku University, Tokyo, Japan.",
"authors": "Takase|Chihiro|C|;Shirai|Kentaro|K|;Matsumura|Yu|Y|;Watanabe|Tomohiro|T|;Watanabe|Akimitsu|A|;Hirasawa-Inoue|Ayaka|A|;Mizuguchi|Takeshi|T|;Matsumoto|Naomichi|N|;Sugai|Kenji|K|;Hayashi|Masaharu|M|",
"chemical_list": "D000996:Antitussive Agents; C585122:KCNT1 protein, human; D009419:Nerve Tissue Proteins; D010880:Piperidines; D000081033:Potassium Channels, Sodium-Activated; C028458:tipepidine; D003915:Dextromethorphan; D011802:Quinidine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2020.05.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "42(8)",
"journal": "Brain & development",
"keywords": "Epilepsy of infancy with migrating focal seizures; KCNT1; Nonnarcotic antitussive drugs; Quinidine",
"medline_ta": "Brain Dev",
"mesh_terms": "D000996:Antitussive Agents; D003915:Dextromethorphan; D004569:Electroencephalography; D004827:Epilepsy; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins; D010880:Piperidines; D000081033:Potassium Channels, Sodium-Activated; D011802:Quinidine; D012640:Seizures; D017211:Treatment Failure; D016896:Treatment Outcome",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "607-611",
"pmc": null,
"pmid": "32505479",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "KCNT1-positive epilepsy of infancy with migrating focal seizures successfully treated with nonnarcotic antitussive drugs after treatment failure with quinidine: A case report.",
"title_normalized": "kcnt1 positive epilepsy of infancy with migrating focal seizures successfully treated with nonnarcotic antitussive drugs after treatment failure with quinidine a case report"
} | [
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"medicinalproduct": "POTASSIUM BROMIDE"
}
],
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"reaction": [
{
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}
],
"summary": null
},
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"literaturereference": "TAKASE C, SHIRAI K, MATSUMURA Y, WATANABE T, WATANABE A, HIRASAWA-INOUE A ET AL. KCNT1-POSITIVE EPILEPSY OF INFANCY WITH MIGRATING FOCAL SEIZURES SUCCESSFULLY TREATED WITH NONNARCOTIC ANTITUSSIVE DRUGS AFTER TREATMENT FAILURE WITH QUINIDINE: A CASE REPORT. BRAIN AND DEVELOPMENT. 2020. DOI:10.1016/J.BRAINDEV.2020.05.002",
"literaturereference_normalized": "kcnt1 positive epilepsy of infancy with migrating focal seizures successfully treated with nonnarcotic antitussive drugs after treatment failure with quinidine a case report",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200630",
"receivedate": "20200630",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
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"sendertype": "2"
},
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"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
},
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-250280",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
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},
"drugadditional": null,
"drugadministrationroute": "065",
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},
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"drugindication": "COUGH",
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"medicinalproduct": "TIPEPIDINE"
},
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},
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"drugcumulativedosagenumb": null,
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"medicinalproduct": "PERAMPANEL"
},
{
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},
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"medicinalproduct": "DIAZEPAM."
}
],
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"reaction": [
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiac disorder",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "TAKASE C, SHIRAI K, MATSUMURA Y, WATANABE T, WATANABE A, HIRASAWA?INOUE A ET AL. KCNT1?POSITIVE EPILEPSY OF INFANCY WITH MIGRATING FOCAL SEIZURES SUCCESSFULLY TREATED WITH NONNARCOTIC ANTITUSSIVE DRUGS AFTER TREATMENT FAILURE WITH QUINIDINE: A CASE REPORT. BRAIN DEV. 2020?JUN 3",
"literaturereference_normalized": "kcnt1 positive epilepsy of infancy with migrating focal seizures successfully treated with nonnarcotic antitussive drugs after treatment failure with quinidine a case report",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200908",
"receivedate": "20200623",
"receiver": {
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},
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},
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}
] |
{
"abstract": "OBJECTIVE\nThis study aims at examining the potential survival benefits of primary versus secondary surgery of children diagnosed with advanced infantile (iFS) and adult-type fibrosarcoma (aFS).\n\n\nMETHODS\nTreatment and outcome of 89 children with FS treated within prospective Cooperative Studiengruppe (CWS) trials (1981-2016) were analyzed retrospectively.\n\n\nRESULTS\nLocalized disease (LD) was diagnosed in 87 patients: 64/66 patients with iFS (≤2 years) and 23 with aFS (>2 ≤ 18 years). Two patients (iFS) had metastatic disease. Resection was the mainstay of therapy of patients with LD resulting in microscopically complete (R0, IRS group I) (n = 29/87, 33%), microscopically incomplete (R1, IRS group II) (n = 17/87, 20%) and macroscopically incomplete (R2, IRS group III) (n = 41/87, 47%). Advanced LD (IRS group III) was present in 32/64 (50%) patients with iFS and in 9/23 (39%) with aFS. Chemotherapy was added predominantly in patients with advanced disease and an assessable objective response to CHT was seen in 71% iFS and 75% aFS. The 5-year event-free survival (EFS) of patients with iFS and aFS was 81% (±10, 95% CI) and 70% (±19, 95% CI) (p = 0.24); the 5-year overall survival (OS) was 98% (±3, 95% CI) and 82% (±16, 95% CI) (p = 0.02). Primary resection was no prognostic factor. Secondary R0/ R1 resection in patients with advanced disease improved 5-year EFS and OS in aFS (p = 0.002 and p = 0.000) but not in infants.\n\n\nCONCLUSIONS\nSecondary resection improves outcome in advanced aFS but not in infants. Mutilating surgery in infants should be avoided.\nTreatment study: patients were enrolled in five prospective studies and one registry, prognosis study: retrospective study.\n\n\nMETHODS\nII/ III.\nFibrosarcoma is a very rare malignant tumor. Little is known about differences of local treatment of advanced infantile and adult-type. Data of 89 patients registered in five prospective trials and one registry of the Cooperative Weichteilsarkom Studiengruppe (CWS) (1981-2016) were analyzed.",
"affiliations": "Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany. Electronic address: M.Sparber-Sauer@klinikum-stuttgart.de.;Kiel Pediatric Tumor Registry, Section of Pediatric Pathology Department of Pathology, Kiel, Germany.;University Children's Hospital Marburg, Department of Pediatric Surgery, Marburg, Germany.;Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.;Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.;Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Olgahospital, Institute of Radiology, Stuttgart, Germany.;Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany.;Klinikum Stuttgart, Institute of Radiotherapy, Stuttgart, Germany.;Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany; University of Muenster, Department of Pediatric Hematology and Oncology, Muenster, Germany.;St. Anna Kinderspital, Pediatric Oncology, Wien, Austria.;Department of Pediatric Oncology, University of Zurich, Zurich, Switzerland.;University of Uppsala, Children's University Hospital, Department of Women's and Children's Health, Uppsala, Sweden.;University Children's Hospital, Department of Pediatric Surgery and Urology, Tuebingen, Germany.;University of Frankfurt, Department for Children and Adolescents, Goethe University, Frankfurt/M., Germany.;Klinikum Stuttgart - Olgahospital, Stuttgart Cancer Center, Zentrum für Kinder-, Jugend- und Frauenmedizin, Pediatrics 5 (Oncology, Hematology, Immunology), Stuttgart, Germany; Children's Hospital, Department of Pediatric Hematology and Oncology, Tuebingen, Germany.",
"authors": "Sparber-Sauer|Monika|M|;Vokuhl|Christian|C|;Seitz|Guido|G|;Stegmaier|Sabine|S|;Hallmen|Erika|E|;von Kalle|Thekla|T|;Scheer|Monika|M|;Münter|Marc|M|;Bielack|Stefan S|SS|;Ladenstein|Ruth|R|;Niggli|Felix|F|;Ljungman|Gustaf|G|;Fuchs|Joerg|J|;Klingebiel|Thomas|T|;Koscielniak|Ewa|E|;|||",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpedsurg.2019.10.051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3468",
"issue": "55(9)",
"journal": "Journal of pediatric surgery",
"keywords": "Adult-type; CWS group; Fibrosarcoma; Infantile",
"medline_ta": "J Pediatr Surg",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005354:Fibrosarcoma; D006801:Humans; D007223:Infant; D000077982:Progression-Free Survival; D012189:Retrospective Studies",
"nlm_unique_id": "0052631",
"other_id": null,
"pages": "1740-1747",
"pmc": null,
"pmid": "31753608",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The impact of local control in the treatment of children with advanced infantile and adult-type fibrosarcoma: Experience of the cooperative weichteilsarkom studiengruppe (CWS).",
"title_normalized": "the impact of local control in the treatment of children with advanced infantile and adult type fibrosarcoma experience of the cooperative weichteilsarkom studiengruppe cws"
} | [
{
"companynumb": "DE-TEVA-2020-DE-1835737",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
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},
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},
{
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},
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"medicinalproduct": "ACTINOMYCIN D"
},
{
"actiondrug": "5",
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"activesubstancename": "VINCRISTINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
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"drugcharacterization": "1",
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"drugindication": "FIBROSARCOMA",
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}
],
"patientagegroup": null,
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Fanconi syndrome",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SPARBER-SAUER M, VOKUHL C, SEITZ G, STEGMAIER S, HALLMEN E, VON KALLE T, ET AL. THE IMPACT OF LOCAL CONTROL IN THE TREATMENT OF CHILDREN WITH ADVANCED INFANTILE AND ADULT-TYPE FIBROSARCOMA: EXPERIENCE OF THE COOPERATIVE WEICHTEILSARKOM STUDIENGRUPPE (CWS). J-PEDIATR-SURG 2020?55(9):1740-1747.",
"literaturereference_normalized": "the impact of local control in the treatment of children with advanced infantile and adult type fibrosarcoma experience of the cooperative weichteilsarkom studiengruppe cws",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20201012",
"receivedate": "20201008",
"receiver": {
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},
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"safetyreportversion": 2,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 1,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210114"
}
] |
{
"abstract": "Severe acute respiratory syndrome (SARS) is a newly discovered infectious disease caused by a novel coronavirus. During the community outbreak in Hong Kong, 5 liveborn infants were born to pregnant women with SARS. A systematic search for perinatal transmission of the SARS-associated coronavirus, including serial reverse transcriptase-polymerase chain reaction assays, viral cultures, and paired serologic titers, failed to detect the virus in any of the infants. In addition, none of the infants developed clinical, radiologic, hematologic, or biochemical evidence suggestive of SARS. One preterm infant developed jejunal perforation and another developed necrotizing enterocolitis with ileal perforation shortly after birth. This case series is the first report to describe the clinical course of the first cohort of liveborn infants born to pregnant women with SARS.",
"affiliations": "Department of Paediatrics and Adolescent Medicine, Princess Margaret Hospital, Lai Chi Kok, New Territories, Hong Kong.",
"authors": "Shek|Chi C|CC|;Ng|Pak C|PC|;Fung|Genevieve P G|GP|;Cheng|Frankie W T|FW|;Chan|Paul K S|PK|;Peiris|Malik J S|MJ|;Lee|Kim H|KH|;Wong|Shell F|SF|;Cheung|Hon M|HM|;Li|Albert M|AM|;Hon|Ellis K L|EK|;Yeung|Chung K|CK|;Chow|Chun B|CB|;Tam|John S|JS|;Chiu|Man C|MC|;Fok|Tai F|TF|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D012254:Ribavirin; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.112.4.e254",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "112(4)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D002585:Cesarean Section; D015331:Cohort Studies; D004196:Disease Outbreaks; D020345:Enterocolitis, Necrotizing; D005260:Female; D005317:Fetal Growth Retardation; D006723:Hong Kong; D006801:Humans; D007077:Ileal Diseases; D007231:Infant, Newborn; D007234:Infant, Premature; D018445:Infectious Disease Transmission, Vertical; D007416:Intestinal Perforation; D007579:Jejunal Diseases; D008297:Male; D008775:Methylprednisolone; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012127:Respiratory Distress Syndrome, Newborn; D012254:Ribavirin; D045473:SARS Virus; D045169:Severe Acute Respiratory Syndrome",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e254",
"pmc": null,
"pmid": "14523207",
"pubdate": "2003-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Infants born to mothers with severe acute respiratory syndrome.",
"title_normalized": "infants born to mothers with severe acute respiratory syndrome"
} | [
{
"companynumb": "HK-PFIZER INC-2020223759",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
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"drugdosageform": "POWDER FOR SOLUTION FOR INJECTION",
"drugdosagetext": "500 MG (2 COURSES OF PULSED METHYLPREDNISOLONE)",
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"drugindication": "SEVERE ACUTE RESPIRATORY SYNDROME",
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"drugdosagetext": "3 G (2 COURSES OF PULSED METHYLPREDNISOLONE)",
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{
"abstract": "Mucormycosis is an uncommon fungal infection caused by the members of the order Mucorales. In susceptible patients, mucormycosis can infect any tissue or organ, and without suitable treatment (i.e., debridement and antifungal therapy), this infection can be fatal. Our patient was a woman with lymphoma and cerebral mucormycosis who was treated with antifungals and without any neurosurgical debridement.\nHerein, we present the case of a 35-year-old woman with diagnosis of B-cell lymphoma and rhino-orbito-cerebral mucormycosis (ROCM). She was a candidate for enucleation of the left eye, orbital decompression, and sinocerebral debridement. Nevertheless, the patient refused eye enucleation and craniotomy. Finally, she was treated with a combination of antifungals and sinus debridement without eye enucleation and craniotomy.\ndebridement, along with a combination of liposomal amphotericin B (LAMB) and posaconazole, may be a suitable therapeutic option for patients with ROCM, who are not eligible candidates for extensive surgery or craniotomy.",
"affiliations": "Imam Khomeini Complex Hospital, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran.;Department of Adult Hematology and Oncology, Imam Khomeini Complex Hospital, Tehran University of Medical Sciences, Tehran, Iran.;School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.;Imam Khomeini Complex Hospital, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran.;School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.;Department of Medical Mycology and Parasitology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.;Ziaeian Hospital, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran.;Imam Khomeini Complex Hospital, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran.;Imam Khomeini Complex Hospital, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Salehi|Mohammadreza|M|;Shahi|Farhad|F|;Rizvi|Fatema Sadaat|FS|;Ghaderkhani|Sara|S|;Zainaldain|Hamed|H|;Khodavaisy|Sadegh|S|;Jamali-Moghaddam|Saeed Reza|SR|;Dehghan Manshadi|Seyed Ali|SA|;Rezahosseini|Omid|O|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.22088/cjim.11.2.227",
"fulltext": "\n==== Front\nCaspian J Intern Med\nCaspian J Intern Med\nCJIM\nCaspian Journal of Internal Medicine\n2008-6164 2008-6172 Babol University of Medical Sciences Babol, Iran \n\n10.22088/cjim.11.2.227\nCase Report\nCombination antifungal therapy without craniotomy in an immunocompromised patient with rhino-orbito-cerebral mucormycosis: A case report \nSalehi Mohammadreza MD1 Shahi Farhad MD2 Rizvi Fatema Sadaat 3 Ghaderkhani Sara MD1 Zainaldain Hamed 3 Khodavaisy Sadegh Ph.D4 Jamali-Moghaddam Saeed Reza MD5 Dehghan Manshadi Seyed Ali MD1* Rezahosseini Omid MD16 \n1 Imam Khomeini Complex Hospital, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran\n\n2 Department of Adult Hematology and Oncology, Imam Khomeini Complex Hospital, Tehran University of Medical Sciences, Tehran, Iran\n\n3 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran\n\n4 Department of Medical Mycology and Parasitology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran\n\n5 Ziaeian Hospital, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran\n\n6 Viro-immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark\n* Correspondence: Seyed Ali Dehghan Manshadi, Department of Infectious Diseases, Imam Khomeini Complex Hospital, Keshavarz blvd, Dr Gharib Street, Tehran, 1419733141, Iran. E-mail: sealdema@yahoo.com, Tel: 0098 2166581598, Fax: 0098 2166581598\n2020 \n11 2 227 230\n4 2 2019 26 5 2019 26 6 2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nMucormycosis is an uncommon fungal infection caused by the members of the order Mucorales. In susceptible patients, mucormycosis can infect any tissue or organ, and without suitable treatment (i.e., debridement and antifungal therapy), this infection can be fatal. Our patient was a woman with lymphoma and cerebral mucormycosis who was treated with antifungals and without any neurosurgical debridement.\n\nCase Presentation:\nHerein, we present the case of a 35-year-old woman with diagnosis of B-cell lymphoma and rhino-orbito-cerebral mucormycosis (ROCM). She was a candidate for enucleation of the left eye, orbital decompression, and sinocerebral debridement. Nevertheless, the patient refused eye enucleation and craniotomy. Finally, she was treated with a combination of antifungals and sinus debridement without eye enucleation and craniotomy.\n\nConclusion:\ndebridement, along with a combination of liposomal amphotericin B (LAMB) and posaconazole, may be a suitable therapeutic option for patients with ROCM, who are not eligible candidates for extensive surgery or craniotomy.\n\nKey Words\nMucormycosisInvasive fungal infectionCombination drug therapiesLiposomal amphotericin BPosaconazole\n==== Body\nMucormycosis is an uncommon fungal infection caused by the members of the order Mucorales (1, 2). Sporangiospores are ubiquitously found in decaying organic materials and soil. Mucormycosis mostly transmits to humans via inhalation of sporangiospores, and occasionally by traumatic inoculation (3). Mucorales may also be found in the air and water of healthcare settings and tongue depressors; they are also found in the nose and mouth of healthy individuals (4). The main risk factors for mucormycosis include immunosuppressive and chemotherapy agents, poorly controlled diabetes mellitus, hematologic malignancies (e.g., leukemia and lymphoma), hematopoietic stem cell or solid organ transplantation, and some other factors (1, 5). Although Mucorales can infect any tissue, rhino-orbito-cerebral mucormycosis (ROCM), cutaneous mucormycosis, and pulmonary mucormycosis are more commonly reported. The common presentations of ROCM include perinasal cellulitis, facial pain and paresthesias, headache, lethargy, visual loss, proptosis, and/or palatal ulcer (2, 6). The mortality rate of patients with ROCM, even with treatment, is more than 60% (5). Therefore, prompt debridement of necrotic tissues, systemic administration of antifungal agents, dose reduction of immunosuppressants, and control of underlying diseases can be life-saving (1). Lipid formulations of amphotericin B are the first-line antifungal agents for the treatment of ROCM. \n\nHowever, there has been a growing interest in new azoles, such as posaconazole and isavuconazole in recent years. Most of our knowledge about the treatment of mucormycosis is based on the findings of case reports (5). Therefore, experiences and rare cases of this disease are worth reporting. Herein, we present a patient with ROCM, who was treated with a combination of antifungals, i.e., liposomal amphotericin B (LAMB) plus posaconazole, and sinus debridement without craniotomy. The aim of this case report was to demonstrate the clinical course of this patient and increase the current awareness of the efficiency of combination therapy for patients with ROCM, who refuse surgery.\n\nCase presentation\nThe patient was a 35-year-old woman with a confirmed diagnosis of high-grade B-cell lymphoma under rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) regimens. In the final phase of chemotherapy, an infectious disease consultation was requested because of fever (axillary temperature, 38.9°C) and neutropenia (absolute neutrophil count, 200 cell/mL).\n\nOn the physical examination, the patient’s left eyelid was swollen and erythematous. She also had headaches and blurred vision (figure 1).\n\nSince opportunistic infections were highly probable, chemotherapy was immediately stopped, and broad-spectrum antibiotics, including meropenem (2 g q8h), vancomycin (1 g q12h), and LAMB (300 mg/daily), were prescribed. In addition, paranasal sinus (PNS) CT scan and brain magnetic resonance imaging (MRI) were requested. The PNS CT scan showed mucosal thickening in both maxillary sinuses (figure 2). The brain MRI images revealed an intracranial lesion (about 20×20 mm) in the left frontal cortex (MRI-T2 flair view) (figure 3). Her laboratory tests revealed C-reactive protein (CRP): +++, erythrocyte sedimentation rate (ESR): 83 mm/h, galactomannan: 0.3 and blood cultures: negative.\n\nFigure 1 The swollen erythematous left eyelid\n\nFigure 2 The PNS CT scan (axial view-without contrast) shows a mucosal thickening in both maxillary sinuses\n\nFigure 3 The brain MRI image (MRI-T2 flair view) of an intracranial hyper-intense lesion with dimensions of 20×20 mm in the left frontal lobe (Red arrow)\n\nThe findings were compatible with ROCM; accordingly, sinus endoscopic biopsy and debridement was carried out, and the specimens were sent to the laboratory. Ribbon-like hyphae, compatible with mucormycosis, were reported in the histopathological examination (figure 4). Considering the extent of ROCM, the patient was a candidate for enucleation of the left eye, orbital decompression, and sinocerebral debridement. Nevertheless, the patient refused eye enucleation and craniotomy. Therefore, multiple endoscopic sinus debridement procedures were carried out, and posaconazole (200 mg /Q 6 hours) was added to LAMB as a combination antifungal treatment. \n\nFigure 4 The histological examination of sinus debridement (aseptate ribbon-like hyphae)\n\nDuring the third week of combination therapy, there was a remarkable improvement in the patient’s clinical signs and symptoms. Also, in the follow-up brain MRI images, the frontal lobe lesion was completely resolved (figure 5). The combination antifungal therapy continued for four weeks, and the patient was discharged in the twelfth week. In the weekly follow-ups, no relapse in ROCM was found during the first three months of discharge. However, after three months, the patient died because of relapse in hematologic disease and bleeding due to severe thrombocytopenia. \n\nFigure 5 Follow-up MRI after three weeks of combination therapy and four sinus debridement procedures\n\nDiscussion\nIn recent years, the number of diagnosed cases of mucormycosis has increased probably due to increased awareness of the signs and symptoms of this infection and/or improvement of diagnostic techniques (7). Early diagnosis, debridement of necrotized tissues, and prompt initiation of antifungal therapy are the cornerstones of successful treatment for invasive mucormycosis, which can reduce the associated morbidity and mortality (1). \n\nAlthough surgery is an important part of treatment for mucormycosis, some patients do not meet the essential preoperative criteria or refuse to undergo surgery (similar to our case). Generally, there is scarce information about clinical decision-making in these patients, especially when there is an intracranial invasion. Therefore, in this study, we reported our successful experience in a patient with such conditions. In our patient, a combination antifungal therapy, concomitant with multiple endoscopic sinus debridement procedures, was effective in the treatment of ophthalmic involvement and intracranial lesion, as confirmed by the follow-up MRI images.\n\nLAMB has an excellent inhibitory concentration in the eye and brain tissues (8). Although the concentration of posaconazole in the eye and brain tissues is low, its concentration increases in inflamed tissues (8). Combination antifungal therapy with LAMB plus posaconazole has a remarkable synergistic effect on the inhibition of Mucorales species in vitro (9). One of the possible explanations for this effect is that LAMB can create membrane holes in Mucorales species and facilitate the entry of posaconazole into the cells (10). The efficacy of this regimen in patients with mucormycosis has been indicated in some previous reports (1, 11, 12).\n\nIn this regard, in a case series of 32 patients with hematologic malignancies and mucormycosis, who had received a combination of LAMB and posaconazole, favorable clinical responses were reported in 56% of patients (12). In this study, the median duration of maintenance therapy was 74 days in patients with a good therapeutic response (12). However, the mentioned study did not report the efficacy of combination therapy in the improvement of intracranial lesions without craniotomy. \n\nIn summary, endoscopic debridement, along with a combination of LAMB and posaconazole, may be a proper therapeutic option for patients with ROCM, who are not eligible candidates for extensive surgery or craniotomy.\n\nAcknowledgments\nWe appreciate the utmost cooperation of the Pathology and Radiology Departments of Imam Khomeini Hospital.\n\nConflict of Interests:\nAuthors have no conflict of interests related to this work.\n==== Refs\nReferences\n1 Sipsas NV Gamaletsou MN Anastasopoulou A Kontoyiannis DP Therapy of mucormycosis J Fungi (Basel) 2018 4 E90 30065232 \n2 Anand A Anand N Anand A Rhinocerebral mucormycosis: Cure without surgery Arch Intern Med 1996 156 2262 2269 \n3 Skiada A Pagano L Groll A Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007 Clin Microbiol Infect 2011 17 1859 67 21199154 \n4 Rammaert B Lanternier F Zahar JR Healthcare-associated mucormycosis Clin Infect Dis 2012 54 S44 54 22247444 \n5 Jeong W Keighley C Wolfe R The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports Clinical Microbiol Infect 2019 25 26 34 30036666 \n6 Kolekar JS Rhinocerebral mucormycosis: a retrospective study Indian J Otolaryngolo Head Neck Surg 2015 67 93 6 \n7 Meletiadis J Roilides E Rare Invasive fungal infections: epidemiology, diagnosis and management Curr Fungal Infect Rep 2013 7 351 60 \n8 Felton T Troke PF Hope WW Tissue penetration of antifungal agents Clin Microbiol Rev 2014 27 68 88 24396137 \n9 Ballester F Pastor FJ Guarro J In vitro activities of combinations of amphotericin B, posaconazole and four other agents against Rhizopus J Antimicrob Chemother 2008 61 755 7 18227092 \n10 Perkhofer S Locher M Cuenca-Estrella M Posaconazole enhances the activity of amphotericin B against hyphae of zygomycetes in vitro Antimicrob Agents Chemother 2008 52 2636 8 18458135 \n11 Mardani M Yadegarynia D Tehrani S Combination antifungal treatment for sino-orbito-cerebral mucormycosis: a case report Arch Clin Infect Dis 2016 11 e28345 \n12 Pagano L Cornely OA Busca A Combined antifungal approach for the treatment of invasive mucormycosis in patients with hematologic diseases: a report from the SEIFEM and FUNGISCOPE registries Haematologica 2013 98 e127 30 23716556\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2008-6164",
"issue": "11(2)",
"journal": "Caspian journal of internal medicine",
"keywords": "Combination drug therapies; Invasive fungal infection; Liposomal amphotericin B; Mucormycosis; Posaconazole",
"medline_ta": "Caspian J Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101523876",
"other_id": null,
"pages": "227-230",
"pmc": null,
"pmid": "32509254",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25621242;21199154;22247444;24396137;30065232;18458135;30036666;8885828;23716556;18227092",
"title": "Combination antifungal therapy without craniotomy in an immunocompromised patient with rhino-orbito-cerebral mucormycosis: A case report.",
"title_normalized": "combination antifungal therapy without craniotomy in an immunocompromised patient with rhino orbito cerebral mucormycosis a case report"
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"literaturereference": "SALEHI M, SHAHI F, RIZVI FS, GHADERKHANI S, ZAINALDAIN H, KHODAVAISY S, ET AL. COMBINATION ANTIFUNGAL THERAPY WITHOUT CRANIOTOMY IN AN IMMUNOCOMPROMISED PATIENT WITH RHINO-ORBITO-CEREBRAL MUCORMYCOSIS: A CASE REPORT. CASPIAN J INTERN MED. 2020?11(2):227-230.",
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{
"abstract": "A 63-year-old woman previously stable on a regimen of atorvastatin 40 mg daily, carvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily, spironolactone 25 mg daily, rivaroxaban 15 mg daily, and enalapril 20 mg twice daily for heart failure developed rhabdomyolysis 26 days after enalapril was stopped and sacubitril/valsartan (Entresto™) started. The patient received sacubitril/valsartan at 24/26 mg twice daily for heart failure; however, after 26 days she developed muscle and skin pain. Investigations revealed elevated creatine kinase and liver function tests, and rhabdomyolysis with raised transaminases was diagnosed. Sacubitril/valsartan and atorvastatin were discontinued and the patient was hydrated. She returned to baseline in 23 days and has not had any reoccurrence of rhabdomyolysis and elevated transaminases for 46 days. A Naranjo assessment score of 5 was obtained, indicating a probable relationship between the patient's rhabdomyolysis and her use of sacubitril/valsartan. The Drug Interaction Probability Scale score was 3, consistent with a possible interaction as a cause for the reaction, with sacubitril/valsartan as the precipitant drug and atorvastatin as the object drug.",
"affiliations": "Department of Family Medicine, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Suite B, Brooklyn, NY, 11203, USA. Eve.faber@downstate.edu.;Department of Family Medicine, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Suite B, Brooklyn, NY, 11203, USA.;Department of Family Medicine, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Suite B, Brooklyn, NY, 11203, USA.;Department of Family Medicine, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Suite B, Brooklyn, NY, 11203, USA.",
"authors": "Faber|Eve S|ES|;Gavini|Madhavi|M|;Ramirez|Ronald|R|;Sadovsky|Richard|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40800-016-0036-6",
"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 278041003610.1007/s40800-016-0036-6Case ReportRhabdomyolysis After Coadministration of Atorvastatin and Sacubitril/Valsartan (Entresto™) in a 63-Year-Old Woman Faber Eve S. (718) 270-1801Eve.faber@downstate.edu Gavini Madhavi Ramirez Ronald Sadovsky Richard Department of Family Medicine, SUNY-Downstate Medical Center, 450 Clarkson Avenue, Suite B, Brooklyn, NY 11203 USA 2 11 2016 2 11 2016 12 2016 3 14© The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.A 63-year-old woman previously stable on a regimen of atorvastatin 40 mg daily, carvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily, spironolactone 25 mg daily, rivaroxaban 15 mg daily, and enalapril 20 mg twice daily for heart failure developed rhabdomyolysis 26 days after enalapril was stopped and sacubitril/valsartan (Entresto™) started. The patient received sacubitril/valsartan at 24/26 mg twice daily for heart failure; however, after 26 days she developed muscle and skin pain. Investigations revealed elevated creatine kinase and liver function tests, and rhabdomyolysis with raised transaminases was diagnosed. Sacubitril/valsartan and atorvastatin were discontinued and the patient was hydrated. She returned to baseline in 23 days and has not had any reoccurrence of rhabdomyolysis and elevated transaminases for 46 days. A Naranjo assessment score of 5 was obtained, indicating a probable relationship between the patient’s rhabdomyolysis and her use of sacubitril/valsartan. The Drug Interaction Probability Scale score was 3, consistent with a possible interaction as a cause for the reaction, with sacubitril/valsartan as the precipitant drug and atorvastatin as the object drug.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nKey Points\n\nSacubitril/valsartan is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker, indicated to decrease the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure.\t\nA patient previously stable on atorvastatin developed severe rhabdomyolysis and an elevation of transaminases within 26 days of initiation of sacubitril/valsartan.\t\n\n\n\nIntroduction\nRhabdomyolysis is a syndrome characterized by skeletal muscle cell damage, leading to elevated creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotranferase (AST), which can result in severe sequelae, including renal failure, cardiac arrhythmia, hyperthermia and death [1]. Associated elevations in transaminases may be seen, even in the absence of significant liver injury [2]. Clinically, rhabdomyolysis classically presents with muscle pain, weakness and dark, red or tea-colored urine; however, less than 10% of patients will demonstrate all three components of this triad [3]. Rhabdomyolysis may be triggered by hereditary and/or acquired mechanisms, with approximately 75% of initial episodes being a result of acquired causes [3]. In particular, a large number of prescription drugs and drugs of abuse can cause rhabdomyolysis, with statins being one of the top three prescription drugs most commonly responsible for rhabdomyolysis for this syndrome [4]. Myopathy and myositis have been reported in conjunction with all of the currently available statins and are considered to be a class effect of these medications. In addition, it has been recognized that statin-associated muscle complaints are dose-related and drug–drug interactions that cause an elevation of statin levels have been identified. Subgroups of patients at greater risk of statin-associated muscle pathology have been identified and include age >70 years, impaired renal function, and impaired hepatic function [5].\n\nEntresto™ is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB), indicated to decrease the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (New York Heart Association [NYHA] class II–IV) and reduced ejection fraction. Sacubitril/valsartan is usually administered in conjunction with other heart failure drug regimens instead of an angiotensin-converting enzyme inhibitor (ACEi) or another ARB. The commonly occurring (≥5%) adverse reactions reported are hypotension, hyperkalemia, cough, dizziness, and renal failure [6, 7]. Sacubitril/valsartan has not been associated with rhabdomyolysis and is commonly used in patients who are also receiving statin therapy.\n\nCase Report\nA 63-year-old Guyanese woman with hypertension, hyperlipidemia, congestive heart failure (CHF), atrial fibrillation, and peripheral vascular disease presented to her primary care provider’s office with a complaint of an episode of weakness at home associated with general malaise. She was receiving atorvastatin 40 mg daily, carvedilol 25 mg twice daily, digoxin 0.125 mg daily, furosemide 40 mg daily, spironolactone 25 mg daily, rivaroxaban 15 mg daily, and sacubitril/valsartan 24/26 mg twice daily. She was initiated on sacubitril/valsartan 22 days before her clinical presentation and had been on all of her other concurrent medications for more than 1 year. On the review of systems, the patient reported generalized weakness, pain in her knees, and an ill-defined stinging pain in the skin of her arms and legs. Her physical examination was non-focal, with no muscle weakness or tenderness of either the skin or muscles noted. Laboratory tests performed on presentation were significant for elevated AST/alanine aminotransferase (ALT) of 351 u/L/131 u/L. At the time she was believed to be having a reaction to her statin therapy prescribed for hyperlipidemia and therefore the atorvastatin was withheld. She was scheduled to return in 4 days for repeat laboratory testing and re-evaluation.\n\nWhen the patient returned in 4 days, she complained of dark urine, generalized weakness, and increased muscle and skin pain throughout her body. She was then found to have rhabdomyolysis, with CK at 58,349 u/L (>50× the upper limit of normal). She was admitted to hospital where she was hydrated and monitored. Her electrolytes were normal on admission and remained so throughout her stay. Sacubitril/valsartan was stopped at this time as it was the only new medication in her regimen. The CK level decreased steadily and her symptoms resolved over the course of a 5-day hospitalization (Fig. 1). Her renal function was preserved throughout and her bilirubin and transaminases briefly increased and also subsequently steadily decreased (Figs. 2, 3). During her hospital stay, the patient was tested for Epstein–Barr virus, hepatitis A, herpes simplex virus, HIV, and cytomegalovirus (CMV). She was found to be immune to hepatitis A, Epstein–Barr virus, and herpes simplex virus, and had negative hepatitis A and B, HIV, HSV. and CMV tests.Fig. 1 Creatine kinase values during and post hospitalization. CK creatine kinase\n\n\nFig. 2 Total bilirubin values during and post hospitalization. T. Bili total bilirubin\n\n\nFig. 3 Transaminase values during and post hospitalization. AST aspartate aminotransferase, ALT alanine aminotransferase\n\n\n\n\nBy 23 days after her initial presentation, the patient no longer had any muscle or skin pain and her CK and liver function test (LFT) levels were completely normalized. The patient has not had any reoccurrence of rhabdomyolysis and elevated transaminases for 46 days, and her bilirubin and transaminase levels also returned to normal (Figs. 2, 3). One week later, the patient was started on an alternate statin at a low dose (rosuvastatin 5 mg) and the CK levels and LFTs have remained stable. There are no plans to restart sacubitril/valsartan.\n\nDiscussion\nThis patient had been on a variety of statins for more than 7 years, including atorvastatin, simvastatin, and rosuvastatin. Her baseline CK and LFTs were normal prior to the initiation of sacubitril/valsartan. She had previously experienced two transient elevations in CK, to a maximum of 1608 u/L, while hospitalized for an implantable defibrillator infection and explanation complicated by an acute CHF exacerbation and a recurrent CHF exacerbation in the 3 years prior to the current admission. Her CK levels returned to normal after her acute illnesses, without change in her LFTs. In this case, the immediate cause of her rhabdomyolysis was unknown, but the new medication in her profile seemed to be the likely trigger. Due to the severity of her rhabdomyolysis, the decision was made to not re-initiate sacubitril/valsartan. The Naranjo Adverse Drug Reaction Probability Scale score was 5, making it probable that the adverse drug reaction was precipitated by sacubitril/valsartan [8]. The Drug Interaction Probability Scale score was 3, consistent with a possible interaction as a cause for the reaction, with sacubitril/valsartan as the precipitant drug and atorvastatin as the object drug [9].\n\nOf note, one of the concurrent medications, carvedilol, is a P-glycoprotein inhibitor that may increase the serum concentration of atorvastatin, a P-glycoprotein substrate; however, the patient was stable on this combination for 7 years before sacubitril/valsartan was initiated. None of the other medications taken by this patient are known to cause rhabdomyolysis or an elevation in transaminases.\n\nA literature search regarding a drug interaction between sacubitril and statins yielded no reports of rhabdomyolysis with statins. As per a recent study, coadministration of sacubitril/valsartan with atorvastatin led to a twofold increase in the maximum concentration (C\nmax) of atorvastatin and its metabolites [10]. In addition, the US and Canadian package inserts of sacubitril/valsartan cite in vitro data showing sacubitril inhibiting organic anion transporting polypeptides (OATP) 1B1 and 1B3, resulting in increased C\nmax and area under the curve (AUC) of atorvastatin with coadministration of sacubitril/valsartan [6, 7]. The Canadian version of the product insert further states that sacubitril/valsartan may increase the systemic exposure of OATP1B1 and OATP1B3 substrates, such as statins. Sacubitril/valsartan increases the C\nmax of atorvastatin and its metabolites by up to twofold, and AUC by up to 1.3-fold. The Canadian insert recommends that sacubitril/valsartan must be coadministered cautiously with statins, especially simvastatin, a sensitive OATP1B1/1B3 substrate, and a decrease in dose of simvastatin and atorvastatin may be considered when coadministered with sacubitril/valsartan [7]. The interaction between atorvastatin and sacubitril is mentioned in the US product package insert as a theoretical possibility. There is currently no recommendation to increase monitoring or empirically decrease the dose of any statin on initiation of sacubitril/valsartan.\n\nA number of medications are known to inhibit OATPs and have been shown to increase statin plasma concentrations [11]. Many single nucleotide polymorphisms (SNPs) have been found within the SLCO1B1 and/or SLCO1B3 genes encoding OATP1B1 and OATP1B3 proteins, respectively, and were shown to effect the pharmacokinetics and/or pharmacodynamics of statins [12, 13]. The clinical consequences of the drug interactions may vary based on the genetic variation in OATP-encoding genes and inhibition of OATP function. The SLCO1B1*1B haplotype appears to be associated with enhanced hepatic uptake and reduced plasma concentrations of OATP1B1 substrates [14].\n\nDiscontinuation of the statin alone did not result in a decrease in the patient’s LFTs. It was not until sacubitril/valsartan was also discontinued, and treatment for rhabdomyolysis was initiated, that the patient’s symptoms began to improve and her CK and LFTs returned to baseline. This could be due to either a direct effect of sacubitril/valsartan or the increased serum concentration of atorvastatin, as described in the literature. Because of the above-stated pharmacodynamics, we believe that the more likely mechanism is the increased serum concentration of atorvastatin.\n\nCurrently, there is no recommendation regarding the initiation or continuation of statins in patients with NYHA class II–IV heart failure as there is insufficient information on which to base recommendations for or against statin treatment. In these patients, the choice of statin dose, and using a statin for cardiovascular risk reduction benefit, must be weighed against adverse effects, drug–drug interactions, precautions and contraindications to statin therapy [15]. We would have liked to have arranged SLCOB testing for the patient but were unable to. Further research will be useful in identifying patients at risk for this adverse reaction, and will likely include genetic testing.\n\nConclusions\nThis case of severe rhabdomyolysis should stimulate further investigation of the potential negative effects of the initiation of sacubitril/valsartan in patients receiving statin therapy. Since sacubitril/valsartan is targeted for patients with heart failure, we predict that this would comprise a large number of the candidates for treatment. We recommend consideration of obtaining baseline CK levels and LFTs and close observation of patients. In this case, rhabdomyolysis developed within 3 weeks of initiation of sacubitril/valsartan and evaluation within a shorter time frame may be appropriate. Future reports of this reaction may help to define high-risk patients, but it should be noted that our patient had no known high-risk characteristics for the development of rhabdomyolysis, except for prior mild elevations of CK during hospitalizations for CHF exacerbations. We encourage the reporting of any similar reactions to the US FDA, the manufacturer, and the medical community.\n\nCompliance with Ethical Standards\nFunding\nNo sources of funding were used in the preparation of this report.\n\nConflict of interest\nEve S. Faber, Madhavi Gavini, Ronald Ramirez and Richard Sadovsky declare that they have no conflicts of interest that are directly relevant to the content of this report.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent may be requested for review from the corresponding author.\n==== Refs\nReferences\n1. Giannoglou GD Chatzizisis YS Misirli G The syndrome of rhabdomyolysis: pathophysiology and diagnosis Eur J Intern Med. 2007 18 90 100 10.1016/j.ejim.2006.09.020 17338959 \n2. Weibrecht K Dayno M Darling C Liver aminotransaminases are elevated with rhabdomyolysis in the absence of significant liver injury J Med Toxicol. 2010 6 294 300 10.1007/s13181-010-0075-9 20407858 \n3. Zutt R van der Kooi AJ Linthorst GE Rhabdomyolysis: review of the literature Neuromuscul Disord. 2014 24 651 690 10.1016/j.nmd.2014.05.005 24946698 \n4. Melli G Chaudhry V Cornblath DR Rhabdomyolysis: an evaluation of 475 hospitalized patients Medicine (Baltimore). 2005 84 377 10.1097/01.md.0000188565.48918.41 16267412 \n5. Thompson PD Clarkson PM Rosenson RS An assessment of statin safety by muscle experts Am J Cardiol. 2006 97 8A 69C 76C 10.1016/j.amjcard.2005.12.013 16581332 \n6. Entresto™ [package insert]. East Hanover: Novartis Pharmaceuticals Corporation; 2015. https://www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf. Accessed 26 March 2016.\n7. Product monograph for Entresto™. Dorval, QC H9S 1A9. Novartis Pharmaceuticals Canada, Inc.; 2015.\n8. Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther. 1981 30 239 245 10.1038/clpt.1981.154 7249508 \n9. Horn JR Hansten PD Chan LN Proposal for a new tool to evaluate drug interaction cases Ann Pharmacother. 2007 41 674 680 10.1345/aph.1H423 17389673 \n10. Ayalasomayajula, S., Pan, W., Han, Y. et al. Assessment of drug–drug interaction potential between atorvastatin and LCZ696, a novel angiotensin receptor neprilysin inhibitor, in healthy Chinese male subjects. Eur J Drug Metab Pharmacokinet. doi:10.1007/s13318-016-0349-y (Epub 31 May 2016).\n11. Niemi M Pasanen MK Neuvonen PJ Organic anion transporting polypeptide 1b1: a genetically polymorphic transporter of major importance for hepatic drug uptake Pharmacol Rev. 2011 63 157 181 10.1124/pr.110.002857 21245207 \n12. He YJ Zhang W Chen Y Guo D Tu JH Xu LY Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism Clin Chim Acta. 2009 405 49 52 10.1016/j.cca.2009.04.003 19374892 \n13. Romaine SP Bailey KM Hall AS Balmforth AJ The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy Pharmacogenomics J. 2010 10 1 11 10.1038/tpj.2009.54 19884908 \n14. Kalliokoski A Niemi M Impact of OATP transporters on pharmacokinetics Br J Pharmacol. 2009 158 3 693 705 10.1111/j.1476-5381.2009.00430.x 19785645 \n15. Stone NJ Robinson J Lichtenstein AH 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol. 2014 63 2889 2934 10.1016/j.jacc.2013.11.002 24239923\n\n",
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"title": "Rhabdomyolysis After Coadministration of Atorvastatin and Sacubitril/Valsartan (Entresto™) in a 63-Year-Old Woman.",
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"medicinalproduct": "ATORVASTATIN"
},
{
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"activesubstance": {
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},
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"medicinalproduct": "FUROSEMIDE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "19.1",
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},
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
}
],
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},
"primarysource": {
"literaturereference": "FABER E, GAVINI M, RAMIREZ R, SADOVSKY R. RHABDOMYOLYSIS AFTER COADMINISTRATION OF ATORVASTATIN AND SACUBITRIL/VALSARTAN (ENTRESTO) IN A 63-YEAR-OLD WOMAN. DRUG SAF CASE REP. 2016;3(1):.",
"literaturereference_normalized": "rhabdomyolysis after coadministration of atorvastatin and sacubitril valsartan entresto in a 63 year old woman",
"qualification": "1",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "US",
"receiptdate": "20161207",
"receivedate": "20161123",
"receiver": {
"receiverorganization": "FDA",
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},
"reporttype": "1",
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"sender": {
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},
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"seriousnesshospitalization": 1,
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"transmissiondate": "20170207"
}
] |