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{
"abstract": "This retrospective study describes efficacy of Azacitidine on autoimmune disorders (AID) associated with MDS/CMML in 22 patients. Response of AID to Azacitidine was observed in 19 patients (86%). Reduction or discontinuation of steroids and/or immunosuppressive therapy (IST) was possible in 16 cases (73%). Hematologic response was seen in 55% of the patients. MDS/CMML and AID evolution was concordant in 13 cases (59%): both favorable (n=11), both unfavorable (n=2), but AID improved while MDS/CMML worsened (n=8) and vice versa (n=1). Azacitidine frequently seems effective in controlling steroid-dependent AID associated with MDS/CMML, but prospective studies are necessary to confirm those findings.",
"affiliations": "Service de Médecine Interne, Hôpital Jean Verdier, Assistance Publique des Hôpitaux de Paris, Université Paris XIII, France. Electronic address: jeanbaptiste.fraison@aphp.fr.;Service de Médecine Interne, DHU i2B, Inflammation-Immunopathologie-Biothérapie (DHU i2B), Hôpital Saint Antoine, Assistance Publique des Hôpitaux de Paris, Université Paris VI Sorbonne, 75012 Paris, France.;Service d'hématologie, Institut de Cancérologie Gustave Roussy, 94800 Villejuif, France.;Service de Médecine Interne, Hôpital Foch, Suresnes, France.;Service de Médecine Interne, Hôpital Européen Georges Pompidoux, Université Paris V, Paris, France.;Service de Médecine Interne, Centre Hospitalier Universitaire de Rennes, France.;Service de Médecine Interne, Centre Hospitalier de Rochefort, France.;Service de Médecine Interne, Centre Hospitalier de Douai, France.;Service de Rhumatologie, Centre Hospitalier de Romilly, France.;Service de Médecine Interne, Centre Hospitalier Universitaire de Caen, France.;Service de Médecine Interne, Centre Hospitalier Universitaire de Caen, France.;Service de Rhumatologie, Centre Hospitalier Universitaire de Caen, France.;Service de Médecine Interne, Centre Hospitalier Universitaire de Dijon, France.;Service de Médecine Interne, Centre Hospitalier Universitaire de Limoges, France.;Service d'Hématologie, Centre Hospitalier Universitaire de Grenoble, France.;Service d'Hématologie, Hôpital Avicenne, Université Paris XIII, Bobigny, France.;Service de Maladies Infectieuses, Hôpital Necker, Université Paris V, Paris, France.;Service d'hématologie, Institut de Cancérologie Gustave Roussy, 94800 Villejuif, France.;Service d'Hématologie, Hôpital Saint Louis, Université Paris VII, Paris, France.;Service de Médecine Interne, DHU i2B, Inflammation-Immunopathologie-Biothérapie (DHU i2B), Hôpital Saint Antoine, Assistance Publique des Hôpitaux de Paris, Université Paris VI Sorbonne, 75012 Paris, France.;Service d'Hématologie, Hôpital Avicenne, Université Paris XIII, Bobigny, France.",
"authors": "Fraison|Jean-Baptiste|JB|;Mekinian|Arsène|A|;Grignano|Eric|E|;Kahn|Jean-Emmanuel|JE|;Arlet|Jean-Benoit|JB|;Decaux|Olivier|O|;Denis|Guillaume|G|;Buchdahl|Anne-Laure|AL|;Omouri|Mohamed|M|;Maigne|Gwenola|G|;Aouba|Achille|A|;Leon|Nathalie|N|;Berthier|Sabine|S|;Liozon|Eric|E|;Park|Sophie|S|;Gardin|Claude|C|;Lortholary|Olivier|O|;Rossignol|Julien|J|;Fenaux|Pierre|P|;Fain|Olivier|O|;Braun|Thorsten|T|",
"chemical_list": "D001374:Azacitidine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "43()",
"journal": "Leukemia research",
"keywords": "Auto immune disorders; Azacitidine; Myelodysplastic syndromes",
"medline_ta": "Leuk Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases; D001374:Azacitidine; D005260:Female; D006801:Humans; D007249:Inflammation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D012189:Retrospective Studies",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "13-7",
"pmc": null,
"pmid": "26922775",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Efficacy of Azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia.",
"title_normalized": "efficacy of azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia"
} | [
{
"companynumb": "FR-CELGENE-FRA-2015125508",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
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"drugauthorizationnumb": "050794",
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},
{
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"activesubstancename": "AZACITIDINE"
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"drugdosageform": "INJECTION",
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"drugindication": "MYELODYSPLASTIC SYNDROME",
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"medicinalproduct": "AZACITIDINE INJECTABLE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZACITIDINE"
},
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"drugindication": "OFF LABEL USE",
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"medicinalproduct": "AZACITIDINE INJECTABLE"
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Autoimmune disorder",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cerebral haemorrhage",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Deep vein thrombosis",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Paraneoplastic syndrome",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Therapeutic response unexpected",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myocardial infarction",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Interstitial lung disease",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "No therapeutic response",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Acute myeloid leukaemia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FRAISON J, MEKINIAN A, GRIGNANO E, KAHN J, ARLET J, DECAUX O. EFFICACY OF AZACITIDINE IN AUTOIMMUNE AND INFLAMMATORY DISORDERS ASSOCIATED WITH MYELODYSPLASTIC SYNDROMES AND CHRONIC MYELOMONOCYTIC LEUKEMIA. 10TH BIENNIAL INTERNATIONAL CONGRESS ON AUTOIMMUNITY.",
"literaturereference_normalized": "efficacy of azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20160407",
"receivedate": "20160302",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12136219,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160815"
}
] |
{
"abstract": "Accelerated nodulosis during methotrexate therapy for rheumatoid arthritis has been well described. There have been recent reports of nodulosis in patients on methotrexate for other inflammatory conditions. Panniculitis is a newly discovered pathological entity in this setting. We describe a case of panniculitis in a woman receiving methotrexate for mixed connective tissue disease.",
"affiliations": "Service de médecine interne et thérapeutique, Hôpital de Sainte-Marguerite, Marseille, France.",
"authors": "Nézondet-Chetaille|A L|AL|;Brondino-Riquier|R|R|;Villani|Pierre|P|;Bouvenot|Gilles|G|",
"chemical_list": "D018501:Antirheumatic Agents; D008727:Methotrexate",
"country": "France",
"delete": false,
"doi": "10.1016/s1297-319x(02)00401-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "69(3)",
"journal": "Joint bone spine",
"keywords": null,
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D018501:Antirheumatic Agents; D001706:Biopsy; D005260:Female; D006801:Humans; D008727:Methotrexate; D008875:Middle Aged; D008947:Mixed Connective Tissue Disease; D015434:Panniculitis",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "324-6",
"pmc": null,
"pmid": "12102282",
"pubdate": "2002-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Panniculitis in a patient on methotrexate for mixed connective tissue disease.",
"title_normalized": "panniculitis in a patient on methotrexate for mixed connective tissue disease"
} | [
{
"companynumb": "FR-FRESENIUS KABI-FK201703511",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "040263",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MIXED CONNECTIVE TISSUE DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "2",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "199811",
"drugstartdateformat": "610",
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHOTREXATE (MANUFACTURER UNKNOWN)"
}
],
"patientagegroup": null,
"patientonsetage": "56",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Panniculitis",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "NEZONDET-CHETAILLE A,BRONDINO-RIQUIER R,VILLANI P,BOUVENOT G. PANNICULITIS IN A PATIENT ON METHOTREXATE FOR MIXED CONNECTIVE TISSUE DISEASE. BONE SPINE 2002;69 (3):324-326.",
"literaturereference_normalized": "panniculitis in a patient on methotrexate for mixed connective tissue disease",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20170511",
"receivedate": "20170504",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13512503,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
}
] |
{
"abstract": "OBJECTIVE\nThe long-term safety, tolerability, and efficacy of paliperidone extended-release (ER) were evaluated in Chinese patients with schizophrenia.\n\n\nMETHODS\nPatients (aged ≥18 years) with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria) who had completed run-in (8-week), stabilization (6-week), and double-blind (DB) phases (variable) of a phase-3, placebo-controlled study entered this 24-week, open-label extension (OLE) study. These patients, who had either experienced a relapse or remained relapse-free through DB phase of the study, were treated with flexible-dose paliperidone-ER (3-12 mg/day) during the OLE phase. Major safety evaluations included treatment-emergent adverse events (TEAEs) and extrapyramidal symptoms. Efficacy endpoints included changes in Positive and Negative Syndrome Scale total score, Clinical Global Impression-Severity scale, and Personal and Social Performance scale from OLE baseline to OLE endpoint.\n\n\nRESULTS\nOut of 106 patients who entered the OLE phase (placebo: 59, paliperidone-ER: 47), a total of 85 (80%) completed it. Thirty-five (33%) patients experienced at least one TEAE; most common were akathisia, somnolence, nasopharyngitis, and constipation (3.8% each). Serious TEAEs were noted in two patients (completed suicide; schizophrenia worsening). No TEAEs with an onset during the OLE phase led to discontinuation. Extrapyramidal symptoms related-TEAEs were reported in eight (7.5%) patients. Mean (standard deviation) changes in Positive and Negative Syndrome Scale total scores (-10.4 [13.2]), Clinical Global Impression-Severity scores (-0.6 [0.96]) and Personal and Social Performance scores (7.4 [13.2]) from OLE baseline to OLE endpoint showed patients who had been treated with placebo during the DB phase experienced more pronounced improvements.\n\n\nCONCLUSIONS\nIn this OLE study, flexibly dosed paliperidone-ER (3-12 mg/day) was tolerable and efficacious in Chinese patients with schizophrenia.",
"affiliations": "Peking University 6th Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, People's Republic of China.;Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.;Janssen Research & Development, Shanghai, People's Republic of China.;Janssen Research & Development, Shanghai, People's Republic of China.;Janssen Research & Development, Shanghai, People's Republic of China.;Janssen Research & Development, LLC, Titusville, NJ, USA.;Xian Mental Health Center, Xian, People's Republic of China.;Department of Psychiatry, Nanjing Brain Hospital, Nanjing, People's Republic of China.;Mood Disorders Center, Beijing Anding Hospital, Beijing, People's Republic of China.;Janssen Research & Development, LLC, Titusville, NJ, USA.",
"authors": "Zhang|Hongyan|H|;Li|Huafang|H|;Liu|Yanning|Y|;Wu|Cathy|C|;Wu|Qingqi|Q|;Nuamah|Isaac|I|;Shi|Jianguo|J|;Xie|Shiping|S|;Wang|Gang|G|;Gopal|Srihari|S|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S88875",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S88875ndt-12-069Original ResearchSafety and efficacy of paliperidone extended-release in Chinese patients with schizophrenia: a 24-week, open-label extension of a randomized, double-blind, placebo-controlled study Zhang Hongyan 1Li Huafang 2Liu Yanning 3Wu Cathy 3Wu Qingqi 3Nuamah Isaac 4Shi Jianguo 5Xie Shiping 6Wang Gang 7Gopal Srihari 41 Peking University 6th Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, People’s Republic of China2 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China3 Janssen Research & Development, Shanghai, People’s Republic of China4 Janssen Research & Development, LLC, Titusville, NJ, USA5 Xian Mental Health Center, Xian, People’s Republic of China6 Department of Psychiatry, Nanjing Brain Hospital, Nanjing, People’s Republic of China7 Mood Disorders Center, Beijing Anding Hospital, Beijing, People’s Republic of ChinaCorrespondence: Srihari Gopal, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA, Tel +1 609 730 2436, Email sgopal2@its.jnj.com2016 08 1 2016 12 69 77 © 2016 Zhang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2016The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Objectives\nThe long-term safety, tolerability, and efficacy of paliperidone extended-release (ER) were evaluated in Chinese patients with schizophrenia.\n\nMethods\nPatients (aged ≥18 years) with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria) who had completed run-in (8-week), stabilization (6-week), and double-blind (DB) phases (variable) of a phase-3, placebo-controlled study entered this 24-week, open-label extension (OLE) study. These patients, who had either experienced a relapse or remained relapse-free through DB phase of the study, were treated with flexible-dose paliperidone-ER (3–12 mg/day) during the OLE phase. Major safety evaluations included treatment-emergent adverse events (TEAEs) and extrapyramidal symptoms. Efficacy endpoints included changes in Positive and Negative Syndrome Scale total score, Clinical Global Impression-Severity scale, and Personal and Social Performance scale from OLE baseline to OLE endpoint.\n\nResults\nOut of 106 patients who entered the OLE phase (placebo: 59, paliperidone-ER: 47), a total of 85 (80%) completed it. Thirty-five (33%) patients experienced at least one TEAE; most common were akathisia, somnolence, nasopharyngitis, and constipation (3.8% each). Serious TEAEs were noted in two patients (completed suicide; schizophrenia worsening). No TEAEs with an onset during the OLE phase led to discontinuation. Extrapyramidal symptoms related-TEAEs were reported in eight (7.5%) patients. Mean (standard deviation) changes in Positive and Negative Syndrome Scale total scores (−10.4 [13.2]), Clinical Global Impression-Severity scores (−0.6 [0.96]) and Personal and Social Performance scores (7.4 [13.2]) from OLE baseline to OLE endpoint showed patients who had been treated with placebo during the DB phase experienced more pronounced improvements.\n\nConclusion\nIn this OLE study, flexibly dosed paliperidone-ER (3–12 mg/day) was tolerable and efficacious in Chinese patients with schizophrenia.\n\nKeywords\nCGI-S scorepaliperidonePANSS scorePSP score\n==== Body\nIntroduction\nSchizophrenia is a major psychiatric disability, accounting for more than 50% of all psychotic disorders in the adult Chinese population.1 As a result of improved treatment effectiveness and tolerability profiles, use of atypical antipsychotic medications in Chinese patients has increased significantly over the past decade, although clinical trial data in this population remains very limited.2\n\nPaliperidone extended-release (ER) is a once-daily atypical antipsychotic, approved in many countries, including People’s Republic of China, for the treatment of schizophrenia in adults. Several clinical studies were conducted to demonstrate both the short-term and long-term efficacy and safety of paliperidone-ER in patients with schizophrenia.3 The majority of these studies were conducted in Western populations. However, physiological differences between populations can impact drug metabolism and thus its efficacy and safety. Symptom presentation, including suicide prevalence, as well as treatment response to antipsychotic therapy may relate to race and ethnicity differences among patients.4–6\n\nTo date, only three studies of paliperidone-ER have been conducted by the sponsor in Chinese patients: an 8-week, open-label, flexible-dose study of paliperidone-ER in Chinese patients with first-episode psychosis;7 a 12-week, non-randomized, single-arm, multicenter study in Chinese patients with non-acute schizophrenia,8 and a randomized, double-blind (DB), placebo-controlled relapse prevention study.9 Patients enrolled in these studies typically were exposed to paliperidone-ER 2 to 3 months and published data on the long-term safety and efficacy of paliperidone-ER in Chinese patients are lacking.\n\nThe present study was conducted to support the long-term safety, tolerability, and efficacy of paliperidone-ER (3–12 mg/day) in Chinese patients with schizophrenia and is the 6-month, open-label extension (OLE) of the relapse prevention study.9\n\nMethods\nStudy participants\nThis study is registered at ClinicalTrials.gov: NCT01662310. Patients of either sex, aged ≥18 years, diagnosed with schizophrenia, based on Diagnostic and Statistical Manual of Mental Disorders, 4th version, for at least 1 year before screening, and a Positive and Negative Syndrome Scale (PANSS) total score between 70 and 120 (inclusive), at screening and baseline were eligible for enrollment in the study.\n\nMajor exclusion criteria for the study included: drug dependence (excluding nicotine and caffeine dependence) within 6 months before screening according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition, history of cardiovascular, respiratory, neurologic, renal, hepatic, endocrine, or immunologic diseases, presence of circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death, heart rate <50 beats per minute, presence of congenital prolongation of the QT interval or demonstration of repeated prolonged QTc Fridericia interval >450 ms in >1 electrocardiogram (ECG), neuroleptic malignant syndrome and hypersensitivity to risperidone, paliperidone, or their excipients. Patients treated with clozapine for treatment-refractory or treatment-resistant schizophrenia, monoamine oxidase inhibitor antidepressants within 4 weeks before screening, depot antipsychotic drugs within 120 days, paliperidone palmitate within 10 months or electroconvulsive therapy within 60 days before screening, and pregnant and lactating women, were all excluded from the study.\n\nOnly patients who experienced a relapse or remained relapse-free during the DB phase, or who were still enrolled in the DB or run-in/stabilization phase of the study at the time of study termination were eligible to enter the OLE.\n\nThe Independent Ethics Committee or Institutional Review Board at each study site approved the protocol and the study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. All patients provided written informed consent before enrollment.\n\nStudy design\nThis was an OLE (24-week) phase of a randomized, DB, placebo-controlled, parallel group study conducted at 18 sites within the People’s Republic of China from June 2011 to April 2013. Only the data collected from patients who participated in the OLE phase of the study are included in this paper. However, a brief description of the prior phases is provided in Figure 1.\n\nPatients were treated with flexibly dosed paliperidone-ER (3 to 12 mg/day) during the OLE phase. All patients who entered the OLE were provided a starting dose of 6 mg which was given at termination of DB phase of the study. Investigators could adjust the dose with increments or decrements of 3 mg at their discretion. At trial visits, patients were provided medication in a blister pack. Inventory of each blister pack, and the amount of drug used was noted at each study visit. A patient was considered to have completed the OLE phase of the study on completion of all 24 weeks of the OLE phase and having assessments at week 24.\n\nConcomitant medication\nOral acetaminophen, non-steroidal anti-inflammatory drugs, antihypertensives, beta-adrenergic blockers, oral benzodiazepine, and non-benzodiazepine hypnotic agents were allowed during the OLE phase. Monoamine oxidase inhibitors and antipsychotics (oral or injectable) other than paliperidone-ER were not allowed during the OLE phase.\n\nSafety assessments\nSafety evaluations in the OLE phase included treatment-emergent adverse events (TEAEs), Columbia Suicide Severity Rating Scale, serum and urine pregnancy tests for female patients, clinical laboratory parameters, ECGs, weight, vital signs, and physical examinations. Serum concentrations of prolactin were also determined. TEAEs were assessed at each study visit using elicitation by the investigator with an open-ended question. No specific checklists were used. Extrapyramidal symptoms (EPS) were measured using the Abnormal Involuntary Movement Scale for dyskinesia, Barnes Akathisia Rating Scale for akathisia and the Simpson-Angus Scale for Parkinsonism. These three scales for EPS were collected only in the DB portion of the study.\n\nEfficacy assessments\nChanges in PANSS total score, PANSS subscale scores (positive subscale, negative subscale, and the general psychopathology subscale), PANSS factor scores (positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression), Clinical Global Impression-Severity (CGI-S) scale, and Personal and Social Performance (PSP) scale from OLE baseline to OLE endpoint were evaluated as efficacy parameters.\n\nScales used in this study were translated into Mandarin Chinese and administered by qualified raters at each study site. Measures of rater quality compared to a gold standard were performed at the investigator meeting and it was found that the level of agreement was high (kappa >0.60). The validation of these scales was performed elsewhere.10,11\n\nStatistical methods\nIntent-to-treat (OLE) analysis set included all patients who received at least one dose of OLE medication and this set was used for efficacy and safety analyses in the OLE phase. Descriptive summaries for the change in efficacy parameters from OLE baseline over time were presented. Safety and tolerability profile during the OLE phase was also summarized using descriptive statistics. The last observation carried forward (LOCF) approach was implemented when measurements at some intermittent visits were not done or when patients withdrew early from the OLE phase.\n\nResults\nPatient population\nOf the 201 patients enrolled in the run-in phase of the study, 106 entered the OLE phase. These included 59 patients who had received placebo (Pbo/Pali group) and 47 patients who had received paliperidone-ER (Pali/Pali group) in the DB phase of the study. Out of the 106 OLE patients, 85 (80%) completed the 24-week OLE phase of the study (Figure 1). The most frequent reason for discontinuation was withdrawal of consent (8%).\n\nThe majority of patients who entered the OLE phase were women (59%), with a mean (standard deviation [SD]) age of 30.7 (10.5) years at run-in enrollment. At OLE baseline, based on the body mass index (BMI), 62% of the patients were classified as having normal body weight. The mean (SD) OLE baseline body weight was 65.8 (15.0) kg and mean (SD) OLE baseline BMI was 24.5 (4.3) (kg/m2) (Table 1). The mean dose of paliperidone-ER used was 8.62 mg/day and mean exposure duration was 147.1 days.\n\nSafety results\nA total of 35 (33%) patients experienced at least one TEAE in the OLE phase; the incidence was higher in patients from the Pbo/Pali ER group (37.3%) than the Pali/Pali group (27.7%). The most common TEAEs were akathisia, somnolence, nasopharyngitis, and constipation (3.8% each) (Table 2). One patient died (completed suicide: Pali/Pali group) during the OLE phase. Two patients (4.3%; including the one who completed suicide) experienced serious TEAEs (completed suicide and worsening of schizophrenia: Pali/Pali group). No TEAEs leading to permanent discontinuation of the study drug were noted in this phase.\n\nEight out of 106 patients, 7.5% experienced EPS-related TEAEs. The incidence was higher in patients from the Pbo/Pali group (11.9%) than in the Pali/Pali group (2.1%). The most common EPS-related TEAEs were hyperkinesias (5.7%), akathisia (3.8%), and restlessness (1.9%). Prolactin increases were more pronounced in women than in men (Pbo/Pali: 83% women versus 76% men; Pali/Pali: 19% women versus 5% men). Increased prolactin levels were not commonly associated with reported TEAEs. One prolactin-related TEAE (galactorrhea) was noted in a patient from the Pali/Pali group.\n\nA majority of patients (99%) had a maximum Columbia Suicide Severity Rating Scale score of 0 (no suicidal ideation) and 1% of patients had a score of 1 (wish to be dead). There were no significant increases from OLE baseline in fasting glucose values or in body weight. Patients from the Pbo/Pali group showed greater change in mean (SD) BMI (0.39 [1.6] kg/m2) from OLE baseline to endpoint as compared with Pali/Pali group (0.23 [1.2] kg/m2). Similar trend was observed for mean (SD) change in triglycerides (mmol/L) in Pbo/Pali group (0.42 [0.8]) versus Pali/Pali group (0.13 [0.7]). Change in mean (SD) cholesterol (mmol/L) was 0.12 (0.8) for Pbo/Pali group and −0.03 (0.7) for Pali/Pali group. No clinically relevant changes were observed in vital signs, ECG recordings or other clinical laboratory parameters.\n\nEfficacy results\nA decrease of −10.4 (13.2) in the mean (SD) PANSS total score was observed from OLE baseline to endpoint in the total group, indicating improvement in the severity of schizophrenic symptoms (Table 3). Patients from the Pbo/Pali group showed greater improvement in mean (SD) PANSS total score (−15.4 [12.4]) from OLE baseline to endpoint as compared with Pali/Pali group (−3.9 [11.3]) (Figure 2). Overall, patients (total group) showed improvement in mean (SD) PANSS subscale scores (positive subscale: −3.7 [5.0]; negative subscale: −1.5 [3.7]; psychopathology subscale: −5.2 [6.9]) and PANSS factor scores (positive symptoms: −3.3 [4.8]; negative symptoms: −1.5 [3.96]; disorganized thoughts: −2.0 [3.4]; uncontrolled hostility/excitement: −2.1 [3.7]; anxiety/depression: −1.4 [2.6]) from OLE baseline to endpoint. Similarly, greater improvements were noted from OLE baseline to OLE endpoint in Pbo/Pali group than the Pali/Pali group for the mean (SD) CGI-S scores (Table 4, Figure 3) and PSP scores (Table 4, Figure 4).\n\nDiscussion\nThe safety and tolerability profile of paliperidone-ER over the course of a 24-week period in the OLE phase of this study was generally consistent with the earlier open-label, phase-3 paliperidone-ER study of shorter duration (8-week) in patients with schizophrenia from People’s Republic of China7 as well as with placebo-controlled studies conducted in more global populations.12 Safety results of this current OLE were also consistent with a previous long-term OLE study conducted in a Western population.13\n\nThe incidences of EPS-related TEAEs and increased prolactin levels in this OLE were less than those in the DB phase of the same study, as well as compared with previous short-term paliperidone-ER studies conducted in People’s Republic of China,8,13 short-term pivotal global studies,14–16 and a long-term (1-year) OLE global study17 without any known reason. No TEAEs leading to permanent discontinuation of the study drug were noted in this OLE study, indicating that the TEAEs did not have a major impact on patients continuing on long-term paliperidone-ER treatment. Also, the number of patients receiving anti-EPS medication in the OLE phase of the study was numerically lower as compared with the DB phase.\n\nPatients who entered the OLE phase of the study showed clinically meaningful improvements in efficacy parameters. As would be expected, patients previously treated with placebo in the DB phase had greater improvements in total PANSS-, CGI-S-, and PSP scores during the OLE phase, where they received active drug, as compared to those patients who had been previously treated with paliperidone-ER during the DB phase and then continued with active treatment during the OLE.\n\nThere was no active or placebo comparator used in this OLE phase, which limits the ability to draw conclusions relative to a control population. In addition, because of the lack of a comparator group, conducting inferential statistical analysis was not possible, so the results are descriptive only. However, the open-label flexible-dose treatment design used in this study more closely approximates clinical treatment practice used in hospital settings.\n\nIn this OLE study, 24-week treatment with flexibly dosed paliperidone-ER (3–12 mg/day) was tolerable and efficacious, consistent with findings from previous pivotal and open-label (1-year) global studies. These results support long-term paliperidone-ER treatment in patients from People’s Republic of China with schizophrenia.\n\nThese data were presented as a poster at the XVI Word Congress of Psychiatry, Madrid, Spain, September 14–18, 2014.\n\nAcknowledgments\nThe authors thank Rishabh Pandey (SIRO Clinpharm Pvt. Ltd.) for writing assistance and Dr Wendy P Battisti (Janssen Research & Development, LLC) for additional editorial assistance. The authors also thank the study participants, without whom this study would not have been accomplished, as well as the following investigators for their participation in this study:\n\nQinggang Chen; Chengge Gao; Tiansheng Guo; Jian Hu; Huafang Li; Keqing Li; Luxian Lv; Yuping Ning; Jianguo Shi; Qingrong Tan; Gang Wang; Xiaoping Wang; Shiping Xie; Xiufeng Xu; Fude Yang; Hongyan Zhang; Kerang Zhang; Jingping Zhao.\n\nDisclosure\n\nThis study was funded by Janssen Research and Development, LLC, New Jersey, USA. The sponsor also provided a formal review of this manuscript. Drs Srihari Gopal, Cathy Wu, Qingqi Wu, Isaac Nuamah and Ms Yanning Liu are employed by Janssen Research and Development. The other authors report no conflicts of interest in this work.\n\nAuthors’ contributions\n\nDrs Srihari Gopal, Cathy Wu, Qingqi Wu, Isaac Nuamah, and Ms Yanning Liu were involved in study design, study conduct, data interpretation, and drafting the manuscript; Drs Hongyan Zhang, Huafang Li, Jianguo Shi, Shiping Xie and Gang Wang participated as principal investigators and were involved in data collection, data interpretation, and manuscript composition. All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data and made the final decision about where to present these data.\n\nFigure 1 Study design and patient disposition.\n\nAbbreviations: Pbo, placebo; Pali, paliperidone extended-release.\n\nFigure 2 Arithmetic mean (±SE) PANSS total score over time – LOCF (run-in, stabilization, DB, OLE).\n\nAbbreviations: BL, baseline; DB, double-blind; LOCF, last observation carried forward; OLE, open-label extension; PANSS, Positive and Negative Syndrome Scale; Pali, paliperidone; ER, extended release; Pbo, placebo; RI, run-in; SE, standard error; ST, stabilization.\n\nFigure 3 CGI-S frequency at baseline (run-in), baseline (DB), baseline (OLE) and endpoint (OLE).\n\nAbbreviations: OLE, open-label extension; Pbo, placebo; Pali, paliperidone extended-release; CGI-S, Clinical Global Impression-Severity; DB, double-blind; RI, run-in.\n\nFigure 4 Arithmetic mean (±SE) PSP score over time – LOCF (run-in, stabilization, DB, OLE).\n\nAbbreviations: SE, standard error; PSP, personal and social performance; LOCF, last observation carried forward; BL, baseline; OLE, open-label extension; Pbo, placebo; Pali, paliperidone; ER, extended release; CGI-S, Clinical Global Impression-Severity; DB, double-blind; RI, run-in; ST, stabilization.\n\nTable 1 Demographic and baseline (OLE) characteristics (ITT)\n\n\tPbo/Pali (N=59)\tPali/Pali (N=47)\tTotal (N=106)\t\nAge, years (at RI baseline)\t\n Category, n (%)\t\n 18–25\t25 (42)\t19 (40)\t44 (42)\t\n 26–50\t30 (51)\t27 (57)\t57 (54)\t\n 51–65\t4 (7)\t1 (2)\t5 (5)\t\n Mean (SD)\t30.9 (11.59)\t30.4 (9.03)\t30.7 (10.49)\t\nSex, n (%)\t\n Women\t36 (61)\t27 (57)\t63 (59)\t\n Men\t23 (39)\t20 (43)\t43 (41)\t\nSub population, n (%)\t\n Chinese (HAN)\t57 (97)\t46 (98)\t103 (97)\t\n Other\t2 (3)\t1 (2)\t3 (3)\t\nBaseline weight (kg)\t\n Mean (SD)\t64.5 (14.82)\t67.5 (15.21)\t65.8 (15.00)\t\nBaseline BMI (kg/m2)\t\n Category, n (%)\t\n Normal <25\t40 (68)\t26 (55)\t66 (62)\t\n Overweight 25–<30\t13 (22)\t18 (38)\t31 (29)\t\n Obese ≥30\t6 (10)\t3 (6)\t9 (8)\t\n Mean (SD)\t23.91 (4.59)\t25.12 (3.76)\t24.45 (4.26)\t\nCurrent nicotine user, n (%)\t\n Yes\t7 (12)\t3 (6)\t10 (9)\t\n No\t52 (88)\t44 (94)\t96 (91)\t\nBaseline (OLE) PANSS total score\t\n N\t59\t47\t106\t\n Mean (SD)\t7.2 (14.67)\t56.4 (14.72)\t62.4 (15.58)\t\nBaseline (OLE) CGI-S\t\n Category, n (%)\t\n Not ill\t0\t1 (2)\t1 (1)\t\n Very mild\t4 (7)\t12 (26)\t16 (15)\t\n Mild\t14 (24)\t19 (40)\t33 (31)\t\n Moderate\t27 (46)\t11 (23)\t38 (36)\t\n Marked\t10 (17)\t3 (6)\t13 (12)\t\n Severe\t4 (7)\t1 (2)\t5 (5)\t\nBaseline (OLE) PSP\t\n N\t59\t47\t106\t\n Mean (SD)\t60.6 (15.63)\t66.9 (15.50)\t63.4 (15.81)\t\nAbbreviations: BMI, body mass index; CGI-S, Clinical Global Impression-Severity; ITT, intent-to-treat; OLE, open-label extension; Pbo, placebo; Pali, paliperidone extended-release; RI, run-in phase; PANSS, Positive and Negative Syndrome Scale; PSP, personal and social performance; SD, standard deviation.\n\nTable 2 Treatment-emergent adverse events during the open-label extension phase in at least 3% patients in any group (ITT)\n\n\tPbo/Pali (N=59)\n\tPali/Pali (N=47)\n\tTotal (N=106)\n\t\nn (%)\tn (%)\tn (%)\t\nTotal number of patients with TEAEs\t22 (37.3)\t13 (27.7)\t35 (33.0)\t\nNervous system disorders\t9 (15.3)\t3 (6.4)\t12 (11.3)\t\n Akathisia\t3 (5.1)\t1 (2.1)\t4 (3.8)\t\n Somnolence\t3 (5.1)\t1 (2.1)\t4 (3.8)\t\nInvestigations\t4 (6.8)\t4 (8.5)\t8 (7.5)\t\n Weight increased\t2 (3.4)\t0\t2 (1.9)\t\nPsychiatric disorders\t4 (6.8)\t4 (8.5)\t8 (7.5)\t\n Restlessness\t2 (3.4)\t0\t2 (1.9)\t\n Schizophrenia\t0\t2 (4.3)\t2 (1.9)\t\nInfections and infestations\t4 (6.8)\t2 (4.3)\t6 (5.7)\t\n Nasopharyngitis\t3 (5.1)\t1 (2.1)\t4 (3.8)\t\nGastrointestinal disorders\t3 (5.1)\t2 (4.3)\t5 (4.7)\t\n Constipation\t2 (3.4)\t2 (4.3)\t4 (3.8)\t\nGeneral disorders and administration site conditions\t2 (3.4)\t0\t2 (1.9)\t\n Fatigue\t2 (3.4)\t0\t2 (1.9)\t\nAbbreviations: ITT, intent-to-treat; TEAEs, treatment-emergent adverse events; Pbo, placebo; Pali, paliperidone extended-release.\n\nTable 3 PANSS total score: mean change from baseline (OLE) to endpoint (OLE) – LOCF (ITT)\n\n\tPbo/Pali\n(N=59)\tPali/Pali\n(N=47)\tTotal\n(N=106)\t\nBaseline (OLE)\t\n Mean (SD)\t67.2 (14.67)\t56.5 (14.86)\t62.5 (15.62)\t\nEndpoint (OLE)\t\n Mean (SD)\t51.7 (12.04)\t52.6 (14.51)\t52.1 (13.12)\t\nChange from baseline (OLE)\t\n Mean (SD)\t−15.4 (12.41)\t−3.9 (11.30)\t−10.4 (13.20)\t\nAbbreviations: ITT, intent-to-treat; LOCF, last observation carried forward; OLE, open-label extension; PANSS, positive and negative syndrome scale; SD, standard deviation; Pbo, placebo; Pali, paliperidone extended-release.\n\nTable 4 Change from baseline (OLE) to endpoint (OLE) in CGI-S and PSP – (ITT analysis set)\n\n\tPbo/Pali (N=59)\tPali/Pali (N=47)\tTotal (N=106)\t\nCGI-S\t\n Baseline (OLE)\t\n Mean (SD)\t3.9 (0.98)\t3.1 (1.02)\t3.6 (1.07)\t\n Median (range)\t4.0 (2;6)\t3.0 (1;6)\t4.0 (1;6)\t\n Endpoint (OLE)\t\n Mean (SD)\t3.0 (1.06)\t2.9 (0.94)\t3.0 (1.00)\t\n Median (range)\t3.0 (1;6)\t3.0 (1;5)\t3.0 (1;6)\t\n Change from baseline (OLE)\t\n Mean (SD)\t−0.9 (0.97)\t−0.2 (0.78)\t−0.6 (0.96)\t\n Median (range)\t−1.0 (−3;2)\t0.0 (−3;1)\t0.0 (−3;2)\t\nPSP\t\n Baseline (OLE)\t\n Mean (SD)\t60.6 (15.63)\t66.8 (15.68)\t63.4 (15.88)\t\n Endpoint (OLE)\t\n Mean (SD)\t71.4 (10.62)\t69.9 (13.99)\t70.7 (12.17)\t\n Change from baseline (OLE)\t\n Mean (SD)\t10.7 (14.01)\t3.1 (10.88)\t7.4 (13.24)\t\nAbbreviations: ITT, intent-to-treat; OLE, open-label extension; SD, standard deviation; Pbo, placebo; Pali, paliperidone extended-release; CGI-S, Clinical Global Impression-Severity; PSP, personal and social performance.\n==== Refs\nReferences\n1 Li H Rui Q Ning X Xu H Gu NA Comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 2011 35 4 1002 1008 21315787 \n2 Leucht S Cipriani A Spineli L Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis Lancet 2013 382 9896 951 962 23810019 \n3 Canuso CM Battisti WP Paliperidone extended-release: a review of efficacy and tolerability in schizophrenia, schizoaffective disorder and bipolar mania Expert Opin Pharmacother 2010 11 15 2557 2567 20854185 \n4 Versola-Russo JM Cultural and demographic factors of schizophrenia The International Journal of Psychosocial Rehabilitation 2006 10 89 103 \n5 Williams DR Earl TR Commentary: Race and mental health – more questions than answers Int J Epidemiol 2007 36 4 758 760 17566003 \n6 Zhang XY Al Jurdi RK Zoghbi AW Prevalence, demographic and clinical correlates of suicide attempts in Chinese medicated chronic inpatients with schizophrenia J Psychiatr Res 2013 47 10 1370 1375 23791457 \n7 Si T Tan Q Zhang K Wang Y Rui Q An open-label, flexible-dose study of paliperidone extended-release in Chinese patients with first-onset psychosis Neuropsychiatr Dis Treat 2015 11 87 95 25657581 \n8 Zhang H Hao X Wang X An open-label study on the safety and efficacy of paliperidone extended-release in non-acute schizophrenic patients Chinese Journal of Psychiatry 2012 45 1 \n9 Rui Q Wang Y Liang S Relapse prevention study of paliperidone extended-release tablets in Chinese patients with schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 2014 53 45 53 24576532 \n10 Jiang J Sim K Lee J Validated five-factor model of positive and negative syndrome scale for schizophrenia in Chinese population Schizophr Res 2013 143 1 38 43 23148897 \n11 Tianmei S Liang S Yun’ai S The Chinese version of the Personal and Social Performance Scale (PSP): validity and reliability Psychiatry Res 2011 185 1–2 275 279 20542575 \n12 Meltzer HY Bobo WV Nuamah IF Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week, placebo-controlled studies J Clin Psychiatry 2008 69 5 817 829 18466043 \n13 Guoxing C Guojian X Observation of efficacy and safety of paliperidone sustained release tablets and domestic olanzapine in treatment of schizophrenia Chongqing Medicine 2011 17 13 \n14 Davidson M Emsley R Kramer M Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study Schizophr Res 2007 93 1–3 117 130 17466492 \n15 Kane J Canas F Kramer M Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial Schizophr Res 2007 90 1–3 147 161 17092691 \n16 Marder SR Kramer M Ford L Efficacy and safety of paliperidone extended-release tablets: results of a 6-week, randomized, placebo-controlled study Biol Psychiatry 2007 62 12 1363 1370 17601495 \n17 Kramer M Simpson G Maciulis V One-year open-label safety and efficacy study of paliperidone extended-release tablets in patients with schizophrenia CNS Spectr 2010 15 8 506 514 20703197\n\n",
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"title": "Safety and efficacy of paliperidone extended-release in Chinese patients with schizophrenia: a 24-week, open-label extension of a randomized, double-blind, placebo-controlled study.",
"title_normalized": "safety and efficacy of paliperidone extended release in chinese patients with schizophrenia a 24 week open label extension of a randomized double blind placebo controlled study"
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{
"abstract": "We present a case of hyperfibrinolysis induced by oxaliplatin-derived anaphylactic shock, which was diagnosed with rotational thromboelastometry (ROTEM). A 57-year-old male patient underwent a second course of oxaliplatin (126 mg/m/course)-based chemotherapy for stage IV metastatic rectal cancer. Two minutes after the infusion of oxaliplatin, the patient lost consciousness and developed generalized urticarial lesions, followed by hemodynamic instability and respiratory insufficiency. He was diagnosed anaphylactic shock and transported to emergency department (ED) after intramuscular injection of 0.2 mg of adrenaline, an intravenous injection of 100 mg of hydrocortisone, and 500 mg of methylprednisolone. After arriving in the ED, the patient remained in shock and early resuscitation with administration of 5 mg of D-chlorpheniramine maleate and 20 mg of famotidine was performed. He recovered from his state of shock 30 min after the resuscitation. ROTEM findings showed fulminant hyperfibrinolysis with minimal changes in standard coagulation tests (SCTs) and no remarkable coagulopathy. Seven hours after the attack, he became asymptomatic and follow-up ROTEM revealed values within normal limits with the exception of sustained slight abnormalities of SCTs. He was discharged the next day without any signs of spontaneous bleeding and has continued his outpatient chemotherapy uneventfully. A review of the literature on anaphylaxis-induced hyperfibrinolysis and a discussion of the mechanism between anaphylactic shock and hyperfibrinolysis were performed. Although administration of tissue-type plasminogen activator can play a vital role in anaphylactic shock-induced hyperfibrinolysis, early effective resuscitation is imperative to prevent severe hemorrhagic complications. Therefore, ROTEM is a useful tool that can detect these dynamic changes faster and more accurately than SCTs.",
"affiliations": "Center for Emergency and Critical Care Medicine, Saga University Hospital, Saga, Japan.",
"authors": "Koami|Hiroyuki|H|;Sakamoto|Yuichiro|Y|;Furukawa|Takashi|T|;Imahase|Hisashi|H|;Iwamura|Takashi|T|;Inoue|Satoshi|S|",
"chemical_list": "D018926:Anti-Allergic Agents; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002744:Chlorpheniramine; D015738:Famotidine",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000441",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0957-5235",
"issue": "27(4)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000707:Anaphylaxis; D018926:Anti-Allergic Agents; D000970:Antineoplastic Agents; D058070:Asymptomatic Diseases; D001780:Blood Coagulation Tests; D002744:Chlorpheniramine; D015738:Famotidine; D005342:Fibrinolysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012004:Rectal Neoplasms; D013916:Thrombelastography",
"nlm_unique_id": "9102551",
"other_id": null,
"pages": "450-3",
"pmc": null,
"pmid": "26569513",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Utility of rotational thromboelastometry for the diagnosis of asymptomatic hyperfibrinolysis secondary to anaphylaxis.",
"title_normalized": "utility of rotational thromboelastometry for the diagnosis of asymptomatic hyperfibrinolysis secondary to anaphylaxis"
} | [
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},
{
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{
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},
{
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},
{
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},
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},
{
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},
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}
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}
],
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},
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"transmissiondate": "20161109"
}
] |
{
"abstract": "In patients who develop liver damage following moderate paracetamol overdose in the order of 5-10 g daily, recent fasting and nutritional impairment have been identified as key precipitants. Hepatotoxicity caused by paracetamol at recommended dosage, in the absence of exposure to enzyme-inducing drugs, has recently been described as an idiosyncratic phenomenon. The possible importance of fasting and malnutrition in this setting is uncertain. We report a severely malnourished 53-year-old woman who developed severe hepatotoxicity whilst receiving paracetamol at recommended dosage (4 g daily) following a period of fasting, in the absence of enzyme-inducing agents. Subsequent paracetamol exposure up to 2.6 g daily thrice weekly, in the setting of ongoing malnutrition and fasting as before, did not lead to recurrent liver damage. These findings indicate that paracetamol-related liver damage occurring within recommended dosage guidelines can be a dose-dependent rather than necessarily idiosyncratic phenomenon, at least in the setting of recent fasting and severe malnutrition.",
"affiliations": "Gastrointestinal and Liver Unit, The Prince of Wales Hospital and University of New South Wales, Barker Street, Randwick 2031, Sydney, New South Wales, Australia.",
"authors": "Kurtovic|J|J|;Riordan|S M|SM|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "England",
"delete": false,
"doi": "10.1046/j.1365-2796.2003.01097.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6820",
"issue": "253(2)",
"journal": "Journal of internal medicine",
"keywords": null,
"medline_ta": "J Intern Med",
"mesh_terms": "D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D001005:Anus Neoplasms; D001918:Brachytherapy; D002292:Carcinoma, Renal Cell; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D008875:Middle Aged",
"nlm_unique_id": "8904841",
"other_id": null,
"pages": "240-3",
"pmc": null,
"pmid": "12542566",
"pubdate": "2003-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paracetamol-induced hepatotoxicity at recommended dosage.",
"title_normalized": "paracetamol induced hepatotoxicity at recommended dosage"
} | [
{
"companynumb": "AU-JNJFOC-200303-1673",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
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"medicinalproduct": "PARACETAMOL"
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{
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},
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "DAILY DOSE TEXT: 4 GM QD THEN REDUCED TO 1.3 TO 2.6 GM 3 X WEEKLY",
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"medicinalproduct": "PARACETAMOL"
},
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},
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"medicinalproduct": "MORPHINE"
}
],
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"reactionmeddrapt": "Hepatotoxicity",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
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},
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"literaturereference": "KURTOVIC J. PARACETAMOL-INDUCED HEPATOTOXICITY AT RECOMMENDED DOSAGE. JOURNAL OF INTERNAL MEDICINE 01-FEB-2003;253:240 - 243",
"literaturereference_normalized": "paracetamol induced hepatotoxicity at recommended dosage",
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "OBJECTIVE\nThe association of overall survival (OS) with tumor burden, including contrast enhanced (CE) volume on CE T1-weighted images, fluid-attenuated inversion recovery (FLAIR) hyperintense volume, and 3, 4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) hypermetabolic volume, in isocitrate dehydrogenase (IDH) wild-type gliomas remains unclear. This study aimed to assess the association between biological tumor burden in pre- and post-operative status and OS in IDH wild-type gliomas, and evaluated which volume was the best predictor of OS.\n\n\nMETHODS\nThirty-four patients with treatment-naïve IDH wild-type gliomas (WHO grade II 6, III 15, IV 13) were retrospectively included. Three pre-operative tumor regions of interest (ROIs) were segmented based on the CE, FLAIR hyperintense, and FDOPA hypermetabolic regions. Resected ROIs were segmented from the post-operative images. Residual CE, FLAIR hyperintense, and FDOPA hypermetabolic ROIs were created by subtracting resected ROIs from pre-operative ROIs. Cox regression analysis was conducted to investigate the association of OS with the volume of each ROI, and Akaike information criterion was used to assess the fitness.\n\n\nRESULTS\nResidual CE volume had a significant association with OS [hazard ratio (HR) = 1.26, p = 0.039], but this effect disappeared when controlling for tumor grade. Residual FDOPA hypermetabolic volume best fit the regression model and was significantly associated with OS (HR = 1.18, p = 0.008), even when controlling for tumor grade. FLAIR hyperintense volume showed no significant association with OS.\n\n\nCONCLUSIONS\nResidual FDOPA hypermetabolic burden predicted OS for IDH wild-type gliomas, regardless of the tumor grade. Furthermore, removing hypermetabolic and CE regions may improve the prognosis.",
"affiliations": "UCLA Brain Tumor Imaging Laboratory (BTIL), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;UCLA Brain Tumor Imaging Laboratory (BTIL), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 924 Westwood Blvd., Suite 615, Los Angeles, CA, 90024, USA.;UCLA Brain Tumor Imaging Laboratory (BTIL), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;Department of Radiological Science, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA.;UCLA Brain Tumor Imaging Laboratory (BTIL), David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA. bellingson@mednet.ucla.edu.",
"authors": "Tatekawa|Hiroyuki|H|;Uetani|Hiroyuki|H|;Hagiwara|Akifumi|A|;Bahri|Shadfar|S|;Raymond|Catalina|C|;Lai|Albert|A|;Cloughesy|Timothy F|TF|;Nghiemphu|Phioanh L|PL|;Liau|Linda M|LM|;Pope|Whitney B|WB|;Salamon|Noriko|N|;Ellingson|Benjamin M|BM|http://orcid.org/0000-0002-2764-6640",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12149-021-01637-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0914-7187",
"issue": "35(9)",
"journal": "Annals of nuclear medicine",
"keywords": "18F-DOPA PET; Biological tumor burden; IDH wild-type diffuse glioma; Prognosis",
"medline_ta": "Ann Nucl Med",
"mesh_terms": null,
"nlm_unique_id": "8913398",
"other_id": null,
"pages": "1022-1029",
"pmc": null,
"pmid": "34121166",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": "27157931;32027343;31621885;32315266;29040703;30948373;25609769;27554774;27282449;21497925;19240609;32646876;8782226;1330984;9800714;31981013;16741298;26250565;24475840;25701198;25192475;30529899;23087667;29948765;24161427;25852010;32005771;8121569;26188660",
"title": "Worse prognosis for IDH wild-type diffuse gliomas with larger residual biological tumor burden.",
"title_normalized": "worse prognosis for idh wild type diffuse gliomas with larger residual biological tumor burden"
} | [
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}
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] |
{
"abstract": "Trichomegaly is a rare side effect of epidermal growth factor receptor inhibitors. We present here 4 patients who treated with cetuximab (an epidermal growth factor receptor inhibitor) for metastatic colorectal cancer. All of the cases were treated with cetuximab 500 mg/m biweekly in combination protocol. The mean period from the start of the treatment until the development the trichomegaly was 4.75 (3-6) months. In all of the patients after the end of the cetuximab therapy, trichomegaly was regressed. Only 1 case resolved with topical treatment that conjunctivitis with trichomegaly. Trichomegaly is an important ocular toxicity of cetuximab that can cause visual discomfort and corneal damages. However, these side effects usually do not require discontinuation of treatment.",
"affiliations": "Department of Medical Oncology, Faculty of Medicine, Bilim University, Istanbul, Turkey.",
"authors": "Koksal|Ulkuhan I|UI|;Pilanci|Kezban N|KN|;Ordu|Cetin|C|;Okutur|Kerem|K|;Saglam|Sezer|S|;Demir|Gokhan|G|",
"chemical_list": "D000068818:Cetuximab",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000189",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(5)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D005140:Eyelashes; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013997:Time Factors",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e1226-9",
"pmc": null,
"pmid": "26079631",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Trichomegaly Induced by Cetuximab: Case Series and Review the Literature.",
"title_normalized": "trichomegaly induced by cetuximab case series and review the literature"
} | [
{
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] |
{
"abstract": "Ventricular assist device (VAD) support inpatients with a prosthetic heart valve had previously been considered a relative contraindication due to an increased risk of thromboembolic complications. We report our clinical experience of VAD implantation in patients with prosthetic heart valves, including both mechanical and bioprosthetic valves. The clinical records of 133 consecutive patients who underwent VAD implantation at a single institution from January 2002 through June 2009 were retrospectively reviewed. Six of these patients had a prosthetic valve in place at the time of device implantation. Patient demographics,operative characteristics, and postoperative complications were reviewed.Of the six patients,four were male.The mean age was 57.8 years (range 35–66 years). The various prosthetic cardiac valves included a mechanical aortic valve (n = 2), a bioprosthetic aortic valve (n = 3), and a mechanical mitral valve (n = 1).The indications for VAD support included bridge to transplantation (n = 2), bridge to recovery (n = 1), and postcardiotomy ventricular failure(n = 3). Three patients underwent left ventricular assist device placement and three received a right ventricular assist device. Postoperatively, standard anticoagulation management began with a heparin infusion (if possible)followed by oral anticoagulation.The 30-day mortality was50% (3/6). The mean duration of support among survivors was 194.3 days (range 7–369 days) compared with 16.0 days(range 4–29 days) for nonsurvivors. Of the three survivors,two were successfully bridged to heart transplantation and one recovered native ventricular function.Among the three nonsurvivors,acute renal failure developed in each case, and two developed heparin-induced thrombocytopenia. This study suggests that VAD placement in patients with a prosthethic heart valve, either mechanical or bioprosthetic,appears to be a reasonable option.",
"affiliations": "Division of Cardiac Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.",
"authors": "Mokashi|Suyog A|SA|;Schmitto|Jan D|JD|;Lee|Lawrence S|LS|;Rawn|James D|JD|;Bolman|R Morton|RM|;Shekar|Prem S|PS|;Couper|Gregory S|GS|;Chen|Frederick Y|FY|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1525-1594.2010.01102.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-564X",
"issue": "34(11)",
"journal": "Artificial organs",
"keywords": null,
"medline_ta": "Artif Organs",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000368:Aged; D000925:Anticoagulants; D001705:Bioprosthesis; D001900:Boston; D005260:Female; D006333:Heart Failure; D016027:Heart Transplantation; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D006353:Heart-Assist Devices; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011474:Prosthesis Design; D012042:Registries; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013921:Thrombocytopenia; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "7802778",
"other_id": null,
"pages": "1030-4",
"pmc": null,
"pmid": "21137108",
"pubdate": "2010-11",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Ventricular assist device in patients with prosthetic heart valves.",
"title_normalized": "ventricular assist device in patients with prosthetic heart valves"
} | [
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"reactionoutcome": "5"
}
],
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},
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"literaturereference": "Mokashi, S.. Ventricular assist device in patients with prosthetic heart valves.. Artificial Organs. 2010;34(11):1030-1034",
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},
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},
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"transmissiondate": "20220423"
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"reactionoutcome": "5"
}
],
"summary": null
},
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"literaturereference": "Mokashi, S.. Ventricular assist device in patients with prosthetic heart valves.. Artificial Organs. 2010;34(11):1030-1034",
"literaturereference_normalized": "ventricular assist device in patients with prosthetic heart valves",
"qualification": "3",
"reportercountry": "US"
},
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{
"abstract": "OBJECTIVE\nSevere metabolic acidosis during cardiopulmonary resuscitation is an important and yet unresolved issue. The potential use of hemodialysis for severe metabolic acidosis during cardiopulmonary resuscitation was investigated.\n\n\nMETHODS\nAcute hemodialyses between January 2012 and April 2017 were reviewed for patients with concomitant hemodialysis and cardiopulmonary resuscitation. In addition, MEDLINE was searched for similar reports. Data were extracted from hospital records.\n\n\nRESULTS\nTwo patients (36M, 70F) were found to study, without similar reports in MEDLINE. Cardiac arrests (in-hospital) occurred due to severe metabolic acidosis in both patients (due to ethylene glycol and metformin intoxications, respectively). Return of spontaneous circulation could not be obtained within the first 28 and 30 min of cardiopulmonary resuscitation only, whereas both patients had return of spontaneous circulation following at least 45 min of concomitant hemodialysis and cardiopulmonary resuscitation. One patient (70F) was discharged with good neurological outcome, but the other died.\n\n\nCONCLUSIONS\nThe addition of high-efficiency hemodialysis during cardiopulmonary resuscitation may contribute to the return of spontaneous circulation in patients with severe metabolic acidosis due to intoxication.",
"affiliations": "1 Nephrology Unit, Şanlıurfa Mehmet Akif Inan Education and Research Hospital, Şanlıurfa, Turkey.;2 Pulmonary Medicine, Sanliurfa Education and Research Hospital, Şanlıurfa, Turkey.",
"authors": "Sahutoglu|Tuncay|T|;Sahutoglu|Elif|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0391398818784275",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0391-3988",
"issue": "41(8)",
"journal": "The International journal of artificial organs",
"keywords": "Cardiopulmonary resuscitation; hemodialysis; intoxication; metabolic acidosis",
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D000138:Acidosis; D000328:Adult; D000368:Aged; D016887:Cardiopulmonary Resuscitation; D003131:Combined Modality Therapy; D005260:Female; D006323:Heart Arrest; D006801:Humans; D008297:Male; D006435:Renal Dialysis; D016896:Treatment Outcome",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "431-436",
"pmc": null,
"pmid": "29976124",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemodialysis during cardiopulmonary resuscitation in patients with severe metabolic acidosis.",
"title_normalized": "hemodialysis during cardiopulmonary resuscitation in patients with severe metabolic acidosis"
} | [
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] |
{
"abstract": "BACKGROUND\nThe coexistence of psoriasis and lupus erythematosus (LE) is rare. Anecdotal evidence suggests that anti-tumor necrosis factor alfa (TNF-α) agents may be efficacious in LE, although their use is commonly avoided in this disease because of concern for lupus flare.\n\n\nOBJECTIVE\nWe sought to describe the epidemiology, serologic findings, and therapeutic choices in patients with coexistent psoriasis/psoriatic arthritis and LE and to determine the risk of lupus flares with TNF-α inhibitors.\n\n\nMETHODS\nWe performed a retrospective multicenter study of patients given the diagnoses of psoriasis (or psoriatic arthritis) and lupus erythematosus (systemic LE or cutaneous LE, including either subacute cutaneous LE or discoid LE) at 2 academic tertiary-care centers.\n\n\nRESULTS\nA total of 96 patients with a mean age of 56 years was included. We report higher-than-expected rates of white race and psoriatic arthritis. One clinical lupus flare was observed in a patient receiving a TNF-α inhibitor, resulting in an incidence of 0.92% lupus flares per patient-year of TNF-α inhibitor use.\n\n\nCONCLUSIONS\nRetrospective chart review, small sample size, and limited documentation.\n\n\nCONCLUSIONS\nAnti-TNF-α agents, ustekinumab, and abatacept may be valid treatment options for patients with concomitant LE and psoriasis. Clinical lupus flares in LE patients treated with TNF-α inhibitors were infrequent.",
"affiliations": "Department of Dermatology, Tufts University Medical Center, Boston, Massachusetts; Jefferson Medical College, Philadelphia, Pennsylvania.;Department of Dermatology, Tufts University Medical Center, Boston, Massachusetts; Tufts University School of Medicine, Boston, Massachusetts.;Department of Dermatology and Division of Rheumatology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Dermatology, Tufts University Medical Center, Boston, Massachusetts.;Department of Dermatology, Tufts University Medical Center, Boston, Massachusetts. Electronic address: suzanne.tintle@gmail.com.",
"authors": "Varada|Sowmya|S|;Gottlieb|Alice B|AB|;Merola|Joseph F|JF|;Saraiya|Ami R|AR|;Tintle|Suzanne J|SJ|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept; D000069549:Ustekinumab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "72(2)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "lupus erythematosus; psoriasis; tumor necrosis factor alfa",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000069594:Abatacept; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D008178:Lupus Erythematosus, Cutaneous; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D011565:Psoriasis; D012189:Retrospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D000069549:Ustekinumab",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "253-60",
"pmc": null,
"pmid": "25486913",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment of coexistent psoriasis and lupus erythematosus.",
"title_normalized": "treatment of coexistent psoriasis and lupus erythematosus"
} | [
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{
"abstract": "Levofloxacin, a third-generation fluoroquinolone antibiotic, is rarely associated with neurotoxicity. Patients with advanced kidney disease are particularly vulnerable to this adverse effect. We present two elderly patients with kidney failure who developed levofloxacin-induced neurotoxicity, which was successfully treated with frequent hemodialysis, resulting in the full resolution of their symptoms. Neurotoxicity is a well-known side effect of fluoroquinolone antibiotics. Postulated mechanisms include inhibition of the gamma-aminobutyric acid A receptors and activation of the excitatory N-methyl-D-aspartate receptors. Risk factors include older age, kidney disease, pre-existing neurological disorders, and drug-drug interactions. While management of levofloxacin-induced neurotoxicity includes discontinuation of the drug and supportive care, hemodialysis is not recommended, despite available pharmacokinetic data in support of its dialyzability. The successful use of hemodialysis for the treatment of levofloxacin-induced neurotoxicity observed in our two patients with kidney failure should be further considered for rapid resolution of this rare fluoroquinolone-related adverse effect in patients with impaired kidney function.",
"affiliations": "Department of Medicine, Division of Nephrology, St. Elizabeth's Medical Center, Boston, Massachusetts, USA.;Department of Medicine, Division of Nephrology, St. Elizabeth's Medical Center, Boston, Massachusetts, USA.;Department of Medicine, Division of Nephrology, St. Elizabeth's Medical Center, Boston, Massachusetts, USA.;Department of Medicine, Division of Nephrology, St. Elizabeth's Medical Center, Boston, Massachusetts, USA.",
"authors": "Idrees|Najia|N|;Almeqdadi|Mohammad|M|;Balakrishnan|Vaidyanathapuram S|VS|;Jaber|Bertrand L|BL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin",
"country": "Canada",
"delete": false,
"doi": "10.1111/hdi.12687",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1492-7535",
"issue": "23(2)",
"journal": "Hemodialysis international. International Symposium on Home Hemodialysis",
"keywords": "adverse effect; drug clearance; hemodialysis; levofloxacin; neurotoxicity",
"medline_ta": "Hemodial Int",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D064704:Levofloxacin; D020258:Neurotoxicity Syndromes; D006435:Renal Dialysis; D012307:Risk Factors",
"nlm_unique_id": "101093910",
"other_id": null,
"pages": "E40-E45",
"pmc": null,
"pmid": "30255655",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemodialysis for treatment of levofloxacin-induced neurotoxicity.",
"title_normalized": "hemodialysis for treatment of levofloxacin induced neurotoxicity"
} | [
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{
"abstract": "BACKGROUND\nCerebral spinal fluid (CSF) dynamics are complex and changes in spinal anatomy may influence the rostrocaudal movement of intrathecal medications. We present the first reported case demonstrating that acute cervical spinal stenosis may impede the distribution of adjacent intrathecal medications, and that correction of such stenosis and the resulting changes in CSF flow may necessitate significant adjustments in the intrathecal infusates.\n\n\nMETHODS\nWe present a case of a 60-year-old male patient with a cervicothoracic intrathecal pump (ITP) infusing morphine, bupivacaine, and baclofen for chronic neck pain. The alert and oriented patient had a recent fall resulting in an acute severe cervical stenosis and cord compression which required urgent surgical decompression. Postoperatively, after the cervical decompression, the patient had significant altered mental status requiring a naloxone infusion. Multiple attempts to reduce the naloxone infusion were initially not successful due to worsened somnolence. The previously tolerated ITP medications were continuously reduced over the next 14 days, allowing concomitant decrease and eventual cessation of the naloxone infusion while maintaining patient mental status. The only opioids the patient received during this period were from the ITP.\n\n\nCONCLUSIONS\nThis case presents clinical evidence that severe spinal stenosis may impede the rostral CSF distribution of intrathecal medications. Intrathecal medications previously tolerated by patients prior to decompression may need to be significantly reduced in the postoperative period.",
"affiliations": "Department of Anesthesiology and Pain Medicine, University of California Davis Health System, Sacramento, California, USA.;Department of Anesthesiology and Pain Medicine, University of California Davis Health System, Sacramento, California, USA.;Department of Anesthesiology, University of California San Diego School of Medicine, La Jolla, California, USA.;Department of Anesthesiology and Pain Medicine, University of California Davis Health System, Sacramento, California, USA.;Department of Orthopedic Surgery, University of California Davis Health System, Sacramento, California, USA.;Department of Anesthesiology and Pain Medicine, University of California Davis Health System, Sacramento, California, USA michael.jung.md.mba@gmail.com.",
"authors": "Sanghvi|Chinar|C|;Su|Tiffany|T|;Yaksh|Tony L|TL|;Copenhaver|David J|DJ|;Klineberg|Eric O|EO|;Jung|Michael J|MJ|http://orcid.org/0000-0002-8892-072X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/rapm-2021-103041",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-7339",
"issue": "46(12)",
"journal": "Regional anesthesia and pain medicine",
"keywords": "analgesics; chronic pain; neck pain; opioid; pain management",
"medline_ta": "Reg Anesth Pain Med",
"mesh_terms": null,
"nlm_unique_id": "9804508",
"other_id": null,
"pages": "1100-1102",
"pmc": null,
"pmid": "34489354",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe altered mentation due to cervicothoracic intrathecal pump after correction of cervical stenosis: a case report.",
"title_normalized": "severe altered mentation due to cervicothoracic intrathecal pump after correction of cervical stenosis a case report"
} | [
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"literaturereference": "Jung, M.. Severe altered mentation due to cervicothoracic intrathecal pump after correction of cervical stenosis: a case report. Regional anesthesia and pain medicine. 2021;10.1136/rapm-2021-103041.",
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{
"abstract": "We previously reported the efficacy of nab-paclitaxel added to cisplatin, 5-FU, and cetuximab (APF-C) followed by concurrent high dose bolus cisplatin and radiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). In this phase II trial, we determined the efficacy of APF (without cetuximab) followed by CRT in similar patients.\n\n\n\nEligible patients had stage III-IV oropharynx (OP), larynx, or hypopharynx SCC and adequate organ function and performance status. T1 tumors were excluded. Patients were treated with three cycles of APF followed by CRT. Efficacy endpoints included two-year disease-specific survival (DSS), progression-free survival (PFS), overall survival (OS), and relapse rate.\n\n\n\nThirty patients were enrolled. Most patients were smokers (77%) with bulky T3/4 (73%) and N2/3 (83%) tumors. Analyses were stratified for human papilloma virus (HPV) status: HPV-related OPSCC (n=17; 57%) and HPV-unrelated HNSCC (n=13; 43%). With a minimum follow-up of 21months, relapse occurred in 1 (3%) patient. Two-year DSS was 94% in HPV-related OPSCC and 100% in HPV-unrelated HNSCC. Two-year PFS was 94% in HPV-related OPSCC and 100% in HPV-unrelated HNSCC. Two-year OS was 94% in HPV-related OPSCC and 92% in HPV-unrelated HNSCC. Causes of death were relapse (1), treatment-related mortality (1), and co-morbidity (1). Two patients with HPV-unrelated HNSCC treated with APF declined CRT and remained free of relapse at 36 and 28months of follow-up.\n\n\n\nThis phase II trial demonstrated favorable two-year DSS, PFS, and OS and a low relapse rate in HPV-unrelated HNSCC and HPV-related OPSCC treated with APF followed by CRT.",
"affiliations": "Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States. Electronic address: dadkins@dom.wustl.edu.;Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States.;Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States; Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States.",
"authors": "Adkins|Douglas|D|;Ley|Jessica|J|;Michel|Loren|L|;Wildes|Tanya M|TM|;Thorstad|Wade|W|;Gay|Hiram A|HA|;Daly|Mackenzie|M|;Rich|Jason|J|;Paniello|Randal|R|;Uppaluri|Ravindra|R|;Jackson|Ryan|R|;Trinkaus|Kathryn|K|;Nussenbaum|Brian|B|",
"chemical_list": "D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1368-8375",
"issue": "61()",
"journal": "Oral oncology",
"keywords": "5-Fluorouracil; Chemotherapy; Cisplatin; Head and neck cancer; Induction; nab-Paclitaxel",
"medline_ta": "Oral Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D005260:Female; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D000077195:Squamous Cell Carcinoma of Head and Neck",
"nlm_unique_id": "9709118",
"other_id": null,
"pages": "1-7",
"pmc": null,
"pmid": "27688097",
"pubdate": "2016-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "10655437;12365889;14645636;16467544;17960012;17960013;18784101;19412420;19704061;19917840;20530316;21079141;21798893;21798897;22065749;22981388;22991252;23414589;23566410;23619167;23619168;23665962;24696319;24958820;25049329;25497105;25619559;28029303;6204738;8040671",
"title": "nab-Paclitaxel, cisplatin, and 5-fluorouracil followed by concurrent cisplatin and radiation for head and neck squamous cell carcinoma.",
"title_normalized": "nab paclitaxel cisplatin and 5 fluorouracil followed by concurrent cisplatin and radiation for head and neck squamous cell carcinoma"
} | [
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{
"reactionmeddrapt": "Squamous cell carcinoma of head and neck",
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{
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"literaturereference": "ADKINS D. NAB-PACLITAXEL, CISPLATIN, AND 5-FLUOROURACIL FOLLOWED BY CONCURRENT CISPLATIN AND RADIATION FOR HEAD AND NECK SQUAMOUS CELL CARCINOMA. ORAL ONCOLOGY. 2016;.",
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{
"abstract": "The cumulative risk of therapy-related myelodysplastic syndrome (t-MDS) in breast cancer patients exposed to chemotherapy and/or radiotherapy is significantly high compared to that in other cancer patients. This report reviews the use of hypomethylating agents (HMAs) to treat a 57-year-old woman newly diagnosed with MDS during palliative chemotherapy for metastatic breast cancer. Over a period of 6 years, the patient received several DNA-damaging chemotherapeutics including doxorubicin, cyclophosphamide, and paclitaxel. Repeated thrombocytopenia was the main reason for suspecting secondary hematologic malignancy. She was diagnosed with t-MDS based on bone marrow examination and her treatment history for breast cancer. While azacitidine was originally administered to stabilize MDS, it also stabilized the patient's lung and lymph node metastases without any major toxicity. Therefore, the current case highlights the promising effects of HMAs for treating t-MDS following heavily pretreated breast cancer.",
"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 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.;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;Lee|Soo Jung|SJ|https://orcid.org/0000-0003-0066-4109;Sohn|Sang Kyun|SK|https://orcid.org/0000-0002-1874-3959;Moon|Joon Ho|JH|https://orcid.org/0000-0003-3756-796X;Chae|Yee Soo|YS|https://orcid.org/0000-0002-8585-4982",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4048/jbc.2019.22.e50",
"fulltext": "\n==== Front\nJ Breast CancerJ Breast CancerJBCJournal of Breast Cancer1738-67562092-9900Korean Breast Cancer Society 10.4048/jbc.2019.22.e50Case ReportClinical Effects of Hypomethylating Agents in Patients with Newly Diagnosed Myelodysplastic Syndrome Who Received DNA-Damaging Chemotherapy for Metastatic Breast Cancer https://orcid.org/0000-0003-4446-1549Baek Dong Won https://orcid.org/0000-0003-0066-4109Lee Soo Jung https://orcid.org/0000-0002-1874-3959Sohn Sang Kyun https://orcid.org/0000-0003-3756-796XMoon Joon Ho https://orcid.org/0000-0002-8585-4982Chae Yee Soo Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.Correspondence 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.kr12 2019 05 11 2019 22 4 647 652 25 6 2019 05 10 2019 © 2019 Korean Breast Cancer Society2019Korean 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.The cumulative risk of therapy-related myelodysplastic syndrome (t-MDS) in breast cancer patients exposed to chemotherapy and/or radiotherapy is significantly high compared to that in other cancer patients. This report reviews the use of hypomethylating agents (HMAs) to treat a 57-year-old woman newly diagnosed with MDS during palliative chemotherapy for metastatic breast cancer. Over a period of 6 years, the patient received several DNA-damaging chemotherapeutics including doxorubicin, cyclophosphamide, and paclitaxel. Repeated thrombocytopenia was the main reason for suspecting secondary hematologic malignancy. She was diagnosed with t-MDS based on bone marrow examination and her treatment history for breast cancer. While azacitidine was originally administered to stabilize MDS, it also stabilized the patient's lung and lymph node metastases without any major toxicity. Therefore, the current case highlights the promising effects of HMAs for treating t-MDS following heavily pretreated breast cancer.\n\nAzacitidineBreast neoplasmsDNA methylationMyelodysplastic syndrome\n==== Body\nINTRODUCTION\nTherapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myeloid leukemia (AML) are both clonal hematopoietic stem cell disorders that result in abnormal hematopoiesis and account for 15%–20% of all MDS/AML cases [1]. The t-MDS is diagnosed based on a patient history of exposure to cytotoxic chemotherapy and/or radiation therapy for hematologic malignancies, as well as solid neoplasms. Importantly, MDS incidence is higher among patients who have been exposed to DNA-damaging therapy than among unexposed patients [12]. Moreover, patients with t-MDS have worse survival outcomes than patients with de novo MDS [3].\n\nDNA-methylation plays an important role in tumorigenesis and cancer progression by interfering with cell cycle control, apoptosis, and DNA repair [4]. Furthermore, various genes affected by hypermethylation have already been reported to induce anticancer drug resistance and poor prognosis [56], making DNA-hypermethylation an attractive target for treatment and overcoming drug resistance by influencing tumor biology. Hypomethylating agents (HMAs) were first discovered in the early sixties, including 5-azacytidine (azacitidine, AZA) and its derivate 5-2′-deoxycytidine (decitabine, DAC). Although several studies have shown promising results for using HMAs to treat solid tumors [7], AZA and DAC are currently only approved by the US Food and Drug Administration for treating hematologic malignancies, such as MDS and AML.\n\nThe standard treatment for MDS depends on the disease status according to the International Prognostic Scoring System (IPSS), and is similar for patients with t-MDS [8]. In the case of young patients with a high-risk of transformation to AML, an allogeneic hematopoietic stem cell transplant can be beneficial, whereas HMA therapy can be an option for patients who are not transplant candidates or do not have a donor [9].\n\nThe cumulative risk of t-MDS for breast cancer patients exposed to chemotherapy and/or radiotherapy is known to be significantly higher when compared to other cancer patients [2]. However, t-MDS following breast cancer treatment is not fully understood yet. Therefore, this report reviews the use of HMAs to treat a 57-year-old woman newly diagnosed with MDS during palliative chemotherapy for metastatic breast cancer.\n\nCASE REPORT\nIn March 2012, a 57-year-old Korean female was diagnosed with resectable invasive ductal carcinoma in her left breast. The pathologic results revealed hormone receptor positive and human epidermal growth receptor 2 (HER2) positive status. The patient was administered neo-adjuvant chemotherapy with 4 cycles of doxorubicin plus cyclophosphamide, followed by 4 cycles of docetaxel. At the time of the first chemotherapy, blood tests and complete blood counts showed no abnormalities. After modified radical mastectomy, the patient received adjuvant radiotherapy and trastuzumab with an aromatase inhibitor for a year and continued to take the aromatase inhibitor thereafter. In January 2014, the patient complained of a right supraclavicular lymph node enlargement, which turned out to be metastatic carcinoma. Therefore, the patient was administered palliative chemotherapy with capecitabine + lapatinib from March 2014. In July 2015, after the 24th chemotherapy cycle of capecitabine + lapatinib, multiple lung metastases were found in a chest computed tomography (CT). Due to these lung metastases, vinorelbine plus trastuzumab were administered until disease progression. Figure 1 summarizes the overall treatments administered.\n\nFigure 1 Treatment history for breast cancer.\nIn April 2017, administration of ado-trastuzumab emtansine was delayed due to low platelet (PLT) count, in the range of 28,000–41,000/mm3. Owing to repeated thrombocytopenia and a prolonged recovery after every chemotherapy, the patient underwent a bone marrow (BM) aspiration and biopsy in October 2018. BM examination revealed myelodysplastic syndrome with 3.7% blasts and a complex karyotype, and the following serum findings: white blood cell (WBC) count 1,170/mm3 (absolute neutrophil count [ANC] 470/mm3), hemoglobin (Hb) 10.8 g/dL, and PLT count 12,000/mm3. According to the IPSS, the risk group was intermediate-2. Even though disease progression was found in both lungs and the brain, the patient requested systemic treatment for MDS and metastatic breast cancer. Therefore, the patient was given AZA subcutaneously at a dose of 75 mg/m2 per day for 7 days every 4 weeks, along with tamoxifen and anti-HER2 targeted therapy for metastatic breast cancer. This treatment was well tolerated, with only mild fatigue as a side effect.\n\nAfter 4 cycles of AZA, the complete blood count improved as follows: WBC count 3,900/mm3 (ANC 1,980/mm3), Hb 10.1 g/dL, and PLT count 125,000/mm3 without transfusion (Figure 2). In the follow-up BM examination, the blasts were reduced to 2.4% and their karyotype was normal. Moreover, chest CT showed a slight decrease in the size of lung metastases and enlarged lymph nodes, suggesting a stable disease (Figure 3). Recently, the patient completed her 6th cycle of AZA with good performance and no further progression of metastatic breast cancer.\n\nFigure 2 Improved platelets after hypomethylating agent therapy.\nt-MDS = therapy-related myelodysplastic syndrome; HMA = hypomethylating agent.\n\nFigure 3 Chest computed tomography (CT) scan before (August 2018) and after (April 2019) the azacitidine (AZA) treatment. (A) Multiple lung metastases (arrow) were found in the chest CT scan. (B) After 4 cycles of AZA, size of right upper lung mass was decreased (arrowhead).\nThis study was approved by the Institutional Review Board of Kyungpook National University Chilgok Hospital (KNUCH 2019-10-031), and informed consent was obtained.\n\nDISCUSSION\nThis case report reviews the successful use of AZA to treat a heavily pretreated metastatic breast cancer patient newly diagnosed with MDS. The patient had already been treated for 6 years with several DNA-damaging chemotherapeutics including doxorubicin, cyclophosphamide, and paclitaxel. Repeated thrombocytopenia following chemotherapy led to concerns regarding secondary hematologic malignancy, which resulted in a diagnosis of t-MDS based on a BM examination combined with the treatment history for breast cancer. Although AZA was originally administered to stabilize MDS, it was also found to stabilize the patient's lung and lymph node metastases without any major toxicity.\n\nThe t-MDS is a heterogeneous and poorly defined disease. Although the exact mechanism is still unknown, its most likely cause is the accumulation of genetic mutations in myeloid clones induced by preceding cancer treatments [10]. Patients with t-MDS often show a similar level of cytopenia as de novo MDS, and high-risk cytogenetics are observed in a large number of patients. Breast cancer is the most common type of solid cancer in t-MDS patients, with a relatively longer latency period of up to 10 years [11]. As patients with t-MDS have a higher risk of transformation to AML and resistance to conventional therapies, their prognosis is generally poor with a median survival of 8 to 9 months [3]. The major risk factor for t-MDS in breast cancer survivors is a treatment history of chemotherapeutic agents and radiation [2], where doxorubicin is particularly well known to have a strong association with t-MDS in breast cancer patients [12]. As most cases of t-MDS develop in breast cancer patients heavily pretreated with cytotoxic chemotherapeutic agents, their treatment options are invariably limited due to treatment-related complications and comorbidities, or the cancer itself. However, significant developments in breast cancer treatments have recently improved survival while reducing adverse side effects and comorbidities. Therefore, based on their relatively mild or manageable side effects, HMAs can be reasonably selected for treating t-MDS patients with heavily pretreated breast cancer [713].\n\nThe mechanism of HMAs in breast cancer is not completely understood yet. In the current case, the patient received AZA for MDS combined with tamoxifen and anti-HER2 targeted therapy without definitive clinical evidence on the concomitant use of these drugs. Izbicka et al. [14] reported that tamoxifen resistance frequently occurs due to the transcriptional inactivation of the estrogen receptor gene, and HMAs can restore the estrogen sensitivity in hormone-positive breast cancer cells. These findings were also supported by an in vitro experiment where epigenetic drugs such as AZA provided a potential therapeutic avenue for the management of anti-hormone-resistant breast cancer [15]. However, further studies are needed to evaluate whether anti-HER2 therapy has an additional synergistic effect on treatment with HMAs and tamoxifen in heavily pretreated hormone-positive HER2-positive breast cancer patients.\n\nIn the current case, the patient was administered AZA for t-MDS, regardless of her breast cancer, but her lung and lymph node metastases showed meaningful improvement after receiving AZA. However, it should be noted that the efficacy of HMAs in solid tumors is less evident compared to that in hematologic malignancies. In previous MDS studies, a sufficient follow-up time was proven necessary for evaluating the clinical response to HMAs. However, in most solid tumor studies, HMAs have been administered to patients at a highly pre-treated and advanced stage, meaning that the life expectancy has been invariably inadequate to identify the clinical benefits of HMAs for treating solid tumors. Therefore, this suggests that the benefits of HMAs for treating solid tumors should be explored in patients with earlier stage cancers.\n\nIn the current case review, when safely combined with tamoxifen, HMAs showed promising effects in t-MDS following heavily pretreated breast cancer. Although HMAs are still not approved for the treatment of solid tumors, recent preclinical evidence on the effect of HMAs in hormone-receptor-positive breast cancers highlights the need for well-designed prospective, randomized, controlled studies to identify the predictive role of HMAs in treating solid tumors.\n\nConflict of Interest: The authors declare that they have no competing interests.\n\nAuthor Contributions:\nConceptualization: Baek DW, Lee SJ, Sohn SK, Moon JH, Chae YS.\n\nInvestigation: Baek DW, Sohn SK, Moon JH, Chae YS.\n\nVisualization: Baek DW.\n\nWriting - original draft: Baek DW, Lee SJ, Sohn SK, Moon JH, Chae YS.\n\nWriting - review & editing: Baek DW, Chae YS.\n==== Refs\n1 Shenolikar R Durden E Meyer N Lenhart G Moore K Incidence of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with ovarian or breast cancer in a real-world setting in the United States Gynecol Oncol 2018 151 190 195 30268525 \n2 Kaplan HG Malmgren JA Atwood MK Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990–2005 BMC Cancer 2011 11 260 21693006 \n3 El-Fattah MA Clinical features and outcomes of 666 cases with therapy-related myelodysplastic syndrome (t-MDS) Indian J Hematol Blood Transfus 2018 34 83 90 29398804 \n4 Merlo A Herman JG Mao L Lee DJ Gabrielson E Burger PC 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers Nat Med 1995 1 686 692 7585152 \n5 Glasspool RM Teodoridis JM Brown R Epigenetics as a mechanism driving polygenic clinical drug resistance Br J Cancer 2006 94 1087 1092 16495912 \n6 de Sousa E Melo F Colak S Buikhuisen J Koster J Cameron K de Jong JH Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients Cell Stem Cell 2011 9 476 485 22056143 \n7 Linnekamp JF Butter R Spijker R Medema JP van Laarhoven HW Clinical and biological effects of demethylating agents on solid tumours - a systematic review Cancer Treat Rev 2017 54 10 23 28189913 \n8 Greenberg PL Tuechler H Schanz J Sanz G Garcia-Manero G Solé F Revised international prognostic scoring system for myelodysplastic syndromes Blood 2012 120 2454 2465 22740453 \n9 Malmgren JA Calip GS Pyott SM Atwood MK Kaplan HG Therapy-related myelodysplastic syndrome following primary breast cancer Leuk Res 2016 47 178 184 27414978 \n10 Larson RA Therapy-related myeloid neoplasms Haematologica 2009 94 454 459 19336749 \n11 Maung SW Burke C Hayde J Walshe J McDermott R Desmond R A review of therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: a single centre experience Hematology 2017 22 341 346 28196450 \n12 Ando M Narabayashi M Watanabe T Kamiya Y Togitani K Tanosaki R Therapy-related leukemia and myelodysplastic syndrome in breast cancer patients treated with cyclophosphamide or anthracyclines Jpn J Clin Oncol 1999 29 28 32 10073148 \n13 Cruijsen M Lübbert M Wijermans P Huls G Clinical results of hypomethylating agents in AML treatment J Clin Med 2014 4 1 17 26237015 \n14 Izbicka E Davidson KK Lawrence RA MacDonald JR Von Hoff DD 5,6-Dihydro-5′-azacytidine (DHAC) affects estrogen sensitivity in estrogen-refractory human breast carcinoma cell lines Anticancer Res 1999 19 1293 1298 10368690 \n15 Stone A Valdés-Mora F Gee JM Farrow L McClelland RA Fiegl H Tamoxifen-induced epigenetic silencing of oestrogen-regulated genes in anti-hormone resistant breast cancer PLoS One 2012 7 e40466 22808167\n\n",
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"issue": "22(4)",
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"keywords": "Azacitidine; Breast neoplasms; DNA methylation; Myelodysplastic syndrome",
"medline_ta": "J Breast Cancer",
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"title": "Clinical Effects of Hypomethylating Agents in Patients with Newly Diagnosed Myelodysplastic Syndrome Who Received DNA-Damaging Chemotherapy for Metastatic Breast Cancer.",
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"abstract": "Data on the radiologic evaluation of perianal fistulizing Crohn's disease (PFCD) naïve to anti-tumor necrosis factor therapy are scarce, especially in Asian populations. We assessed the effectiveness of infliximab (IFX) on PFCD and explored predictors of 'deep remission' based on clinical and radiologic assessments.\nPatients with Crohn's disease and active anal fistulas attending our care center for IFX therapy were prospectively enrolled. Each patient underwent clinical examination according to the Fistula Drainage Assessment Index, endoscopy for assessment of Crohn's Disease Activity Index (CDAI) and Perianal Crohn's Disease Activity Index (PCDAI), magnetic resonance imaging (MRI) to determine Van Assche score and Ng score, and laboratory tests up to 2 weeks prior to the start of and up to 2 weeks after the sixth IFX therapy (Week 32).\nAmong 38 patients treated with IFX, 52.6% achieved clinical remission based on the Fistula Drainage Assessment Index and 42.1% achieved deep remission based on Ng score. Van Assche score (from 14.5 ± 4.26 to 7.36 ± 7.53), CDAI (from 170 ± 92 to 71 ± 69) and PCDAI (from 7.45 ± 2.65 to 2.44 ± 3.20) decreased significantly after six IFX treatments. The only predictor of deep remission was simple fistula (P = 0.004, odds ratio = 3.802, 95% confidence interval: 1.541-9.383).\nIFX has been shown to have appreciable effectiveness in Chinese patients with PFCD. MRI is the gold standard for evaluating PFCD, but Van Assche score has some limitations.",
"affiliations": "Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Shanghai Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Shanghai Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Shanghai Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Shanghai Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Shanghai Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.;Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Shanghai Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.",
"authors": "Yan|Xiaohan|X|;Zhu|Mingming|M|;Feng|Qi|Q|;Yan|Yunqi|Y|;Peng|Jiangchen|J|;Xu|Xitao|X|;Xu|Antao|A|;Ran|Zhihua|Z|",
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"doi": "10.1093/gastro/goy036",
"fulltext": "\n==== Front\nGastroenterol Rep (Oxf)Gastroenterol Rep (Oxf)gastroGastroenterology Report2052-0034Oxford University Press 10.1093/gastro/goy036goy036Original ArticlesEvaluating the effectiveness of infliximab on perianal fistulizing Crohn’s disease by magnetic resonance imaging Yan Xiaohan 1Zhu Mingming 1Feng Qi 2Yan Yunqi 2Peng Jiangchen 1Xu Xitao 1Xu Antao 1Ran Zhihua 11 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Shanghai Inflammatory Bowel Disease Research Center; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China2 Department of Radiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaCorresponding author. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health;Shanghai Inflammatory Bowel Disease Research Center;Renji Hospital, School of Medicine, Shanghai Jiao Tong University; 145 Middle Shandong Road, Shanghai 200001, China. Tel: +86-13801868827; Email: zhihuaran@vip.163.comThese authors Xiaohan Yan, Mingming Zhu, and Qi Feng contributed equally to this work.\n\n2 2019 24 10 2018 24 10 2018 7 1 50 56 4 4 2018 11 6 2018 5 7 2018 © The Author(s) 2018. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-Sen University2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground and aim\nData on the radiologic evaluation of perianal fistulizing Crohn’s disease (PFCD) naïve to anti-tumor necrosis factor therapy are scarce, especially in Asian populations. We assessed the effectiveness of infliximab (IFX) on PFCD and explored predictors of ‘deep remission’ based on clinical and radiologic assessments.\n\nMethods\nPatients with Crohn’s disease and active anal fistulas attending our care center for IFX therapy were prospectively enrolled. Each patient underwent clinical examination according to the Fistula Drainage Assessment Index, endoscopy for assessment of Crohn’s Disease Activity Index (CDAI) and Perianal Crohn’s Disease Activity Index (PCDAI), magnetic resonance imaging (MRI) to determine Van Assche score and Ng score, and laboratory tests up to 2 weeks prior to the start of and up to 2 weeks after the sixth IFX therapy (Week 32).\n\nResults\nAmong 38 patients treated with IFX, 52.6% achieved clinical remission based on the Fistula Drainage Assessment Index and 42.1% achieved deep remission based on Ng score. Van Assche score (from 14.5 ± 4.26 to 7.36 ± 7.53), CDAI (from 170 ± 92 to 71 ± 69) and PCDAI (from 7.45 ± 2.65 to 2.44 ± 3.20) decreased significantly after six IFX treatments. The only predictor of deep remission was simple fistula (P = 0.004, odds ratio = 3.802, 95% confidence interval: 1.541–9.383).\n\nConclusions\nIFX has been shown to have appreciable effectiveness in Chinese patients with PFCD. MRI is the gold standard for evaluating PFCD, but Van Assche score has some limitations.\n\nCrohn’s diseaseperianal fistulamagnetic resonance imaginginfliximabNational Natural Science Foundation of China10.13039/501100001809813020928130209581600435Fundamental Research Funds for the Central UniversitiesYG2015QN38Foundation for Fostering Clinical Research of Renji HospitalPYMDT-005\n==== Body\nIntroduction\nPerianal fistulizing Crohn’s disease (PFCD) has a serious impact on quality of life and mental health [1]. It is always indicative of a more aggressive and refractory disease phenotype [2]. A population-based study found that the incidence of perianal fistula in patients with Crohn’s disease (CD) is 21–23% and that the cumulative incidences of the condition at 1, 5, 10 and 20 years are 12, 15, 21 and 26%, respectively [3–5]. Large prospective and retrospective studies have shown that two-thirds of patients with PFCD experience relapses; thus, the treatment of PFCD is challenging [6, 7].\n\nMedical treatments for PFCD include antibiotics, immunosuppressants (ISs) and anti-tumor necrosis factor (TNF) agents, and surgical treatments include seton, fistulotomy, fistulectomy, advancement flap, fecal diversion and proctectomy [8–11]. Nearly 40% of PFCD patients underwent proctectomy before the clinical application of biologic agents [12]. Biologic agents such as infliximab (IFX) have brought new hope to PFCD patients: after continuous treatment for 1 year, one-third of patients maintain clinical remission [13]. Personalized treatments are required based on magnetic resonance imaging (MRI) findings [14]. Pelvic enhancement MRI is the first choice for evaluating PFCD and monitoring the effects of treatment [10]. When used in combination with examination under anesthesia, its specificity and sensitivity are increased [11].\n\nExploring predictors of the need for different therapies is an important guide for treatment selection for PFCD. Fistula healing based on MRI evaluation is always later than that based on clinical evaluation. Therefore, in the Second European Evidence-Based Consensus on the Diagnosis and Management of Crohn’s Disease [15], it was proposed that a clinical examination should be combined with MRI as the basis of an effective clinical evaluation. Most previous studies have evaluated treatment efficacy based on clinical evaluation rather than endoscopic or radiologic findings. However, the assessment of treatment efficacy should be based on ‘deep remission’ (the absence of anal canal ulcers and presence of healing on MRI in association with clinical remission) or the combination of clinical assessment and objective radiologic and endoscopic evaluations. T2-weighted imaging (T2WI) and fat-suppression sequences are the gold standard for the MRI evaluation of fistulas [16]. Imaging-based scoring, although not yet widely used in clinical practice, can reflect disease activity.\n\nIn this study, we describe the clinical and radiologic courses of PFCD treated by IFX, evaluate the efficacy of IFX for the condition and explore the predictors of deep remission.\n\nPatients and methods\nPatients and protocol\nBetween September 2015 and May 2017, all consecutive patients diagnosed with CD and at least one draining fistula who attended our center for IFX therapy were prospectively enrolled. CD diagnosis was based on a combination of clinical, serologic, endoscopic and pathologic examinations. The diagnosis of anal fistula was based on examination under anesthesia and MRI. IFX therapy consisted of induction therapy (5 mg/kg at Weeks 0, 2 and 6) followed by maintenance therapy (5 mg/kg every 8 weeks). The exclusion criteria included age less than 18 years, pregnancy and unwillingness to undergo IFX therapy or follow-up at our center for more than 6 months.\n\nThe data retrieved from medical records included: age; sex; date of diagnosis; smoking history; family history of inflammatory bowel disease (IBD); disease distribution according to the Montreal classification; treatments (antibiotics, setons, immunomodulators) before IFX therapy; type of fistula; concomitant treatment; adverse events; need for surgical treatment; and early IFX withdrawal because of adverse events or lack of efficacy.\n\nUp to 2 weeks prior to the start of IFX therapy and up to 2 weeks after the sixth IFX therapy (Week 32), each patient underwent clinical assessment of their fistulas according to the Fistula Drainage Assessment Index, MRI to determine Van Assche score, Ng score, main fistula length, endoscopy, assessment of Crohn’s Disease Activity Index (CDAI) and Perianal Crohn’s Disease Activity Index (PCDAI) and laboratory tests for the following parameters: white blood-cell count; neutrophil count; hemoglobin concentration (HB); hematocrit; platelet count (PLT); C-reactive protein concentration (CRP); erythrocyte sedimentation rate (ESR); and Albumin concentration (ALB). Concurrent therapies for CD, including antibiotics and ISs, were permitted. Seton placement was allowed before IFX therapy. All participants of this study provided written informed consent. The study protocol was approved by the Research Ethics Committee of Renji Hospital (School of Medicine, Shanghai Jiao Tong University, Shanghai, China).\n\nEvaluation of effectiveness\nCDAI was applied to evaluate the disease activity of CD in terms of general well-being, abdominal pain, abdominal mass, diarrhea, the need for diphenoxylate/atropine or opiates for diarrhea, hematocrit, weight and complications [17]. PCDAI was assessed on the basis of five clinical symptoms: discharge; restriction of activities; restriction of sexual activity; type of perianal disease; and degree of induration [18]. Each section was rated from 0–5 according to severity.\n\nClinical evaluation was performed according to the Fistula Drainage Assessment Index. The definition of ‘clinical remission’ was the absence of any draining fistulas and any drainage episodes self-reported by the patient in two successive evaluations under gentle finger compression. ‘Clinical response’ meant reducing the number of draining fistulas by half or more from baseline under gentle finger compression at the clinical evaluation. In all other circumstances, patients were considered ‘non-responders’ [19]. All clinical examinations were performed by the same senior physician specialized in IBD dedicated to each patient. We no longer assess the Van Assche score of the MRIs of healed fistulas according to Ng score: the Van Assche scores of these MRIs were regarded as zero.\n\nA senior radiologist specialized in gastrointestinal radiology with more than 10 years of experience evaluated the MRIs by calculating the main fistula length and diameter, abscess volume, proctitis, Van Assche score and Ng score. The radiologist used the same standardized report for the initial and follow-up MRIs and was blinded to each patient’s medical history and clinical outcome. The Van Assche score included six items, with higher scores indicating severe disease (ranging from 0–22): complexity of the fistula tracts; location relative to the sphincters; extension; hyperintensity on T2WI; presence of abscesses; and rectal wall involvement [20]. We used the predetermined MRI definitions proposed by Ng et al. [21, 22] to classify the radiologic findings (Table 1).\nTable 1. Ng Score for perianal Crohn’s disease severity\n\nTerms\tDefinition\t\nHealed\tAbsence of high-signal tracks on fat-saturated T2-weighted sequences\t\nPartial response\tReduction in the number of fistula tracts and/or draining cavities and/or a reduction in the volume of inflammation of 10% or more\t\nUnchanged\tSimilar number of tracts and volume of inflammation\t\nDeterioration\tDevelopment of new tracts or collections, or an increase in the size or number of any previous cavities or fistula tracts\t\n\n\nThe need for surgery, severe secondary effects requiring discontinuation of medical therapy and voluntary discontinuation of the treatment were considered treatment failures.\n\nMRI parameters\nMRI examinations were performed using a Philips Achieva 3.0-T scanner with a cardiac phased-array coil (Philips Medical Systems, Amsterdam, The Netherlands) and a Philips Ingenia 3-T scanner with a torso phased-array coil (Philips Medical Systems). Patients did not receive any bowel preparation. All patients underwent examination in the supine position. The MRI sequence protocol is presented in Supplementary Table 1. The intravenous injection was a mean dose of 15–20 ml gadolinium-diethylenetriamine penta-acetic acid (Magnevist®; Schering AG, Berlin, Germany) and the scan delay was 60 s. The oblique coronal plane was placed parallel to and the oblique transverse plane was placed perpendicular to the long axis of the anal canal. Patients with contraindications to MRI, such as severe claustrophobia, pacemakers or metallic implants, were excluded.\n\nStatistical analysis\nContinuous variables are presented as means and standard deviation, and categorical variables as percentages and 95% confidence intervals (CIs). Comparison of patients was conducted using the χ2 test for categorical variables and the Student’s t-test for continuous variables. The κ-statistic was used to assess the correlation between clinical response and radiologic indices. Predictors of deep remission were assessed using multiple logistic regression analysis. Models of logistic regression were performed. The results were considered statistically significant at a P-value of <0.05. We used SPSS 18.0 (SPSS Inc., Chicago, IL, USA) for all statistical analyses.\n\nResults\nPatient characteristics\nA total of 38 patients (26.3% women) with a mean age of 28.5 ± 8.2 years scheduled for IFX therapy were prospectively enrolled. Of them, 68.4% had complex fistulas and 5.3% had anorecto-vaginal fistulas. Among them, 8 patients were receiving a combination of IFX and azathioprine (AZA), whereas 30 patients were receiving IFX alone. The baseline characteristics of this study population are presented in Table 2.\nTable 2. Baseline characteristics of 38 patients with perianal fistulizing Crohn’s disease\n\nVariables\tIFX patients (n = 38)\t\nSex\t\t\n Male\t28 (73.7%)\t\n Female\t10 (26.3%)\t\nAge, years\t28.5 ± 8.2\t\nSmokers\t2 (5.3%)\t\nIBD family history\t0 (0%)\t\nCD disease location\t13 (34.2%)\t\n L1 (Ileal)\t3 (7.9%)\t\n L2 (Colonic)\t22 (57.9%)\t\n L3 (Ileocolonic)\t\t\nDuration, years\t1.95 ± 3.01\t\nFistula location\t\t\n Superficial\t1 (2.6%)\t\n Intersphincteric\t19 (50%)\t\n Transphincteric\t14 (36.8%)\t\n Suprasphincteric\t2 (5.3%)\t\n Extrasphincteric\t2 (5.3%)\t\nFistula type\t\t\n Simple fistula\t12 (31.6%)\t\n Complex fistula\t26 (68.4%)\t\nAnorecto-vaginal fistula\t2 (5.3%)\t\nProctitis\t20 (52.6%)\t\nAbscess\t20 (52.6%)\t\nPrevious surgery\t\t\n Drainage techniques\t10 (26.3%)\t\n Seton or fistulotomy\t9 (23.7%)\t\n Fistulectomy\t5 (13.2%)\t\n Segmental bowel resection\t2 (5.3%)\t\nTreatment\t\t\n Infliximab\t30 (78.9%)\t\n Infliximab + azathioprine\t8 (21.1%)\t\nTime between initial and follow-up MRI\t6 infliximab therapy\t\nIFX, infliximab; IBD, inflammatory bowel disease; CD, Crohn’s disease; MRI, magnetic resonance imaging.\n\n\n\nClinical and radiologic responses\nFour patients discontinued because of adverse effects or subjective reluctance, whereas 20 (52.6%) were in clinical remission, 9 (23.7%) exhibited a clinical response and 5 (13.2%) were non-responders after six IFX therapies. CDAI and PCDAI decreased significantly from 170 ± 92 and 7.45 ± 2.65 at baseline to 71 ± 69 and 2.44 ± 3.2 after six IFX therapies, respectively (both P < 0.05). According to Ng score, 16 (42.1%) of the patients achieved deep remission, 11 (28.9%) exhibited a partial response, 4 (10.5%) remained unchanged and 3 (7.9%) deteriorated (Table 3). The healing rates of patients receiving IFX therapy alone and those receiving AZA + IFX were 40% (12/30) and 50% (4/8), respectively. Van Assche score decreased significantly from 14.50 ± 4.26 at baseline to 7.36 ± 7.53 after six IFX therapies (Figure 1). The changes in patient ratios for the six components of the Van Assche score are shown in detail in Figure 2.\nTable 3. Clinical and radiologic evaluation of infliximab (IFX) efficacy\n\nOutcomes\tIFX patients (n = 38)\t\nDiscontinued\t4 (10.5%)\t\nClinical evaluation\t\nFistula Drainage Assessment Index\t\t\n Clinical remission\t20 (52.6%)\t\n Clinical response\t9 (23.7%)\t\n Non-response\t5 (13.2%)\t\nCrohn’s Disease Activity Index\t\t\n Baseline\t170 ± 92\t\n Follow-up\t71 ± 69*\t\nPerianal Crohn's Disease Activity Index\t\t\n Baseline\t7.45 ± 2.65\t\n Follow-up\t2.44 ± 3.20*\t\nRadiologic evaluation\t\nNg score\t\t\n Healed\t16 (42.1%)\t\n Partial response\t11 (28.9%)\t\n Unchanged\t4 (10.5%)\t\n Deterioration\t3 (7.9%)\t\nHealing rate of complex fistulas\t8/26 (30.8%)\t\nVan Assche score\t\t\n Baseline\t14.5 ± 4.26\t\n Follow-up\t7.36 ± 7.53*\t\nMaximum fistula length, mm\t\t\n Baseline\t41.4 ± 20.7\t\n Follow-up\t17.2 ± 23.1*\t\nMaximum fistula diameter, mm\t\t\n Baseline\t3.39 ± 1.81\t\n Follow-up\t1.18 ± 1.58*\t\n* P < 0.05.\n\n\n\nFigure 1. Van Assche scores were significantly reduced after six infliximab (IFX) treatments, from 14.5 ± 4.26 to 7.36 ± 7.53\n\nFigure 2. Patient ratios of the six components (complexity of fistula tracks, location relative to the sphincters, extension, hyperintensity on T2-weighted imaging, presence of abscesses and rectal wall involvement) of the Van Assche score on initial and follow-up magnetic resonance imaging\n\nThe changes in serologic findings are shown in Supplementary Table 2. ESR (from 18.6 ± 19.4 to 11 ± 12.3 mm/h, P < 0.05), CRP (from 9.59 ± 11.3 to 4.24 ± 8.09 mg/L, P < 0.05) and PLT (from [286 ± 88] × 109 to [260 ± 91] × 109, P < 0.05) decreased significantly between baseline and after six IFX therapies, whereas ALB (from 39.8 ± 6.2 to 43.7 ± 5.16 g/L, P < 0.05) and HB (from 125 ± 21.8 to 134 ± 23 g/L, P < 0.05) increased significantly.\n\nCorrelation between clinical and radiologic responses\nClinical examination according to the Fistula Drainage Assessment Index and MRIs were performed in each patient. Sixteen of the 20 patients (80%) who were in clinical remission exhibited healed fistula tracts on MRI and six of the nine patients (66.7%) who exhibited a clinical response demonstrated a partial response on MRI (κ-statistic = 0.613, P < 0.001).\n\nPredictors of deep remission\nIn a univariate analysis, deep remission was significantly associated with low initial Van Assche score (12.6 ± 4.3 vs 15.9 ± 3.7, P = 0.015), absence of proctitis (P = 0.047) and simple fistula (P = 0.002), but showed no relationship with sex, age, duration of disease, smoking history, surgery history, absence of abscesses, combinatorial treatment with AZA, CD disease location, main fistula length on initial MRI, main fistula diameter on initial MRI, the five components of Van Assche score except fistula type, initial CDAI, initial PCDAI or initial laboratory findings (all P > 0.05). In a multivariate analysis, deep remission was only significantly associated with simple fistula (odds ratio 3.802, 95% CI: 1.541–9.383, P = 0.004).\n\nSafety of IFX therapy\nFour patients were considered to have experienced treatment failure. One patient discontinued because of pre-excitation syndrome after the first IFX therapy, one because of hepatapostema at the fourth IFX therapy, one because of pulmonary infection at the fifth IFX therapy and one postponed the sixth IFX therapy because of upper respiratory tract infection then discontinued for being reluctant to follow IFX therapy. In addition, two patients presented minor adverse effects (dermatitis) that did not require cessation of the therapy.\n\nDiscussion\nAnti-TNF therapies have revolutionized the management of PFCD. Several randomized controlled trials have proven their efficacy at achieving and maintaining remission of PFCD [23, 24]. However, few studies have focused on deep remission as the therapeutic outcome of interest and, to the best of our knowledge, there are no studies involving Asian populations. In this study, we prospectively examined the clinical and radiologic evaluation of IFX therapy for PFCD: 52.6% of our patients receiving IFX therapy achieved clinical remission, whereas 42.1% exhibited deep remission.\n\nRegarding the basic characteristics of the 38 participants of this study, the male:female ratio was 28:10, which is consistent with the epidemiology of PFCD in China, but different from that in Europe and the USA [25]. The proportion of smokers was only 5.3%, which is much lower than that in Western countries. The family history of IBD was 0%, which may be due to the low incidence and low detection rate of the condition in China 10 years ago. Other basic patient information was similar to that in research in China and abroad.\n\nPublished studies on the efficacy of IFX therapy for PFCD as evaluated by MRI are summarized in Table 4 [13, 25–28]. The clinical and deep remission rates observed in this study were higher than those presented in Table 4. The reasons are as follows.\nTable 4. Previous studies on the radiologic evaluation of infliximab efficacy\n\nReference\tPublication year and type\tTreatment\tNo. of patients\tComplex fistulas\tDuration, year\tFollow-up, months\tOutcome\tRisk factors\t\nThomassin [27]\t2017, retrospective\tIFX/ADA and IS\t49\t–\t6\t40\tDeep remission: 33%\tRectal involvement\t\nTozer [13]\t2012, retrospective\tIFX and TP\t32\t83%\t10\t6\tRadiologic healing: 25%\tNumber of fistulas\t\nNg [28]\t2009, prospective\tIFX/ADA or with AZA\t26\t–\t12\t6\tDeep remission: 20%\tProctitis\t\nTougeron [29]\t2008, retrospective\tIFX or with IS\t26\t69%*\t13\t59\tClinical remission: 42%\tProctitis\t\nKarmiris [30]\t2011, retrospective\tIFX or with IS\t29\t85%\t9\t9\tReduction of fistula number: 14%\tNone\t\n* Anorecto-vaginal fistula: 30%. IFX, infliximab; ADA, adalimumab; TP, thiopurine; IS, immunosuppressants; AZA, azathioprine.\n\n\n\nFirst, not all patients in earlier studies were naïve to anti-TNF agents. Several patients had refractory PFCD that had already failed to respond to other anti-TNF agents. Despite the similar efficacy of each anti-TNF agent, the use of a second anti-TNF agent is often not as effective as that of the initial anti-TNF agent, but it is still effective in some patients [26]. Currently, of the anti-TNF drugs available for the treatment of CD, only IFX is approved in China. All patients in this study were naïve to IFX. A retrospective study of patients naïve to adalimumab therapy showed that 39% of patients achieved radiologic remission after 6 months [22]—a higher proportion than those of the five studies listed in Table 4 in which patients were not naïve to IFX.\n\nSecond, the patients studied in the papers listed in Table 4 were Europeans and Americans, whereas the patients enrolled in this study were Han Chinese. It has been shown that the expression of five genes (S100A8, S100A9, G0S2, TNFAIP6 and IL11) has an etiologic role in the IFX response pathway and predicts the response to IFX of patients with CD [29]. However, the susceptibility genes of CD differ between Chinese and Western patients. It can be inferred from the results of this study that the efficacy of IFX for PFCD is better in Chinese patients than in Western patients.\n\nThird, studies have shown that the shorter the disease duration, the higher the response rate to biologic agents [30, 31]. A retrospective study with a small sample size showed that patients with PFCD with disease durations (before the beginning of anti-TNF treatment) of less than 3, 3–6 and >6 years achieved radiographic healing rates of 50, 38 and 14%, respectively [26]. The average disease duration in this study was 1.95 ± 3.01 years—well below those of the five studies presented in Table 4.\n\nFourth, in this study, 68.4% of the patients had complex fistulas and 5.3% had anorecto-vaginal fistulas—well below the proportions of patients with these conditions in the studies listed in Table 4. In combination with the fact that several patients had already failed to respond to other anti-TNF agents, the PFCD described in those papers presented in Table 4 was more refractory than that described in this study. Furthermore, the number of fistulas was a risk factor for no response to IFX therapy in patients with PFCD [13].\n\nIFX is safe and efficient for the treatment of PFCD. However, treatment options for PFCD are limited and biologics are expensive. Consequently, it is important to explore the predictors of treatment response. In the first study listed in Table 4, 33% of patients achieved deep remission 2 years after receiving anti-TNF agents and the absence of rectal involvement on MRI was the only predictor of deep remission [25]. Other studies in Table 4 showed that a large number of fistulas [13] and proctitis [26, 27] are risk factors for no response to IFX. Another study showed that proctitis is a predictor of poor response and even proctectomy [32]. In addition, a single-center study showed that a history of perianal abscesses and antibiotic treatment in the course of anti-TNF therapy were predictors of poor response in PFCD [33]. Moreover, individuals with a younger age at onset, male sex, rectal lesions and non-white or Jewish ethnicities were at high risk of developing perianal lesions [8, 34]. However, our study indicated that the only predictor of deep remission was simple anal fistula.\n\nOne study showed that an aggregate length of ≥2.5 cm predicted disease progression, whereas a maximum single fistula length of <2.5 cm on MRI predicted treatment response; thus, the authors recommended that the measurement of fistula length should be incorporated into routine clinical practice [35]. We measured both the length and diameter of the main fistula using MRI. Unfortunately, neither the length nor the diameter of the main fistula was a risk factor in univariate or multivariate analyses.\n\nIn the current study, only 21.1% of the patients were treated with a combination of IFX and AZA in this study (lower than the proportions in the studies listed in Table 4): the rest were treated with IFX alone. A study demonstrated that AZA maximizes the long-term effects of antibiotics [36]. Similarly, studies on IFX in combination with thiopurines have shown that thiopurines increase the extent and duration of the response to IFX [37, 38]. The European Evidence-Based Consensus on the Diagnosis and Management of Crohn’s Disease 2016 stated that combination of anti-TNF treatment with thiopurines may enhance the effects of anti-TNF agents on complex fistulizing disease [39]. However, some studies asserted that IFX alone achieves better outcomes than in combination with AZA. It was inferred from the subgroups of the ACCENT I and II trials that the use of IFX in combination with ISs does not increase its efficacy or pharmacokinetics [40]. In addition, a randomized controlled study showed that the mucosal healing of the combination of IFX and ISs was not statistically superior to IFX alone after continuous treatment for 6 months [41]. Another retrospective study showed that the improvement rates in MRI findings of IFX alone and IFX in combination with ISs at 12 months were 53 and 67%, respectively [26]. Therefore, whether the combination of IFX and AZA is superior to IFX alone is inconclusive. However, in current clinical practice in China, monotherapy is preferable. First, Chinese patients have better response to biologic agents. Second, Chinese patients have more side effects when receiving combination of IFX and AZA.\n\nCurrently, Van Assche score is widely used in clinical research [20]. However, our findings suggest that this score has some limitations related to its inability to reflect new fistulas and abscesses in some circumstances [42]. For example, when a third fistula emerges when two initial fistulas are unchanged, Van Assche score remains unchanged because of the invariability of the complexity of the fistula tracks. In this case, Van Assche score no longer reflects the deterioration of the disease, and vice versa when one of the three initial fistulas heals. Also, when the original abscess lesion turns into granulation tissue, Van Assche score does not show any improvement. In order to better reflect the changes evident on imaging, a more standard, effective and uniform grading standard needs to be developed. Hence, in this study, we used Ng score to compare the changes between the initial and follow-up MRIs in each patient, which is more objective and suitable for monitoring the therapeutic effect.\n\nIn this study, the consistency of the clinical and radiologic evaluations was high. Fistula closure is often later on MRI than on clinical evaluation. When the fistula has not yet fully undergone fibrosis and closure of the external orifice, there is a risk of recurrence. Therefore, pelvic enhancement MRI is essential for the assessment of PFCD.\n\nOur study has several limitations. We did not measure anti-IFX antibody concentration or serum trough level. The IFX dose was 5 mg/kg all the time in all patients. Patients with a poor response should receive an increased dose of IFX or switch to another biologic agent according to anti-IFX antibody concentration and serum trough level, which is not yet renewed in the guideline of China. Furthermore, higher IFX serum trough level (>9–10 μg/mL) is favorable for fistula healing [43, 44]. Nonetheless, IFX is the only anti-TNF drug approved for the treatment of CD in China. However, the association between IFX levels and outcomes is beyond the studying scope of this study.\n\nIn conclusion, IFX is safe and effective for PFCD with a high deep remission rate. The only predictor of deep remission is simple fistula. MRI is the gold standard for evaluating PFCD, but Van Assche score has some limitations.\n\nFunding\nThis work was supported by the National Natural Science Foundation of China (No. 81302092, 81302095 and 81600435), the Fundamental Research Funds for the Central Universities (No. YG2015QN38) and the Foundation for Fostering Clinical Research of Renji Hospital (No. PYMDT-005).\n\nSupplementary Material\nSupplementary Tables Click here for additional data file.\n\n Acknowledgements\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the Research Ethics Committee of Renji Hospital (School of Medicine, Shanghai Jiao Tong University, Shanghai, China) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.\n\n\n\nConflict of interest statement: none declared.\n==== Refs\nReferences\n1 \nMaconi G , Gridavilla D , Vigano C. \nPerianal disease is associated with psychiatric co-morbidity in Crohn’s disease in remission . Int J Colorectal Dis 2014 ;29 :1285 –90 .24986138 \n2 \nBeaugerie L , Seksik P , Nion-Larmurier I \net al\nPredictors of Crohn’s disease . Gastroenterology 2006 ;130 :650 –6 .16530505 \n3 \nHellers G , Bergstrand O , Ewerth S \net al\nOccurrence and outcome after primary treatment of anal fistulae in Crohn’s disease . Gut 1980 ;21 :525 –7 .7429313 \n4 \nSchwartz DA , Loftus EV , Tremaine WJ \net al\nResponse to infliximab in Crohn’s disease: genetic analysis supporting expression profile the natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota . 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Tech Coloproctol 2017 ;21 :119 –24 .28066859 \n34 \nTozer PJ , Burling D , Gupta A \net al\nReview article: medical, surgical and radiological management of perianal Crohn’s fistulas . Aliment Pharmacol Ther 2011 ;33 :5 –22 .21083581 \n35 \nShenoy-Bhangle A , Nimkin K , Goldner D \net al\nMRI predictors of treatment response for perianal fistulizing Crohn disease in children and young adults . Pediatr Radiol 2014 ;44 :23 –9 .24005981 \n36 \nDejaco C , Harrer M , Waldhoer T \net al\nAntibiotics and azathioprine for the treatment of perianal fistulas in Crohn’s disease . Aliment Pharmacol Ther 2003 ;18 :1113 –20 .14653831 \n37 \nViscido A , Habib FI , Kohn A \net al\nInfliximab in refractory pouchitis complicated by fistulae following ileo-anal pouch for ulcerative colitis . Aliment Pharmacol Ther 2003 ;17 :1263 –71 .12755839 \n38 \nTopstad DR , Panaccione R , Heine JA \net al\nCombined seton placement, infliximab infusion, and maintenance immunosuppressives improve healing rate in fistulizing anorectal Crohn’s disease: a single center experience . Dis Colon Rectum 2003 ;46 :577 –83 .12792431 \n39 \nGionchetti P , Dignass A , Danese S \net al\n3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: Part 2: Surgical management and special situations . J Crohns Colitis 2017 ;11 :135 –49 .27660342 \n40 \nLichtenstein GR , Diamond RH , Wagner CL \net al\nClinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials . Aliment Pharmacol Ther 2009 ;30 :210 –26 .19392858 \n41 \nVan Assche G , Magdelaine-Beuzelin C , D’Haens G \net al\nWithdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial . Gastroenterology 2008 ;134 :1861 –8 .18440315 \n42 \nKorelitz BI , Adler DJ , Mendelsohn RA \net al\nLong-term experience with 6-mercaptopurine in the treatment of Crohn’s disease . Am J Gastroenterol 1993 ;88 :1198 –205 .8338087 \n43 \nDavidov Y , Ungar B , Bar-Yoseph H \net al\nAssociation of induction infliximab levels with clinical response in perianal Crohn’s disease . J Crohns Colitis 2017 ;11 :549 –55 .28453755 \n44 \nYarur AJ , Kanagala V , Stein DJ \net al\nHigher infliximab trough levels are associated with perianal fistula healing in patients with Crohn’s disease . Aliment Pharmacol Ther 2017 ;45 :933 –40 .28211593\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": null,
"issue": "7(1)",
"journal": "Gastroenterology report",
"keywords": "Crohn’s disease; infliximab; magnetic resonance imaging; perianal fistula",
"medline_ta": "Gastroenterol Rep (Oxf)",
"mesh_terms": null,
"nlm_unique_id": "101620508",
"other_id": null,
"pages": "50-56",
"pmc": null,
"pmid": "30792866",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": "10228190;11095340;11910338;12047962;1248701;12591051;12755839;12792431;12940928;14653831;14985485;16530505;16905369;17720635;18440315;19003531;19392858;19575762;19755971;21056696;21083581;21122490;22223472;24005981;24951257;24986138;25159455;25485513;25663759;25746229;26339133;26826183;27660342;27751880;28066859;28211593;28453755;28694669;28852521;7429313;7884173;8338087;8549948",
"title": "Evaluating the effectiveness of infliximab on perianal fistulizing Crohn's disease by magnetic resonance imaging.",
"title_normalized": "evaluating the effectiveness of infliximab on perianal fistulizing crohn s disease by magnetic resonance imaging"
} | [
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{
"abstract": "BACKGROUND\nNeuroleptic malignant syndrome (NMS) is a rare life-threatening disorder resulting from treatment with neuroleptic agents and other drugs that act as dopamine antagonists. NMS most often occurs shortly after the initiation, dose increase or withdrawal of the offending agent, but can rarely occur after long-term treatment at stable doses. Immediate discontinuation of the causative agent (or re-administration if the cause is the withdrawal of neuroleptic therapy) along with supportive therapy to maintain cardiorespiratory stability and to reduce fever are the cornerstone of the management of NMS. Additional 'specific' treatments include dantrolene, bromocriptine and amantadine, but their role in the management of NMS is controversial.\n\n\nMETHODS\nThis study reports the case of NMS associated with long-term treatment with olanzapine at a stable dose. Administration of dantrolene was well-tolerated and resulted in prompt resolution of NMS symptoms.",
"affiliations": "First Propedeutic Department of Internal Medicine and.",
"authors": "Kouparanis|Antonios|A|;Bozikas|Andreas|A|;Spilioti|Martha|M|;Tziomalos|Konstantinos|K|",
"chemical_list": "D001569:Benzodiazepines; D003620:Dantrolene; D000077152:Olanzapine",
"country": "England",
"delete": false,
"doi": "10.3109/02699052.2014.1002002",
"fulltext": null,
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"issue": "29(5)",
"journal": "Brain injury",
"keywords": "Amantadine; atypical antipsychotics; bromocriptine; olanzapine",
"medline_ta": "Brain Inj",
"mesh_terms": "D000369:Aged, 80 and over; D001569:Benzodiazepines; D003620:Dantrolene; D005260:Female; D006801:Humans; D009459:Neuroleptic Malignant Syndrome; D000077152:Olanzapine",
"nlm_unique_id": "8710358",
"other_id": null,
"pages": "658-60",
"pmc": null,
"pmid": "25625410",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neuroleptic malignant syndrome in a patient on long-term olanzapine treatment at a stable dose: Successful treatment with dantrolene.",
"title_normalized": "neuroleptic malignant syndrome in a patient on long term olanzapine treatment at a stable dose successful treatment with dantrolene"
} | [
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},
{
"reactionmeddrapt": "Hyperhidrosis",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Muscle rigidity",
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},
{
"reactionmeddrapt": "Stupor",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Aphasia",
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},
{
"reactionmeddrapt": "Cardiac arrest",
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},
{
"reactionmeddrapt": "Pyrexia",
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},
{
"reactionmeddrapt": "Atrophy",
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"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KOUPARANIS A, BOZIKAS A, SPILIOTI M, TZIOMALOS K.. NEUROLEPTIC MALIGNANT SYNDROME IN A PATIENT ON LONG TERM OLANZAPINE TREATMENT AT A STABLE DOSE: SUCCESSFUL TREATMENT WITH DANTROLENE.. BRAIN-INJ. 2015;29(5):658-660",
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"qualification": "3",
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},
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
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"transmissiondate": "20150821"
},
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"medicinalproduct": "OLANZAPINE."
},
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],
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"reaction": [
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{
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}
],
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},
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20151125"
}
] |
{
"abstract": "We report a case of probable iatrogenic vitamin K deficiency in the context of antibiotic treatment for endocarditis. The patient was initially admitted with breathlessness and treated for an exacerbation of chronic obstructive pulmonary disease. However, during this period the patient was further diagnosed with endocarditis following repeated temperature spikes. Following initiation of antibiotic treatment for endocarditis the patient was noted to become increasingly anaemic. The patient was noted to have prolonged prothrombin time despite no anticoagulants. Antibiotics have been reported to alter the gut flora causing vitamin K deficiency; thereby, resulting in coagulopathy. We give a brief overview and literature review regarding potential vitamin K deficiency in this clinical context.",
"affiliations": "Lagan Valley Hospital, Lisburn, UK. mak83@mail2world.com",
"authors": "Alkhalil|Mohammad|M|;Tate|Stephen|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D012293:Rifampin",
"country": "England",
"delete": false,
"doi": null,
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"pmid": "22791499",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7661184;11994567;21687331;9216218;7895417",
"title": "Does endocarditis require routine coagulation screening?",
"title_normalized": "does endocarditis require routine coagulation screening"
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{
"abstract": "Dermatomyositis (DM) is a rare inflammatory disorder affecting the muscle and skin. DM patients can present with spontaneous muscle hemorrhage, a potentially fatal complication. The best practice for management of hemorrhagic myositis in these patients remains unclear. Here we discuss the case of a patient who presented with progressive muscle weakness and intermittent rash that was diagnosed with dermatomyositis. During admission, she developed spontaneous hemorrhagic myositis of the right pectoralis major treated with surgical evacuation. She also developed a spontaneous left anterior thigh hematoma which was treated conservatively. She recovered and showed no evidence of recurrent bleeding at either location. We performed a literature review and identified ten cases of spontaneous hemorrhage in DM patients, with a 60% mortality rate among reported cases. Given the high mortality rate associated with spontaneous hemorrhage in DM patients, it is important for physicians to be aware of the diagnosis, workup, and management strategies.",
"affiliations": "Department of Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Rm H3591, Stanford, CA, 94305, USA. jchand@stanford.edu.;Stanford University School of Medicine, Stanford, CA, 94305, USA.;Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.;Department of Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Rm H3591, Stanford, CA, 94305, USA.",
"authors": "Chandler|Julia M|JM|http://orcid.org/0000-0001-9922-612X;Kim|Yoo Jung|YJ|;Bauer|Justin L|JL|;Wapnir|Irene L|IL|",
"chemical_list": "D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D009173:Mycophenolic Acid; D011241:Prednisone; D008775:Methylprednisolone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-019-04501-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-8172",
"issue": "40(2)",
"journal": "Rheumatology international",
"keywords": "Dermatomyositis complications; Hematoma; Hemorrhage; Myositis",
"medline_ta": "Rheumatol Int",
"mesh_terms": "D058128:Compression Bandages; D000072700:Conservative Treatment; D003882:Dermatomyositis; D004322:Drainage; D004791:Enzyme Inhibitors; D005260:Female; D005938:Glucocorticoids; D006406:Hematoma; D006470:Hemorrhage; D006488:Hemostasis, Surgical; D006801:Humans; D007022:Hypotension; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D008775:Methylprednisolone; D008875:Middle Aged; D009026:Mortality; D009135:Muscular Diseases; D009173:Mycophenolic Acid; D010369:Pectoralis Muscles; D011241:Prednisone; D052097:Quadriceps Muscle",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "331-336",
"pmc": null,
"pmid": "31872270",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "20376685;15020349;29416342;20083689;9843089;19309387;25379317;18713785;14500287;25876592;19089428;26066549;22865055;30923638;30327927;18460893;30565491",
"title": "Dilemma in management of hemorrhagic myositis in dermatomyositis.",
"title_normalized": "dilemma in management of hemorrhagic myositis in dermatomyositis"
} | [
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{
"reactionmeddrapt": "Polymyositis",
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},
{
"reactionmeddrapt": "Dermatomyositis",
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},
{
"reactionmeddrapt": "Microangiopathy",
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},
{
"reactionmeddrapt": "Condition aggravated",
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}
],
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"abstract": "BACKGROUND\nPosterior reversible encephalopathy syndrome (PRES) is a subacute syndrome causing characteristic neurologic and radiologic findings. PRES is predominantly caused by malignant hypertension though it has been associated with immunosuppressive treatments such as chemotherapy.\nWe describe a case of a 58 year old female who developed fluctuant level of consciousness, agitation.\n\n\nMETHODS\nMRI findings were in keeping with posterior reversible encephalopathy syndrome following cycle 6 of palliative gemcitabine and cisplatin therapy for metastatic cholangiocarcinoma.\n\n\nMETHODS\nThe patient was managed with magnesium supplementation for hypomagnesemia and amlodipine.\n\n\nRESULTS\nThe patient's level of consciousness returned to normal though she had residual neurologic deficits impairing her ability to drive and impacting her balance.\n\n\nCONCLUSIONS\nCisplatin is a documented causative agent of PRES though gemcitabine is rarely associated with the syndrome. Combination cisplatin and gemcitabine therapy causing radiologically proven PRES has been documented in only 3 previous case reports. Gemcitabine's poor blood-brain barrier penetration makes it an unlikely culprit of central nervous system (CNS) toxicities. Our case and previous reports suggest higher doses may contribute to CNS toxicities such as PRES. Additionally, an emerging trend of hypomagnesemia associated with PRES has been documented inside and outside the context of malignancy and suggests a possible target for treatment and prevention warranting further investigation.",
"affiliations": "Department of Internal Medicine, University of Alberta, Edmonton, Alberta Cross Cancer Institute, Edmonton, Alberta, Canada.",
"authors": "Cherniawsky|Hannah|H|;Merchant|Neesha|N|;Sawyer|Micheal|M|;Ho|Maria|M|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 28225482MD-D-16-0541610.1097/MD.0000000000005850058505700Research ArticleClinical Case ReportA case report of posterior reversible encephalopathy syndrome in a patient receiving gemcitabine and cisplatin Cherniawsky Hannah MD, BMedScia∗Merchant Neesha MDbSawyer Micheal MD, BSc PhmbHo Maria MDbZhou. Wen a Department of Internal Medicine, University of Alberta, Edmonton, Albertab Cross Cancer Institute, Edmonton, Alberta, Canada.∗ Correspondence: Hannah Cherniawsky, Department of Internal Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada (e-mail: hchernia@ualberta.ca).2 2017 24 2 2017 96 8 e585026 8 2016 13 12 2016 14 12 2016 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. http://creativecommons.org/licenses/by-nd/4.0Abstract\nRationale:\nPosterior reversible encephalopathy syndrome (PRES) is a subacute syndrome causing characteristic neurologic and radiologic findings. PRES is predominantly caused by malignant hypertension though it has been associated with immunosuppressive treatments such as chemotherapy.\n\nPatient Concerns:\nWe describe a case of a 58 year old female who developed fluctuant level of consciousness, agitation.\n\nDiagnosis:\nMRI findings were in keeping with posterior reversible encephalopathy syndrome following cycle 6 of palliative gemcitabine and cisplatin therapy for metastatic cholangiocarcinoma.\n\nInterventions:\nThe patient was managed with magnesium supplementation for hypomagnesemia and amlodipine.\n\nOutcomes:\nThe patient's level of consciousness returned to normal though she had residual neurologic deficits impairing her ability to drive and impacting her balance.\n\nConclusions:\nCisplatin is a documented causative agent of PRES though gemcitabine is rarely associated with the syndrome. Combination cisplatin and gemcitabine therapy causing radiologically proven PRES has been documented in only 3 previous case reports. Gemcitabine's poor blood-brain barrier penetration makes it an unlikely culprit of central nervous system (CNS) toxicities. Our case and previous reports suggest higher doses may contribute to CNS toxicities such as PRES. Additionally, an emerging trend of hypomagnesemia associated with PRES has been documented inside and outside the context of malignancy and suggests a possible target for treatment and prevention warranting further investigation.\n\nKeywords\ncisplatingemcitabineposterior reversible encephalopathyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPosterior reversible encephalopathy syndrome (PRES) is a syndrome characterized by subacute neurologic and radiographic findings.[1–4,9–12,15] It occurs due to a number of causes, predominantly malignant hypertension, eclampsia, and medical treatments such as immunosuppressive therapy. Patients often present with headaches, seizures, visual changes, or altered mental status hours to months after the inciting insult.[9–12,15,17] Diagnosis of PRES relies on history, clinical examination, and radiologic findings of symmetric bilateral hyper-intensities on T2-weighted magnetic resonance imagings (MRIs) representing vasogenic edema.[1,4,9,15] This edema most commonly affects the posterior occipital and parietal lobes but may be seen throughout the frontal and temporal lobes, cerebellum, or brainstem.[12,15]\n\nPRES's pathogenesis remains unclear though its association with malignant hypertension, renal dysfunction, and now immunosuppressant use is well documented.[2,4,9–13,15] Management of PRES includes removal of any offending agents, blood pressure, and seizure management.[1] Current hypothesis proposes dysfunctional cerebral vascular auto-regulation leading to a cascade of arteriolar vasodilation, capillary damage, and subsequent cortical and subcortical vasogenic edema as a possible mechanism.[2,3,7,9–11,13] It has also been proposed that cytotoxic edema due to chemotherapy induced tumor destruction and subsequent dysfunctional cerebovascular auto-regulation may play an additional role.[1,2,9]\n\nCisplatin has been a documented culprit of PRES; however, gemcitabine remains a rare causative agent.[2,3,8–10,12,15,16] We will explore the relation of combination cisplatin and gemcitabine therapy and PRES through the following case.\n\n2 Case report\nMR is a 58-year-old woman with medical history of depression and smoking who was diagnosed with cholangiocarcinoma in fall of 2012. She was initially treated surgically with partial hepatectomy and total extra-hepatic bile duct removal followed by several biliary reconstructions. Pathology showed a cholangiocarcinoma T2bN0M0.\n\nAfter 18 months of remission, MR experienced increasing abdominal pain accompanied by rising carbohydrate antigen 19-9 levels prompting a Positron emission tomography/computed tomography (CT) scan which demonstrated Fluorodeoxyglucose-avid peri-portal and para-aortic lymphadenopathy. She was started on palliative cisplatin and gemcitabine chemotherapy. Cisplatin was not administered in cycle 1 due to a reduced Eastern cooperative oncology group status of 2. MR tolerated cycle 1 of gemcitabine monotherapy without complications. Cisplatin was subsequently added during cycle 2 of chemotherapy dosed at 34 mg (20 mg/m2) IV on days 1 and 8 of cycles 2 to 6. Gemcitabine was dosed at 1700 mg (1000 mg/m2) IV on days 1 and 8 of all cycles.\n\nMR had no complications in cycles 1 to 5 and tolerated chemotherapy quite well. However, 24 h after day 1 of chemotherapy cycle 6, she became increasingly somnolent which worsened over 3 days and prompted her presentation to emergency medical services. At presentation in the Emergency Room, she was agitated and confused with a fluctuant Glasgow Coma Scale (GCS) of 9 to 12. She had no new medications, infectious prodrome, or trauma prior to admission. Vital signs were stable and within normal limits with no tachycardia, fever, or hypertension. Her neurologic examination was without focal deficits and she had no neck stiffness. Cardiac, respiratory, and abdominal examinations were also unremarkable. MR's laboratories indicated hypokalemia (2.6 mmol/L) and hypomagnesemia (0.49 mmol/L). All other laboratories, chest X-ray and head CT were unremarkable (Fig. 1).\n\nFigure 1 Computed tomography imaging of patient MR showing no abnormalities.\n\nMR was started on empiric antibiotics and antivirals (ampicillin, ceftriaxone, vancomycin, and acyclovir) after a lumbar puncture was performed. The lumbar puncture results eventually returned negative for viral or bacterial pathogens. MRI of the head revealed bilateral cortical and subcortical edema in the posterior regions of the occipital, parietal, and frontal lobes confirming the PRES diagnosis (Fig. 2).\n\nFigure 2 (A) T1-weighted MRI of patient MR reveals minimal abnormality. (B) T2-weighted MRI reveals bilateral symmetric hyper-intensities in the posterior occipital lobe consistent with vasogenic edema of PRES. (C) FLAIR sequence again reveals bilateral symmetric hyper-intensities of the posterior occipital lobe consistent with PRES. MRI = magnetic resonance imaging, PRES = Posterior reversible encephalopathy syndrome.\n\nDuring her weeklong admission, MR was given amlodipine for blood pressure management and further chemotherapy was held. Her mental status cleared and she was discharged within 1 week of presentation on amlodipine 10 mg PO daily. She continued to experience residual visual changes and loss of balance compromising her ability to drive. She was able to ambulate and carry out all her activities of daily living. MR did not pursue any further chemotherapy and passed away peacefully surrounded by family in fall of 2015. Her family consented to publication of her presentation on her behalf.\n\n3 Discussion\nPRES is a rare but treatable complication of chemotherapy first described by Hinchey et al in 1996. There have been 3 published case reports of radiologically proven PRES in patients receiving combination gemcitabine and cisplatin chemotherapy alone despite its widespread use (Table 1).[7,8,11,16] Case reports of PRES induced by gemcitabine with other platinum analogs have also been described as have reports of PRES induced by gemcitabine alone (Table 1).[21–23] Connolly et al[16] described a patient undergoing treatment for nonsmall cell lung cancer with cisplatin 80 mg/m2 and gemcitabine 1000 mg/m2 (days unspecified) presenting with seizures, hypertension (184/92 mm Hg), and MRI indicating subcortical occipito-parietal T2 hyperintensities consistent with PRES. The patient had normal magnesium levels though IV MgSO4 was used as a blood pressure control agent with improvement in the patient's condition. Maeda et al[7] described a patient with urethral carcinoma presenting with GCS of 4 and MRI findings consistent with PRES who was being treated with cisplatin 56 mg/m2 day 1 and gemcitabine 1000 mg/m2 days 1, 8, and 15. In comparison to the previous case study, Maeda et al's patient was normotensive and magnesium levels were unreported.[7]\n\nTable 1 Previous case reports of PRES in patients treated with gemcitabine, and cisplatin combination chemotherapy or gemcitabine monotherapy.\n\nThough peripheral neurotoxicity and somnolence are known complications of gemcitabine, it is historical described as having poor blood–brain barrier penetration making it an unlikely culprit of central nervous system (CNS) toxicity.[2,3,5,6,9] Two case reports have described PRES related to gemcitabine monotherapy (Table 1). Han and Findlay[23] first described a case on PRES in a patient on gemcitabine monotherapy, 1000 mg/m2 days 1, 8, and 15 of a 21-day cycle, while Stukov et al[6] documented effects of gemcitabine in intracranial tumors which may be dose-dependent.[9] As such, higher doses of gemcitabine may contribute to its ability to induce PRES though this was not the case in our patient and requires further investigation. Conversely, PRES is a rare but well-documented complication of cisplatin chemotherapy.[3,10] Cisplatin boasts poor blood–brain barrier penetration though it is known to rarely cause severe CNS toxicity by way of seizures, hemiparesis, cortical blindness, or coma.[20] The greater association of cisplatin with CNS toxicity as compared to gemcitabine may account for the increased frequency of PRES associated with cisplatin therapy.\n\nMRI is the modality of choice for diagnosis of PRES and reveals bilateral subcortical white matter changes in the posterior aspect of the brain suggestive of edema though expansion to adjacent subcortical and brainstem structures may be present. Singer et al[14] described large discrepancies between CT and MRI in patients with PRES noting that of their 31 patients diagnosed with chemotherapy induced PRES, 37% had normal CT imaging. Though CT imaging is critical to rule out other life-threatening diagnoses, it cannot reliably assess for the presence or absence of PRES. As such, we recommend urgent MRI for further diagnostic evaluation of patients presenting with symptoms of PRES in whom CT imaging returns normal or nondiagnostic.\n\nHypertension is present in 53% of patients diagnosed with PRES and remains one of the main targets of treatment.[1] Chemotherapy-induced PRES is no exception to this association.[9–11,16,17] Several theories attempt to explain the pathogenesis of PRES as it relates to both hypertension and chemotherapy. The vasogenic theory suggests that elevated mean arterial pressure overcomes cerebral auto-regulation leading to elevated hydrostatic pressures within the cerebral vasculature, dysfunctional tight junctions, and subsequent edema.[1] The greater sensitivity of posterior vessels to hypertensive damage explains the posterior location of PRES.[1] However, this theory does not account for normotensive patients presenting with PRES such as our patient and that described by Maeda et al.[7] The cytotoxic theory suggests that chemotherapy causes release of chemokines into the bloodstream leading to dysfunctional endothelium and cerebral edema. However, molecules responsible for this effect and predisposition of posterior circulation to such dysfunction are not yet known.[1,22]\n\nThough the population of study is small, an emerging trend of hypomagnesemia at presentation has also been noted in previous case reports of PRES inside and outside the context of malignancy.[2,10,11,18,19,22] Hypomagnesemia is known to be associated with primary hypertension though these features are not mutually present in all patients with PRES.[18,19,22] Boulos et al[18] described a case of a normotensive patient presenting with PRES attributable to severe hypomagnesemia (0.15 mmol/L). They illustrate hypertension and hypomagnesemia as independent agents in the pathogenesis of PRES as was the case with our patient.[19] Much like the case described by Connolly et al,[16] Boulos et al[18] utilized supplemental magnesium as treatment with excellent results. The prevalence of hypomagnesemia in patients with PRES is an area that warrants further investigation and may implicate magnesium levels in the prevention, early detection, and treatment of chemotherapy-induced PRES by treatment of hypertension and stabilization of the vascular endothelium.[16,18]\n\n4 Conclusion\nGiven its life-altering and life-threatening outcomes, PRES should be considered in all patients undergoing chemotherapy presenting with characteristic neurologic findings. The classical history and physical examination findings in the setting of chemotherapy should lead the clinician toward a diagnosis of PRES. Differential diagnosis of stroke, brain metastasis, meningeal bleeds, and metabolic derangements of infectious etiologies can generally be assessed with use of routine laboratories and CT scan. With a negative workup we recommend consideration of prompt MRI to assess for this serious and treatable diagnosis.\n\nAbbreviations: CA 19-9 = carbohydrate antigen 19-9, CNS = central nervous system, ER = Emergency Room, FDG = Fluorodeoxyglucose, GCS = Glasgow Coma Scale, MRI = magnetic resonance imaging, PE = Pulmonary embolism, PRES = Posterior reversible encephalopathy syndrome.\n\nMS and MH are co-senior authors.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Granata G Grecco A Iannella G \nPosterior reversible encephalopathy syndrome—insight into pathogenesis, clinical variants and treatment approaches . Autoimmun Rev \n2015 ;14 :830 –6 .25999210 \n[2] Cioffi P Laudadio L Nuzzo A \nGemcitabine-induced posterior reversible encephalopathy syndrome: a case report . J Oncol Pharm Pract \n2012 ;18 :299 –302 .22065198 \n[3] Rajasekhar A George TJ \nGemcitabine-induced reversible posterior leukoencephalopathy syndrome: a case report and review of literature . Oncologist \n2007 ;12 :1332 –5 .18055853 \n[4] Hinchey J Chaves C Appignani B \nA reversible posterior leukoencephalopathy syndrome . N Engl J Med \n1996 ;334 :494 –500 .8559202 \n[5] Davis JR Fernandes C Zalcberg JR \nGemcitabine and blood brain barrier . Aust N J Med \n1999 ;29 :831 –2 .\n[6] Stukov AN Filatove LV Latipova DK \nTherapeutic activity of gemcitabine in intracranial tumors . Vopr Onkol \n2015 ;61 :274 –9 .26087611 \n[7] Maeda T Kikuchi E Matsumoto K \nGemcitabine and cisplatin chemotherapy induced reversible posterior leukoencephalopathy syndrome in a bladder cancer patient . Int J Clin Oncol \n2010 ;15 :508 –11 .20352464 \n[8] Larsen FO Hansen SW \nSevere neurotoxicity caused by gemcitabine treatment . Acta Oncol \n2004 ;43 :590 –1 .15370618 \n[9] Marrone LCP Marrone BF de la Puerta Raya J \nGemcitabine monotherapy associated with posterior reversible encephalopathy syndrome . Case Rep Oncol \n2011 ;4 :82 –7 .21475595 \n[10] Ito Y Arahata Y Goto Y \nCisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome . AJNR Am J Neuroradiol \n1998 ;19 :415 –7 .9541291 \n[11] Kwon EJ Kim SW Kim KK \nA case of gemcitabine and cisplatin associated posterior reversible encephalopathy syndrome . Cancer Res Treat \n2009 ;41 :53 –5 .19688073 \n[12] Truong QV Abraham J Nagaiah G \nGemcitabine associated with posterior reversible encephalopathy syndrome (PRES): a case report and review of the literature . Clin Adv Hematol Oncol \n2012 ;10 :611 –3 .23073128 \n[13] Mitsuya K Nakasu Y Hayashi N \nPosterior reversible encephalopathy syndrome associated with cancer therapy . No Shinkei Geka \n2016 ;44 :211 –9 .26965062 \n[14] Singer S Grommes C Reiner AS \nPosterior reversible encephalopathy syndrome in patients with cancer . Oncologist \n2015 ;20 :806 –11 .26032137 \n[15] Russell MT Nassif AS Cacayorin ED \nGemcitabine-associated posterior reversible encephalopathy syndrome: MR imaging and MR spectroscopy findings . Magn Reson Imaging \n2001 ;19 :129 –32 .11295355 \n[16] Connolly RM Doherty CR Beddy R \nChemotherapy induced reversible posterior leukoencephalopathy syndrome . Lung Cancer \n2007 ;58 :459 –63 .\n[17] Dersh R Stich O Goller K \nAtypical posterior reversible encephalopathy syndrome associated with chemotherapy with bevacizumab, gemcitabine and cisplatin . J Neurol \n2003 ;260 :1406 –7 .\n[18] Boulos M Shoamanesh A Aviv R \nSevere hypomagnesemia associated with reversible subacute ataxia and cerebellar hyperintensities on MRI . Neurologist \n2012 ;18 :223 –5 .22735253 \n[19] te Riele M Verrips A \nSevere hypomagnesaemia causing reversible cerebellopathy . Cerebellum \n2014 ;13 :659 –62 .24838431 \n[20] Zahir M Masood N Shabbir-Moosajee M \nCisplatin-induced posterior reversible encephalopathy syndrome and successful re-treatment in a patient with non-seminomatous germ cell tumor: a case report . J Med Case Rep \n2012 ;6 :409 .23194133 \n[21] Chang Y Mbeo G Littman S \nReversible posterior leukoencephalopathy syndrome associated with concurrent bevacizumab, gemcitabine, and oxaliplatin for cholangiocarcinoma . J Gastrointest Cancer \n2012 ;43 :505 –7 .21556724 \n[22] Bhatt A Farooq MU Majid A \nChemotherapy-related posterior reversible leukoencephalopathy syndrome . Nat Clin Pract Neurol \n2009 ;5 :163 –9 .19262592 \n[23] Han C Findlay M \nChemotherapy-induced posterior reversible leukoencephalopathy syndrome . Intern Med J \n2010 ;40 :153 –9 .20446957\n\n",
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{
"abstract": "BACKGROUND\nStereotactic ablative body radiation (SABR) is a novel and sophisticated radiation modality that involves the irradiation of extracranial tumors through precise and very high doses in patients with oligometastatic lung disease and primary lung tumors.\n\n\nMETHODS\nA 52-year-old female with subclinical idiopathic interstitial lung disease (ILD) and oligometastatic lung disease from squamous urethral cancer who was treated with SABR for a metastatic lesion located in the right lower pulmonary lobe. The patient received a hypo-fractionated course of SABR. A 3D-conformal multifield technique was used with six coplanar and one non-coplanar statics beams. A 48 Gy total dose in three fractions over six days was prescribed to the 95% of the PTV. The presence of idiopathic ILD and other identifiable underlying lung conditions were not taken into account as a constraint to prescribe a different than standard total dose or fractionation schedule. Six months after the SABR treatment, a CT-scan showed the presence of a pneumomediastinum with air outside the bronchial tree and within the subcutaneous tissue without co-existing pneumothorax. To our knowledge, this is the first case of pneumomediastinum appearing 6 months after SABR treatment for a lung metastasis located in the perihiliar/central tumors region as defined by the RTOG protocols as the proximal bronchial tree.\n\n\nCONCLUSIONS\nRadiation oncologist should be aware of the potential risk of severe lung toxicity caused by SABR in patients with ILD, especially when chemotherapy-induced pulmonary toxicity is administered in a short time interval.",
"affiliations": null,
"authors": "Rodríguez-Ruiz|María Esperanza|ME|;Arévalo|Estefanía|E|;Gil-Bazo|Ignacio|I|;Olarte García|Alicia|A|;Valtueña|German|G|;Moreno-Jiménez|Marta|M|;Arbea-Moreno|Leire|L|;Aristu|Javier|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13014-015-0330-y",
"fulltext": "\n==== Front\nRadiat OncolRadiat OncolRadiation Oncology (London, England)1748-717XBioMed Central London 2561257533010.1186/s13014-015-0330-yCase ReportPneumomediastinum as a complication of SABR for lung metastases Rodríguez-Ruiz María Esperanza mrruiz@unav.es Arévalo Estefanía e.arevalo-vazquez@hotmail.com Gil-Bazo Ignacio igbazo@unav.es García Alicia Olarte aolarte@unav.es Valtueña German gvaltuena@unav.es Moreno-Jiménez Marta mmorenoji@unav.es Arbea-Moreno Leire larbea@unav.es Aristu Javier jjaristu@unav.es Department of Radiation Oncology, Clínica Universidad de Navarre, Avda. Pío XII s/n, 31008 Pamplona, Navarre Spain Department of Medical Oncology, Clínica Universidad de Navarre, Avda. Pío XII s/n, 31008 Pamplona, Navarre Spain 23 1 2015 23 1 2015 2015 10 251 8 2014 7 1 2015 © Rodriguez-Ruiz et al. ; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nStereotactic ablative body radiation (SABR) is a novel and sophisticated radiation modality that involves the irradiation of extracranial tumors through precise and very high doses in patients with oligometastatic lung disease and primary lung tumors.\n\nCase presentation\nA 52-year-old female with subclinical idiopathic interstitial lung disease (ILD) and oligometastatic lung disease from squamous urethral cancer who was treated with SABR for a metastatic lesion located in the right lower pulmonary lobe. The patient received a hypo-fractionated course of SABR. A 3D-conformal multifield technique was used with six coplanar and one non-coplanar statics beams. A 48 Gy total dose in three fractions over six days was prescribed to the 95% of the PTV. The presence of idiopathic ILD and other identifiable underlying lung conditions were not taken into account as a constraint to prescribe a different than standard total dose or fractionation schedule. Six months after the SABR treatment, a CT-scan showed the presence of a pneumomediastinum with air outside the bronchial tree and within the subcutaneous tissue without co-existing pneumothorax. To our knowledge, this is the first case of pneumomediastinum appearing 6 months after SABR treatment for a lung metastasis located in the perihiliar/central tumors region as defined by the RTOG protocols as the proximal bronchial tree.\n\nConclusion\nRadiation oncologist should be aware of the potential risk of severe lung toxicity caused by SABR in patients with ILD, especially when chemotherapy-induced pulmonary toxicity is administered in a short time interval.\n\nKeywords\nOligometastatic lung diseasePneumomediastinumSABR (stereotactic ablative body radiation)SBRT (stereotactic beam radiation therapy)issue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nStereotactic ablative body radiation (SABR) is a novel and sophisticated radiation modality that involves the irradiation of extracranial tumors using precise and very high doses of radiation delivered in one to five fractions. This modality has been used in the treatment of non-metastatic primary cancer and also in the case of oligometastases [1]. Phase I/II studies data from patients with oligometastatic lung disease who were treated with SABR or SBRT (stereotactic body radiation therapy), seem to be very promising with high local control rates and long-term survivors in properly selected patients [2,3].\n\nSABR for lung metastases can produce several lung toxicities, such as airways collapse, atelectasis, symptomatic pneumonitis, fibrosis and pathological vertebral fracture [4]. The incidence of symptomatic radiation pneumonitis or grade 3–4 pneumonitis is low, in the range of 0-5% [5]. The risk of pneumonitis is associated with the type of chemotherapy regimen previously administrated, dosimetric parameters, and patient’s age. Non-pulmonary adverse effects, such as esophagitis, esophageal stenosis, massive hemoptysis, pleural effusion and pericardial effusion have been described in patients treated with SABR. The development of these adverse events depend on the location of the tumor and the dose regimen used. A phase II study conducted at Indiana University observed excessive toxicities in 70 patients with central and perihiliar lung tumors treated with high doses of radiation delivered during SBRT (60–66 Gy in three fractions) [3]. In their cohort, twenty percent of patients experienced severe toxicity, including decline in pulmonary function tests, pleural effusion, and pneumonia. Authors informed of 6 treatment-related deaths, the majority of which were due to pneumonia. Moreover, patients with central tumors showed an 11-fold increased risk of presenting a severe toxicity compared to patients with peripheral lesions.\n\nTo our knowledge, we report the first case of pneumomediastinum appearing 6 months after treatment with SABR for a solitary lung metastasis located in the perihiliar/central tumors region defined by the RTOG protocols as the proximal bronchial tree.\n\nCase presentation\nA 52-year-old woman with idiopathic interstitial lung disease was referred to our department in March 2010 for a second opinion regarding a metastatic urethral carcinoma. Her history began one year ago when she noticed a node in the urethral meatus by self-palpation associated with perineal pain. Magnetic Resonance (MR) images demonstrated a 2 x 1.5 cm urethral nodule with urethral thickening including the trigone and a single iliac lymph node of 1.2 cm of diameter. A cystoscopy with biopsy revealed a well differentiated infiltrating epidermoid urethral cancer with positive surgical margins. Staging CT-scans were performed showing no distant metastatic disease. On July 2010, the patient underwent anterior pelvic exenteration, urostomy with ileal bladder reconstruction and vaginal reconstruction with a transverse rectus abdominis myocutaneous (TRAM) flap.\n\nThe disease was followed until November 2010, when the physical examination demonstrated the presence of a nodule of 3 cm in the right subvaginal space and bilateral metastatic inguinal lymph nodes. The positron emission tomography/computed tomography (PET-CT) revealed tumor recurrence near of the neovagina, the presence of bilateral inguinal lymph nodes and a single lung metastases. A fine-needle aspiration biopsy was obtained from inguinal lymph nodes and the pathologic study confirmed lymph node metastasis of squamous-cell carcinoma of the urethra. The patient was initially treated with six cycles of chemotherapy using paclitaxel 175 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1 and capecitabine 750 mg/m2 on days 1–15 every 21 days. Complete clinical response was observed after six cycles of chemotherapy.\n\nBetween March and May 2011, a consolidation hypofractionated course of IMRT (intensity-modulated radiation therapy) was delivered using the step-and-shoot technique. The IMRT dose administrated was 62 Gy prescribed to the 95% of the clinical target volume (CTV = urethra and inguino-pelvic lymph node (LN) in 25 fractions, 2.48 Gy/fraction. Three cycles of chemotherapy with paclitaxel 50 mg/m2 and Cisplatin 30 mg/m2 on a weekly regimen were concomitantly given throughout the whole course of IMRT. IMRT was followed by a short course of high-dose-rate (HDR) intravaginal brachytherapy. A dose of 4.75 Gy was prescribed at minimum target dose (MTD), over three consecutive days with a total dose of 19 Gy.\n\nThe patient was followed until June 2011, when the image studies confirmed a single metastatic lesion on the right lower lung lobe as the unique location of metastatic disease. With the diagnosis of disease progression with a single lung metastatic lesion measuring 30 X 26 mm, a hypofractionated course of SABR was delivered to the metastatic lung tumor. She was placed in supine position and was immobilized using an alpha cradle device to improve patient position reproducibility during daily treatments. Respiratory tumor movement was observed under fluoroscopy. A planning CT scan was performed with a combination of three sets of CT scans obtained during free breathing, deep inspiration and deep expiration to generate an internal target volume (ITV) that accounts for respiratory motion. The gross tumor volume (GTV) was the lung nodule, and the PTV included the ITV with a symmetric 0.5 cm margin (Figure 1). “Organs at risk (OARS) were delimited and constraints were established based on recommendations used in recent RTOG SABR trials (RTOG 0618, 0813 and 0915) and NCCN guidelines (Figure 2). This guidelines concluded that to minimize toxicity when treating lesions in close proximity to the bronchial tree, the Dmax of the trachea and proximal bronqui should be < 30 Gy. In this patient, the Dmax was 12.51 Gy (10.5 cc) and 30,9 Gy (1,69 cc), respectively”.Figure 1 \nA combination set of three CT scans obtained during free breathing (pink), deep inspiration (yellow) and deep expiration (blue) were used to generate an internal target volume (ITV) that accounts for respiratory motion (red). The blue dots outline the lung structure and the red dots indicate the radiation target. Digital Reconstructed Radiography (DRR) show the trachea (blue) and bronchial tree (yellow) structure and the targets volumenes (the lung nodule (green), and the PTV (dark blue) included the ITV (red) with a symmetric 0.5 cm margin.\n\nFigure 2 \nDose volume histograms showing dosimetric parameters analyzed including targets and organs at risk.\n\n\n\n\nA 3D-conformal multi-field technique was selected with six coplanar and one non-coplanar statics beams. SABR was delivered by a linear accelerator (Oncor, Siemens, Palo Alto, California, USA) with 6-MV photons. A total dose of 48 Gy in three fractions over a six days period was prescribed to the 95% of the PTV (Figure 3). Patient positioning and isocenter verification were checked using cone beam CT. The patient had an excellent inmediate tolerance to the SABR treatment.Figure 3 \nDose distribution in the treatment course: Radiotherapy treatment planning with high conformity. Pink, green and dark blue and light blue areas represent 47 Gy, 45 Gy, 40 Gy and 30 Gy, respectively. The blue dots outline the lung structure and the sky-blue dots indicate the radiation target.\n\n\n\nResults\nThe patient continued a regular follow-up program including clinical history, physical examination, complete blood count, liver and renal function tests and thoracic, abdominal, and pelvic CT scans every 3 months. Six months after the SABR procedure she referred cervical pain and progressive respiratory deterioration with cough, expectoration and dyspnea. Chest X-ray showed diffuse reticular interstitial lesions in both lungs. The bacteriological and fungal culture of blood and sputum were negative. The chest CT scan continued to show complete response of the metastatic lung disease with signs of radiation pneumonitis and a reticular pattern with shaped diffuse irregular interlobular thickness and little honeycombing pattern of the right lung in accordance with her known chronic lung fibrosis. Surprisingly, the CT scan also illustrated a new image of a pneumomediastinum with air outside the bronchial tree with the presence of diffuse subcutaneous air without co-existing pneumothorax. The patient was diagnosed of radiation pneumonitis and pneumomediastinum in an idiopathic pulmonary fibrosis setting (Figure 4). A bronchoscopy was done to rule out the presence of an airway leak showing no pathological findings at the procedure. clarithromycin 500 mg/12 h, steroid therapy with dexametasone 4 mg/8 h and, E-vitamin were administered for inflammatory lung disease. Two weeks after treatment initiation, the patient remained clinically stabilized and radiological response of pneumomediastinum but a MRI of the spinal cord was performed due to the appearance of moderate neck pain. MRI showed a massive vertebral metastatic (C3) lesion that was treated with palliative radiation therapy (35 Gy in 14 fractions). The patient continued a regular follow-up program and remained asymptomatic but she was diagnosed of multiple bilateral lung metastases in a CT scan and multiple spinal cord metastases in MR images. A second line of chemotherapy was initiated with carboplatin (AUC 3) and gemcitabine 1300 mg/m2 every two weeks. Despite this treatment the patient had a progressive clinical and radiological worsening and she died on November 6, 2011. The family refused autopsy.Figure 4 \nAP and lateral view of Chest X-ray show the presence of free air in the mediastinal cavity. Transverse Chest computed tomography (CT) after SBRT shows ground-glass opacities, bleeds confined to the right upper lung, and diffuse ground-glass attenuation, bleeds in the marginal areas, airspace consolidation, free air in the mediastinal cavity and fibrosis in the bilateral upper and lower lung fields. Transverse chest CT view of radiation dose distribution in the treatment course. Pink, green and dark blue, light blue and orange areas represent 47 Gy, 45 Gy, 40 Gy, 30 Gy and 20 Gy, respectively.\n\n\n\nDiscussion\nThe development of novel and sophisticated irradiation techniques such as SABR represents a progress in planning and delivering external beam radiotherapy. SABR delivers large doses of radiation in few fractions, and it has been demonstrated to be a safe, effective and promise ablative technique for the treatment of selected patients with lung metastases. Patients diagnosed of oligometastatic lung disease who are considered inoperable or patients that are not candidates for surgical treatment, SABR emerges as a practical option. The reported 2-year overall survival ranges from 67% to 100% and the 2-year local control rate has been established between 92% and 95% [6].\n\nWe present the first case of SABR-induced pneumomediastinum in a patient with a solitry lung metastasis and subclinical interstitial lung disease (ILD). A total dose of 48 Gy in three fractions over six days was administered to the 95% of the PTV (Figures 3-4). The PTV, which includes setup uncertainty and residual target motion was designed from the GTV by enlarging the volume 0.5 cm in the axial plane and 1.0 cm in the cranial-caudal plane in all directions. In this particular case, we discard abdominal compression to reduce respiratory motion because comparing free breathing and abdominal compression there was no differences in tumor motion.\n\nRadiation pneumonitis (RP) is one of the most significant complications for patients treated with SBRT [7] and fatal radiation toxicity has been reported in patients with centrally-located stage I lung cancer [3]. Timmerman et al. described six SBRT-related deaths in patients with inoperable stage I lung cancer treated with 60–66 Gy in three fractions during 1–2 weeks. The causes of death were pneumonia, pericardial effusion and massive hemoptysis.\n\nSubclinical ILD was not found to be a significant factor for grade 2–5 RP or clinical outcomes in a recent Japanese study where 100 patients with 124 lung tumors were treated with SABR. Patients with subclinical (untreated and oxygen-free) ILD were treated with SABR (48 Gy in four fractions), while those with clinical ILD (post- or under treatment) were not. However, a significant finding was the presence of uncommon extensive RP in patients with subclinical ILD [8]. Our patient was previously diagnosed of subclinical ILD and she presented pneumomediastinum confirmed by the presence of free air in the mediastinal structures 6 months after SBRT. Another risk factor in this patient associated with severe toxicity is the administration of very high doses of radiation in three fractions (16 Gy x 3) in a lesion located in the perihiliar region. In the other hand, we think that the presence of idiopathic ILD and other lung disease should be taken into account as a more restrictive constraint trying to achieve a BED > =100 Gy. These selected patients can be treated with 4 to 10 fractions risk-adapted SABR regimens.\n\nTo our knowledge, pneumomediastinum has not been associated as a complication related to SABR of a primary lung cancer or lung metastasis. Pneumomediastinum was described in the early 19th century by the pathologist R. T. Läennec, who first observed this condition in trauma patients [9]. Primary or spontaneous pneumomediastinum (SPM) is caused by increased pressure gradient between the alveoli and pulmonary interstitium. SPM represents approximately 1% of all cases of pneumomediastinum (PM) and is generally a benign process that mainly affects young people, especially male smokers [10]. Underlying lung conditions as asthma, ILD (loss of integrity of the alveolar-capillary membrane), pneumonia, bullous lung, and radiation therapy for lung cancer have all been associated with SPM [10]. ILD has been identified as the most frequent predisposing factor to PM [11]. Franquet et al. [12] found SPM in 4 patients of 78 patients (5.1%) with idiopathic pulmonary fibrosis. They assessed the presence and distribution of pulmonary parenchymal abnormalities on CT images at the time of detection of pneumomediastinum, and the author observed parenchymal abnormalities such as ground-glass attenuation or honeycombing pattern with a subpleural predominant distribution.\n\nIn a study of 34 patients with interstitial pulmonary fibrosis, Fujiwara et al. [13] identified pneumomediastinum on chest CT scans in 5 patients (14.7%). However, they did not assess parenchymal abnormalities at the onset of pneumomediastinum, and assumed that honeycombing pattern and violent cough were predisposing factors for pneumomediastinum.\n\nOur patient had evidence of idiopathic ILD observed several years ago in CT images showing an irregular septal and reticular pattern located in the axial and subpleural interstitium predominantly in the peripheral and basal regions. Reviewing the treatment plan, the treated metastatic lesion was located into the area with higher density of interstitial pattern, the volume receiving at least 20 Gy (V20) was 18% and the mean lung dose was 7.81 Gy (Figure 3-4). These dosimetric parameters are considered in the literature as low risk of pneumonitis after SBRT. To our knowledge, the spontaneous pneumomediastinum and pneumotorax in lung cancer following chemotherapy and radiotherapy may occur due to a variety of mechanisms such as: 1) the rapid tumor lysis and defective tissue repair leading to rupture of a periphereal necrotic pulmonary nodule into the pleural space and/or the bronchus resulting in a bronchopleural fistula and pneumotorax; or 2) the rapid formation of a tumor cavity after radiation therapy with subsequent enlargement and penetration into pleural space. No radiation dose–response effect has been described in the literature, although pneumothorax and pneumomediatinum were not observed in patients who received less than 3000 cGy [14,15]. Chemotherapy also does not appear to correlate with the occurrence of SPT. However, SPT in patients with ILD receiving potentially pneumotoxic chemotherapy, such as chemotherapy-induced interstitial fibrosis and pneumonia, usually SPT is severe, bilateral, and/or recurrent [16].\n\nIn addition to ILD, our patient had other lung conditions associated with PM as to have a metastatic cancer in the lung and to receive pneumotoxic chemotherapy.\n\nPulmonary toxicities due to gemcitabine have been reported. Dyspnea occurs in approximately 25% of patients treated with gemcitabine, whereas serious pulmonary toxicities are much less common, approximately 0.3% of patients present severe pulmonary adverse effects [17]. Gemcitabine can induce radiation recall reactions [18] and the elapsed time required for recall reaction after gemcitabine administration range from 3 days to 8 months [19]. Our patient developed pneumomediastinum 2 weeks after gemcitabine administration and 6 months after SBRT treatment and it is difficult to asses the relative input of gemcitabine in the development of pneumomediastinum but a probable synergistic effect between gemcitabine and SBRT could have been responsible for this severe pulmonary toxicity.\n\nPerhaps, the presence in this patient of multiple predisposing factors with the addition of a precipitating factor such as the delivering of an ablative radiation dose have caused the loss of integrity of the alveolar-capillary membrane and consequently the development of pneumomediastinum.\n\nConclusions\nWe describe a 52-year-old female with oligometastatic lung disease from squamous-cell urethral carcinoma who was treated with SABR for a solitary metastatic lesion located in the right lower pulmonary lobe. The presence of idiopathic ILD and other identifiable underlying lung conditions were not taken into account as a constraint to prescribe a different total dose or fractionation schedule.\n\nRadiation oncologist should be aware of the potential risk of severe lung toxicity caused by SBRT in patients with ILD, especially when pulmonary toxicity-inducible chemotherapy is administered in a short time interval.\n\nConsent\nWritten informed consent was obtained from the patient for the publication of this case report and any accompanying images.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAll authors contributed to drafting the manuscript and all authors reviewed and approved the final manuscript.\n==== Refs\nReferences\n1. Chang BK Timmerman RD Stereotactic body radiation therapy: a comprehensive review Am J Clin Oncol 2007 30 637 644 10.1097/COC.0b013e3180ca7cb1 18091059 \n2. McGarry RC Papiez L Williams M Whitford T Timmerman RD Stereotactic body radiation therapy of early-stage non-small-cell lung carcinoma: phase I study Int J Radiat Oncol Biol Phys 2005 63 1010 1015 10.1016/j.ijrobp.2005.03.073 16115740 \n3. Timmerman R McGarry R Yiannoutsos C Papiez L Tudor K DeLuca J Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer J Clin Oncol 2006 24 4833 4839 10.1200/JCO.2006.07.5937 17050868 \n4. Rodríguez-Ruiz ME San Miguel I Gil-Bazo I Perez-Gracia JL Arbea L Moreno-Jimenez M Pathological vertebral fracture after stereotactic body radiation therapy for lung metastases. Case report and literature review Radiat Oncol 2012 7 50 10.1186/1748-717X-7-50 22455311 \n5. Yamashita H Nakagawa K Nakamura N Koyanagi H Tago M Igaki H Exceptionally high incidence of symptomatic grade 2–5 radiation pneumonitis after stereotactic radiation therapy for lung tumors Radiat Oncol 2007 2 21 32 10.1186/1748-717X-2-21 17553175 \n6. Rusthoven KE Kavanagh BD Burri SH Chen C Cardenes H Chidel MA Multi-institutional phase I/II trial of stereotactic body radiation therapy for ung metastases J Clin Oncol 2009 27 1579 84 10.1200/JCO.2008.19.6386 19255320 \n7. Rodrigues G Lock M D’Souza D Yu E Van Dyk J Prediction of radiation pneumonitis by dose-volume histogram parameters in lung cancer: a systematic review Radiother Oncol 2004 71 127 38 10.1016/j.radonc.2004.02.015 15110445 \n8. Yamaguchi S Ohguri T Ide S Aoki T Imada H Yahara K Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: the potential risk of extensive radiation pneumonitis Lung Cancer 2013 82 260 5 10.1016/j.lungcan.2013.08.024 24054547 \n9. Roguin A Rene theophile hyacinthe laënnec (1781–1826): The man behind the stethoscope Clin Med Res 2006 4 230 5 10.3121/cmr.4.3.230 17048358 \n10. Newcomb AE Clarke CP Spontaneous pneumomediastinum: a benign curiosity or a significant problem? Chest 2005 128 3298 302 10.1378/chest.128.5.3298 16304275 \n11. Iyer VN Mandrekar JN Danielson RD Zubkov AY Elmer JL Wijdicks EF Validity of the FOUR Score Coma Scale in the Medical Intensive Care Unit Mayo Clin Proc 2009 84 694 701 10.4065/84.8.694 19648386 \n12. Galvão FH Pestana JO Capelozzi VL Fatal gemcitabine-induced pulmonary toxicity in metastatic gallbladder adenocarcinoma Cancer Chemother Pharmacol 2010 65 607 10 10.1007/s00280-009-1167-6 19904536 \n13. Fujiwara T Pneumomediastinum in pulmonary fibrosis. Detection by computed tomography Chest 1993 104 44 6 10.1378/chest.104.1.44 8325115 \n14. Pezner RD Horak DA Sayegh HO Lipsett JA Spontaneous pneumothorax in patients irradiated for Hodgkin’s disease and other malignant lymphoma Int J Radiat Oncol Biol Phys 1990 18 193 8 10.1016/0360-3016(90)90284-Q 2298622 \n15. Penniment MG O’Brien PC Penumothorax following thoracic radiation therapy for Hodgkin’s disease Thorax 1994 49 936 7 10.1136/thx.49.9.936 7940440 \n16. Minegishi Y Takenaka K Mizutani H Sudoh J Noro R Okano T Exacerbation of idiopathic interstitial pneumonias associated with lung cancer therapy Intern Med 2009 48 9 665 72 10.2169/internalmedicine.48.1650 19420811 \n17. Chi DC Brogan F Turenne I Zelonis S Schwartz L Saif MW Gemcitabine-induced pulmonary toxicity Anticancer Res 2012 32 4147 9 22993376 \n18. Pa F Bansal R Schwartz L Gemcitabine-related radiation recall preferentially involves internal tissue and organs Cancer 2004 100 1793 9 10.1002/cncr.20229 15112258 \n19. Jeter MD Jane PA Brooks S Burstein HJ Wen P Fuchs CS Gemcitabine-induced radiation recall Int J Radiat Oncol Biol Phys 2002 53 394 400 10.1016/S0360-3016(02)02773-6 12023144\n\n",
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"abstract": "BACKGROUND\nPeptide receptor radionuclide therapy with 177Lu-Dotatate represents a major breakthrough in the treatment of metastatic well differentiated neuroendocrine tumors. This treatment is generally well tolerated. Reported severe long-term hematological side effects are rare and include hematopoietic neoplasms and bone marrow failure.\nWe describe the case of a patient presenting spontaneous bleeding and bruising occurring 6 weeks after the first administration of 177Lu-Dotatate. Blood tests showed anemia, thrombocytopenia, prolonged clotting times, profound fibrinolysis and low levels of coagulation factors II and V. There were no signs of tumor lysis syndrome.\nWe made the diagnosis of acute disseminated intravascular coagulation.\n\n\nMETHODS\nTreatment consisted of multiple transfusions of fresh frozen plasma, fibrinogen and platelets, and corticosteroids. Acute disseminated intravascular coagulation (DIC) persisted for 10 days and then resolved.\n\n\nRESULTS\nMetabolic imaging 5 months after the 177Lu-Dotatate administration showed disease progression. Treatment with 177Lu-Dotatate was not rechallenged due to the occurrence of DIC.\n\n\nCONCLUSIONS\nOur case suggests that acute hemorrhagic disseminated intravascular coagulation can be a rare and life-threatening subacute side effect of 177Lu-Dotatate peptide receptor radionuclide therapy.",
"affiliations": "Rouen University Hospital, Department of Internal Medicine, Rouen, France.;Rouen University Hospital, Department of Internal Medicine, Rouen, France.;Normandie Univ, UNIROUEN, Inserm U1096, Rouen University Hospital, Hemostasis Unit, Rouen, France.;Rouen University Hospital, Department of Internal Medicine, Rouen, France.;Rouen University Hospital, Department of Hepato-gastroenterology, Rouen, France.;UNICANCER, Comprehensive Cancer Centre F. Baclesse, Department of Nuclear Medicine, Caen, France.",
"authors": "Worbe|Noémie|N|0000-0002-0192-952;Damian|Louise|L|;Le Cam-Duchez|Véronique|V|;Levesque|Hervé|H|;Michel|Pierre|P|;Quak|Elske|E|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-21-04224\n10.1097/MD.0000000000027455\n27455\n5700\nResearch Article\nClinical Case Report\nHemorrhagic disseminated intravascular coagulation after 177Lu-Dotatate in metastatic midgut neuroendocrine tumor\nA case report\nhttp://orcid.org/0000-0002-0192-952X\nWorbe Noémie MD a ∗\nDamian Louise MD a\nLe Cam-Duchez Véronique MD, PhD b\nLevesque Hervé MD, PhD a\nMichel Pierre MD, PhD c\nQuak Elske MD d\nSaranathan. Maya\na Rouen University Hospital, Department of Internal Medicine, Rouen, France\nb Normandie Univ, UNIROUEN, Inserm U1096, Rouen University Hospital, Hemostasis Unit, Rouen, France\nc Rouen University Hospital, Department of Hepato-gastroenterology, Rouen, France\nd UNICANCER, Comprehensive Cancer Centre F. Baclesse, Department of Nuclear Medicine, Caen, France.\n∗ Correspondence: Noémie Worbe, Rouen University Hospital, Department of Internal Medicine, Service de Médecine Interne, CHU de Rouen, 1, rue de Germont, 76031 Rouen Cedex, France (e-mail: noemie.worbe@chu-rouen.fr).\n08 10 2021\n08 10 2021\n100 40 e2745521 7 2021\n6 9 2021\n20 9 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nPeptide receptor radionuclide therapy with 177Lu-Dotatate represents a major breakthrough in the treatment of metastatic well differentiated neuroendocrine tumors. This treatment is generally well tolerated. Reported severe long-term hematological side effects are rare and include hematopoietic neoplasms and bone marrow failure.\n\nPatients concerns:\n\nWe describe the case of a patient presenting spontaneous bleeding and bruising occurring 6 weeks after the first administration of 177Lu-Dotatate. Blood tests showed anemia, thrombocytopenia, prolonged clotting times, profound fibrinolysis and low levels of coagulation factors II and V. There were no signs of tumor lysis syndrome.\n\nDiagnoses:\n\nWe made the diagnosis of acute disseminated intravascular coagulation.\n\nIntervention:\n\nTreatment consisted of multiple transfusions of fresh frozen plasma, fibrinogen and platelets, and corticosteroids. Acute disseminated intravascular coagulation (DIC) persisted for 10 days and then resolved.\n\nOutcomes:\n\nMetabolic imaging 5 months after the 177Lu-Dotatate administration showed disease progression. Treatment with 177Lu-Dotatate was not rechallenged due to the occurrence of DIC.\n\nLessons:\n\nOur case suggests that acute hemorrhagic disseminated intravascular coagulation can be a rare and life-threatening subacute side effect of 177Lu-Dotatate peptide receptor radionuclide therapy.\n\nKeywords\n\n177Lu-Dotatate\ncase report\ndisseminated intravascular coagulation\nneuroendocrine tumor\npeptide receptor radionuclide therapy\nOPEN-ACCESSTRUE\n==== Body\npmc1 Introduction\n\nTargeted treatment with the radiolabeled somatostatin analogue 177Lu-Dotatate represents a breakthrough in the systemic treatment of metastatic well differentiated neuroendocrine tumors (WD-NET), as most classic anticancer treatments have minor efficacy in this disease. In the NETTER-1 trial, progression free survival, overall response rate and quality of life were markedly improved in midgut NET patients treated with 177Lu-Dotatate as compared to a high dose of somatostatin analogues, validating 177Lu-Dotatate as second-line systemic therapy.[1] In the main clinical trials, subacute grade 3 to 4 hematological toxicity is reported in 11% of patients.[1,2] Long-term hematological toxicity (hematopoietic neoplasms or bone marrow failure) occurs in 1% to 4% of cases after a latency period of several years.[3,4] No acute disseminated intravascular coagulation (DIC) has been reported.\n\n2 Case report\n\nWritten informed consent was obtained from the patient for publication of this case report.\n\nWe describe the case of a fifty five-year-old woman who developed spontaneous bleeding and bruising 6 weeks after the first 177Lu-Dotatate administration. She had been diagnosed 10 years earlier with metastatic ileal WD-NET. She had no other medical history except controlled hypertension. Previous treatment lines included surgery, somatostatine analogues and transarterial chemoembolization of hepatic metastases. As the disease progressed despite previous treatment lines and ongoing therapy with somatostatine analogues, a treatment with 177Lu-Dotatate was initiated thirteen months after the last transarterial chemoembolization. Pretreatment blood tests were normal. She received a standard dosage of 7.4 Gigabecquerel intravenously. The first injection was administered without immediate side effects. Blood tests at week 2 and 4 after treatment showed grade 1 thrombocytopenia. At week 6, she presented to the emergency department with spontaneous gingivorrhagia and bruising. She had no fever; her general condition was good and clinical examination was unremarkable except for gum bleeding and multiple cutaneous ecchymosis. Initial laboratory tests showed normocytic regenerative anemia (hemoglobin 85 g/dL), thrombocytopenia (54 × 10.9 /L), no signs of hemolysis, no schistocytes, prolonged prothrombin time (25.8 seconds, 35%) and prolonged activated partial thromboplastin time (1.63), low fibrinogen (0.3 g/L), elevated fibrin monomer (>400 μg/mL) and elevated fibrin degradation products (>20 μg/mL). Coagulation factors II (49%) and V (44%) were low; factors VII (97%) and X (81%) were normal. Liver function tests were normal with the exception of moderate elevation of gamma Glutamyl Transferase (γGT = 100 UI/L, N < 38 UI/L). C-reactive protein was <5 mg/L. There was no sign of tumor lysis syndrome. The bone marrow aspirate and medullar karyotype were normal. Computed tomography showed stable metastatic disease, including a large stable necrotic liver metastasis.\n\nAcute hemorrhagic DIC was diagnosed (International Society of Thrombosis and Haemostasis DIC Score = 8).[5] For the next 10 days, as her clinical situation worsened with bleeding manifestations, including a voluminous compressive chest wall hematoma following bone marrow aspiration despite preventive fibrinogen transfusion, 10 fresh frozen plasma, 6 fibrinogen and 4 platelet transfusions were administered (Fig. 1). Because of the ineffectiveness of fibrinogen concentrates, we investigated and eliminated the presence of an anti-fibrinogen antibody.\n\nFigure 1 Evolution of platelet and fibrinogen levels.\n\nPrednisone 40 mg/day was started on day 7 to reduce possible DIC-aggravating cancer or radiation related inflammation.\n\nThe evolution was favorable under corticosteroids and fibrinogen replacement therapy leading to normal hemostasis parameters and platelet count. Transfusions were stopped on day 11 and the patient was dismissed on day 13.\n\nTreatment with 177Lu-Dotatate was not restarted. Metabolic imaging 5 months after the 177Lu-Dotatate administration showed disease progression.\n\n3 Discussion\n\nTo our knowledge, this is the first report of acute DIC as a life-threatening subacute side effect of 177Lu-Dotatate peptide receptor radionuclide therapy in a patient with metastatic midgut WD-NET. The acute hemorrhagic DIC due to consumption coagulopathy required hemostatic treatment by multiple transfusions and fibrinogen injections. Recovery was slow. Causal link to the patient's long-term concomitant anti-hypertensive treatment (lercanidipine, irbesartan, and hydrochlorothiazide) was ruled out.\n\nSeveral mechanisms might explain the occurrence of acute DIC in our patient. Firstly, cancer itself can activate the coagulation pathways and patients with cancer are at increased risk of thrombotic complications. However, DIC associated with solid tumors is usually chronic and indolent. Chronic DIC is typically treated with therapeutic doses of heparin.[6,7] For our patient, there were no pretherapeutic signs of indolent DIC that might have aggravated due to treatment. In the literature, we found 2 cases of disseminated intravascular coagulation in metastatic neuroendocrine cancer, both associated with a pancreatic primary tumor. In 1 case, the patient died of DIC due to tumor lysis syndrome after disease manipulation by core biopsy and cytotoxic therapy. In the other case, DIC was reported to be related to the metastatic disease, and not a side effect of antineoplastic treatment. The DIC resolved after cytotoxic treatment.[8]\n\nAggressive hemorrhagic DIC can be associated with hematological malignancies at an early stage, such as acute promyelocytic leukemia, and is characterized by marked hyperfibrinolysis.[9] In this situation, treatment of the underlying cancer and hematologic support can reverse the coagulopathy. Prothrombin time and platelets must always be monitored, as well as fibrinogen and fibrin degradation products. In case of bleeding, guidelines recommend the transfusion of platelet concentrates and plasma. Antifibrinolytic agents could also be effective in this situation. Fibrinogen concentrate substitution therapy is not recommended as first-line treatment of this type of DIC.\n\nSecondly, for our patient, as the onset of DIC was rapid and severe and the metastatic midgut neuroendocrine tumor was stable, we supposed 177Lu-Dotatate was responsible for the consumption coagulopathy. DIC induced by antineoplastic treatment in solid cancers has been described, for example with vemurafenib in metastatic melanoma.[10] We also hypothesized tumor necrosis induced by 177Lu-Dotatate could have stimulated the coagulation cascade. Tumor lysis syndrome is a rare complication of cancer therapy leading to metabolic abnormalities including hyperkalemia, hypophosphatemia, hyperuricemia and hypocalcemia frequently associated with severe kidney injury. Pro-inflammatory cytokines could be the link between tumor lysis syndrome and DIC. However, our patient had no biological and imaging signs of tumor lysis syndrome induced by 177Lu-Dotatate.\n\nLastly, the question remains whether the administration of the beta and gamma emitting radioisotope 177Lutetium could have provoked radiation induced DIC. Radiation induced DIC is described in animal experiments as part of space radiation research.[11] In humans, bleeding and clotting disorders have been studied and described in atomic bomb casualties and victims of accidental whole-body irradiation.[12] Acute radiation induced DIC due to the internal use of radioisotopes in medicine, some of which have been in use for decades, has only been reported in 2 cases of 89Strontium treatment for prostate cancer bone metastases.[13,14] Therefore, as radiation can induce activation of the coagulation cascade resulting in DIC, the hypothesis of radiation induced DIC cannot be refuted. Moreover, as radiation is known to provoke inflammation, and inflammation in its turn can activate the coagulation cascade, this might explain why our patient responded so well to corticosteroid treatment.\n\nAlthough in this single patient case no definite conclusions can be drawn concerning the cause of acute DIC, which was probably multifactorial, alertness is warranted. As the field of peptide receptor radionuclide therapy is expanding and other targeted radionuclide therapies are on their way in less-rare cancer types, as for example 177Lu- prostate-specific-membrane-antigen targeting prostate-specific-membrane-antigen in metastatic prostate cancer, the frequency of this rare and possibly fatal subacute side effect might increase in the coming years.\n\nAcknowledgments\n\nThe authors thank Alisson Johnson for her assistance in drafting the manuscript.\n\nAuthor contributions\n\nConceptualization: Louise Damian.\n\nSupervision: Véronique Le Cam-Duchez, Hervé Levesque, Pierre Michel, Elske Quak.\n\nValidation: Véronique Le Cam-Duchez, Hervé Levesque, Pierre Michel, Elske Quak.\n\nWriting – original draft: Noémie Worbe, Louise Damian, Elske Quak.\n\nWriting – review & editing: Louise Damian, Elske Quak.\n\nAbbreviations: DIC = acute disseminated intravascular coagulation, WD-NET = well differentiated neuroendocrine tumors.\n\nHow to cite this article: Worbe N, Damian L, Le Cam-Duchez V, Levesque H, Michel P, Quak E. Hemorrhagic disseminated intravascular coagulation after 177Lu-Dotatate in metastatic midgut neuroendocrine tumor: a case report. Medicine. 2021;100:40(e27455).\n\nThe patient gave us her written permission to use her medical information for the publication of this case report.\n\nH. Levesque is a consultant and speaker at scientific events for Novo Nordisk and Takeda.\n\nP. Michel received speaker fees from Ipsen and Novartis.\n\nE. Quak received speaker fees from Advanced Accelerator Applications.\n\nThe authors have no other conflicts of interests to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n[1] Strosberg J El-Haddad G Wolin E . Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017;376 :125–35. Doi: 10.1056/NEJMoa1607427.28076709\n[2] Bergsma H Konijnenberg MW Kam BLR . Subacute haematotoxicity after PRRT with 177Lu-DOTA-octreotate: prognostic factors, incidence and course. Eur J Nucl Med Mol Imaging 2016;43 :453–63.26419852\n[3] Bergsma H Lom Kvan Konijnenberg M . Therapy-related hematological malignancies after peptide receptor radionuclide therapy with 177Lu-DOTA-Octreotate: incidence, course & predicting factors in patients with GEP-NETs. J Nucl Med 2017;Published online August 3. jnumed.117.189712. doi:10.2967/jnumed.117.189712.\n[4] Brabander T Zwan WAvan der Teunissen JJM . Long-term efficacy, survival, and safety of [177Lu-DOTA0, Tyr3] octreotate in patients with Gastroenteropancreatic and Bronchial neuroendocrine tumors. Clin Cancer Res 2017;23 :4617–24.28428192\n[5] Bakhtiari K Meijers JCM de Jonge E Levi M . Prospective validation of the International society of Thrombosis and Haemostasis scoring system for disseminated intravascular coagulation. Crit Care Med 2004;32 :2416–21.15599145\n[6] Wada H Matsumoto T Yamashita Y . Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care 2014;2 :15 doi: 10.1186/2052-0492-2-15.25520831\n[7] Levi M . Management of cancer-associated disseminated intravascular coagulation. Thromb Res 2016;140 :S66–70.27067981\n[8] Davies RS Wells T Gwynne S . Disseminated intravascular coagulation in a patient with metastatic pancreatic neuroendocrine tumor: a case report and review of the literature. Case Rep Clin Med 2014;3 :549–53.\n[9] Levi M . Clinical characteristics of disseminated intravascular coagulation in patients with solid and hematological cancers. Thromb Res 2018;164 :S77–81.29703488\n[10] van den Brom RRH Mäkelburg ABU Schröder CP de Vries EGE Hospers GAP . Vemurafenib-induced disseminated intravascular coagulation in metastatic melanoma. J Clin Oncol 2014;33 :e133–4.24778390\n[11] Krigsfeld GS Savage AR Billings PC Lin L Kennedy AR . Evidence for radiation-induced disseminated intravascular coagulation as a major cause of radiation-induced death in ferrets. Int J Radiat Oncol Biol Phys 2014;88 :940–6.24495588\n[12] Kennedy AR Maity A Sanzari JK . A review of radiation-induced coagulopathy and new findings to support potential prevention strategies and treatments. Radiat Res 2016;186 :121–40.27459701\n[13] Leong C McKenzie MR Coupland DB Gascoyne RD . Disseminated intravascular coagulation in a patient with metastatic prostate cancer: fatal outcome following strontium-89 therapy. J Nucl Med Off Publ Soc Nucl Med 1994;35 :1662–4.\n[14] Paszkowski AL Hewitt DJ Taylor AJ . Disseminated intravascular coagulation in a patient treated with strontium-89 for metastatic carcinoma of the prostate. Clin Nucl Med 1999;24 :852.10551466\n\n",
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{
"abstract": "Lactic acidosis metformin-related is a potentially fatal complication. Reviews show a stable prevalence of this phenomenon, but nephrological experience is required since it is frequently involved in therapeutic management. Here we report the cases of two old patients with severe lactic acidosis and acute renal failure treated with hemodiafiltration.",
"affiliations": null,
"authors": "Manes|Massimo|M|;Pellu|Valentina|V|;Caputo|Donatella|D|;Molino|Andrea|A|;Paternoster|Giuseppe|G|;Gabrielli|Danila|D|;Nebiolo|Pier Eugenio|PE|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "Italy",
"delete": false,
"doi": null,
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"issn_linking": "0393-5590",
"issue": "31(6)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": null,
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D000140:Acidosis, Lactic; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25504165",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin- related lactic acidosis.",
"title_normalized": "metformin related lactic acidosis"
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{
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{
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{
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}
],
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},
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"literaturereference": "MANES M. METFORMIN- RELATED LACTIC ACIDOSIS. GIORNALE ITALIANO DI NEFROLOGIA. 2014;31(6):1-5",
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},
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"receivedate": "20161219",
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}
] |
{
"abstract": "It has been postulated that gastroesophageal reflux plays a role in the etiology of head and neck squamous cell carcinomas (HNSCC) and contributes to complications after surgery or during radiotherapy. Antacid medications are commonly used in patients with HNSCC for the management of acid reflux; however, their relationship with outcomes has not been well studied. Associations between histamine receptor-2 antagonists (H2RA) and proton pump inhibitors (PPI) use and treatment outcomes were determined in 596 patients with previously untreated HNSCC enrolled in our SPORE epidemiology program from 2003 to 2008 (median follow-up 55 months). Comprehensive clinical information was entered prospectively in our database. Risk strata were created on the basis of possible confounding prognostic variables (age, demographics, socioeconomics, tumor stage, primary site, smoking status, HPV16 status, and treatment modality); correlations within risk strata were analyzed in a multivariable model. Patients taking antacid medications had significantly better overall survival (OS; PPI alone: P < 0.001; H2RA alone, P = 0.0479; both PPI + H2RA, P = 0.0133). Using multivariable Cox models and adjusting for significant prognostic covariates, both PPIs and H2RAs used were significant prognostic factors for OS, but only H2RAs use for recurrence-free survival in HPV16-positive oropharyngeal patients. We found significant associations between the use of H2RAs and PPIs, alone or in combination, and various clinical characteristics. The findings in this large cohort study indicate that routine use of antacid medications may have significant therapeutic benefit in patients with HNSCC. The reasons for this association remain an active area of investigation and could lead to identification of new treatment and prevention approaches with agents that have minimal toxicities.",
"affiliations": "Department of Otolaryngology-Head and Neck Surgery University of Michigan Medical School, Ann Arbor, Michigan. Department of Periodontics-Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan. silvanap@umich.edu.;Center for Cancer Biostatistics, University of Michigan, Ann Arbor, Michigan.;Department of Otolaryngology-Head and Neck Surgery University of Michigan Medical School, Ann Arbor, Michigan.;Department of Otolaryngology-Head and Neck Surgery University of Michigan Medical School, Ann Arbor, Michigan.;Department of Otolaryngology-Head and Neck Surgery University of Michigan Medical School, Ann Arbor, Michigan.;Department of Otolaryngology-Head and Neck Surgery University of Michigan Medical School, Ann Arbor, Michigan.;Clinical Informatics, Comprehensive Cancer Center Bioinformatics Core, University of Michigan, Ann Arbor, Michigan. Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan.;Center for Cancer Biostatistics, University of Michigan, Ann Arbor, Michigan. Department of Biostatistics, University of Michigan Medical School, Ann Arbor, Michigan.;Department of Otolaryngology-Head and Neck Surgery University of Michigan Medical School, Ann Arbor, Michigan. School of Nursing, University of Michigan, Ann Arbor, Michigan. Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan. VA Ann Arbor Healthcare System, University of Michigan, Ann Arbor, Michigan.;Department of Otolaryngology-Head and Neck Surgery University of Michigan Medical School, Ann Arbor, Michigan.",
"authors": "Papagerakis|Silvana|S|;Bellile|Emily|E|;Peterson|Lisa A|LA|;Pliakas|Maria|M|;Balaskas|Katherine|K|;Selman|Sara|S|;Hanauer|David|D|;Taylor|Jeremy M G|JM|;Duffy|Sonia|S|;Wolf|Gregory|G|",
"chemical_list": "D006635:Histamine H2 Antagonists; D054328:Proton Pump Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1158/1940-6207.CAPR-14-0002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1940-6215",
"issue": "7(12)",
"journal": "Cancer prevention research (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Cancer Prev Res (Phila)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell; D005260:Female; D005500:Follow-Up Studies; D005764:Gastroesophageal Reflux; D006258:Head and Neck Neoplasms; D006635:Histamine H2 Antagonists; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D054328:Proton Pump Inhibitors; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101479409",
"other_id": null,
"pages": "1258-69",
"pmc": null,
"pmid": "25468899",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "16175178;23558285;21461873;2545340;17295779;19010263;21329756;18270337;19320589;10685065;14695770;19460203;10919677;18474879;10796074;20451455;20145161;21716948;21447181;18042931;11391152;11891950;10852522;22183632;14705380;22360553;9422633;16818644;21327325;18235120;23585151;11870500;11746205;21667401;14761893;10796075;23703970;16104125;22252715;18981014;20530316;8605731;18334711;15991089;18377797;10793107",
"title": "Proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma.",
"title_normalized": "proton pump inhibitors and histamine 2 blockers are associated with improved overall survival in patients with head and neck squamous carcinoma"
} | [
{
"companynumb": "US-JNJFOC-20150109301",
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"literaturereference": "PAPAGERAKIS S, BELLILE E, PETERSON LA, PLIAKAS M, BALASKAS K, SELMAN S, ET AL. PROTON PUMP INHIBITORS AND HISTAMINE 2 BLOCKERS ARE ASSOCIATED WITH IMPROVED OVERALL SURVIVAL IN PATIENTS WITH HEAD AND NECK SQUAMOUS CARCINOMA. 01-DEC-2014;146 (6):1258-1269.",
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},
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}
] |
{
"abstract": "Eradication of minimal residual disease (MRD) after allotransplantation in persons with chronic lymphocytic leukemia (CLL) is associated with lower rates of relapse. Rapid engraftment of donor lymphocyte elements can contribute to MRD control, but it remains unclear whether this strategy will benefit patients. In this study, we report the incidence of MRD eradication and graft-versus-host disease (GvHD) in persons with rapid versus later donor T lymphocyte engraftment after lymphodepleting chemotherapy and reduced intensity conditioning (RIC) allotransplantation. Twenty-seven subjects received lymphodepleting chemotherapy to facilitate donor engraftment followed by fludarabine and cyclophosphamide RIC and a blood cell allograft. MRD was monitored by multicolor flow cytometry after transplantation. Complete donor T lymphoid chimerism (TLC) and myeloid chimerism (MC) were achieved in 25 subjects at a median of 28 days (range, 14-60 days) and 21 days (range, 14-180 days), respectively. Achieving complete donor TLC by day 14 versus day 28 or later correlated with occurrence of grade 2 or higher acute GvHD (90% [95% confidence interval {CI}, 78-100%] versus 35% [95% CI, 16-54%]; p = 0.014) and better control of MRD in the bone marrow at day 100, median 0% (range, 0-0.1%) versus 8.5% (range, 0-92%; p = 0.016). Among 11 persons with early donor TLC, none had progressive disease, and seven died of treatment -related mortality (TRM). In persons with later development of TLC, 8 of 16 had progressive disease and 2 died of TRM. Time to donor myeloid chimerism had no effect on outcomes. Rapid establishment of donor TLC resulted in more complete eradication of early MRD, but greater incidence of acute GvHD and TRM in persons with CLL undergoing RIC allotransplantation.",
"affiliations": "Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. shafferbc@mail.nih.gov",
"authors": "Shaffer|Brian C|BC|;Modric|Marko|M|;Stetler-Stevenson|Maryalice|M|;Arthur|Diane C|DC|;Steinberg|Seth M|SM|;Liewehr|David J|DJ|;Fowler|Daniel H|DH|;Gale|Robert P|RP|;Bishop|Michael R|MR|;Pavletic|Steven Z|SZ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-472X",
"issue": "41(9)",
"journal": "Experimental hematology",
"keywords": null,
"medline_ta": "Exp Hematol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D005260:Female; D005500:Follow-Up Studies; D006085:Graft Survival; D006086:Graft vs Host Disease; D020544:Graft vs Leukemia Effect; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D013601:T-Lymphocytes; D013997:Time Factors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "0402313",
"other_id": null,
"pages": "772-8",
"pmc": null,
"pmid": "23689118",
"pubdate": "2013-09",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural",
"references": "16338616;11136261;8338937;18955982;8652811;20007560;22005648;17084369;18794548;9383097;15821766;8193379;20872890;15848518;18418404;15352988;15226174;10556212;10816026;10204198;18940684;12652466;22331940;19377072;20637879;19641189;14551148;20595516;16278397;21224011;22312100;10347989;20528878;7687667",
"title": "Rapid complete donor lymphoid chimerism and graft-versus-leukemia effect are important in early control of chronic lymphocytic leukemia.",
"title_normalized": "rapid complete donor lymphoid chimerism and graft versus leukemia effect are important in early control of chronic lymphocytic leukemia"
} | [
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"reaction": [
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],
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] |
{
"abstract": "Albendazole is used as a typical antiparasitic agent worldwide. The side effects of albendazole may include nausea, vomiting, abdominal pain, dizziness, headache, alopecia, and increased liver enzymes. Mild elevation of the liver enzyme has been reported in more than 10% of cases, but drug induced liver injury was reported to be very rare. A 30-year-old woman visited the Dong-A University Hospital with anorexia, nausea, jaundice, and elevated liver enzyme. For diagnosis, other acute hepatitis etiologies were excluded, but the prophylactic administration of albendazole was verified. This paper introduces a case of drug-induced liver injury through the prophylactic administration of albendazole. Physicians should be aware of severe liver injury as one of the side effects of albendazole.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Dong-A University Hospital, Busan, Korea.;Division of Gastroenterology, Department of Internal Medicine, Dong-A University Hospital, Busan, Korea.;Division of Gastroenterology, Department of Internal Medicine, Dong-A University Hospital, Busan, Korea.",
"authors": "Moon|Sang Yi|SY|;Baek|Yang Hyun|YH|;Lee|Sung Wook|SW|http://orcid.org/0000-0001-9243-8488",
"chemical_list": "D000871:Anthelmintics; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D015766:Albendazole",
"country": "Korea (South)",
"delete": false,
"doi": "10.4166/kjg.2019.73.6.360",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1598-9992",
"issue": "73(6)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": "Albendazole; Drug induced liver injury",
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D015766:Albendazole; D000871:Anthelmintics; D001219:Aspartate Aminotransferases; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D014463:Ultrasonography",
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "360-364",
"pmc": null,
"pmid": "31234627",
"pubdate": "2019-06-25",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Drug Induced Liver Injury by Prophylactic Administration of Albendazole.",
"title_normalized": "drug induced liver injury by prophylactic administration of albendazole"
} | [
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"companynumb": "KR-IMPAX LABORATORIES, LLC-2019-IPXL-01376",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
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},
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"reaction": [
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Jaundice",
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"reactionoutcome": "2"
},
{
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"reactionmeddraversionpt": "22.0",
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},
{
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},
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},
{
"reactionmeddrapt": "Bilirubin conjugated increased",
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},
{
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Activated partial thromboplastin time prolonged",
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},
{
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},
{
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},
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},
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},
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
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"abstract": "The term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.",
"affiliations": "Department of Obstetrics and Gynecology, PGIMER, Chandigarh, India.;Department of Obstetrics and Gynecology, PGIMER, Chandigarh, India.;Department of Obstetrics and Gynecology, PGIMER, Chandigarh, India.;Medical Oncology Regional Cancer Centre, PGIMER, Chandigarh, India.;Department of Pathology, PGIMER, Chandigarh, India.;Department of General Surgery, PGIMER, Chandigarh, India.",
"authors": "Thakur|Surekha|S|;Saha|S C|SC|;Sikka|Pooja|P|;Das|Chandan Krushna|CK|;Arpitha|Kollabathula|K|;Thakur|Uttam Kumar|UK|",
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"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789 Elsevier \n\nS2352-5789(20)30159-4\n10.1016/j.gore.2020.100693\n100693\nCase Report\nMetastatic dysgerminoma in a young patient with 46 XY DSD: A rare case report\nThakur Surekha surekha12gmc@gmail.coma⁎ Saha S.C. a Sikka Pooja a Das Chandan Krushna b Arpitha Kollabathula c Thakur Uttam Kumar d a Department of Obstetrics and Gynecology, PGIMER, Chandigarh, India\nb Medical Oncology Regional Cancer Centre, PGIMER, Chandigarh, India\nc Department of Pathology, PGIMER, Chandigarh, India\nd Department of General Surgery, PGIMER, Chandigarh, India\n⁎ Corresponding author at: House number 141, Sector 11-A, Chandigarh, India. surekha12gmc@gmail.com\n31 12 2020 \n2 2021 \n31 12 2020 \n35 10069328 11 2020 23 12 2020 26 12 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• A rare case of metastatic dysgerminoma in a young patient with 46XY DSD.\n\n• Incidence of DSD is 1:5000 with 90% of patients having 46XX chromosome and only 10% have 46 XY chromosome.\n\n• Individuals with an underlying DSD, especially with Y chromosome have an increased risk of developing germ cell tumor.\n\n• Dysgerminoma is highly chemosensitive tumor.\n\n• Multidisciplinary approach is required in management of such cases.\n\n\n\nThe term DSD (Disorders of Sex development) is issued to define those conditions in whom disharmony exists between chromosomal, hormonal and anatomical sex. Parental and patient mental health and quality of life are adversely affected by these conditions. Moreover, individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor. Here, we present a unique case of 46XY DSD with bilateral dysgerminomas presenting with abdominal mass at the age of 24 years, who was treated with one cycle of chemotherapy comprising of Carboplatin and Etoposide, following which he developed tumor lysis syndrome and later underwent exploratory laparotomy.\n\nKeywords\nDisorders of sex development46XYDysgerminoma\n==== Body\n1 Introduction\nDisorders of Sex development (DSD) are congenital conditions of incomplete or disordered gonadal development leading to discordance between genetic sex, gonadal sex, and phenotypic sex (Hughes et al., 2006). Estimated incidence of DSD is 1:5000 (Hughes et al., 2006). Individuals with an underlying DSD, especially those with specific Y chromosomal material in their karyotype have an increased risk for developing a germ cell tumor/cancer (GCC) (Cools et al., 2006). GCCs arise from primordial germ cells (PGC) and can be subdivided into seminomas/dysgerminomas and non-seminomas with carcinoma in situ (CIS) or gonadoblastoma (GB) as precursor lesions (Oosterhuis and Looijenga, 2005, Hersmus et al., 2008). GCC risk varies, but is estimated to be over 30% in patients with complete gonadal dysgenesis and is often bilateral (Cools et al., 2006). DSDs significantly impact individuals and their families due to their sensitive nature and stigma surrounding gender identity and gender roles. Due to several sociocultural factors, individuals who reside in developing countries with limited access to healthcare are affected more adversely.\n\n1.1 Case study\nThis patient had ambiguous genitalia at birth. He was reared as a male without any further evaluation However at the age of 10 years, he noticed bilateral breast development with increase in size of phallus. Two years later, he developed cyclical hematuria. He used to bleed for 2,3 days while passing urine every month. Health care consultation was not taken due to social stigma and fear. Now at the age of 24 years, patient presented with history of abdominal pain and abdominal mass for two years. There was history of loss of weight and appetite. His height was 165 cm and weight was 48 kg. On examination, per abdomen, a large, movable, abdominopelvic mass measuring 15 × 18 cm extending upto epigastric region was palpable. On local examination microphallus of size 4 cm without urethral opening was seen. Urethra was located 4 cm below the microphallus. Labia majora and labia minora were completely fused as shown in Fig. 1. Bilateral gonads were not palpable.Fig. 1 External genitalia with urinary catheter insitu.\n\n\n\nOn laboratory assessment, complete blood count, urinalysis, renal and liver function tests, serum and urine electrolytes, and thyroid function tests were in normal range. Hormonal profile showed low testosterone, dehydroepiandrosterone sulphate (DHEAS) and anti-mullerian hormone (AMH) levels. Leutenizing hormone (LH), follicle stimulating hormone (FSH) and estradiol ( E2-17B was 75.9) were within normal limits. On further evaluation, MRI (Magnetic rersonance imaging) showed uterus and two well defined abdominopelvic masses (14.4cmx8.5 cm and 15cmx9cm) with possible gonadal origin based on blood supply. During hospital stay LH surge was seen which was followed by hematuria. This suggests he had functional ovaries with low ovarian reserve as suggested by low AMH. Beta HCG, CA19-9, AFP, CEA were normal but CA125 (128.6) and LDH (600) were elevated. His genitogram was inconclusive. PET-CT showed multiple FDG avid lymph nodes in the abdomen (periportal and mesenteric lymph nodes), mediastinum, neck, left axilla, and diaphragm. FDG avid bilateral lung lesions were noted. On karyotyping (GTG-Banding with Trypsin and Giemsa stain), 20 metaphases were analyzed, all cells showed 46 XY.\n\nAn ultrasound guided FNAC from abdominopelvic mass showed aggregates of tumor cells having vesicular chromatin, prominent nucleoli, in a tigroid background. In addition, many scattered sarcoid like granulomas admixed with lymphocytes and occasional multinucleated giant cells were also noted. Immunocytochemistry done on the cell block showed that these tumor cells were positive for SALL4 and OCT4 while negative for CD30 and AFP, suggestive of dysgerminoma as shown in Fig. 2.Fig. 2 (a) Cytology smears showing singly scattered as well as small cohesive clusters of tumour cells. (b) Tumor cells showing vesicular chromatin, prominent nucleoli and moderate amount of cytoplasm. (c) Smears showing many scattered sarcoid like granuloma admixed with lymphocytes and occasional multinucleated giant cells. (d) Cell block section showing nuclear positivity for OCT-4 in tumor cells. (a-b MGG;c-H&E;d-IPOX).\n\n\n\nDiagnosis of DSD with possibility of ovotesticular or mixed gonadal dysgenesis with metastatic gonadal dysgerminoma was made. A comprehensive psychology analysis regarding gender identity was done and patient wished to remain as a male. In view of COVID induced disruption of normal oncology practice, neoadjuvant chemotherapy (NACT) comprising of Carboplatin and Etoposide (Carboplatin-450 mg and Etoposide-200 mg) was started. However, following the first cycle of chemotherapy only, he developed febrile neutropenia along with renal failure. Blood and urine culture showed growth of Escherichia coli. In view of neutropenia, he was given G-CSF (Granulocyte-colony stimulating factor) 5 mcg/kg for four days following which he had an increase in total leucocyte count. In view of renal insufficiency (urea/creatinine 195/7.5) along with hyperkalemia, three sessions of hemodialysis were given. Possibility of tumor lysis syndrome and sepsis related AKI (Acute kidney injury) was considered. So further chemotherapy was deferred. He was again admitted after one month with complaint of severe abdominal pain and fever. On examination, there was a tender mass with guarding and rigidity. CECT (Contrast enhanced computed tomography) abdomen revealed large abdominopelvic mass with calcification and areas of high attenuation suggestive of haemorrhage. Suspicion of hemorrhage, infection and torsion in the mass was very high. Parenteral antibiotics, analgesics were given and after stabilization exploratory laparotomy was done.\n\nIntraoperatively, omentum was adherent to the mass and covering it completely. Omental adhesions were separated. A twisted mass of 15 × 11 × 8 cm size arising from left gonad was seen, which was necrosed. Another mass of size 10 × 6 × 4 cm seen on right side arising from right adnexa. Uterus was small in size measuring 4 × 3 × 1 cm and cervix was long and tubular measuring 5 × 1 cm extending upto pelvic floor. Bilateral tubes were normal. Gut loops were distended and adherent to the mass. There was constriction of gut at the point of adhesion at approximately 10 cm distal to duodenojejunal junction. Adhesiolysis was done and contents aspirated from gut through Ryles tube by retrograde milking of gut. Bilateral adnexal masses were excised after de-torsion of left adnexal mass. Subtotal hysterectomy was done and 2–3 cm of cervix was left behind. Infra-colic omentectomy was done. Pelvic and retroperitoneal lymph nodes were not enlarged and suspicious. Post operative period was uneventful and patient discharged under stable condition.\n\nOn histopathology examination, the cut sections of the larger mass revealed homogenous reddish brown soft areas with no viable or normal ovarian parenchyma. The smaller mass revealed grey white firm areas. Multiple sections examined from bilateral adnexal masses showed extensive areas of infarction, necrosis, haemorrhage, foci of calcification and collection of hemosiderin laden macrophages. No viable tumor or normal ovarian parenchyma identified. Sections from the uterus and fallopian tube were unremarkable. Sections from the omentum showed extensive mesothelial cell proliferation, areas of haemorrhage, fibrosis, mixed inflammatory cells along with many hemosiderin laden macrophages. No viable tumor cells were seen as shown in Fig. 3.Fig. 3 (a) Gross image of bilateral adnexae showing homogenous soft reddish brown mass in the larger mass and grey white firm areas in the smaller mass. (b) Small sized uterus measuring 4 × 3 × 1 cm. (c) sections from uterus showing Endometrium in proliferative phase (d-e) sections from bilateral adnexa showing large areas of infarction necrosis, hyalinisation admixed with mixed inflammatory cells and pigment laden macrophages.\n\n\n\nOur further plan is to administer atleast two more cycles of chemotherapy and later perform a genital reconstructive surgery in this patient.\n\n2 Discussion\nGenital ambiguity is seen in 1 in 5000 births (Hughes et al., 2006). The term DSD issued to define those congenital conditions in which disharmony exists in between chromosomal, hormonal and anatomical sex (Hughes et al., 2006). DSDs have been cassified on the basis of sex chromosome. Our patient has 46, XY DSD. It could be either ovotesticular or mixed gonadal dysgenesis type.\n\nIn ovotesticular DSD, both Mullerian and Wolffian duct derivatives are present in the same individual and the genitalia are of ambiguous nature (Swain et al., 2014). A variety of phenotypes is seen of both external and internal genitalia. Most of these patients have a well-formed uterus present (SwainS et al., 2014). The gonads may be ovotestis or a combination of ovary on one side and testis on the other. These patients are usually reared as male because of the size of the phallus and labioscrotal fusion which is of varying degrees. At puberty, feminization and menstruation occurs. Various chromosomal abnormalities have been described in these individuals and include 46,XX, 46,XY, 46,XX/46,XY, 47,XXY, 47,XYY, 45X, and 46,XX/47,XXY mosaicism. 90% of the patients have 46 XX karyotype and 10% of patients have 46XY karyotype as seen in our case (Donahoe and Schnitzer, 1996).\n\nMixed gonadal dysgenesis is characterized by a unilateral testis (often intra-abdominal), a contra-lateral streak gonad, persistent Mullerian duct structures and various degrees of inadequate masculinization. The most common karyotype is 45,XO/46,XY, other mosaics have also been reported with structurally normal or abnormal Y chromosome.\n\nOur patient had characterstics of ovotesticular DSD but we do not have histological evidence of ovotestes, which may be because of chemotherapy induced necrosis of gonads, as dysgerminoma is highly chemosensitive tumor.\n\nPatients with Y chromosome or Y-derived sequences are at increased risk (10–30%) of developing gonadal tumors (Verp and Simpson, 1987). The most common neoplasm is a Germ cell tumour, with dysgerminoma being the most common histological type. Our patient had FNAC based diagnosis of germ cell tumor with ICC suggesting dysgerminoma. He recieved one cycle of NACT with EP (etoposide and carboplatin) due to covid pandemic. There was a remarkable response to NACT suggested by histopathology findings post-operatively. This highlights highly chemosensitive nature of dysgerminoma. In a series of NACT for OGCT (Ovarian germ cell tumor), Talukdar et al. presented 23 cases from 1988 to 2009 in which patients with stage III and IV malignant OGCT received four cycles of BEP NACT (Talukdar et al., 2014). Dysgerminomas accounted for 14 cases. Twenty-one patients with OGCT experienced either a complete response (CR) or partial response (PR), of whom 12 had dysgerminoma. All 21 patients were alive and disease-free. Authors compared this to 43 cases over the same time period that were treated with surgery followed by chemotherapy. Thirty-four patients had greater than 2 cm of residual tumor. Of these 43 patients, 30 were alive and disease-free at analysis (Talukdar et al., 2014). Their findings suggest that NACT resulted in better survival. Our case supports the use of NACT in patients with metastatic dysgerminoma, provided there is careful monitoring for risk of tumor lysis syndrome.\n\nCareful evaluation and early diagnosis of DSDs are very important. However, the optimal protocol of management for DSD patients remains controversial (Crone et al., 2002). Some tertiary health care centers have a multidisciplinary DSD team that addresses the psychological, medical, and surgical needs of children and adolescents with DSD and their families. The team often includes pediatric providers in psychology or psychiatry, genetics, gynecology, endocrinology, surgery, and urology as well as social work and nursing support. Treatment in cases of DSD may involve medical treatment, surgical correction of ambiguous genitalia and removal of dysgenic gonads or mullerian components, and psychological counselling, especially in patients who have presented during their adolescence or adulthood (Hughes et al., 1958”.). Educating medical and paramedical staff is crucial to ensure adequate early assessment, diagnosis, counselling and appropriate management.\n\n3 Conclusion\nEarly detection and referral of a patient with ambiguous genitalia can provide improved quality of life, and prevent gender dysphoria and psychosocial dilemmas. Prophylactic removal of the dysgenetic gonad may prevent risk for malignant transformation.\n\nEthical clearance: Since it is a case report so no ethical clearance is required.\n\nFinancial support: Nil.\n\nThe manuscript has not been published previously and is not under consideration elsewhere.\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nDeclaration of Competing Interest\nThe authors declare that there is no conflict of interest.\n==== Refs\nReferences\nCools M. Drop S.L. Wolffenbuttel K.P. Oosterhuis J.W. Looijenga L.H. Germ cell tumors in the intersex gonad: Old paths, new directions, moving frontiers Endocr. Rev. 27 2006 468 484 16735607 \nCrone J. Amann G. Gheradini R. Kirchlechner V. Fekete C.N. Management of 46, XY Partial gonadal dysgenesis - revisited Wien Klin. Wochenschr 114 2002 462 467 12422582 \nDonahoe P.K. Schnitzer J.J. Evaluation of the infant who has ambiguous genitalia, and principles of operative management Semin. Pediatr. Surg. 5 1 1996 Feb 30 40 8988295 \nHersmus R. de Leeuw B.H. Wolffenbuttel K.P. Drop S.L. Oosterhuis J.W. New insights into type II germ cell tumor pathogenesis based on studies of patients with various forms of disorders of sex development (DSD) Mol. Cell Endocrinol. 291 2008 1 10 18403106 \nHughes W. Erickson C.C. Fleischmann W. Etteldorf J.N. True hermaphroditism J. Pediatr. 52 6 1958 662 669 13550033 \nHughes, I.A., Houk, C., Ahmed, S.F., Lee, P.A., Group, L.C., et al., 2006. Consensus statement on management of intersex disorders. Arch. Dis. Child. 91, 554–563.\nOosterhuis J.W. Looijenga L.H. Testicular germ-cell tumours in a broader perspective Nat. Rev. Cancer. 5 2005 210 222 15738984 \nSwainS Pradhan L Satpathy R. Mahapatra P. A rare case report on ovotesticular disorders of sex development (DSD) 46XY variant Int. J. ReprodContraceptObstet. Gynecol. 3 4 2014 Dec 1163 1166 \nTalukdar S. Kumar S. Bhatla N. Mathur S. Thulkar S. Kumar L. Neo-adjuvant chemotherapy in the treatment of advanced malignant germ cell tumors of ovary Gynecol. Oncol. 132 1 2014 28 32 24145115 \nVerp M.S. Simpson J.L. Abnorma sexual differentiation and neoplasia Cancer Genet. Cytogenet. 25 1987 191 218 3548944\n\n",
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"abstract": "Lactic acidosis is associated with high morbidity and mortality in hospitalized patients. Treatment of lactic acidosis is targeted on correcting the underlying causes and optimizing adequate oxygen delivery to the tissues. Even though evidence is lacking, continuous renal replacement therapy (CRRT) and dialysis have been advocated as treatments for lactic acidosis. We report a 28-year-old Caucasian male with a history of hemophagocytic lymphohistiocytosis who presented with septic shock, severe lactic acidosis and multiple organ failure. Metabolic acidosis was corrected after bicarbonate therapy and CRRT with a hemofiltration rate of 7 L/h (58 mL/kg/h). Lactate clearance was calculated to be 79 mL/min. Compared with reported rates of lactate overproduction in septic shock, the rate of lactate clearance is quite small. Our case suggests that CRRT with high-volume hemofiltration is not effective for severe lactic acidosis. Lactic acidosis alone should not be considered as a nonrenal indication for CRRT.",
"affiliations": "Division of Nephrology and Hypertension , Mayo Clinic , Rochester, MN , USA.;Division of Nephrology and Hypertension , Mayo Clinic , Rochester, MN , USA.;Division of Nephrology and Hypertension , Mayo Clinic , Rochester, MN , USA.;Division of Nephrology and Hypertension , Mayo Clinic , Rochester, MN , USA.;Division of Nephrology and Hypertension , Mayo Clinic , Rochester, MN , USA ; Division of Hematology , Mayo Clinic , Rochester, MN , USA.",
"authors": "Cheungpasitporn|Wisit|W|;Zand|Ladan|L|;Dillon|John J|JJ|;Qian|Qi|Q|;Leung|Nelson|N|",
"chemical_list": null,
"country": "England",
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"doi": "10.1093/ckj/sfv045",
"fulltext": "\n==== Front\nClin Kidney JClin Kidney JckjndtplusClinical Kidney Journal2048-85052048-8513Oxford University Press 10.1093/ckj/sfv045sfv045ContentsHaemodialysisLactate clearance and metabolic aspects of continuous high-volume hemofiltration Cheungpasitporn Wisit 1Zand Ladan 1Dillon John J. 1Qian Qi 1Leung Nelson 121 Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA2 Division of Hematology, Mayo Clinic, Rochester, MN, USACorrespondence to: Nelson Leung; E-mail: leung.nelson@mayo.edu8 2015 17 6 2015 17 6 2015 8 4 374 377 10 4 2015 18 5 2015 19 5 2015 © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comLactic acidosis is associated with high morbidity and mortality in hospitalized patients. Treatment of lactic acidosis is targeted on correcting the underlying causes and optimizing adequate oxygen delivery to the tissues. Even though evidence is lacking, continuous renal replacement therapy (CRRT) and dialysis have been advocated as treatments for lactic acidosis. We report a 28-year-old Caucasian male with a history of hemophagocytic lymphohistiocytosis who presented with septic shock, severe lactic acidosis and multiple organ failure. Metabolic acidosis was corrected after bicarbonate therapy and CRRT with a hemofiltration rate of 7 L/h (58 mL/kg/h). Lactate clearance was calculated to be 79 mL/min. Compared with reported rates of lactate overproduction in septic shock, the rate of lactate clearance is quite small. Our case suggests that CRRT with high-volume hemofiltration is not effective for severe lactic acidosis. Lactic acidosis alone should not be considered as a nonrenal indication for CRRT.\n\ncontinuous renal replacement therapy (CRRT)lactic acidosismetabolic acidosis\n==== Body\nIntroduction\nLactic acidosis is the most common anion gap metabolic acidosis in hospitalized patients [1]. Tissue hypoperfusion in shock, leading to increased anaerobic metabolism, is responsible for the Type A lactic acidosis. Conversely, Type B lactic acidosis occurs without evidence of systemic hypoperfusion and may be seen in association with systemic diseases such as hepatic failure, or malignancies or occur as a result of certain classes of drugs such as biguanides [2, 3]. Increased plasma lactate level (hyperlactatemia) in critically ill patients is associated with high morbidity and mortality [4]. The effective treatment for lactic acidosis (Type A) is correcting the underlying cause and improving tissue oxygenation. Applicable measures include cardiopulmonary support and treatment of sepsis [5]. Even though supporting evidence is lacking, continuous renal replacement therapy (CRRT) is used commonly in the intensive care unit (ICU) to correct acidemia among patients with lactic acidosis and renal failure. We present a case of acute kidney injury (AKI) and severe lactic acidosis from septic shock requiring CRRT. Lactic acidosis improved significantly as the patient achieved more stable hemodynamics. A lactate clearance evaluation was performed to determine the effect of CRRT on lactate removal. We report our findings.\n\nCase presentation\nClinical history\nA 28-year-old Caucasian male police officer with a past medical history of hemophagocytic lymphohistiocytosis (HLH) was referred to our hospital from an outside facility for evaluation of a 1-week history of fever, acute diarrhea and poor oral intake. The patient was diagnosed with HLH 4 months prior to admission after presenting with fever, pancytopenia and splenomegaly. A bone marrow (BM) biopsy at the time confirmed the diagnosis of HLH which was in the setting of positive Epstein–Barr virus (EBV) titers. The patient was treated with dexamethasone, intravenous (IV) immunoglobulin and etoposide followed by cyclosporine. Surveillance imaging studies, including computerized tomography chest, abdomen, and pelvis and positron emission tomography scan revealed no evidence of malignancy and suggested a good response to therapy. The patient was doing well until his most recent presentation. His initial evaluation at the outside hospital revealed febrile neutropenia and the patient was empirically treated with IV vancomycin and cefepime and then transferred to our hospital for further management. On admission to our hospital, the temperature was 38.5°C, the blood pressure was 116/60 mmHg, the heart rate was 80 beats/min and the weight was 120 kg. The physical examination was normal except for a 2-cm left cervical lymph node that was noted on palpation.\n\nInitial laboratory data and investigations\nLaboratory testing, demonstrated in Table 1, revealed serum creatinine 2.6 mg/dL (creatinine was 0.9 mg/dL 3 months prior). Arterial blood gas (ABG) was pH 7.23, pCO2 24 mmHg, pO2 101 mmHg, HCO3 10 mmol/L, indicating an anion gap metabolic acidosis with respiratory compensation (expected pCO2 of 24–28). The urinalysis demonstrated granular casts and renal epithelial cells consistent with acute tubular necrosis. The patient underwent a cervical lymph node biopsy and a repeat BM biopsy which demonstrated a new diagnosis of peripheral T-cell lymphoma. The stool was positive for Clostridium difficile.\nTable 1. Laboratory data\n\nLaboratory testing\tAt presentation\tReference range\t\nHb (g/dL)\t10.7\t13.5–17.5\t\nWBC (×103/L)\t0.6\t3.5–10.5\t\nNeutrophils (×103/L)\t0.37\t1.7–7.0\t\nPlatelet (×109/L)\t65\t150–450\t\nSerum sodium (mmol/L)\t138\t135–145\t\nSerum potassium (mmol/L)\t4.6\t3.6–5.2\t\nSerum chloride (mmol/L)\t103\t100–108\t\nSerum bicarbonate (mmol/L)\t12\t22–29\t\nSerum creatinine (mg/dL)\t2.6\t0.8–1.3\t\nBUN (mg/dL)\t62\t8–24\t\nSerum albumin (g/dL)\t2.3\t3.5–5.0\t\nSerum calcium (mg/dL)\t8.9\t8.9–10.1\t\nTriglyceride (mg/dL)\t644\t<150\t\nFibrinogen (mg/dL)\t60\t200–375\t\nSerum ferritin (µg/L)\t91 400\t24–336\t\nPlasma lactate (mmol/L)\t16.8\t0.6–2.3\t\nBUN, blood urea nitrogen; Hb, hemoglobin; WBC, white blood cell.\n\n\n\nDiagnosis\n(i) Peripheral T-cell lymphoma; (ii) relapsing HLH; (iii) C. difficile colitis; (iv) acute kidney injury; (v) lactic acidosis.\n\nClinical follow-up\nThe patient was treated with oral vancomycin for his C. difficile colitis, as well as dexamethasone, etoposide, basiliximab, cyclosporin, alemtuzumab, nitrogen mustard and rituximab for relapsing HLH in the setting of concurrent EBV viremia (15 100 copies/mL) and T-cell lymphoma (Figure 1). On Day 2 of hospitalization, the patient developed septic shock and multiorgan system failure requiring multiple vasopressors. Continuous venovenous hemofiltration (CVVH) was started with a replacement fluid rate of 3.6 L/h (30 mL/kg/h), with 50% of the replacement fluid prefilter and 50% postfilter. Anticoagulant citrate dextrose solution A was administered at a rate of 300 mL/h prefilter for anticoagulation. Given the absence of improvement in his hyperkalemia and acid–base status after 8 h, the hemofiltration rate was increased to 7 L/h (58 mL/kg/h) with high bicarbonate (32 mEq/L) and low-potassium (2 meq/L) replacement fluid. Despite the increase in the hemofiltration rate, the patient continued to have persistent hyperkalemia (potassium 6.7 mmol/L) and severe lactic acidosis (pH 7.13 and plasma lactate 20.1 mmol/L). Intermittent hemodialysis (IHD) alternating with CVVH was performed to correct hyperkalemia and severe metabolic acidosis (Figure 1). However, the interruption of CVVH caused worsening volume overload and hypoxemia. The continuous venovenous hemodialysis (CVVHD) with a dialysate rate of 7 L/h and CVVH with replacement fluid at 5 L/h were initiated with the use of two machines (Figure 1). Twenty-four hours after initiating this hemofiltration rate, on Day 6 of hospitalization, the patient's volume status and hemodynamics stabilized with decreasing requirements for vasopressors and an improved serum lactate level of 11.4 mmol/L. We subsequently stopped CVVHD and continued only CVVH with the hemofiltration rate of 5 L/h using one machine. The plasma lactate level continued to decrease to 7.1 mmol/L at a relatively constant rate (Figure 1). Since the rate at which the serum lactate concentration decreased was not different between the lower and higher hemofiltration rates, further investigations were performed.\nFig. 1. Demonstrated serum lactate and bicarbonate levels during hospitalization; CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; IHD, intermittent hemodialysis.\n\n\n\nWe measured lactate concentrations in samples of plasma and effluent from our patient to calculate the lactate clearance by the hemofiltration. The patient's calculated lactate clearance was 79 mL/min or 0.56 mmol/min calculated using UV/P [6]. The effluent fluid lactate (U) was 6.2 mmol/L, the CVVH output (total replacement fluid, citrate and additional volume removed) (V) was 91 mL/min and the plasma lactate (P) was 7.1 mmol/L. The patient's calculation of lactate clearance and plasma lactatefilter were demonstrated as following [7]: Plasmalactatefilter=[(plasmalactate×plasmaflowrate)+(replacementlactate×replacementflowrate)+(citratelactate×citrateflowrate)]/(plasmaflowrate+replacementflowrate+citrateflowrate) \n Plasma lactatefilter=[(7.1×153)+(3×42)+(0×1)]/(153+42+1)=6.2mmol/L \n Lactateclearance=effluentlactate×effluentrate/plasmalactate=6.2×(83+1+7)/7.1 =79mL/min \n\n\nDespite a further reduction in the total CVVH replacement fluid rate from 5 L/h to 3.6 L/min (30 mL/kg/h), the plasma lactic acid level continued to decrease to 5.6 mmol/L with improvement in the metabolic acidosis (ABG, pH of 7.35, pCO2 of 35 mmHg and HCO3 of 18 mmol/L). The patient was able to be weaned off of vasopressors with improvement in his mental status to the point that he was able to communicate with his family. Unfortunately, the patient developed massive lower gastrointestinal bleeding from severe thrombocytopenia and ischemic colitis. Clinically, he continued to deteriorate. After discussion with his family, the patient received palliative treatment and passed away peacefully on Day 24 of hospitalization.\n\nDiscussion\nLactic acidosis can be classified into Type A which occurs as the result of tissue hypoperfusion and Type B seen in the absence of hypoperfusion and associated with toxin-induced impairment of cellular metabolism as could be seen with certain medications or malignancies (Table 2). In this case presentation, the lactic acidosis is likely due to a combination of Type A (from tissue hypoperfusion in the setting of septic shock) and Type B (from underlying malignancy). We presented this case report showing that severe lactic acidosis alone should not be considered as a nonrenal indication for CRRT.\nTable 2. Causes of lactic acidosis\n\nCauses of lactic acidosis\t\nType A\nAcute hypoxia\n\nAnemia\n\nCarbon monoxide poisoning\n\nCardiogenic shock\n\nHemorrhagic shock\n\nSeptic shock\n\nType B\nSystemic disease\nLiver failure\n\nMalignancy\n\n\n\nDrugs or toxins\nMetformin\n\nCyanide\n\nSalicylate, ethylene glycol, methanol, propylene glycol\n\nLinezolid\n\nPropofol\n\nStavudine, didanosine\n\nIsoniazid\n\n\n\nHereditary enzyme deficiency\n\n\t\n\n\nTreatment of lactic acidosis is directed toward correcting the underlying cause and optimizing adequate oxygen delivery to the tissues [5]. There have been many efforts to study the treatment of lactic acidosis. Proposed treatments include bicarbonate therapy [8, 9], alternatives to bicarbonate therapy such as tromethamine [10], carbicarb [11] and dichloroacetate [12], IHD and CRRT [13–16]. The role of bicarbonate in patients with lactic acidosis is controversial [8, 9, 17]. Several studies have suggested that bicarbonate use may in fact cause harm by increasing the arterial and tissue capillary PCO2 and worsening intracellular acidosis [18, 19]. Moreover, bicarbonate therapy may lead to electrolyte disturbances, such as hypokalemia and hypocalcemia. Alternative agents to bicarbonate thus far have not shown any clinical benefit in treatment of patients with lactic acidosis [10, 11].\n\nDialysis and hemofiltration may be required in ICU patients with severe AKI. Even though evidence is lacking, their use is still advocated as treatment modalities for lactic acidosis [5]. Prolonged hemodialysis was reported as a possible treatment option for metformin-induced lactic acidosis [20]. In addition, Schetz [16] included lactic acidosis as one of the nonrenal indications for CRRT. It was believed that extracorporeal elimination with high-volume hemofiltration or dialysis might result in clinically significant reduction of lactate level by increasing the clearance of lactate. However, in this case presentation, we showed that lactate removal by high-volume hemofiltration (58 mL/kg/h in our case) was ineffective in comparison to rate of lactate production in septic shock. Our patient's calculated lactate clearance by CVVH was 79 mL/min (0.56 mmol/min or 4.67 µmmol/kg/min) which was significantly lower than the rate of lactate production in the setting of septic shock (54 µmol/kg/min [21] or 6.4 mmol/min for 120 kg body weight).\n\nThe lactate clearance by CVVH in our case presentation was higher than a reported result in a previous study by Levraut et al. [14] which found a lactate clearance with continuous venovenous hemofiltration with dialysis (CVVHDF) range of 7–36 mL/min a median filter lactate clearance of 24.2 mL/min. This discrepancy could be explained by much lower flow rates of CVVHDF in their study (blood flow rate was 100 mL/min, dialysate 1000 mL/h, median effluent 714 mL/h) than used in our patient as shown in Figure 1. The findings of an ongoing prospective observational study on effects of CVVH on plasma lactate in critically ill patients by Liu et al. (ClinicalTrials.gov identifier, NCT01824771) will elucidate if the dose of CVVH affects lactate clearance.\n\nAlthough lactate clearance by CRRT cannot meet lactate overproduction, our patient's metabolic acidosis did improve with the use of bicarbonate therapy in CRRT as evidenced by the improvement in serum pH (from 7.10 to 7.35) and bicarbonate (from 11 to 18 mmol/L) levels.\n\nNo study has shown that correcting acidosis improves survival especially when the serum pH is higher than 7.1 [8, 9]. The reduction of lactate level during hemofiltration reflects an improvement in patients' hemodynamic status leading to enhanced lactate metabolism [14]. In this case presentation, CRRT helped improve the volume status and optimize the metabolic derangements in the setting of AKI until the effect of treatment for the septic shock and malignancy occurred. The lactic acidosis subsequently improved with the increased lactate metabolism.\n\nIn our case presentation, citrate was used as an anticoagulant for CRRT. Since citrate toxicity is an important cause of high anion gap metabolic acidosis in patients with decreased hepatic blood flow (e.g. in sepsis or other shock states) [22] and studies have demonstrated that lactic acidosis is a risk factor for citrate toxicity [23, 24], patients on CRRT given citrate-based replacement solution need careful monitoring of total calcium concentration along with ionized calcium concentration. In our case report, the patient was found to have lactic acidosis prior to the initiation of CRRT, and there was no evidence of citrate toxicity during CRRT treatment.\n\nCRRT or IHD should only be considered in treatment of patients with severe lactic acidosis if the patient has other indications for initiation of dialysis such as volume overload, metabolic disturbances [25]. Filtered lactate clearance by high-volume CRRT is small compared with overproduction of lactic acid in septic shock. Therefore, lactic acidosis alone should not be the sole indication for initiation of CRRT.\n\nConclusion\nIn summary, although metabolic acidosis is corrected by CRRT, high-volume hemofiltration is not effective for severe lactic acidosis, and this suggests that lactic acidosis may not be an indication for CRRT alone.\n\nAuthors' contributions\nAll authors were involved and approved the final manuscript. All authors had access to the data and a role in writing the manuscript.\n\nConflicts of interest statement\nNone declared.\n==== Refs\nReferences\n1 Madias NE \nLactic acidosis . Kidney Int \n1986 ; 29 : 752 –774 3702227 \n2 Correia CS Bronander KA \nMetformin-associated lactic acidosis masquerading as ischemic bowel . Am J Med \n2012 ; 125 : e9 22365024 \n3 Kreisberg RA \nLactate homeostasis and lactic acidosis . Ann Intern Med \n1980 ; 92 : 227 –237 6766289 \n4 Bakker J Jansen TC \nDon't take vitals, take a lactate . Intensive Care Med \n2007 ; 33 : 1863 –1865 17618419 \n5 Luft FC \nLactic acidosis update for critical care clinicians . J Am Soc Nephrol \n2001 ; 12 (Suppl 17 ): S15 –S19 11251027 \n6 Cockcroft DW Gault MH \nPrediction of creatinine clearance from serum creatinine . Nephron \n1976 ; 16 : 31 –41 1244564 \n7 Meyer TW Walther JL Pagtalunan ME \nThe clearance of protein-bound solutes by hemofiltration and hemodiafiltration . Kidney Int \n2005 ; 68 : 867 –877 16014068 \n8 Cooper DJ Walley KR Wiggs BR \nBicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study . Ann Intern Med \n1990 ; 112 : 492 –498 2156475 \n9 Mathieu D Neviere R Billard V \nEffects of bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic acidosis: a prospective, controlled clinical study . Crit Care Med \n1991 ; 19 : 1352 –1356 1935152 \n10 Nahas GG Sutin KM Fermon C \nGuidelines for the treatment of acidaemia with THAM . Drugs \n1998 ; 55 : 191 –224 9506241 \n11 Leung JM Landow L Franks M \nSafety and efficacy of intravenous Carbicarb in patients undergoing surgery: comparison with sodium bicarbonate in the treatment of mild metabolic acidosis. SPI Research Group. Study of Perioperative Ischemia . Crit Care Med \n1994 ; 22 : 1540 –1549 7924363 \n12 Stacpoole PW Wright EC Baumgartner TG \nA controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group . N Engl J Med \n1992 ; 327 : 1564 –1569 1435883 \n13 Hilton PJ Taylor J Forni LG \nBicarbonate-based haemofiltration in the management of acute renal failure with lactic acidosis . QJM \n1998 ; 91 : 279 –283 9666950 \n14 Levraut J Ciebiera JP Jambou P \nEffect of continuous venovenous hemofiltration with dialysis on lactate clearance in critically ill patients . Crit Care Med \n1997 ; 25 : 58 –62 8989177 \n15 Mariano F Benzi L Cecchetti P \nEfficacy of continuous venovenous haemofiltration (CVVH) in the treatment of severe phenformin-induced lactic acidosis . Nephrol Dial Transplant \n1998 ; 13 : 1012 –1015 9568872 \n16 Schetz M \nNon-renal indications for continuous renal replacement therapy . Kidney Int Suppl \n1999 ; 72 : S88 –S94 10560814 \n17 Kraut JA Kurtz I \nUse of base in the treatment of severe acidemic states . Am J Kidney Dis \n2001 ; 38 : 703 –727 11576874 \n18 Adrogue HJ Rashad MN Gorin AB \nAssessing acid-base status in circulatory failure. Differences between arterial and central venous blood . N Engl J Med \n1989 ; 320 : 1312 –1316 2535633 \n19 Weil MH Rackow EC Trevino R \nDifference in acid-base state between venous and arterial blood during cardiopulmonary resuscitation . N Engl J Med \n1986 ; 315 : 153 –156 3088448 \n20 Guo PY Storsley LJ Finkle SN \nSevere lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin . Semin Dial \n2006 ; 19 : 80 –83 16423187 \n21 Revelly JP Tappy L Martinez A \nLactate and glucose metabolism in severe sepsis and cardiogenic shock . Crit Care Med \n2005 ; 33 : 2235 –2240 16215376 \n22 Oudemans-van Straaten HM Kellum JA Bellomo R \nClinical review: anticoagulation for continuous renal replacement therapy—heparin or citrate? \nCrit Care \n2011 ; 15 : 202 21345279 \n23 Meier-Kriesche HU Gitomer J Finkel K \nIncreased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation . Crit Care Med \n2001 ; 29 : 748 –752 11373461 \n24 Kramer L Bauer E Joukhadar C \nCitrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients . Crit Care Med \n2003 ; 31 : 2450 –2455 14530750 \n25 Schetz MR \nClassical and alternative indications for continuous renal replacement therapy . Kidney Int Suppl \n1998 ; 66 : S129 –S132 9573589\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2048-8505",
"issue": "8(4)",
"journal": "Clinical kidney journal",
"keywords": "continuous renal replacement therapy (CRRT); lactic acidosis; metabolic acidosis",
"medline_ta": "Clin Kidney J",
"mesh_terms": null,
"nlm_unique_id": "101579321",
"other_id": null,
"pages": "374-7",
"pmc": null,
"pmid": "26251702",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": "22365024;9666950;7924363;3088448;11576874;6766289;3702227;21345279;2535633;16423187;9506241;2156475;1935152;16014068;9573589;11251027;1244564;17618419;10560814;14530750;8989177;11373461;16215376;9568872;1435883",
"title": "Lactate clearance and metabolic aspects of continuous high-volume hemofiltration.",
"title_normalized": "lactate clearance and metabolic aspects of continuous high volume hemofiltration"
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"abstract": "OBJECTIVE\nThe aim of this study was to study the effect of modified maintenance doses (MDs) of infliximab on the quality of life (QoL) of patients with ankylosing spondylitis (AS) over a period of 3 years.\n\n\nMETHODS\nMedical records of AS patients (n = 25) who received a normal induction dose but modified MDs as required were retrospectively analyzed. After induction dose and the first MD, patients were followed up every month and were treated with infliximab whenever Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was 4 or greater. The study end points were the percentage of responders defined as reduction of 40% or greater in BASDAI score and improvement in QoL defined by mean change in SF-36 Physical Component Summary score, SF-36 Mental Component Summary score, and Ankylosing Spondylitis Quality of Life (ASQoL) values at week 6 and after the last MD (ie, at the end of 3 years) compared with baseline.\n\n\nRESULTS\nMajority of the patients were males (n = 20), and the mean age of the analysis population was 40.6 ± 10.79 years. At the end of 6 weeks and after the last MD, BASDAI 40 scores were achieved in 100% and 92% of the patients, respectively. From baseline, the mean change in BASDAI score at the end of 6 weeks and after the last MD is -3.56 and -3.40, respectively. The overall mean change in scores (BASDAI, SF-36 Physical and Mental Component Summary, and ASQoL) versus baseline, at 6 weeks, and after the last MD was statistically significant (P < 0.0001).\n\n\nCONCLUSIONS\nThe results of the study suggest that initial induction and an on-demand MD regimen of infliximab based on BASDAI were associated with significant improvement in disease activity and QoL.",
"affiliations": "From the Departments of *Medicine & Rheumatology and †Neurology and Rheumatology, B. R. Singh Hospital & Centre for Medical Education & Research, Kolkata, West Bengal, India.",
"authors": "Sengupta|Sarbani|S|;Ray|Jayanti|J|;Ghosh|Bhaskar|B|",
"chemical_list": "D018501:Antirheumatic Agents; D000069285:Infliximab",
"country": "United States",
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"doi": "10.1097/RHU.0000000000000295",
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"issue": "21(7)",
"journal": "Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases",
"keywords": null,
"medline_ta": "J Clin Rheumatol",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000069285:Infliximab; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D012189:Retrospective Studies; D013167:Spondylitis, Ankylosing; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9518034",
"other_id": null,
"pages": "355-8",
"pmc": null,
"pmid": "26398462",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Quality of Life and Clinical Response to On-Demand Maintenance Doses of Infliximab in Patients With Ankylosing Spondylitis.",
"title_normalized": "quality of life and clinical response to on demand maintenance doses of infliximab in patients with ankylosing spondylitis"
} | [
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"literaturereference": "SENGUPTA S, RAY J, GHOSH B. QUALITY OF LIFE AND CLINICAL RESPONSE TO ON-DEMAND MAINTENANCE DOSES OF INFLIXIMAB IN PATIENTS WITH ANKYLOSING SPONDYLITIS. JOURNAL OF CLINICAL RHEUMATOLOGY 2015?21 (7):355-358.",
"literaturereference_normalized": "quality of life and clinical response to on demand maintenance doses of infliximab in patients with ankylosing spondylitis",
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{
"abstract": "BACKGROUND\nDrug-eluting stent (DES) implantation in a patient with factor V deficiency (F5D) is very complex. No antithrombotic therapy study has been reported for F5D patients who undergo a coronary stenting procedure.\nA 73-year-old woman presented with chest discomfort and exertional dyspnea. Coronary stenting was performed successfully using DES stents.\nThe D-dimer, prothrombin time, and partial thromboplastin time prolongation persisted from admission until 24 hours after coronary stenting. Epistaxis and blood-tinged sputum occurred on day 3. The antiplatelet therapy measured using a Multiplate Analyzer was adequate, and other laboratory findings except factor V activity (14%) were within normal ranges; she was diagnosed with F5D based on low factor V activity.\n\n\nMETHODS\nWhile taking 90 mg of ticagrelor and 100 mg of aspirin daily, the patient revisited due to recurrent epistaxis, hemoptysis, and coughing on day 26. Epistaxis and hemoptysis stopped after the aspirin was discontinued. Finally, the daily maintenance dose was reduced to 90 mg of ticagrelor once.\n\n\nRESULTS\nShe led healthy life for 9 months without any recurrent symptoms and the test results also were stabilized.\n\n\nCONCLUSIONS\nWe report a case of an F5D patient who underwent coronary stenting in the absence of frozen fresh plasma transfusion who received successful maintenance therapy using a single antiplatelet agent (90 mg of ticagrelor/day) with recurrent multiple mucosal bleeding events after coronary stenting.",
"affiliations": "Department of Cardiology, Hanyang University Hanmaem Changwon Hospital, Changwon-si, Republic of Korea.",
"authors": "Choi|Seongil|S|;Song|MooKon|M|",
"chemical_list": "D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor; D000241:Adenosine",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29390379MD-D-17-0553410.1097/MD.0000000000009274092744800Research ArticleClinical Case ReportSuccessful coronary stenting in a patient with factor V deficiency in the absence of fresh frozen plasma transfusion Case reportChoi Seongil MD, PhD∗Song MooKon MDGuo. Weimin Department of Cardiology, Hanyang University Hanmaem Changwon Hospital, Changwon-si, Republic of Korea.∗ Correspondence: Seongil Choi, Department of Cardiology, Hanyang University Hanmaem Changwon Hospital, 21, Woni-daero 682beon-gil, Seongsan-gu, Changwon-si, Gyeongsangnam-do 51497, Republic of Korea (e-mail: saint536@hanmail.net).12 2017 15 12 2017 96 50 e92744 9 2017 21 11 2017 23 11 2017 Copyright © 2017 the Author(s). Published by Wolters Kluwer Health, Inc.2017This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0Abstract\nRationale:\nDrug-eluting stent (DES) implantation in a patient with factor V deficiency (F5D) is very complex. No antithrombotic therapy study has been reported for F5D patients who undergo a coronary stenting procedure.\n\nPatient concerns:\nA 73-year-old woman presented with chest discomfort and exertional dyspnea. Coronary stenting was performed successfully using DES stents.\n\nDiagnoses:\nThe D-dimer, prothrombin time, and partial thromboplastin time prolongation persisted from admission until 24 hours after coronary stenting. Epistaxis and blood-tinged sputum occurred on day 3. The antiplatelet therapy measured using a Multiplate Analyzer was adequate, and other laboratory findings except factor V activity (14%) were within normal ranges; she was diagnosed with F5D based on low factor V activity.\n\nInterventions:\nWhile taking 90 mg of ticagrelor and 100 mg of aspirin daily, the patient revisited due to recurrent epistaxis, hemoptysis, and coughing on day 26. Epistaxis and hemoptysis stopped after the aspirin was discontinued. Finally, the daily maintenance dose was reduced to 90 mg of ticagrelor once.\n\nOutcomes:\nShe led healthy life for 9 months without any recurrent symptoms and the test results also were stabilized.\n\nLessons:\nWe report a case of an F5D patient who underwent coronary stenting in the absence of frozen fresh plasma transfusion who received successful maintenance therapy using a single antiplatelet agent (90 mg of ticagrelor/day) with recurrent multiple mucosal bleeding events after coronary stenting.\n\nKeywords\nblood transfusionfactor V deficiencypercutaneous coronary interventionplatelet aggregation inhibitorOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nFactor V deficiency (F5D) is a rare hematological disorder with an estimated incidence of 1 case per million people.[1,2] Until now, more than 200 cases have been recorded worldwide in the literature.[2] F5D patients present with various clinical manifestations. Although mucosal bleeding is the most common, fatal bleeding complications are also possible. Thus, F5D increases the difficulty of invasive testing, and surgical and procedural treatments. When long-term antithrombotic drugs, including antiplatelet agents and anticoagulants, are required in patients at high risk of bleeding, one of the biggest challenges is coronary intervention to treat coronary artery disease. Most studies recommend preinterventional or preoperative supplementation with fresh frozen plasma (FFP) to reduce bleeding risk.[2,3] However, in addition to the bleeding risk caused by antithrombotic therapy, the hypercoagulable state in coronary intervention has an adverse effect on stent thrombosis, mortality, and prognosis during the postinterventional period.[4] The contemporary standard therapy for significant coronary artery stenosis is implanting a drug-eluting stent (DES). However, because implanting a DES delays endothelial healing and requires long-term antithrombotic therapy, DES implantation in an F5D patient is very complex. No antithrombotic therapy study to date has been reported for F5D patients undergoing coronary stenting. Herein, we report a case of an F5D patient who underwent coronary stenting in the absence of an FFP transfusion and who received successful maintenance therapy using a single antiplatelet agent with recurrent multiple mucosal bleeding events after coronary stenting.\n\n2 Case report\nA 73-year-old woman presented with chest discomfort and New York Heart Association class 2 dyspnea when she climbed stairs 2 weeks ago. She was not taking any medication except hypnotics, and her only cardiovascular risk factor was old age. Although she had had 3 natural childbirths, she had no history of surgery or blood transfusions. No specific findings were observed upon physical examination, electrocardiography (ECG), or chest x-ray imaging, and cardiac biomarkers were within the normal range, but the D-dimer, prothrombin time (PT), partial thromboplastin time (PTT), and activated PTT levels were prolonged. Transthoracic echocardiography showed a normal left ventricular ejection fraction and no regional wall motion abnormality. On the basis of the exercise-induced ECG changes in the treadmill exercise test, coronary angiography was planned to conduct decision-making for appropriate management and prognosis assessment (class I, level of evidence B).[5] After 300 mg of aspirin and 180 mg of ticagrelor were administered, coronary angiography was performed via the right radial artery. A significant stenosis was noted in the left anterior descending coronary artery and right coronary artery; thus coronary stenting was performed successfully using DES stents (Fig. 1). Unexpectedly, D-dimer, PT, and PTT prolongation were maintained at 6 and 24 hours after coronary stenting, and hemoglobin (HgB) decreased from 11.3 to 9.5 g/dL. Although ecchymosis and oozing were present at the right radial artery puncture site, no evidence of bleeding was observed. Aspirin (100 mg daily) and ticagrelor (90 mg twice daily) were administered to prevent a stent thrombosis. The test values to identify the causes of prolonged coagulopathy fell within the normal range. Epistaxis and blood-tinged sputum occurred on day 3 after coronary stenting. Because HgB had dropped to 8.5 g/dL, chest and abdominal computed tomography scans were performed to confirm the possibility of internal bleeding; however, no abnormal findings were observed except aortic calcification. The antiplatelet therapy measured using the Multiplate Analyzer (Roche Diagnostics, Mannheim, Germany) was adequate, but the daily dose of the antithrombotic agent was reduced to 100 mg of aspirin and 90 mg of ticagrelor. After transfusing 2 units of packed red cells, HgB remained >10 g/dL (Fig. 2). On day 5, factor V activity was 14% (reference range 60%–120%), but other laboratory findings, including factor VIII activity, were all within normal ranges; she was diagnosed with F5D based on low factor V activity. Hematochezia occurred on day 6, and ischemic colitis was confirmed via sigmoidoscopy (Fig. 3). After fasting, except antithrombotic agents and intravenous antibiotic treatment, a general diet was made available starting on day 8, and HgB was maintained consistently above 10 g/dL. However, PT, PTT, and D-dimer prolongation persisted. The area under the curve (AUC) was 20 (reference range 1–41) for ticagrelor and 18 (reference range 1–29) for aspirin with the daily maintenance dose of 90 mg of ticagrelor and 100 mg of aspirin, with which she was discharged on day 10.\n\nFigure 1 Coronary angiography. Significant stenoses are evident from the proximal to the mid-portion of the left anterior descending artery and the distal portion of the right coronary artery; the coronary artery vessel sizes were normalized after stenting.\n\nFigure 2 Clinical course and laboratory findings. The prolonged prothrombin time (PT) and partial thromboplastin time (PTT) values were consistent and factor V activity was consistently measured as low (15%); aspirin discontinuance abruptly increased the value of the area under the curve for ticagrelor from 22 to 52. AD = admission day, aPTT = activated PTT, AUC_aspirin = area under the curve for aspirin, AUC_ticagrelor = area under the curve for ticagrelor, HgB = hemoglobin, INR = international normalized ratio, IV = intravenous, PRC = packed red cell, PT = prothrombin time, PTT = partial thromboplastin time.\n\nFigure 3 Sigmoidoscopic findings. Sigmoidoscopy showed mucosal friability, petechial hemorrhage, and discrete ulcers with surrounding edema.\n\nThe patient was readmitted due to recurrent epistaxis, hemoptysis, and cough on day 26 after coronary stenting. HgB and the AUCs of aspirin and ticagrelor were 10.7 g/dL, 19, and 22, respectively, whereas PT, PTT, and factor V activity showed no significant changes (Fig. 2). Due to the recurrent epistaxis and oozing of the nasal mucus membrane, the aspirin was stopped and only the daily maintenance dose of 90 mg of ticagrelor was maintained. HgB remained constant at 9.5 g/dL, and epistaxis and hemoptysis both stopped. The factor V activity and AUC value of ticagrelor 5 days after stopping aspirin were 12 and 52, respectively. After symptoms improved, she was discharged on day 35 with only 90 mg of ticagrelor daily.\n\nThe HgB level was 10 g/dL and the AUC of ticagrelor was 24 at 9 weeks (Fig. 2), and the patient led healthy life for 9 months without any recurrent symptoms. At the 9-month follow-up, the AUC of ticagrelor was stabilized at 18 and the other test results were more stabilized compared with those at the start of coronary stenting (Fig. 2).\n\n3 Discussion\nWe present the case of a patient with F5D and unstable angina who underwent coronary stenting and antithrombotic maintenance therapy with a single antiplatelet agent due to recurrent multiple mucosal bleeding shortly after coronary stenting. In particular, for the first time, we have described maintenance therapy after coronary stenting in an F5D patient. As F5D is a rare hematological disease with an incidence of approximately 1 in a million, it has no established treatment guidelines. Furthermore, there are no guidelines or studies on antithrombotic therapy after coronary stenting in F5D patients.\n\nAlthough F5D is defined as a mild and severe disease in cases with activity >5% and <1%, respectively, factor V activity does not necessarily predict bleeding severity or clinical features, and many patients may present with a mild disease even with factor V activity of <1%.[2] However, F5D therapy depends on the factor V activity level, and is classified as bleeding control and the removal of inhibitors or antibodies of factor V. FFP or platelet transfusion is recommended to control bleeding. In particular, transfusing FFP is recommended to maintain factor V activity at >25% to 30% in cases of bleeding, invasive testing, or surgery.[3,6] In this case, FFP was not transfused because coronary stenting was performed without knowledge of the degree of factor V activity or the existence of F5D. We recognized F5D due to hemoptysis, epistaxis, and hematochezia after coronary stenting. However, we first planned to reduce or modify the dosage of antithrombotic drugs due to the risk of stent thrombosis. This strategy was based on previous reports in which factor V activity was not related to bleeding severity.[2,6] Moreover, successful childbirth delivery was possible without an FFP transfusion, and the success rate for bleeding control was low with FFP transfusion.[3,6] Fortunately, mucosal bleeding in the present case was controlled by adjusting the antithrombotic drug dose. Treatments for the inhibitors or antibodies to factor V are another option and include plasmapheresis, immunosuppressants, steroids, intravenous globulins, and a monoclonal antibody.[2] Such therapies were not used in our case because the inhibitors and autoantibodies for factor V were unknown and such therapies have weak evidence.\n\nAnother notable finding is the effect of 100 mg of aspirin daily on mucosal bleeding in F5D patients. P2Y12 generally plays a key role in dual antiplatelet therapy (DAPT). In this instance, the AUC values of aspirin and ticagrelor were 8 and 10, with 100 mg of aspirin daily and 90 mg of ticagrelor twice a day, respectively. The AUC value for ticagrelor was 22 for a daily regimen of 100 mg of aspirin and 90 mg of ticagrelor, but the AUC for ticagrelor increased to 52 when only the 90 mg of ticagrelor was maintained. This observation emphasizes that ticagrelor's antithrombotic effect is affected by aspirin. In fact, the Platelet Inhibition and Patient Outcomes trial showed that daily combination of 100 mg of aspirin and ticagrelor was superior to aspirin and clopidogrel combined, but the use of 300 mg/day of aspirin wiped out the benefit.[7] Moreover, Kirkby et al[8] demonstrated that aspirin provides additional antiaggregatory effects when only a partial P2Y12 blockade is achieved. Daily 90 mg of ticagrelor administration means incomplete P2Y12 inhibition and 100 mg of aspirin has the enhancing effect of suppressing platelet aggregation for the daily dose of 90 mg of ticagrelor. Aspirin discontinuance with a daily dose of 90 mg of ticagrelor causes ticagrelor to have a weakened antiplatelet effect, which can be expressed as an increased AUC value for ticagrelor. Meanwhile, it is unclear whether the disappearance of mucosal bleeding after stopping aspirin can be ascribed to the antithrombotic effect of aspirin itself or its excessive dose (100 mg/day). However, as the daily dose of 100 mg of aspirin may have had a strong antithrombotic effect in a patient with F5D and mucosal bleeding; aspirin may have to be stopped to control mucosal bleeding when simultaneously taking a P2Y12 receptor blocker.\n\nThe initial loading dose of aspirin, a P2Y12 receptor blocker, and intravenous heparin were used to prevent thrombosis (particularly stent thrombosis) during coronary stenting and standard maintenance antithrombotic therapy after implanting a DES composed of DAPT (aspirin and a P2Y12 receptor blocker). Generally, the optimal range for the antithrombotic effect is known as mid-third platelet inhibition.[4,9] F5D was detected after the coronary stenting procedure; thus, the routine DAPT protocol was applied to coronary intervention, and a decrease in HgB was observed that started on the day of coronary stenting. This finding indicates that a weaker antithrombotic effect is recommended for coronary intervention in patients with F5D. In particular, recurrent mucosal bleeding for daily doses of 90 mg of ticagrelor and 100 mg of aspirin suggests that a weakened antithrombotic effect is also required during maintenance therapy after coronary stenting. The disappearance of mucosal bleeding after stopping the 100 mg of aspirin means that ticagrelor may be more effective than aspirin for controlling mucosal bleeding and maintaining antithrombosis in F5D patients after coronary stenting.\n\nAnother unusual feature of this case beyond the antithrombotic therapy is ischemic colitis. Unlike mucosal bleeding, such as epistaxis or hemoptysis, ischemic colitis is ascribed to tissue hypoperfusion through the reduced blood supply to the mesenteric artery rather than bleeding tendency or a coagulation disorder. In this patient, tissue hypoperfusion may occur due to transient blood flow reduction, suggesting old age, abdominal aortic calcification, and a sudden drop in the hemoglobin level. Thus, it is unclear whether the ischemic colitis seen here was related to F5D. Furthermore, additional evidence is needed regarding whether antithrombotic therapy presents a risk factor for F5D patients developing ischemic colitis.\n\nFinally, the result of mixing tests in which test plasma is combined with normal plasma was normal, and the absence of inhibitors, including anticoagulants, lupus anticoagulant, or another inhibitor type, was documented. However, we neither performed genetic testing nor investigated autoantibodies for factor V due to the testing cost and the fact that it would provide no additional benefit.\n\n4 Conclusions\nWe report a patient with F5D and multiple mucosal bleeding events after coronary stenting who was successfully treated by reducing the daily antithrombotic maintenance dose from DAPT to 90 mg of ticagrelor.\n\nAbbreviations: AUC = area under the curve, DAPT = dual antiplatelet therapy, DES = drug-eluting stent, ECG = electrocardiography, F5D = factor V deficiency, FFP = fresh frozen plasma, HgB = hemoglobin, PT = prothrombin time, PTT = partial thromboplastin time.\n\nPubMed indexing: Choi SI and Song MK.\n\nInformed consent was obtained from the patient. However, because this case report was based on medical records, a waiver of informed consent was obtained for this case report with the ethical approval of the Institute Review Board.\n\nThe author(s) declare no conflicts of interest.\n==== Refs\nReferences\n[1] Thakar K Parikh K Chen Y \nIsolated factor V deficiency in a patient with elevated PT and aPTT during routine pre-operative laboratory screening . Stem Cell Investig \n2014 ;1 :4 .\n[2] Park YH Lim JH Yi HG \nFactor V deficiency in Korean patients: clinical and laboratory features, treatment, and outcome . J Korean Med Sci \n2016 ;31 :208 –13 .26839474 \n[3] Zhang YH Hong DF Hu ZM \nSuccessful laparoscopic common bile duct exploration in a patient with factor V deficiency, a case report and review of literature . Int J Clin Exp Med \n2015 ;8 :14254 –6 .26550406 \n[4] Tantry US Bonello L Aradi D \nConsensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding . J Am Coll Cardiol \n2013 ;62 :2261 –73 .24076493 \n[5] Amsterdam EA Wenger NK Brindis RG \n2014 AHA/ACC Guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . J Am Coll Cardiol \n2014 ;64 :e139 –228 .25260718 \n[6] SanneVellinga ES IngeVangenechten AG \nSuccessful pregnancy in a patient with factor V deficiency: case report and review of the literature . Thromb Haemost \n2006 ;95 :896 –7 .16676084 \n[7] Mahaffey KW Wojdyla DM Carroll K \nTicagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial . Circulation \n2011 ;124 :544 –54 .21709065 \n[8] Kirkby NS Leadbeater PDM Chan MV \nAntiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by either ticagrelor or prasugrel . J Thromb Haemost \n2011 ;9 :2103 –5 .21812912 \n[9] Vries MJ Bouman HJ Olie RH \nDeterminants of agreement between proposed therapeutic windows of platelet function tests in vulnerable patients . Eur Heart J Cardiovasc Pharmacother \n2017 ;3 :11 –7 .27609198\n\n",
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"mesh_terms": "D000241:Adenosine; D000368:Aged; D001780:Blood Coagulation Tests; D023921:Coronary Stenosis; D054855:Drug-Eluting Stents; D005166:Factor V Deficiency; D005260:Female; D006801:Humans; D058921:Purinergic P2Y Receptor Antagonists; D000077486:Ticagrelor",
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"abstract": "Objective Painless thyroiditis (PT) is characterized by transient hyperthyroidism with a low 99mTc uptake. We herein describe 11 cases of PT that occurred during treatment with potassium iodide (KI) for Graves' disease (GD). Methods From August 2016 to December 2018, 11 women with GD who developed PT during treatment with KI were enrolled. Of these patients, 10 discontinued antithyroid drug (ATD) because of side effects and began KI, and 1 patient switched from thiamazole to KI because she was planning a pregnancy. The mean patient age was 40.1 years old. Thyroid function tests, thyroid autoantibodies including anti thyroglobulin antibody (TgAb), anti-thyroperoxidase antibody (TPOAb), and M22-TRAb, and the 99mTc uptake were evaluated at the time of PT. Results All 11 women patients presented with transient thyrotoxicosis in which 99mTc scans revealed a low uptake of 0.34±0.15% (normal 0.70-1.02%). M22-TRAb was absent in all cases except for one (2.4 IU/L), whereas TgAb and TPOAb were present in 10 and 6 cases, respectively. Ten patients returned to a euthyroid status without passing through the post-hypothyroid phase, and one patient underwent total thyroidectomy during the euthyroid phase of PT. Only four patients require beta-blocker therapy. All patients with KI-induced PT except 1 displayed GD remission during a mean observation period of 23.3 months, and 1 patient had recurrence of GD after PT. Conclusion We encountered 11 GD patients who developed PT during treatment with KI, which was initiated after ATD had been discontinued due to side effects.",
"affiliations": "Department of Internal Medicine, Kamijo Thyroid Clinic, Japan.",
"authors": "Kamijo|Keiichi|K|",
"chemical_list": "D013956:Antithyroid Agents; D001323:Autoantibodies; D011193:Potassium Iodide",
"country": "Japan",
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"doi": "10.2169/internalmedicine.6411-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n33431733\n10.2169/internalmedicine.6411-20\nOriginal Article\nClinical Studies on Potassium Iodide-induced Painless Thyroiditis in 11 Graves' Disease Patients\nKamijo Keiichi 1\n1 Department of Internal Medicine, Kamijo Thyroid Clinic, Japan\nCorrespondence to Dr. Keiichi Kamijo, katt@cocoa.ocn.ne.jp\n\n8 1 2021\n1 6 2021\n60 11 16751680\n1 10 2020\n19 11 2020\nCopyright © 2021 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nObjective\n\nPainless thyroiditis (PT) is characterized by transient hyperthyroidism with a low 99mTc uptake. We herein describe 11 cases of PT that occurred during treatment with potassium iodide (KI) for Graves' disease (GD).\n\nMethods\n\nFrom August 2016 to December 2018, 11 women with GD who developed PT during treatment with KI were enrolled. Of these patients, 10 discontinued antithyroid drug (ATD) because of side effects and began KI, and 1 patient switched from thiamazole to KI because she was planning a pregnancy. The mean patient age was 40.1 years old. Thyroid function tests, thyroid autoantibodies including anti thyroglobulin antibody (TgAb), anti-thyroperoxidase antibody (TPOAb), and M22-TRAb, and the 99mTc uptake were evaluated at the time of PT.\n\nResults\n\nAll 11 women patients presented with transient thyrotoxicosis in which 99mTc scans revealed a low uptake of 0.34±0.15% (normal 0.70-1.02%). M22-TRAb was absent in all cases except for one (2.4 IU/L), whereas TgAb and TPOAb were present in 10 and 6 cases, respectively. Ten patients returned to a euthyroid status without passing through the post-hypothyroid phase, and one patient underwent total thyroidectomy during the euthyroid phase of PT. Only four patients require beta-blocker therapy. All patients with KI-induced PT except 1 displayed GD remission during a mean observation period of 23.3 months, and 1 patient had recurrence of GD after PT.\n\nConclusion\n\nWe encountered 11 GD patients who developed PT during treatment with KI, which was initiated after ATD had been discontinued due to side effects.\n\npainless thyroiditis\npotassium iodide\nGraves' disease\n==== Body\nIntroduction\n\nThe administration of stable iodine to hyperthyroid patients provides a clinical benefit (1-3). In Japan, where the iodine intake is sufficient, among hyperthyroid patients with antithyroid drug (ATD)-associated side effects, potassium iodide (KI) therapy is effective in two-thirds of cases, and about 40% of patients experience remission after KI therapy alone (4). In patients with mild Graves' disease (GD), KI is a possible alternative initial treatment for this condition (5).\n\nPainless thyroiditis (PT also called silent thyroiditis) can be subclassified into the sporadic type (unrelated to pregnancy), postpartum thyroiditis, gestational PT (6), exogenous PT, and others.\n\nWe herein report cases of KI-induced PT that occurred during treatment for GD, mostly after the cessation of ATD due to side effects.\n\nMaterials and Methods\n\nFrom August 2016 to December 2018, 11 patients who met the eligibility criteria and gave their written informed consent were enrolled in the study. The study cohort comprised 11 women who developed PT during treatment with KI at 50 mg or 100 mg daily (50 mg KI is equivalent to 38.2 mg inorganic iodide; Nichiiko, Tokyo, Japan) for GD. These patients were outpatients of the Kamijo Thyroid Clinic, and the median age at the diagnosis was 40 years old (range, 21-56 years old). Ten GD patients discontinued thionamide due to side effects and began to take KI. The remaining patient discontinued methylmercaptoimidazole (MMI) and switched to KI because she was planning a pregnancy.\n\nTests (normal ranges in parentheses) were performed with an electrochemiluminescence immunoassay (Roche Diagnostics, Mannheim, Germany) for free thyroxine (FT4) (0.80 to 1.90 ng/dL), free triiodothyronine (FT3) (2.00-4.40 pg/mL), and thyrotropin (TSH) (0.45-4.50 μU/mL). The thyroid weight was estimated by the previously reported method (7). The normal range of female thyroid weight is 15 to 25 g. The cut-off values of anti-thyroperoxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) were 30 and 40 IU/L, respectively, and the values were calculated by a receiver operating characteristic (ROC) analysis based on patients with Hashimoto's disease and normal controls pathologically diagnosed according to resected tissue (data not shown). The M22-TRAb levels were measured with the inhibition assay kit Elecsys anti-TSH receptor assay (Roche Diagnostic) according to the manufacturer's instructions (8). This assay detects M22-TRAb via the inhibition of a monoclonal antibody (M22), which binds to the extracellular domain of porcine TSH receptor. M22-TRAb was considered present when the value exceeded 2.0 IU/L (8). The intra- and inter-assay coefficients of variation for M22-TRAb in 4 different serum samples ranged from 0.8-9.4% and 1.3-22.0%, respectively. The 20-minute uptake of 99mTc pertechnetate was assessed immediately after thyrotoxicosis was diagnosed. According to the ROC analysis with untreated GD (n=1,234) and PT (n=679), the 99mTc uptake cut-off value was to be 1.02%. The sensitivity and specificity of the optimal cut-off value were 99.8% and 100%, respectively. When the 99mTc uptake is <0.70%, all thyrotoxic patients are considered to have PT. Thus, the reference range is 0.70% to 1.02%.\n\nThe diagnosis of PT was based on 1) a transient increase in FT3 and FT4 with suppressed TSH (<0.01 μU/mL), 2) a painless thyroid gland, and 3) a marked decrease in the thyroid 99mTc uptake. In all cases, PT occurred during treatment with KI. None of the 11 patients were using levothyroxine or amiodarone at the time of the diagnosis.\n\nResults\n\nEnrollment and characteristics of patients with KI-induced PT\n\nTable 1 summarizes the clinical and laboratory findings of the 11 patients. The dose of KI at the diagnosis of PT was 52.1±19.3 (mean±standard deviation) mg daily (range, 38.2-76.4). Routine blood work detected evidence of thyrotoxicosis approximately 18.5±14.5 months (range, 2.0-45.0) after the initiation of KI therapy.\n\nTable 1. Summary of the Clinical and Laboratory Findings and Thyroid Tests at the Diagnosis of PT in 11 Patients with KI-induced PT.\n\nCase No.\tAge (years)\tReason for use of KI\tKI dose (mg)\tFT4 levels (N: 0.80-1.90 ng/dL)\tFT3 levels (N: 2.00-4.40 pg/mL)\tTSH levels (N: 0.45-4.50 μU/mL)\tThyroid weight (10-25 g)\t99mTc uptake (N: 0.70-1.02%)\tM22-TRAb (N: ≤2.0 IU/L)\tTPOAb (N: <30 IU/mL)\tTgAb (N:<40 IU/mL)\t\n1\t29\tSide effect of PTU\t38.2\t2.74\t6.51\t<0.01\t26\t0.59\t0.3\t597.1\t775\t\n2\t21\tSide effect of MMI\t76.4\t3.81\t10.34\t<0.01\t43\t0.27\t0.5\t92.2\t72.7\t\n3\t38\tSide effect of MMI\t38.2\t3.06\t8.53\t<0.01\t36\t0.21\t2.4\t17.4\t2,023\t\n4\t55\tSide effect of MMI\t76.4\t2.04\t6.67\t<0.01\t25\t0.30\t0.3\t<5.0\t301.4\t\n5\t56\tSide effect of MMI\t38.2\t2.34\t4.5\t<0.01\t23\t0.33\t0.7\t126.2\t1,035\t\n6\t53\tSide effect of MMI\t38.2\t4.74\t14.77\t<0.01\t35\t0.65\t0.3\t600\t496.3\t\n7\t37\tSide effect of MMI and PTU\t38.2\t4.64\t10.63\t<0.01\t34\t0.26\t1.3\t14.6\t68.3\t\n8\t38\tPlanning a pregnancy\t38.2\t2.34\t5.73\t<0.01\t33\t0.29\t0.3\t<5.0\t301.4\t\n9\t34\tSide effect of MMI\t76.4\t2.77\t6.55\t<0.01\t36\t0.21\t0.6\t536.3\t684.4\t\n10\t52\tSide effect of MMI\t38.2\t2.51\t5.51\t<0.01\t34\t0.39\t0.3\t119.7\t4,000\t\n11\t28\tSide effect of MMI\t76.4\t2.01\t5.05\t<0.01\t50\t0.20\t1.9\t12.8\t19.5\t\n\t\tMean±standard deviation\t52.1±19.3\t3.00±0.98\t7.71±3.10\t\t34.1±7.0\t0.34±0.15\t\t\t\t\n\t\tRange\t38.2-76.4\t2.01-4.74\t4.50-14.77\t\t23-50\t0.20-0.65\t\t\t\t\nPT: painless thyroiditis, KI: potassium iodide, PTU: propylthiouracil, MMI: methylmercaptoimidazole, TPOAb: anti-thyroperoxidase antibody, TgAb: anti-thyroglobulin antibody\n\nBlood tests revealed suppressed TSH (<0.01 μU/mL) along with elevated FT4 (3.00±0.98 ng/dL (mean±standard deviation) (normal, 0.80-1.90 ng/dL) and FT3 (7.71±3.10 pg/mL (normal, 2.00-4.40 pg/mL). During the thyrotoxic phase, serologic tests and a thyroid scan with 99mTc were performed in all 11 patients. M22-TRAb was negative except in 1 patient whose value (2.4 IU/L) was just above the reference range (normal: <2.0 IU/L). Six patients (54.5%) had elevated TPOAb (>30 IU/mL), and 10 (90.9%) had elevated TgAb (>40 IU/mL). The thyroid weights were mildly enlarged [34.1±7.0 g (normal, 15-25g)]. A thyroid scan with 99mTc revealed a decreased uptake at 0.34±0.15% (reference range, 0.80-1.20%). The thyroid images obtained by 99mTc scan in all patients with KI-induced PT showed an extremely diminished uptake by the thyroid, although a dark structure was visible in the salivary glands, consistent with PT, as shown in Fig. 1.\n\nFigure 1. 99mTc thyroid scan showing an extremely diminished uptake by the thyroid, although a dark structure is visible in the salivary glands.\n\nKI treatment was promptly discontinued after the diagnosis of PT in all patients. During the thyrotoxic phase, 8 patients (73%) were symptomatic, with palpitations being the most common symptom, followed by shortness of breath, tremors, perspiration, heat intolerance, and fatigue. Four patients required temporary β-blocker therapy. No specific therapeutic intervention was required for these patients because their thyroid dysfunction resolved spontaneously.\n\nTimeline of PT\n\nThe details of the clinical course and prognosis of the 11 patients are shown in Table 2. The mean period from thyrotoxicosis to euthyroidism was 72.7±45.9 days (range, 34-174 days). The FT4 levels at 100.4±30.0 days prior to PT were normal at 1.43±0.22 ng/dL (range, 1.00-1.70 ng/dL). The euthyroid condition remained in 9 patients for 315.2±44.1 days (range, 84-558 days) after PT. No hypothyroidism following thyrotoxicosis was observed.\n\nTable 2. The Clinical Course and Prognosis of KI-induced PT.\n\nCase No.\tFT4 value (months: mos) prior to PT\tMonths to PT from KI initiation\tFT4 values at PT\tβ-blocker\tDays to spontaneous normalization\tFT4 values at normalization\tHypothyroid phase\tPrognosis after PT\t\n1\t1.56 (2 mos)\t2\t2.74\tNot\t54\t0.98\tno\tTotal thyroidectomy immediately after recovery from PT\t\n2\t1.53 (2 mos)\t24\t3.81\tPr\t132\t1.51\tno\tGD remission for 14 mos\t\n3\t1.53 (2 mos)\t6\t3.06\tNot\t41\t1.49\tno\tGD remission for 24 mos\t\n4\t1.06 (2 mos)\t36\t2.04\tNot\t34\t1.00\tno\tGD remission for 24 mos\t\n5\t1.58 (4 mos)\t12\t2.34\tNot\t41\t1.30\tno\tGD recurred 49 days after recovery from PT\t\n6\t1.23 (3 mos)\t10\t4.74\tNot\t48\t0.81\tno\tGD remission for 26 mos\t\n7\t1.29 (3 mos)\t45\t4.64\tNot\t45\t1.67\tno\tGD remission for 34 mos\t\n8\t1.31 (4 mos)\t36\t6.89\tPr\t84\t1.22\tno\tGD remission for 22 mos\t\n9\t1.78 (4 mos)\t16\t2.77\tNot\t108\t1.53\tno\tGD remission for 22 mos\t\n10\t1.26 (4 mos)\t9\t2.51\tPr\t44\t1.31\tno\tGD remission for 36 mos\t\n11\t1.70 (2 mos)\t12\t2.01\tPr\t174\t0.94\tno\tGD remission for 8 mos\t\nMean± standard deviation\t1.44±0.22 (2.9±0.9)\t18.9±14.0\t3.41±1.49\t\t73.2±46.1\t1.25±0.29\t\t\t\nRange\t1.06-1.78 (2.0-4.0)\t2.0-45.0\t(2.01-6.89)\t\t(34-174)\t(0.81-1.67)\t\t\t\nKI: potassium iodide, PT: painless thyroiditis, Pr: prescribed, Not: not prescribed, GD: Graves’ disease\n\nIn case 5 only, GD recurred 49 days after PT, as shown in Table 2. Case 1 who was planning a pregnancy underwent total thyroidectomy immediately after recovery from PT, as described in detail below.\n\nPathological findings\n\nCase 1 stopped propylthiouracil (PTU) because of myeloperoxidase-anti-neutrophil cytoplasmic antibody [MPO-ANCA: 14.3 IU/mL (normal, <3.5)]-associated general arthralgia and started KI (50 mg daily). Seventy-seven days after the initiation of KI, she developed PT. The patient received no therapy, and 54 days later she was clinically euthyroid with FT3 2.31 pg/mL, FT4 0.98 ng/dL, and TSH <0.01 μU/mL. She therefore underwent total thyroidectomy 71 days later, as previously decided. The histology of the resected thyroid showed cells in the papillary folds that extended into the lumen of the follicles (Fig. 2a), consistent with GD and disrupted thyroid follicles (Fig. 2b). No oxyphilia or evidence of granulomatous thyroiditis was seen.\n\nFigure 2. Pathology of the resected thyroid gland in a 29-year-old female Graves’ disease patient with KI-induced painless thyroiditis. The cells are present in the papillary folds and extend into the lumen of the follicles [arrow in (a)] and (b) disrupted follicles [arrowhead in (b)] (Hematoxylin and Eosin staining, ×20).\n\nDiscussion\n\nTo our knowledge, the present study is the first case study of patients who developed PT during treatment with KI for GD. Ten patients started KI because of discontinuation of ATD due to side effects. At the diagnosis of the thyrotoxic phase of PT, the mean 99mTc scintigram was 0.34% (range 0.20-0.60%), and all patients spontaneously achieved clinical and biochemical euthyroidism, consistent with PT. In this study, no hypothyroidism following thyrotoxicosis was observed. More recently in 2020, outside of our observation period, two patients with KI-induced PT showed spontaneous resolution with subsequent hypothyroidism. One of these two patients is currently receiving levothyroxine (data unshown).\n\nInterestingly, 60.7% of cases of PT that occurred in GD patients, directly recovered to a euthyroid status without passing through the hypothyroid phase, in contrast with 40% of cases of PT in Hashimoto's thyroiditis patients (6). Regarding the spontaneous remission of GD, Codaccioni et al. (9) reported that treatment of patients with hyperthyroid GD with β-adrenergic antagonist drugs was followed by remission of hyperthyroidism in 30.8% of cases. Their patients showed a homogeneous thyroid 99mTc uptake and 62% of them were positive for TSAb at the diagnosis of GD. In contrast, our reported cases showed an extremely diminished thyroid 99mTc uptake, although the dark structures were visible in the salivary gland. These finding were consistent with PT, that occurred in Hashimoto's thyroiditis patients.\n\nIn our experience, 99mTc uptake was not significantly different between PT occurring in GD remission (n=163) and KI-induced PT (n=11) (0.38±0.19% vs 0.34±0.15%; p=0.4785). However, Hays and Wesselossky (10) reported that Lugol's solution induced the suppression of the 99mTc thyroid uptake. In fact, Hamada et al. (11) reported two patients with mild GD who were misdiagnosed as PT because of low 99mTc uptake during KI therapy. However, they also emphasized that, aside from two cases, the 99mTc uptake could be used to differentiate PT from GD in most of patients with GD receiving KI therapy. Further studies will be needed to establish the effect of iodine on the 99mTc uptake.\n\nIn our study, only 1 patient showed relapse of GD 49 days after PT, and another patient underwent a total thyroidectomy with recovery of euthyroidism as previously decided because she was planning a pregnancy. The mechanism underlying the high remission rates of GD after KI-induced PT remained unclear. However, there was a case report of spontaneous remission of GD preceded by PT (12), suggesting that PT might have some effect on the prognosis of GD.\n\nPhysiologically, iodine is an indispensable constituent of thyroid hormones, and the recommended daily adult iodine intake is 150 μg. The thyroid gland has intrinsic regulatory mechanisms that maintain normal thyroid function even in the presence of iodine excess (13). Wolff and Chaikoff (14) reported that the organic binding of iodide in the rat thyroid is blocked when the plasma iodide level reaches a critical threshold. This acute inhibitory effect of iodide on thyroid hormone synthesis is called the acute Wolf-Chaikoff effect and is due to increased intrathyroid iodine concentration. They next demonstrated that this inhibitory effect of excess iodide is transient, lasting approximately 48 hours, which was known as escape from the acute Wolff-Chaikoff effect. Eng et al. demonstrated the escape from it was caused by a decrease in Na+/I- symporter mRNA with a resultant decreased iodide transport into the thyroid (15).\n\nIn addition to this physiological action of iodide, the administration of stable iodine to hyperthyroid patients produces clinical benefits by inhibiting the release of thyroid hormone (16) and its synthesis due to a decrease in TPO mRNA (12). Historically, iodine was used to treat toxic goiter as early as 1840 by von Basedow, who reported an improvement in all clinical symptoms by iodine administration in one woman (17). From Japan, Okamura et al. (4) reported that KI therapy was effective in two-thirds of patients who discontinued ATD because of side effects, and about 40% of patients experienced remission after KI therapy alone.\n\nIn the present study, we prescribed KI for the treatment of GD patients who discontinued ATD because of adverse effects. Unexpectedly, we found that 11 patients developed PT during KI therapy.\n\nAmiodarone is a benzofuranic derivative that contains approximately 37% iodine by weight. The amount of iodine released is approximately 6 mg/day for each 200-mg tablet. Interestingly, amiodarone also leads to destructive thyrotoxicosis, known as Type 2 amiodarone-induced thyrotoxicosis in the normal thyroid (18). Chiovato et al. (19) demonstrated in an in vitro study that amiodarone has a cytotoxic effect on FRTL-5 cells, CHO cells, and human thyroid follicles obtained from nontoxic goiters at surgery.\n\nIn contrast, KI has a cytotoxic effect on only human thyroid follicles that is abolished by MMI. Furthermore, Xu et al. (20) showed a cytotoxic effect due to KI by demonstrating that excess iodine contributes to autophagy suppression and apoptosis of thyroid follicular cells using a cell line of human thyroid follicular epithelial cells. The pathogenesis of KI-induced PT is unclear but may be related to this cytotoxic effect of KI. In addition, because 10 of the 11 patients in our current study with KI-induced PT were positive for TgAb and/or TPOAb, an autoimmune mechanism may be involved in this process.\n\nFinally, we emphasize that clinicians who manage GD patients who received KI after discontinuing ATD due to side effects., should be alert for KI-induce PT.\n\nStudy limitations\n\nThe present study was limited by the fact that only patients treated for KI for GD after discontinuing ATD due to side effects were evaluated. Future studies should confirm whether or not untreated patients with GD who received initial therapy of KI similarly develop PT.\n\nConclusion\n\nWe herein report for the first time that 11 patients with GD developed PT during treatment with KI following ATD treatment cessation due to side effects.\n\nThe author states that he has no Conflict of Interest (COI).\n==== Refs\n1. Star P , Walcoitt HP , Segall HN , Means JH . The effect of iodin in exophthalmic goiter. Arch Int Med 34 : 352-364, 1924.\n2. Volpé R , Johnston NW . The effect of small doses of stable iodine in patients with hyperthyroidism. Ann Intern Med 56 : 577-589, 1962.13926662\n3. Thalassinos NC , Fraser TR . Effect of potassium iodine on relapse-rate of thyrotoxicosis treated with antithyroid drugs. Lancet 2 : 183-184, 1971.4104847\n4. Okamura K , Sato K , Fujikawa M , Bandai S , Ikenoue H , Takanari K . Remission after potassium iodide therapy in patients with Graves' hyperthyroidism exhibiting thionamide-associated side effects. J Clin Endocrinol Metab 99 : 3995-4002, 2014.25144628\n5. Uchida T , Goto H , Kasai T , et al . Therapeutic effectiveness of potassium iodine in drug-naïve patients with Graves' disease: a single-center experience. Endocrine 47 : 506-511, 2014.24493028\n6. Kamijo K . A case report of gestational painless thyroiditis. J Autoimmune Dis 4 : 1-3, 2018.\n7. Kamijo K . Clues to the discovery of thyroid disease. J Jpn Med Assoc 141 : 2402-2406, 2013(in Japanese).\n8. Kamijo K , Togashi K . ECLIA TRAb and Mc4-TSAb. J Jpn Thyroid Associ 2 : 11-15, 2011(in Japanese).\n9. Codaccioni JL , Orgiazzi L , Blanc P , Pugeat M , Roulier R , Carayon P . Lasting remissions is patients treated for Graves' hyperthyroidism with propranolol alone: a pattern of spontaneous evolution of the disease. J Clin Endocrinol Metab 67 : 656-662, 1988.3417846\n10. Hays MT , Wesselossky B . Simultaneous measurement of thyroidal trapping (99mTcO4-) and binding (131I-): clinical and experimental studies in man. J Nucl Med 14 : 785-792, 1973.4743029\n11. Hamada K , Maruta T , Mizokami T , Higasi K , Tajiri J . Two cases of mild Graves' disease who were misdiagnosed as painless thyroiditis by Tc-99m uptake during KI therapy. J Jpn Thyroid Associ 5 : 121-123, 2014(in Japanese).\n12. Nagai Y , Toya T , Fukuoka K , Tanakadi N , Yanagi S , Kobayashi K . Occurrence and spontaneous remission of Graves hyperthyroidism precede by painless thyroiditis. Endocr J 44 : 881-885, 1997.9622306\n13. Rotti E , Uberti ED . Iodine excess and hyperthyroidism. Thyroid 11 : 493-500, 2001.11396708\n14. Wolff J , Chaikoff H . Plasma inorganic iodide as homeostatic regulator of thyroid function. J Biol Chem 174 : 555-564, 1948.18865621\n15. Eng PHK , Cardoca GR , Fang S-L , et al . Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinology 140 : 3404-3410, 1999.10433193\n16. Wartofsky L , Ransil BJ , Ingbar SH . Inhibition by iodine of the release of thyroxine from the thyroid glands of patients with thryrotoxicosis. J Clin Invest 49 : 78-86, 1970.5409810\n17. Basedow KA . [Exophthalmos due to hypertrophy of tissues in the orbit]. Weekly J General Med No 13 : 197-204, 220-228, 1840.\n18. Bartelena L , Bogazzi F , Chivato L , et al . 2018 European Thyroid Association (ETA) guidelines for the management of amiodarone-associated thyroid dysfunction. Eur Thyroid J 7 : 55-66, 2018.29594056\n19. Chiovato L , Martino E , Tonacchera M , et al . Studies on the in vitro cytotoxic effect of amiodarone. Endocrinology 134 : 2277-2282, 1994.8156930\n20. Xu C , Wu F , Mao C , et al . Excess iodine promotes apotosis of thyroid follicular epithelial cells by inducing autophagy suppression and is associated with Hashimoto thyroiditis disease. J Autoimmunity 75 : 50-57, 2016.27448770\n\n",
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"issn_linking": "0918-2918",
"issue": "60(11)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "Graves' disease; painless thyroiditis; potassium iodide",
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D013956:Antithyroid Agents; D001323:Autoantibodies; D005260:Female; D006111:Graves Disease; D006801:Humans; D011193:Potassium Iodide; D013966:Thyroiditis; D013971:Thyrotoxicosis",
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"title": "Clinical Studies on Potassium Iodide-induced Painless Thyroiditis in 11 Graves' Disease Patients.",
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{
"abstract": "OBJECTIVE\nTo develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients.\n\n\nMETHODS\nA putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed.\n\n\nRESULTS\nAn analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048).\n\n\nCONCLUSIONS\nKeguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).",
"affiliations": "China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Integrative Medical Center, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Integrative Medical Center, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Department of Radiology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Research Center for Clinical and Translational Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Integrative Medical Center, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Integrative Medical Center, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Research Center for Clinical and Translational Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;College of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China.;Integrative Medical Center, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.;Sichuan Evidence-Based Medicine Center of Traditional Chinese Medicine Affliated Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.;Department of Integrated Treatment, General Hospital of Central Theater Command, Wuhan, 430070, China.;National Clinical Research Center for Infectious Diseases, Beijing, 100039, China.;Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. qeq2004@sina.com.;Integrative Medical Center, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. wrl7905@163.com.;China Military Institute of Chinese Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China. pharmacy302xxh@126.com.",
"authors": "Wang|Jia-Bo|JB|;Wang|Zhong-Xia|ZX|;Jing|Jing|J|;Zhao|Peng|P|;Dong|Jing-Hui|JH|;Zhou|Yong-Feng|YF|;Yang|Guang|G|;Niu|Ming|M|;Zhao|Xu|X|;Jiang|Tian-Jun|TJ|;Bi|Jing-Feng|JF|;Xu|Zhe|Z|;Zhang|Ping|P|;Wu|Dan|D|;Bai|Zhao-Fang|ZF|;Guo|Yu-Ming|YM|;Yu|Si-Miao|SM|;Sun|Yong-Qiang|YQ|;Zhang|Zi-Teng|ZT|;Zhan|Xiao-Yan|XY|;Li|Peng-Yan|PY|;Ding|Jin-Biao|JB|;Zhao|Peng-Fei|PF|;Song|Xue-Ai|XA|;Tang|Jian-Yuan|JY|;He|Dong-Chu|DC|;Chen|Zhu|Z|;Qin|En-Qiang|EQ|;Wang|Rui-Lin|RL|;Xiao|Xiao-He|XH|",
"chemical_list": "D004365:Drugs, Chinese Herbal; D016898:Interferon-alpha; D061466:Lopinavir",
"country": "China",
"delete": false,
"doi": "10.1007/s11655-020-3426-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1672-0415",
"issue": "26(9)",
"journal": "Chinese journal of integrative medicine",
"keywords": "COVID-19; Chinese medicine; SARS-CoV-2; acute respiratory distress syndrome",
"medline_ta": "Chin J Integr Med",
"mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000086382:COVID-19; D002681:China; D018352:Coronavirus Infections; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004365:Drugs, Chinese Herbal; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D055048:Integrative Medicine; D016898:Interferon-alpha; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011024:Pneumonia, Viral; D018570:Risk Assessment; D045169:Severe Acute Respiratory Syndrome; D012720:Severity of Illness Index; D015996:Survival Rate",
"nlm_unique_id": "101181180",
"other_id": null,
"pages": "648-655",
"pmc": null,
"pmid": "32676976",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "32020915;32187464;18847397;32109013;10793167;32086938;32065348;29908432;26352116;31872722;16437735;31776962;31986264;16912951;32118371;31216912;31995857;26695637;21457512;15306395;30413355;7652926;26209933;22797452;32105632;28208675",
"title": "Exploring an Integrative Therapy for Treating COVID-19: A Randomized Controlled Trial.",
"title_normalized": "exploring an integrative therapy for treating covid 19 a randomized controlled trial"
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"literaturereference": "WANG J, WANG Z, JING J, ET.AL. EXPLORING AN INTEGRATIVE THERAPY FOR TREATING COVID?19: A RANDOMIZED CONTROLLED TRIAL. CHINESE JOURNAL OF INTEGRATIVE MEDICINE. 2020?.",
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{
"abstract": "The aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU+6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m(-2) i.v. bolus preceded by LV 100 mg m(-2) i.v. bolus on days 1-5, or 6 monthly cycles of sequential MTX 200 mg m(-2) i.v. days 1 and 15 and FU 600 mg m(-2) i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h x 6 doses). Levamisole 50 mg p.o. t.i.d. on days 1-3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX --> FU and FU+LV (77 vs 77% at 5 years; P = 0.90), as were 5-year disease-free survivals (67 vs 63%; P = 0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX --> FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer.",
"affiliations": "Oncologia Medica Ospedale S Martino, Largo Benzi 10, Genova 16132, Italy. alberto.sobrero@hsanmartino.liguria.it",
"authors": "Sobrero|A|A|;Frassineti|G|G|;Falcone|A|A|;Dogliotti|L|L|;Rosso|R|R|;Di Costanzo|F|F|;Costanzo|F D|FD|;Bruzzi|P|P|;|||",
"chemical_list": "D002955:Leucovorin; D005472:Fluorouracil; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1038/sj.bjc.6602276",
"fulltext": "\n==== Front\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group\n\n6602276\n10.1038/sj.bjc.6602276\n15611795\nClinical Studies\nAdjuvant sequential methotrexate → 5-fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer\nSobrero A 1*\nFrassineti G 2\nFalcone A 3\nDogliotti L 4\nRosso R 5\nCostanzo F D 6\nBruzzi P 5\n1 Oncologia Medica Ospedale S Martino, Largo Benzi 10, Genova 16132, Italy\n2 Istituto Oncologico Romagnolo, Forli, Italy\n3 Oncologia medica, Ospedale di Livorno, Italy\n4 Cattedra di Oncologia Medica, Universita' di Torino, Italy\n5 Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy\n6 Oncologia Medica Ospedale di Careggi, Firenze, Italy\n* Author for correspondence: alberto.sobrero@hsanmartino.liguria.it\n7 Intergruppo Nazionale Terapia Adiuvante del Carcinoma del Colon\n\n21 12 2004\n14 01 2005\n17 01 2005\n92 1 2429\n10 08 2004\n12 10 2004\n20 10 2004\nCopyright 2005, Cancer Research UK\n2005\nCancer Research UK\nThe aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU+6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m−2 i.v. bolus preceded by LV 100 mg m−2 i.v. bolus on days 1–5, or 6 monthly cycles of sequential MTX 200 mg m−2 i.v. days 1 and 15 and FU 600 mg m−2 i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h × 6 doses). Levamisole 50 mg p.o. t.i.d. on days 1–3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX → FU and FU+LV (77 vs 77% at 5 years; P=0.90), as were 5-year disease-free survivals (67 vs 63%; P=0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX → FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer.\n\nmethotrexate\n5-fluorouracil\nleucovorin\nadjuvant\ncolorectal cancer\n==== Body\nA series of improvements have been made in the adjuvant treatment of node-positive colon cancer. The first was the demonstrated efficacy of 12 months of 5-fluorouracil (FU) levamisole in 1990 (Moertel et al, 1990) and of FU 6-s-leucovorin (LV) in 1993 (Wolmark et al, 1993), and the second was the proven equivalence of only 6 months of FU LV to the standard 12 months of FU levamisole, 5 years later (Haller et al, 1998). The third was the demonstration that the benefit of adjuvant chemotherapy extends to elderly patients as well (Sargent et al, 2001). And the last advancement regards the additional substantial benefit that the doublet FU+oxaliplatin provides as compared to optimal FU chemotherapy (Andre et al, 2004). Other issues have been addressed and definitely answered by large-scale randomised trials in the last 5 years. Such is the case for the optimal dose of LV to potentiate FU: no need for high dose (Haller et al, 1998; Quasar, 2000); the best schedule of FU LV: equivalence between the weekly and the monthly schedule (Kerr, 2000), the lack of efficacy of levamisole (Haller et al, 1998; Quasar, 2000), the equivalence of the bolus and infusional FU regimens (Andre et al, 2003) and the inefficacy of short-term early postoperative intraportal FU infusions (Liver infusion meta-analysis group, 1997).\n\nINTACC is an Italian intergroup that has recently reported another large-scale randomised trial of adjuvant chemotherapy for colon cancer comparing FU levamisole vs FU LV levamisole (Di Costanzo et al, 2003). When the accrual of that first study was completed in February 1995, levamisole was still considered part of the standard adjuvant treatment. We postulated that our experimental arm in the first study was unlikely to be inferior to the standard arm and used that arm, FU LV levamisole, given for 6 months as control of the second study. The experimental arm was decided to be the sequential combination of methotrexate (MTX) → FU (Marsh et al, 1991) along with levamisole. This choice was based on the results of the meta-analysis on MTX → FU vs FU in the advanced setting (Advanced colorectal cancer metaanalysis, 1994), suggesting that it was reasonable to test this combination in the adjuvant setting. The design of this trial seems definitely outdated in 2004, but at the time of planning, only an alternative modulation of FU other than LV could be feasible within our intergroup.\n\nTo our knowledge, this is the first reported study of adjuvant MTX → FU and we are unaware of any other such study ongoing. As we will discuss, some of the findings of this study may have important implications for the design of future adjuvant studies.\n\nPATIENTS AND METHODS\n\nEligibility criteria\n\nAll patients were required to have had a histological proof of colon carcinoma above the peritoneal reflection, complete resection of the primary tumour without gross or microscopic evidence of residual disease, regional lymph node involvement and or transmural penetration of the muscular wall of the bowel with or without adherence or penetration into an adjacent organ (Dukes' stages B2, B3 and C according to Modified Astler and Coller, 1987 classification). A minimum number of lymph nodes was not required by the protocol for defining a patient as node negative. (AJCC, 1987) ECOG performance status ⩽1, age ⩾18 years, normal hepatic and renal function and informed consent were also required.\n\nThe colon tumour was defined as any lesion of the large bowel which did not require the opening of the pelvic peritoneum to define the distal extent of the tumour and/or >12 cm from pectinate line but with the inferior margin of the tumour above the peritoneal reflection.\n\nPatients were ineligible if they were pregnant or lactating, had had prior or concurrent radiation or chemotherapy for colon cancer, had had previous or concurrent second malignant disease (except superficial squamous or basal-cell skin carcinoma of the skin or in situ carcinoma of the cervix) or nonmalignant systemic disease precluding administration of chemotherapy. Those with WBC count less than 3500 μl−1 and platelet count less than 100 000 μL−1, were ineligible.\n\nPatients were accrued from five central and northern Italian cooperative groups for a total of 71 centres: Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), Gruppo Cooperativo Istituto Nazionale per la Ricerca sul Cancro (Ist-Genova), Gruppo Oncologico del Nord-Ovest (GONO), Gruppo Oncologico Piemontese Tumori Apparato Digerente (GOPTAD) and Istituto Oncologico Romagnolo (IOR).\n\nTreatment\n\nAfter stratification for centre, patients were randomly assigned to receive either 6 monthly cycles of FU 370 mg m−2 i.v. bolus preceded by LV 100 mg m−2 i.v. bolus on days 1–5 or 6 monthly cycles of sequential MTX 200 mg m−2 i.v. days 1 and 15 and FU 600 mg m−2 i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h × 6 doses). No serum MTX level measurements were required on a routine basis. Levamisole 50 mg p.o. t.i.d. on days 1–3, every 14 days for 6 months. was given in both arms. The treatment was started within 60 days from surgery.\n\nToxicity was defined according to the World Health Organisation (WHO) criteria. Treatment was repeated at full doses if WBC was >3500 μl and PLT >100 000 μl; chemotherapy dose was delayed if WBC was <3500 μl and/or PLT <100 000 μl at recycle.\n\nChemotherapy was stopped for any grade (gr) 4 toxicity. FU was repeated at full dose in case of gr 1 diarrhoea or mucositis, whereas the dose was reduced by 25% for gr 2–3. Dose reduction of MTX, LV and levamisole were not allowed, since all these agents were used as modulators of FU. Investigators were required to notify the trial office by telephone of any serious unexpected adverse event.\n\nFollow-up\n\nForms were sent to the Data Centre of the study for each patient upon study entry and every 6 months for the first 3 years and yearly thereafter. Before each course of therapy, patients had to undergo a physical examination, haematologic and renal function studies and serum carcinoembryonic antigen. After completion of therapy, these tests were repeated every 6 months for the first 2 years and then every year for a total of 5 years.\n\nDuring follow-up, colonoscopy or barium enema were recommended every 2 to 3 years. Chest X-ray and hepatic ultrasound or CT scan were performed every 6 months for the first 2 years, then every year until the 5th year. The treatment of relapse was not standardised and was left up to the investigators.\n\nStudy end points and statistical methods\n\nThe main end point of the study was overall survival (OS); the secondary end point was DFS. A minimum sample size of 1500 patients (with annual accrual of 500 for 3 years) was set to ensure an 80% probability of detecting a 20% relative reduction in overall mortality after 5 years of follow-up, assuming a constant hazard rate equal to 8% per year (11) in the control arm, leading to an expected OS of 67% at 5 years.\n\nRandomisation was centralised at the coordinating centres of Genova (for Genova, GONO and GOPTAD), GOIRC and IOR. Randomisation lists were generated with blocks of variable length in random sequence, unknown to clinicians. The clinical centre was the only stratification factor. All the analyses were carried out according to the intention-to-treat principle in that all randomised patients were included in the analyses. Overall survival was computed as the time from randomisation to death due to any cause. Disease-free survival (DFS) was computed as the time from randomisation to the first observation of disease relapse or occurrence of a second primary cancer, or death due to any cause. Kaplan–Meier estimate and log-rank test allowed comparisons among the curves. Overall survival and DFS analyses performed according to the treatment were stratified according to disease stage (TNM stage II and III). Cox's regression analysis was used to model OS and DFS as a function of a set of independent variables. All the variables were categorical: treatment assigned at randomisation (standard, experimental); ECOG performance status (0, 1); histological grading (1=well, 2=moderately well+missing values, 3=poorly differentiated; patients with missing values of grading were considered as G2 patients); TNM stage of disease (stage II, stage III with one to four positive nodes, stage III with ⩾5 positive nodes); gender; and site of disease (1=right colon: caecum, ascending colon and hepatic flexure; 2=left colon: transverse colon, splenic flexure and descending colon; 3=intraperitoneal rectum and sigmoid; 4=multiple locations). Age was used as a stratification factor. For Cox's regression analysis, a backward procedure was used with P in=0.05 and P out=0.10. All P-values were two-sided. SPSS 11.0 statistical package was used for all the analyses.\n\nRESULTS\n\nBetween March 1995 and February 1998, 1945 patients were accrued from 71 Italian centres (Consort diagram, Figure 1) and their characteristics are shown in Table 1. The median number of patients per centre was 19, but more than 50% of the patients were accrued from 14 centres. In terms of age group distribution, 17.0% were older than 70 years and 2.8% younger than 40 years. Among the protocol violations, eight patients had unknown PS, 19 patients were randomised after 60 days from surgery and 73 patients started chemotherapy longer than 8 weeks from surgery. In addition, 23 patients were ineligible for staging problems (five patients were stage I, one stage IV and 17 had no mention of the stage). About 55% patients were stage II and they were equally distributed in the two arms, which were well balanced in terms of the other major patients characteristics; among stage II and III, 91 had no information regarding lymph node status. In most of these cases, 74 of 91, the pathology report stated either ‘Dukes' C' or ‘Dukes' B 2–3', while 17 had missing stage information.\n\nThe median number of lymph nodes recovered according to the pathology report (N=1854 surgical operations) was 12 for stage II (range 0–74) and 12 for stage III patients (range 0–70).\n\nThe median time from surgery to randomisation and to the beginning of chemotherapy were 31 and 39 days, respectively.\n\nCompliance to treatment and toxicity\n\nIn all, 72% of the patients completed the planned six cycles of MTX → FU and 77% completed FU LV; approximately 12% discontinued the treatment after completing only three cycles (3 months) of therapy and 2% never started chemotherapy in either arm. No patients received more than the planned six cycles. Levamisole was never started in 22.2% of the experimental arm and in 21.7% of the control arm, and it was discontinued for toxicity, refusal or other reasons in another 20%, so that only 60% of patients received the immunomodulator according to the protocol. This was not an unexpected finding as this trial accrued patients when levamisole's efficacy was beginning to be challenged.\n\nThere were two toxic deaths in the MTX → FU and none in the control arm. One patient died of diarrhoea, dehydration and sepsis after the first cycle and the other of severe mucositis, diarrhoea and dehydration with shock. Overall, the two treatments had similar degrees of toxicity, although slightly different patterns (Table 2). Thrombocytopenia was more pronounced in the MTX → FU arm (2.2 vs 0.1%, gr 3 and 4). The same was true for mucositis (14.8 vs 11.7%), while the reverse occurred for diarrhoea (6.5 vs 12.6%, gr 3 and 4). Conjunctivitis of low grade (1 and 2) was twice more frequent in the experimental arm (21.2 vs 12.6%). Hand and foot syndrome of low grade occurred in 5% of FU LV- and in 2.8% of MTX → FU-treated patients (P=0.02). Neurotoxicity and hepatotoxicity was reported in fewer than 1% of cases in either arm.\n\nEfficacy\n\nAfter a median follow-up time of 4.2 years, 198 (20.6%) deaths were observed in the experimental arm and 205 (20.5%) in the control arm; recurrences were 269 (28.0%) and 299 (30.3%) in the experimental and in the control arm, respectively. Univariate and multivariate hazard ratios are 0.94 (0.8–1.12) and 0.93 (0.78–1.1) for relapse, and 1.01 (0.83–1.23) and 1.03 (0.84–1.26) for overall mortality.\n\nThe sites of initial recurrence were not significantly different between arms; in patients treated with MTX → FU, they were the liver in 23.2%, other sites within the abdominal cavity in 20.2%, the lungs in 6.8% and multiple in 19.8%, while second primary tumours were reported in 5.7% of cases. Corresponding figures for the control arm were, respectively, 27.7, 17.9, 4.9, 21.4 and 5.3%. Aside from the two toxic deaths described, 37 deaths (10.4%) were unrelated to cancer, 22 (12.7%) in the experimental arm and 15 (8.2%) in the control arm.\n\nFigures 1 and 2 show that survival was similar with MTX → FU and FU+LV (77 vs 77% at 5 years; P=0.90), as were DFSs (67 vs 63% at 5 years; P=0.44). Efficacy results were similar for both stage III and II patients (Figure 3).\n\nThe hazard ratio for recurrence and death adjusted for stage were 0.99 (95% confidence limits=0.82–1.21) and 1.07 (95% confidence limits=0.96–1.19), respectively.\n\nDISCUSSION\n\nAt the time the study was designed, irinotecan and oxaliplatin were not available even for experimental use in the adjuvant setting and it was thought that comparing the sequential MTX → FU combination to standard FU LV (maintaining levamisole in both arms) was reasonable and appealing for a large-scale pragmatic trial for three reasons. First, while the meta-analysis on FU LV vs FU failed to show a significant survival benefit (Advanced colorectal cancer metaanalysis, 1992), the meta-analysis on MTX → FU did so, although the difference was small (Advanced colorectal cancer metaanalysis, 1994). Second, the meta-analysis on MTX → FU included several trials designed without the demonstrated optimal interval between the antifol and the fluoropyrimidine (4–24 h) leaving hope for more substantial efficacy of this sequence with appropriate scheduling, as we chose for our study. Third, while LV modulates FU by enhancing its anti-DNA effects via the inhibition of thymidylate synthase, MTX modulates FU primarily by increasing the incorporation of fluorouracil triphosphate into RNA, adding pharmacodynamic interest to the comparison (Sobrero et al, 1997). In 1995, all these good reasons appeared to justify this adjuvant trial.\n\nDespite a certain percentage of missing data regarding patient and tumour characteristics, understandable in a large pragmatic trial, the overall good quality of colon cancer care in this trial is proven by two indirect indicators: the median number of lymph nodes removed at surgery, 12, and the very good 3-year DFS value, 74%. This value matches well with that of the control arm of the MOSAIC (Andre et al, 2004) study (73%), which in turn was identical to another European large study of adjuvant chemotherapy in this disease (Andre et al, 2003).\n\nThe large sample size of the study and the similarity of the OS and DFS curves in the two arms fail to demonstrate clinically relevant differences in efficacy between the regimens. Since the toxicity and duration of the two treatments are also similar, MTX → FU may be considered an alternative to FU+LV, but offers no advantage, even from the convenience standpoint.\n\nThe equivalence observed allows to speculate on the relevance of the total dose of FU in the adjuvant treatment of this disease. The classic FU levamisole used a total of 27 g m−2, the weekly NSABP regimen employed 18 g m−2 and in a later version 12 g m−2 and the monthly cycle between 11.1 g m−2 (as in the control arm of our trial) and 12.75 g m−2. Our MTX → FU regimen used only 7.2 g m−2. Despite its low activity as single agent against advanced disease, it is possible that MTX contributes as a cytotoxic to the efficacy of FU or that it is a better modulator than LV (as it was our hypothesis), thus accounting for the overall efficacy of so little FU. However, it is also likely that very little FU is needed for efficacy in sensitive patients. And these speculations may be the basis for treatment duration trials in this disease where the new, most efficacious FU+oxaliplatin combination cannot be tolerated by a large proportion of patients because of cumulative neurotoxicity.\n\nAlong the line of speculation, if only very little FU is sufficient, these data may provide additional rationale to identify the sensitive patient population. The recent work on TS, DCC, LOH 18q and MSI (Jen et al, 1994; Lenz et al, 1998; Halling et al, 1999; Gryfe et al, 2000; Watanabe et al, 2001) are good examples of such strategies. For FU-sensitive patients, very few courses of FU adjuvant chemotherapy may be sufficient, for the others, repeated cycles of FU administrations are likely to be entirely ineffective and FU might well be omitted from the adjuvant treatment programme in these patients.\n\nThis work was supported by Grants AIRC, CNR Oncologia.\n\nFigure 1 Consort diagram of the study.\n\nFigure 2 Overall survival and DFS of the entire patient population. Bold lines=MTX → FU levamisole; standard lines=FU LV levamisole.\n\nFigure 3 Overall survival and DFS as a function of stage. Bold lines=MTX → FU levamisole; standard lines=FU LV levamisole.\n\nTable 1 Patient characteristics by treatment arm\n\n \t5-FU+levamisole+MTX (960 pts)\t5-FU+levamisole+LV (985 pts)\tAll patients (1945)\t\nMedian age (years) (range)\t62 (30–83)\t63 (25–80)\t62 (25–83)\t\nGender (%)\t\n Male\t560\t(58.3)\t575\t(58.4)\t1135\t(58.4)\t\n Female\t400\t(41.7)\t410\t(41.6)\t810\t(41.6)\t\n \t \t \t \t \t \t \t\nECOG performance status (%)\t\n 0\t858\t(89.8)\t888\t(90.4)\t1746\t(90.1)\t\n 1\t97\t(10.2)\t94\t(9.6)\t191\t(9.9)\t\n Unknown\t5\t \t3\t \t8\t \t\n \t \t \t \t \t \t \t\nStage (%)\t\n Dukes B\t517\t(54.8)\t543\t(55.5)\t1060\t(55.2)\t\n Dukes C\t423\t(45.2)\t433\t(44.3)\t856\t(44.8)\t\n Other\t14\t \t9\t \t23\t \t\n \t \t \t \t \t \t \t\nTumour location (%)\t\n Right colon\t256\t(27.4)\t311\t(32.5)\t567\t(30.0)\t\n Left colon\t667\t(71.5)\t631\t(65.8)\t1298\t(68.6)\t\n Multiple locations\t10\t(1.1)\t16\t(1.7)\t26\t(1.4)\t\n Unknown\t27\t \t27\t \t54\t \t\n \t \t \t \t \t \t \t\nSurgery (%)\t\n Right hemicolectomy\t289\t(31.0)\t336\t(35.1)\t625\t(33.1)\t\n Left hemicolectomy\t298\t(31.9)\t292\t(30.5)\t590\t(31.2)\t\n Resection of sigmoid\t169\t(18.1)\t174\t(18.1)\t343\t(18.1)\t\n Anterior resection\t91\t(9.8)\t80\t(8.4)\t171\t(9.0)\t\n Other\t86\t(9.2)\t76\t(7.9)\t162\t(8.6)\t\n Unknown\t27\t \t27\t \t54\t \t\n \t \t \t \t \t \t \t\nHistology (%)\t\n Adenocarcinoma\t918\t(99.6)\t951\t(99.7)\t1869\t(99.6)\t\n Undifferentiated\t4\t(0.4)\t3\t(0.3)\t7\t(0.4)\t\n Unknown\t38\t \t31\t \t69\t \t\n \t \t \t \t \t \t \t\nGrade of anaplasia (%)\t\n G1\t84\t(9.6)\t70\t(7.9)\t154\t(8.7)\t\n G2\t657\t(75.2)\t675\t(75.9)\t1332\t(75.6)\t\n G3\t133\t(15.2)\t144\t(16.2)\t277\t(15.7)\t\n Unknown\t86\t \t96\t \t182\t \t\n5-FU=5-fluorouracil; MTX=methotrexate; ECOG=Eastern Cooperative Oncology Group.\n\nTable 2 Grade 3–4 toxicity (%)\n\n \t5-FU+levamisole +MTX (960 pts)\t5-FU+levamisole+LV (985 pts)\tP-value\t\nLeukopenia\t35(4)\t25(2.7)\t0.16\t\nThrombocytopenia\t19(2.2)\t1(0.1)\t<0.0001\t\nAnaemia\t8(0.9)\t4(0.4)\t0.39\t\nMucositis\t131(14.8)\t107(11.7)\t0.048\t\nDiarrhoea\t57(6.5)\t115(12.6)\t<0.0001\t\nNausea and vomiting\t31(3.5)\t21(2.3)\t0.12\t\nConjunctivitis\t6(0.7)\t2(0.2)\t0.13\t\nHand–foot syndrome\t2(0.2)\t7(0.8)\t0.12\n==== Refs\nAdvanced Colorectal Cancer Meta-Analysis Project Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer J Clin Oncol 1994 12 960 969 8164048\nAdvanced Colorectal Cancer Meta-Analysis Project Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate J Clin Oncol 1992 10 896 903 1534121\nAmerican Joint Committee on CancerManual for Staging of Cancer1987Philadelphia: JB Lippincott45493rd edn\nAndre T Boni C Mounedji-Boudiaf L Navarro M Tabernero J Hickish T Topham C Zaninelli M Clingan P Bridgewater J Tabah-Fisch I de Gramont A Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer N Engl J Med 2004 350 2343 2351 15175436\nAndre T Colin P Louvet C Gamelin E Bouche O Achille E Colbert N Boaziz C Piedbois P Tubiana-Mathieu N Boutan-Laroze A Flesch M Buyse M de Gramont A Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial J Clin Oncol. 2003 21 15 2896 2903 12885807\nDi Costanzo F Sobrero A Gasperoni S Dogliotti L Frassineti L Falcone A Lionetto R Bruzzi P Luppi G Gallo L Conte P Comandone A Turci D Marzola M Folco U Pfanner E Mestriner M Boni C Galli C Tonato M Rosso R Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer (INTACC) Adjuvant chemotherapy in the treatment of colon cancer: randomized multicenter trial of the Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer (INTACC) Ann Oncol 2003 14 9 1365 1372 12954574\nGryfe R Kim H Hsieh ET Aronson MD Holowaty EJ Bull SB Redston M Gallinger S Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer N Engl J Med 2000 342 69 77 10631274\nHaller DG Catalano PJ Macdonald JS Meyer RJ Fluorouracil, leucovorin, and levamisolemisole adjuvant therapy for colon cancer: five years final report of INT-0089Proc Am Soc Clin Oncol199817 256(abstract)\nHalling KC French AJ McDonnell SK Burgart LJ Schaid DJ Peterson BJ Moon-Tasson L Mahoney MR Sargent DJ O'Connell MJ Witzig TE Farr GH Jr Goldberg RM Thibodeau SN Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers J Natl Cancer Inst 1999 91 1295 1303 10433618\nJen J Kim H Piantadosi S Liu ZF Levitt RC Sistonen P Kinzler KW Vogelstein B Hamilton SR Allelic loss of chromosome 18q and prognosis in colorectal cancer N Engl J Med 1994 331 213 221 8015568\nKerr DJ Gray R McConkey C Barnwell J for QUASAR Colorectal Cancer Study Group Adjuvant chemotherapy with 5-fluorouracil, L-folinic acid and levamisolemisole for patients with colorectal cancer: non-randomised comparison of weekly versus four-weekly schedules – less pain, same gain Ann Oncol 2000 11 947 955 11038030\nLenz HJ Danenberg KD Leichman CG Florentine B Johnston PG Groshen S Zhou L Xiong YP Danenberg PV Leichman LP p53 and thymidylate synthase expression in untreated stage II colon cancer: associations with recurrence, survival, and site Clin Cancer Res 1998 4 1227 1234 9607581\nLiver infusion meta-analysis group Portal vein chemotherapy for colorectal cancer: a meta analysis of 4000 patients in 10 studies J Natl Cancer Inst 1997 89 497 505 9086006\nMarsh JC Bertino JR Katz KH Davis CA Durivage HJ Rome LS Richards II F Capizzi RL Farber LR Pasquale DN The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer J Clin Oncol 1991 9 371 380 1999706\nMoertel CG Fleming TR Macdonald JS Haller DG Laurie JA Goodman PJ Ungerleider JS Emerson WA Tormey DC Glick JH Levamisolemisole and fluorouracil for adjuvant therapy of resected colon carcinoma N Engl J Med 1990 322 352 358 2300087\nQuasar Comparison of flourouracil with additional levamisolemisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. QUASAR Collaborative Group Lancet 2000 355 9215 1588 1596 10821362\nSargent DJ Goldberg RM Jacobson SD Macdonald JS Labianca R Haller DG Shepherd LE Seitz JF Francini G A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients N Engl J Med 2001 345 15 1091 1097 11596588\nSobrero A Aschele C Bertino J Fluorouracil in colorectal cancer – a tale of two drugs: implications for biochemical modulation J Clin Oncol 1997 15 1 368 381 8996164\nWatanabe T Wu TT Catalano PJ Ueki T Satriano R Haller DG Benson AB III Hamilton SR Molecular predictors of survival after adjuvant chemotherapy for colon cancer N Engl J Med 2001 344 1196 1206 11309634\nWolmark N Rockette H Fisher B Wickerham DL Redmond C Fisher ER Jones J Mamounas EP Ore L Petrelli NJ The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-03 J Clin Oncol 1993 11 1879 1887 8410113\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0007-0920",
"issue": "92(1)",
"journal": "British journal of cancer",
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"medline_ta": "Br J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D015996:Survival Rate",
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"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
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"title": "Adjuvant sequential methotrexate --> 5-fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer.",
"title_normalized": "adjuvant sequential methotrexate 5 fluorouracil vs 5 fluorouracil plus leucovorin in radically resected stage iii and high risk stage ii colon cancer"
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},
{
"companynumb": "IT-PFIZER INC-2019277103",
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{
"actiondrug": "6",
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},
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"medicinalproduct": "FLUOROURACIL."
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{
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},
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"medicinalproduct": "METHOTREXATE SODIUM."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
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"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "15 MG, 4X/DAY (6 DOSES) (RESCUE)",
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"drugindication": "COLON CANCER",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosagenumb": "15",
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"medicinalproduct": "LEUCOVORIN [CALCIUM FOLINATE]"
}
],
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"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Mucosal inflammation",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Shock",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Dehydration",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SOBRERO, A.. ADJUVANT SEQUENTIAL METHOTREXATE -} 5-FLUOROURACIL VS 5-FLUOROURACIL PLUS LEUCOVORIN IN RADICALLY RESECTED STAGE III AND HIGH-RISK STAGE II COLON CANCER. BRITISH JOURNAL OF CANCER. 2005?92 (1):24-29",
"literaturereference_normalized": "adjuvant sequential methotrexate 5 fluorouracil vs 5 fluorouracil plus leucovorin in radically resected stage iii and high risk stage ii colon cancer",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20190701",
"receivedate": "20190701",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 16509213,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
}
] |
{
"abstract": "Pimavanserin, a 5-HT2A inverse agonist, was commercially released in the United States in April 2016 for the treatment of Parkinson disease psychosis. No \"naturalistic\" treatment results have yet been published. Charts from the movement disorders clinic were reviewed for all patients who received this drug as treatment for psychosis associated with primary parkinsonism due to α-synucleinopathies. Data of 10 patients with idiopathic Parkinson disease, including 1 with a long history of schizophrenia, 4 with dementia with Lewy bodies, and 1 with multiple-system atrophy, were reviewed. There were no adverse events reported. Ten patients improved and continue on the drug, whereas 5 stopped because of lack of benefit.",
"affiliations": "Butler Hospital, Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI.",
"authors": "Friedman|Joseph H|JH|",
"chemical_list": "D010880:Piperidines; D058826:Serotonin 5-HT2 Receptor Agonists; D014508:Urea; C510793:pimavanserin",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000219",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "40(4)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D054314:Drug Inverse Agonism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders; D010880:Piperidines; D012189:Retrospective Studies; D058826:Serotonin 5-HT2 Receptor Agonists; D014508:Urea",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "157-159",
"pmc": null,
"pmid": "28622212",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Retrospective Study of Pimavanserin Use in a Movement Disorders Clinic.",
"title_normalized": "a retrospective study of pimavanserin use in a movement disorders clinic"
} | [
{
"companynumb": "US-ACADIA PHARMACEUTICALS INC.-ACA-2017-004286",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PIMAVANSERIN TARTRATE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "207318",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
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"drugindication": "DEMENTIA WITH LEWY BODIES",
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"medicinalproduct": "NUPLAZID"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PIMAVANSERIN TARTRATE"
},
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"drugdosageform": "TABLET",
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"drugindication": "PSYCHOTIC DISORDER",
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"medicinalproduct": "NUPLAZID"
}
],
"patientagegroup": null,
"patientonsetage": "77",
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"patientsex": "1",
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"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug effect incomplete",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FRIEDMAN JH. A RETROSPECTIVE STUDY OF PIMAVANSERIN USE IN A MOVEMENT DISORDERS CLINIC. CLINICAL NEUROPHARMACOLOGY. 2017;00:1-3",
"literaturereference_normalized": "a retrospective study of pimavanserin use in a movement disorders clinic",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170703",
"receivedate": "20170703",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13709664,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20171127"
},
{
"companynumb": "US-ACADIA PHARMACEUTICALS INC.-ACA-2017-004314",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIMAVANSERIN TARTRATE"
},
"drugadditional": null,
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"drugauthorizationnumb": "207318",
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"drugcharacterization": "1",
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"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PARKINSON^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"medicinalproduct": "NUPLAZID"
}
],
"patientagegroup": null,
"patientonsetage": "70",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FRIEDMAN JH. A RETROSPECTIVE STUDY OF PIMAVANSERIN USE IN A MOVEMENT DISORDERS CLINIC. CLINICAL NEUROPHARMACOLOGY. 2017;00:1-3",
"literaturereference_normalized": "a retrospective study of pimavanserin use in a movement disorders clinic",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170814",
"receivedate": "20170814",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13866780,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20171127"
}
] |
{
"abstract": "Type B insulin resistance due to autoantibodies against the insulin receptor is characterized by diabetes refractory to massive doses of insulin, severe hypercatabolism, hyperandrogenism, and a high mortality rate. We analyzed the efficacy of combined immunosuppressive therapy in the management of this extreme form of diabetes.\n\n\n\nWe performed a prospective cohort study including patients with confirmed insulin receptor autoantibodies, monitored for median 72 months (25th, 75th interquartile range 25, 88), and treated with rituximab, high-dose pulsed steroids, and cyclophosphamide until remission, followed by maintenance therapy with azathioprine. Remission was defined as the amelioration of the hyperglycemia and discontinuation of insulin and/or normalization of hyperandrogenemia.\n\n\n\nAll data are given as median (25th, 75th interquartile range). Twenty-two patients aged 42 (25, 57) years, 86.4% women, fulfilled inclusion criteria. At baseline, fasting glucose was 307 (203, 398) mg/dL, HbA1c was 11.8% (9.7, 13.6), total testosterone (women) was 126 (57, 571) ng/dL (normal 8-60), and daily insulin requirement was 1,775 (863, 2,700) units. After 5 (4, 6.3) months, 86.4% (19 of 22) of patients achieved remission, documented by discontinuation of insulin in all patients, normal fasting glucose of 80 (76, 92) mg/dL, HbA1c of 5.5% (5.2, 6), and testosterone (women) of 28 (20, 47) ng/dL. During follow-up of 72 (25, 88) months, 13.6% (3 of 22) of patients developed disease recurrence, occurring 24 (22, 36) months after initial remission, which responded to repeated therapy. None of the patients died.\n\n\n\nCombined immunosuppressive therapy has changed the natural history of this disease, from 54% mortality to a curable form of diabetes and, as such, should be recommended in patients with type B insulin resistance.",
"affiliations": "Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD joanna.klubo-gwiezdzinska@nih.gov.;School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, U.K.;Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.;University of Edinburgh, Edinburgh, U.K.;University of Cambridge, Cambridge, U.K.;Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.;Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.",
"authors": "Klubo-Gwiezdzinska|Joanna|J|0000-0001-8633-4420;Lange|Maria|M|;Cochran|Elaine|E|;Semple|Robert K|RK|0000-0001-6539-3069;Gewert|Cornelia|C|;Brown|Rebecca J|RJ|;Gorden|Phillip|P|",
"chemical_list": "D015703:Antigens, CD; D001323:Autoantibodies; D007166:Immunosuppressive Agents; D007328:Insulin; D000069283:Rituximab; D003907:Dexamethasone; D003520:Cyclophosphamide; C435941:INSR protein, human; D011972:Receptor, Insulin; D001379:Azathioprine; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.2337/dc18-0884",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0149-5992",
"issue": "41(11)",
"journal": "Diabetes care",
"keywords": null,
"medline_ta": "Diabetes Care",
"mesh_terms": "D000328:Adult; D015703:Antigens, CD; D001323:Autoantibodies; D001379:Azathioprine; D015331:Cohort Studies; D003520:Cyclophosphamide; D003907:Dexamethasone; D003922:Diabetes Mellitus, Type 1; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006943:Hyperglycemia; D007166:Immunosuppressive Agents; D007328:Insulin; D007333:Insulin Resistance; D060046:Maintenance Chemotherapy; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D011972:Receptor, Insulin; D012074:Remission Induction; D000069283:Rituximab; D012720:Severity of Illness Index; D013577:Syndrome",
"nlm_unique_id": "7805975",
"other_id": null,
"pages": "2353-2360",
"pmc": null,
"pmid": "30201849",
"pubdate": "2018-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052060:Research Support, N.I.H., Intramural; D013485:Research Support, Non-U.S. Gov't",
"references": "19164855;15232309;25675382;19440117;27254267;27142369;28822702;9702422;21537417;17325257;2261354;19391041;11889410;28056114;28084020;14724317;25522652;29637541;28262212;7149493;27878835;20190490;23346003;21531236;993353;27911591;7639809;25043930;29264467;7133096;25390580;23053690;29044634;2880067;176581;27416845;6350362;20484479;26543549;29644081;170678;18026162;908753;24379345;19203327;29173694",
"title": "Combined Immunosuppressive Therapy Induces Remission in Patients With Severe Type B Insulin Resistance: A Prospective Cohort Study.",
"title_normalized": "combined immunosuppressive therapy induces remission in patients with severe type b insulin resistance a prospective cohort study"
} | [
{
"companynumb": "US-BAXTER-2018BAX031280",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
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"medicinalproduct": "METFORMIN"
},
{
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"activesubstance": {
"activesubstancename": "INSULIN HUMAN"
},
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"medicinalproduct": "U-500 INSULIN"
},
{
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},
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"medicinalproduct": "U-500 INSULIN"
},
{
"actiondrug": null,
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"activesubstancename": "AZATHIOPRINE"
},
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"drugindication": "INSULIN RESISTANCE",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
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"drugindication": "DIABETES PROPHYLAXIS",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "METFORMIN"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "012141",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": "155000",
"drugcumulativedosageunit": "003",
"drugdosageform": "COATED TABLET",
"drugdosagetext": "UNTIL REMISSION WAS ACHIEVED",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INSULIN RESISTANCE",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CYTOXAN"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
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"drugcharacterization": "2",
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"abstract": "BACKGROUND\nPrimitive small cell carcinoma of the ureter is extremely rare, in this case report is meticulously described its aggressive clinical course and the pathological clues that help with the diagnosis. Also, a detailed table with the clinico-pathological features of analogous case reports in literature is provided.\nA 79-year-old female presented with gross hematuria and flank pain.\nSmall cell carcinoma of the ureter. The surgical specimen showed a mixed histology of small cell carcinoma and transitional cell carcinoma; the common neuroendocrine markers (chromogranin A, synaptophysin, CD56) were positive, and vimentin and thyroid transcription factor 1 were negative. The patient had an advanced stage at presentation with regional nodes involvement (pT3N1).\n\n\nMETHODS\nSegmental ureterectomy was performed but it was only possible to administer 1 cycle of platinum-based adjuvant chemotherapy due to the rapid decline of her clinical parameters.\n\n\nRESULTS\nThe disease rapidly spread locally and metastasized.\nThe clinicians must be aware of this aggressive tumor with silent clinical course and advanced stages at presentation.",
"affiliations": "Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa Unit of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma, Pisa, Italy.",
"authors": "Farci|Fabiola|F|;Manassero|Francesca|F|;Baldesi|Ramona|R|;Bartolucci|Annamaria|A|;Boldrini|Laura|L|;Selli|Cesare|C|;Faviana|Pinuccia|P|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 29901633MD-D-18-0155010.1097/MD.0000000000011113111134100Research ArticleClinical Case ReportPrimary small cell carcinoma of the ureter Case report and review of the literatureFarci Fabiola MDa∗Manassero Francesca MDbBaldesi Ramona MDbBartolucci Annamaria MDaBoldrini Laura PhDaSelli Cesare MDbFaviana Pinuccia MDaNA. a Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisab Unit of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma, Pisa, Italy.∗ Correspondence: Fabiola Farci, Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Via Roma 57, Pisa 56126, Italy (e-mail: fabiolafarci@gmail.com).6 2018 15 6 2018 97 24 e1111323 3 2018 23 5 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This 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. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nPrimitive small cell carcinoma of the ureter is extremely rare, in this case report is meticulously described its aggressive clinical course and the pathological clues that help with the diagnosis. Also, a detailed table with the clinico-pathological features of analogous case reports in literature is provided.\n\nPatient concerns:\nA 79-year-old female presented with gross hematuria and flank pain.\n\nDiagnoses:\nSmall cell carcinoma of the ureter. The surgical specimen showed a mixed histology of small cell carcinoma and transitional cell carcinoma; the common neuroendocrine markers (chromogranin A, synaptophysin, CD56) were positive, and vimentin and thyroid transcription factor 1 were negative. The patient had an advanced stage at presentation with regional nodes involvement (pT3N1).\n\nInterventions:\nSegmental ureterectomy was performed but it was only possible to administer 1 cycle of platinum-based adjuvant chemotherapy due to the rapid decline of her clinical parameters.\n\nOutcomes:\nThe disease rapidly spread locally and metastasized.\n\nLesson:\nThe clinicians must be aware of this aggressive tumor with silent clinical course and advanced stages at presentation.\n\nKeywords\ncarcinomacase reportmixed histotypeneuroendocrinepathologysmall cellurologyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPrimary small cell carcinoma (SCC) of the urinary tract is a rare cancer, accounting for less than 0.5% of urinary tract tumors,[1] mostly localized in the bladder and prostate, while its localization in the renal pelvis or in the ureter is extremely rare. Smoking exposure causes reactive and genetic damage to the tissues, and is a main risk factor for urothelial carcinoma and small cell neuroendocrine carcinoma.[2] Being such a rare disease, the pathogenesis is still unclear, and 2 theories have been postulated. The first claims its origin from a neuroendocrine cell population derived from the neural crest (enterochromaffin cells) migrated in the genitourinary tract during embryogenesis; the second theorizes its genesis from the pluripotent epithelial cells of the genitourinary tract. The latter could explain the common finding of a mixed histologic profile (transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcomatoid carcinoma, and sarcoma), often described as a gradual transition from 1 subtype to the other.\n\nSmall cell carcinoma of the ureter has been described in about 40 patients so far[3–35] with similarities in symptoms, management, and outcome, as outlined in Table 1.\n\nTable 1 Small cell carcinoma literature review.\n\n2 Case report\nA 79-year-old female presented with right-sided back pain and gross hematuria. Her clinical history was significant for atrial fibrillation treated with oral anticoagulant, which was suspended due to hematuria. She had a smoking history of more than 20 cigarettes per day for nearly 60 years. Physical examination revealed pain at the right costovertebral angle extended to the right groin over the location of the ureter. Creatinine levels at the admission were 1.37mg/dL. Abdominal ultrasound was immediately performed, revealing a grade 3 right hydronephrosis without lithiasis and hematic material in the bladder. A functional scintigraphy study with 99mTc-diethylene-triamine-penta-acetate revealed a decreased function of the right kidney, and the calculated glomerular filtration rate (GFR, Gates method) was 27 mL/min for the right kidney and 40 mL/min for the left kidney. At cystoscopic examination, the bladder wall was irregular in the right emitrigon, and the right ureteral orifice was swollen and bleeding. Urine cytology showed atypical morphological features, classified as suspicious for high-grade urothelial carcinoma (the Paris System for reporting urinary cytology). The following abdominal computed tomography (CT) scan found thickened walls in the distal part of the right ureter in the absence of lithiasis. A nephroureterectomy was planned, but had to be suspended due to the patient's clinical condition, and a segmental ureterectomy was performed instead. The right distal ureter was resected together with some enlarged regional nodes; its macroscopic inspection showed a thickened and hemorrhagic wall, with a nodular neoplasm of 2 × 1.5 cm obstructing the lumen and infiltrating the surrounding adipose tissue. The tumor was composed of small cell carcinoma admixed with infiltrating transitional cell carcinoma (Fig. 1). The neuroendocrine markers (synaptophysin, chromogranin-A, CD56) were positive in the SCC part of the tumor, the mitotic count was high, and the proliferative index counted by Ki-67 was more than 90%; the tumor was negative for vimentin and TTF-1. The final diagnosis was small cell neuroendocrine carcinoma invading 80% of the surgical specimen associated with high-grade urothelial carcinoma, both infiltrating the ureteral wall, the perineural spaces, and the perivisceral adipose tissue. The ureteral resection margins were negative. The right external iliac and presacral nodes were both metastatic for small cell neuroendocrine carcinoma. The pathological stage at the diagnosis was pT3N1 and the patient underwent a 2-week cycle of etoposide chemotherapy that had to be suspended for renal failure. The disease rapidly progressed: at 2 and a half months after admission and less than a month after segmental ureterectomy, an abdominal CT scan showed a contrast-enhanced 19 × 10 cm mass surrounding and obstructing the ureter, extended without clear margins to the aortocaval space, displacing the iliac vessels and infiltrating the surrounding tissues with diffuse pelvic lymphadenopathy. Chest and cranial CT scan did not detect any other lesions. The patient died for the progression of disease 5 months after admission.\n\nFigure 1 (A) Panoramic view of the ureteral tumor, hematoxylin–eosin stain (H&E). (B) The transitional cell carcinoma (red triangle) infiltrates the ureteral wall together with the small cell carcinoma (SCC) component with a clear lymphovascular invasion (black triangle) (H&E 10x). (C) The transitional cell carcinoma is intermixed with the SCC (H&E 20x). (D–F) The neuroendocrine markers are all positive in the SCC component (D: CD56, 10x; E: synaptophysin, 10x; F: chromogranin-A, 2x). (G) Ki-67 is remarkably high, especially in the SCC component of the tumor (2x). (H) TTF-1 immunohistochemistry is completely negative (2x). (I) The transitional cell carcinoma is CK7 positive (2x).\n\n3 Discussion\nThe usual presentation is flank homolateral pain due to hydronephrosis (with or without irradiation to the groin) and gross hematuria due to the vascular invasion; less frequently the patient laments weight loss, dysuria, and urinary tract infection. When those symptoms appear, the disease might be already at late stages, also because the pain gradually increases over time, becoming chronic, allowing a differential diagnosis from lithiasis that presents as acute pain. Ultrasonography is the initial choice for imaging in a suspected obstruction of the urinary tract, helping the clinician to differentiate between lithiasis and other causes of obstruction; urography and CT scan are second-level procedures that allow to establish the presence of a mass, confirm an associated hydronephrosis due to the obstruction, and the extension of the tumor and the regional node status. Urine cytology can be a precious diagnostic tool, but it requires an expert cytologist to get the right diagnosis, considering the paucity of the neoplastic cells in the smear, the mixed histotypes, and the infrequency of small cell carcinoma. A CT-guided biopsy or a nephro-ureteral resection are the usual choices for the urologist, allowing a pathological diagnosis.\n\nAt gross examination, SCC is usually described as a firm greyish tumor, often with hemorrhagic areas, protruding and occluding the ureteral lumen, with ill-defined borders and with peritumoral wall thickening. Small cell carcinoma has an architecture similar to the neuroendocrine tumors of other sites, composed by solid sheets or different pattern such as rosette or nests, often associated with a desmoplastic reaction. Crush artefact (“Azzopardi effect”) is common. The cells are small to medium-sized with scant cytoplasm and prominent nucleus with granular (classically described as “salt and pepper”) chromatin. Mitosis and necrosis are frequent, and also vascular invasion. As previously mentioned, there may coexist other histological types such as squamous carcinoma, transitional carcinoma, adenocarcinoma, and sarcomatoid carcinoma. The differential diagnoses include poorly differentiated urothelial carcinoma, primitive neuroectodermal tumor, malignant lymphoma, lymphoepithelioma-like carcinoma, and plasmacytoid carcinoma, from which this tumor can be differentiated by immunohistochemistry.[27] The neuroendocrine stains are usually positive (chromogranin A, synaptophysin, CD56, neuron-specific enolase) and it may show positivity for keratins such as cytokeratin (CK)7, epithelial membrane antigen, and pan-CK. Uroplakin III is usually negative, and this may help the differential diagnosis with transitional cell carcinoma. Vimentin expression has been previously related to a higher metastatic potential and a poor outcome in a clinical report.[30] The tumor is frequently diagnosed at late stages, when it has already invaded the peri-uretheral tissues and the surrounding structures. The overall median survival is 17 months, with a 51.9% of 1-year survival rate.[3] The primary treatment is surgical remotion of the tumor by ureterectomy or nephroureterectomy depending on the clinical status of the patient, stage, and localization of the tumor. Due to the aggressive course of SCC, the surgeon must address the radicality of the excision as early as possible, considering that in most cases the resection alone does not seem to stop the progression of the disease. If the clinical parameters of the patient are stable, the surgical treatment is usually followed by adjuvant chemotherapy and radiotherapy. It is important to note that the patient might be anemic for the long-term hematuria, and the obstruction caused by the tumor often causes hydronephrosis and impaired kidney function, so the clinical status of the patient might hinder a radical excision and/or an effective course of a systemic chemotherapy. There are promising reports about neoadjuvant chemotherapy, which has been used successfully to downstage the disease and lengthen the overall survival.[10,11,36]\n\n4 Conclusions\nSmall cell carcinoma of the ureter is an aggressive disease, and the factors that seem correlate with its prognosis are smoking history, age, male sex, tumor size, nodes, metastasis grading and size at diagnosis, the expression of vimentin, and incomplete resection. Although this is a rare tumor, effective targeted therapies are expected to be applied to improve the overall survival.\n\nAuthor contributions\nConceptualization: Fabiola Farci.\n\nData curation: Fabiola Farci, Annamaria Bartolucci, Laura Boldrini.\n\nFormal analysis: Fabiola Farci.\n\nInvestigation: Francesca Manassero, Ramona Baldesi, Annamaria Bartolucci, Laura Boldrini.\n\nResources: Cesare Selli.\n\nSupervision: Cesare Selli, Pinuccia Faviana.\n\nWriting - original draft: Fabiola Farci.\n\nWriting - review & editing: Pinuccia Faviana.\n\nAbbreviations: CT = computed tomography, CK = cytokeratin, SCC = small cell carcinoma, TTF-1 = thyroid transcription factor 1.\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n[1] Acosta AM Kajdacsy-Balla A \nPrimary neuroendocrine tumors of the ureter: a short review . Arch Pathol Lab Med \n2016 ;140 :714 –7 .27362572 \n[2] Church DN Bahl A \nClinical review: small cell carcinoma of the bladder . Cancer Treat Rev \n2006 ;32 :588 –93 .17008012 \n[3] Zhong W Lin R Zhang L \nClinicopathologic characteristics, therapy and outcomes of patients with primary ureteral small cell carcinoma: a case series and systematic review of the literature . Onco Targets Ther \n2017 ;10 :4105 –11 .28860819 \n[4] Hensley PJ Bhalodi AA Gupta S \nPrimary upper urinary tract small cell carcinoma: a case series and literature review . J Endourol Case Rep \n2017 ;3 :165 –8 .29177194 \n[5] Alevizopoulos A Yuen HS Soumadri S \nSmall cell carcinoma of the upper urinary tract: a case. report and review of existing cases . J Clin Case Rep \n2016 ;6 :811 .\n[6] Sood A Williamson SR Leavitt DA \nNeuroendocrine tumor of the ureter: a zebra among horses . J Endourol Case Rep \n2016 ;2 :204 –8 .27868098 \n[7] Ueda N Kobayashi Y Arai H \nIntravesical recurrence of small cell carcinoma of the ureter: a case report . Hinyokika Kiyo \n2016 ;62 :93 –7 .27018413 \n[8] Wang W Liu G Li Y \nNeuroendocrine carcinoma of the ureter: a case report and literature review . Oncol Lett \n2016 ;11 :257 –60 .26870199 \n[9] Acosta AM Hamedani FS Meeks JJ \nPrimary ureteral thyroid transcription factor 1-positive small cell neuroendocrine carcinoma: case report and review of the literature . Int J Surg Pathol \n2015 ;23 :472 –7 .26162396 \n[10] Osaka K Kobayashi K Sakai N \nSuccessful neoadjuvant chemotherapy for primary invasive small-cell carcinoma of the ureter . Can Urol Assoc J \n2015 ;9 :E393 –6 .26225186 \n[11] Ahsaini M Riyach O Tazi MF \nSmall cell neuroendocrine carcinoma of the urinary tract successfully managed with neoadjuvant chemotherapy . Case Rep Urol \n2013 ;2013 :598325 .24024065 \n[12] Yang J Zhao Z Ni J \nUrography and CT features of primary small cell carcinoma of the ureter: a case report . Iran J Radiol \n2013 ;10 :160 –3 .24348603 \n[13] Ping JH Chen ZX Jiong Q \nSmall cell neuroendocrine carcinoma of the ureter: a case report and literature review . Oncol Lett \n2014 ;7 :728 –30 .24520292 \n[14] Zhao Z Wang B Yang J \nPrimary small cell carcinoma of the ureter with hydronephrosis . BJU Int \n2012 ;http://www.bjuinternational.com/case-studies/primary-small-cell-carcinoma-ureter-hydronephrosis/\n[15] Miller RJ Holmang S Johansson SL \nSmall cell carcinoma of the renal pelvis and ureter: clinicopathologic and immunohistochemical features . Arch Pathol Lab Med \n2011 ;135 :1565 –9 .22129185 \n[16] Patil S Kaza RC Kakkar AK \nSmall cell carcinoma of the renal pelvis: a case report and review of the literature . ISRN Urol \n2011 ;2011 :786505 .22084805 \n[17] Kho VKS Chan PH \nPrimary small cell carcinoma of the upper urinary tract . J Chin Med Assoc \n2010 ;73 :173 –6 .20231004 \n[18] Kozyrakis D Papadaniil P Stefanakis S \nSmall cell carcinoma of the urinary tract: a case report . Cases J \n2009 ;2 :7743 .19830006 \n[19] Kuroda N Katto K Tamura M \nUreteral small cell carcinoma . Med Mol Morphol \n2009 ;42 :55 –7 .19294493 \n[20] Terada T \nPrimary small cell carcinoma of the ureter: a case report involving immunohistochemical and molecular genetic analyses of KIT and PDGFRA genes . Pathology \n2009 ;42 :101 –2 .\n[21] Ito H Kodaira K Kosugi M \nPrimary small cell carcinoma of the ureter: a case report . Hinyokika Kiyo \n2009 ;55 :417 –20 .19673430 \n[22] Banerji JS Korula A Panicker JB \nMulticentric small cell neuroendocrine neoplasm of the renal pelvis and ureter with concomitant focal high-grade urothelial carcinoma of the ureter: a case report . Indian J Urol \n2008 ;24 :571 –4 .19468523 \n[23] Masui K Kamba T Watanabe J \nA case of small cell carcinoma of the ureter . Hinyokika Kiyo \n2008 ;54 :411 –3 .18634436 \n[24] Ryu Y Kinoshita N Abe K \nSmall cell carcinoma of the ureter with malignant lymphoma: case report and literature review . Acta Med Nagasaki \n2008 ;53 :29 –32 .\n[25] Sakuma T Ujike T Yoshida T \nUrothelial carcinoma of ureter with neuroendocrine differentiation: a case report . Hinyokika Kiyo \n2008 ;54 :123 –6 .18323171 \n[26] Martin SM Gonzalez JR Lagarto EG \nPrimary small cell carcinoma of the ureter . Int J Urol \n2007 ;14 :771 –3 .17681073 \n[27] Busby JE Brown GA Tamboli P \nUpper urinary tract tumors with non-transitional histology: a single-center experience . Urology \n2006 ;67 :518 –23 .16527570 \n[28] Chang CY Reddy K Chorneyko K \nPrimary small cell carcinoma of the ureter . Can J Urol \n2005 ;12 :2603 –6 .15877943 \n[29] Ishikawa S Koyama T Kumagai A \nA case of small cell carcinoma of the ureter with SIADH-like symptoms . Nihon Hinyokika Gakkai Zasshi \n2004 ;95 :725 –8 .15354720 \n[30] Chuang CK Liao SK \nA retrospective immunohistochemical and clinicopathological study of small cell carcinomas of the urinary tract . Chang Gung Med J \n2003 ;26 :26 –33 .12656306 \n[31] Kim TS Seong DH Ro JY \nSmall cell carcinoma of the ureter with squamous cell and transitional cell carcinomatous components associated with ureteral stone . J Korean Med Sci \n2001 ;16 :796 –800 .11748366 \n[32] Gupta M Xia JR Priminger B \nSmall cell carcinoma of the ureter arising in an adult polycystic kidney disease: a case report . Appl Immunohistochem Mol Morphol \n1999 ;7 :164 –8 .\n[33] Tsutsumi M Kamiya M Sakamoto M \nA ureteral small cell carcinoma mixed with malignant mesodermal and ectodermal elements: a clinicopathological, morphological and immunohistochemical study . Jpn J Clin Oncol \n1993 ;23 :325 –9 .8230759 \n[34] Sakamoto N Hasegawa Y Nakamura M \nA case of small cell carcinoma of the ureter . Rinsho Hinyokika \n1990 ;47 :764 –7 .\n[35] Sakai N Ogawa T Ishibashi Y \nA case of small cell carcinoma of the ureter . Hinyokika Kiyo \n1990 ;36 :1455 –8 .1963758 \n[36] Lynch SP Shen Y Kamat A \nNeoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center . Eur Urol \n2013 ;64 :307 –13 .22564397\n\n",
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{
"abstract": "The ratio of the elderly among psoriasis patients has been increasing. However, satisfactory long-term management of psoriasis for the elderly is challenging because of the more frequent presence of comorbidities, and the higher risk of adverse events from systemic therapeutic agents than younger patients. The use of ustekinumab (UST) appears to be an appropriate systemic treatment because it is considered less likely to cause adverse events than other systemic treatments, as well as necessitating fewer hospital visits. Our retrospective study aimed to evaluate the efficacy and safety profile of UST in elderly patients with psoriasis. The study included 24 patients aged over 65 years (range, 65-88 years; mean, 73.1 years) with moderate to severe plaque psoriasis with impaired quality of life. Efficacy and safety were assessed over a 1-year period using the Psoriasis Area and Severity Index (PASI) and the Dermatology Live Quality Index (DLQI). The efficacy was evaluated by the proportion of subjects who achieved ≥75% reduction in PASI score (PASI 75). PASI 75 responses were 56.5% at week 16, 59.1% at week 28, and 60.0% at week 52. None of the patients developed any serious infection during the 1-year treatment. The mean DLQI score at weeks 0, 16, 28, and 52 was 7.8 ± 6.0, 2.5 ± 3.4, 1.4 ± 1.7, and 1.2 ± 1.7, respectively. UST showed sufficient efficacy for elderly patients with psoriasis without any serious infection over the 1-year treatment. Our results suggest that UST is the preferable agent for the treatment of elderly patients with psoriasis.",
"affiliations": "Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Hayashi|Mitsuha|M|;Umezawa|Yoshinori|Y|;Fukuchi|Osamu|O|;Ito|Toshihiro|T|;Saeki|Hidehisa|H|;Nakagawa|Hidemi|H|",
"chemical_list": "D003879:Dermatologic Agents; D000069549:Ustekinumab",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.12653",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "41(11)",
"journal": "The Journal of dermatology",
"keywords": "biologics; elderly patients; psoriasis; safety; ustekinumab",
"medline_ta": "J Dermatol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001168:Arthritis; D003879:Dermatologic Agents; D005260:Female; D006509:Hepatitis B; D006801:Humans; D008297:Male; D011565:Psoriasis; D016896:Treatment Outcome; D014376:Tuberculosis; D000069549:Ustekinumab",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "974-80",
"pmc": null,
"pmid": "25346301",
"pubdate": "2014-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of ustekinumab treatment in elderly patients with psoriasis.",
"title_normalized": "efficacy and safety of ustekinumab treatment in elderly patients with psoriasis"
} | [
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"abstract": "We report two cases of anaplastic thyroid cancer (ATC) which had a very good response to a treatment with lenvatinib at 14 mg. A 73-year-old man with ATC stage IVB was operated on, undergoing a near-total thyroidectomy, and the pathological remnant tissue showed a quick and partial response to treatment with the drug. The patient had a single metastasis in the brain after 9 months, but then died due to bronchopneumonia after undergoing a neurosurgical intervention for the complete removal of the lesion. A 74-year-old woman with ATC stage IV was operated on, undergoing a near-total thyroidectomy after a neoadjuvant treatment with the drug, that was continued after surgical treatment. She had a partial remission of the local disease and of distant metastasis, which lasted for 14 months. She then died 4 months later due to cancer progression. Lenvatinib at 14 mg appears to be effective, fast and well tolerated.",
"affiliations": "Department of Medicine, UO Endocrinology, USL North West Tuscany, General Hospital of Livorno, Livorno, Italy danielebarbaro1970@libero.it.;Department of Surgery, UO Pathology, USL North West Tuscany Office in Livorno, Livorno, Toscana, Italy.;Department of Surgery, UO Pathology, USL North West Tuscany Office in Livorno, Livorno, Toscana, Italy.;Deparment of Surgery, UO Pathology, University of Pisa, Pisa, Toscana, Italy.",
"authors": "Barbaro|Daniele|D|http://orcid.org/0000-0002-1474-7178;Lapi|Paola|P|;Viacava|Paolo|P|;Torregrossa|Liborio|L|",
"chemical_list": "D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C531958:lenvatinib",
"country": "England",
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"doi": "10.1136/bcr-2020-236934",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2020-236934\n10.1136/bcr-2020-236934\nCase Report\n1506\n1325\n82\n1333\n286\nLow-intermediate dose of lenvatinib in anaplastic thyroid cancer is highly effective and safe\nhttp://orcid.org/0000-0002-1474-7178Barbaro Daniele 1 Lapi Paola 2 Viacava Paolo 2 Torregrossa Liborio 3 1 Department of Medicine, UO Endocrinology, USL North West Tuscany, General Hospital of Livorno, Livorno, Italy\n2 Department of Surgery, UO Pathology, USL North West Tuscany Office in Livorno, Livorno, Toscana, Italy\n3 Deparment of Surgery, UO Pathology, University of Pisa, Pisa, Toscana, Italy\nCorrespondence to Dr Daniele Barbaro; danielebarbaro1970@libero.it\n2020 \n22 12 2020 \n22 12 2020 \n13 12 e23693412 11 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.We report two cases of anaplastic thyroid cancer (ATC) which had a very good response to a treatment with lenvatinib at 14 mg. A 73-year-old man with ATC stage IVB was operated on, undergoing a near-total thyroidectomy, and the pathological remnant tissue showed a quick and partial response to treatment with the drug. The patient had a single metastasis in the brain after 9 months, but then died due to bronchopneumonia after undergoing a neurosurgical intervention for the complete removal of the lesion. A 74-year-old woman with ATC stage IV was operated on, undergoing a near-total thyroidectomy after a neoadjuvant treatment with the drug, that was continued after surgical treatment. She had a partial remission of the local disease and of distant metastasis, which lasted for 14 months. She then died 4 months later due to cancer progression. Lenvatinib at 14 mg appears to be effective, fast and well tolerated.\n\nthyroid diseaseendocrine cancerspecial-featureunlocked\n==== Body\nBackground\nAnaplastic thyroid cancer (ATC) is rare, but is one of the most aggressive cancers in humans. The standard treatment is surgical intervention, when possible, plus chemotherapy and accelerated hyper-fractionated external beam radiotherapy (EBR), usually in combination. 1 2 Despite this aggressive approach, prognosis is severe, and most of these cancers are metastatic at the initial diagnosis. Recently, targeted multi-tyrosine kinase (MTK) inhibitors have appeared to represent a further possibility for treatment to offer to these patients, and one of these, lenvatinib, has been approved in Japan for ATC (3–8). However, progression free survival (PFS) and overall survival (OS) in these patients, although dependent on stage, are still usually poor as regards any type of treatment, and, in fact, prognosis has not changed much over the last few years. We report an unusually long PFS and OS in two consecutive patients treated with a low-intermediate dose (14 mg) of lenvatinib, and speculate about possible explanations.\n\nCase presentation\nCase 1\nA 74-year-old male patient had already undergone a kidney transplant, and he was under treatment with everolimus and ciclosporin. He was in follow-up for inflammatory myofibroblastic tumour of the lung already treated by surgical intervention. During the follow-up, a CT/positron emission tomography (PET) showed a thyroid mass with high uptake (standardised uptake value/SUV 20.1) (figure 1). An ultrasonography confirmed a mass of 7.0 in maximum size in the left lobe and isthmus with a suspected lymph node metastases. A fine needle aspiration (FNA) was suspicious for ATC. The patient, after stoppage of everolimus, was sent for surgical treatment, and it was possible to perform a near-total thyroidectomy, leaving some paratracheal pathological tissue. The histology was: ATC with maximum size 7.5 cm involving the left and right lobe with spindle growth pattern, infiltrating perithyroidal muscles and oesophagus (immunophenotypic investigation showed CKAM 5.2 positive, TTF1 and thyroglobulin negative), one lymph node with metastasis, pT4aN1bMx stage IVB TNM 2017 8th edition. Considering the general clinical context, after obtaining written consent for an off-label treatment, we decided to treat the patient with lenvatinib, and we chose as first line a medium-low dosage of 14 mg, which was initiated 7 days after the surgical intervention.\n\nFigure 1 Whole body (18F)fluorodeoxyglucose positron emission tomography/CT before surgical intervention.\n\nMolecular analysis of tumour pathological tissue was performed, and the data are reported in table 1.\n\nTable 1 Molecular analysis was performed on DNA from formalin-fixed paraffin-embedded tissue\n\nThe targeted panel Myriapod NGS-LT 56G Onco Panel (Diatech Pharmacogenetics) was run on Ion Torrent Ion S5 platform (Thermo Fisher Scientific). Data were analysed by Myriapod NGS Data Analysis Software (Diatech Pharmacogenetics). The main hotspot regions in the below-mentioned genes were analysed.\t\nABL1\tCSF1R\tFBXW7\tGNAS\tKIT\tNPM1\tSKT11\t\nAKT1\tCTNNB1\tFGFR1\tHNF1A\tKRAS\tNRAS\tSMAD4\t\nALK\tDOR2\tFGFR2\tHRAS\tMAP2K1\tPDGFRA\tSMARCB1\t\nAPC\tDNMT3A\tFGFR3\tIDH1\tMET\tPIK3CA\tSMO\t\nATM\tEGFR\tFLT3\tIDH2\tMLH1\tPTEN\tSRC\t\nBRAF\tERBB2\tFOXL2\tJAK2\tMLP\tPTPN11\tTP53\t\nCDH1\tERBB4\tGNA11\tJAK3\tMSH6\tRB1\tTSC1\t\nCDKN2A\tEZH2\tGNAQ\tKDR\tNOTCH\tRET\tVHL\t\nPatient 1 Ref.: I/23022/2017/LS2\t\nPASS VARIANTS\t\nGene\tVariant classification\tcDNA change\tProtein change\tAllele frequency\tClinVar\t\nTP53\tmissense\tc.524G>A\tp.R175H\t63.70%\tPathogenic/likely pathogenic\t\nPTEN\tframeshift\tc.1048delA\tp.T350fs\t5.30%\tNot reported\t\nLOW-QUALITY VARIANTS (confirmation by another tecnique is needed)\t\nGene\tVariant classification\tcDNA change\tProtein change\tAllele frequency\tClinVar\tWARNING\t\nRB1\tnonsense\tc.763C>T\tp.R255*\t38.50%\tPathogenic\tStrand bias\t\nPatient 2 Ref: I/3628/2018/LS3\t\nPASS VARIANTS\t\nGene\tVariant classification\tcDNA change\tProtein change\tAllele frequency\tClinVar\t\nTP53\tmissense\tc.839G>C\tp.R280T\t33.40%\tConflicting interpretations of pathogenicity\t\n‘ClinVar’ (https://www.ncbi.nlm.nih.gov/clinvar) refers to the clinical significance (described or predicted) of the variant (eg, pathogenic or likely pathogenic). ‘Conflicting interpretations of pathogenicity’ indicates controversial data in the literature.\n\n*This sequence change creates a premature translational stop signal in the RB1 gene\n\nOutcome and follow-up\nAfter 3 weeks we performed a first (18-fluorodeoxyglucose (18-FDG)) PET/CT, which showed a pathological tissue remnant with SUV 5.1 (figure 2). Ultrasonography showed only a small paratracheal pathological remnant tissue. Another (18FDG) CT/PET performed at 4 and 8 months, showed only minimal remnant tissue in the neck with a further reduced uptake, SUV 3.1 (figure 3). The patient was in good health, with an Eastern Cooperative Oncology Group (ECOG) score of 1–2. After 9 months, the patient had seizures, and an MRI showed a mass of 2 cm (a previous MRI 2 months before had been negative). The patient underwent neurosurgical intervention with complete removal of the lesion, but he passed away after 10 days due to bronchopneumonia.\n\nFigure 2 Whole body (18F)fluorodeoxyglucose positron emission tomography/CT after 3 weeks of treatment.\n\nFigure 3 Whole body (18F)fluorodeoxyglucose positron emission tomography/CT after 8 months of treatment.\n\nCase presentation\nCase 2\nA 73-year-old female patient presenting with a rapidly growing goitre. At that moment the patient was in good health, and her ECOG score was 0. FNA was suspicious for ATC, and the patient underwent Computerized Tomography) (CT) total body, which showed a mass in the neck which extended into the mediastinum and apex of the lung, as well as lung metastases (figures 4 and 5). During staging, the patient showed not only a visible increase of the mass in the neck, but also a worsening of well-being, with diffuse pain in the chest and rapid deterioration of her clinical status. The patient was referred for surgical treatment, but she refused it, knowing the poor prognosis of the disease and the possibility that the intervention could be only a debulking with positioning of a tracheal cannula.\n\nFigure 4 Chest CT scan at first staging.\n\nFigure 5 CT scan: prevalent lung metastasis at the first staging.\n\nMolecular analysis of tumour pathological tissue was performed, and the data are reported in table 1.\n\nOutcome and follow-up\nWe decided, after written consent, for the off-label use of lenvatinib, and we started the drug at 14 mg/day. At that moment ECOG was 1/2. The patient did not show side effects, and experienced some improvement in quality of life in the first week regarding pain in the chest. A CT scan performed after 3 weeks showed a decrease in the mediastinal mass (figure 6). At this point we exerted great effort to convince the patient to submit to surgical treatment, and she agreed. The histology showed an ATC with a maximum size of 7 cm infiltrating perithyroid muscle TTF1, thyroglobulin, CD30 negative; CKCAM 5.2 positive, pT3bNxcM1 TNM 2017 8th edition stage IVC. During the following months, imaging showed a progressive remission of the disease up to almost complete remission (figures 7 and 8). After 14 months she experienced recurrence with unilateral palsy, and a CT scan showed progressive disease in the mediastinum and chest. Subsequently, the patient developed bilateral recurrent palsy, and underwent a tracheostomy. Exitus occurred after 4 months.\n\nFigure 6 Chest CT scan after 3 weeks of treatment.\n\nFigure 7 Chest CT scan after 12 months of treatment.\n\nFigure 8 Chest CT scan with contrast medium: prevalent metastasis after 12 months of treatment.\n\nDiscussion\nATC is one of the most malignant solid tumours in humans. The prognosis is usually so poor that there is not any real guideline regarding treatment, although surgical intervention is usually considered the first line of treatment.1 2 It can have a debulking aim, or, rarely, offer a possibility of radicality in less advanced cases, and sometimes surgical treatment can follow an attempt of neoadjuvant medical treatment. The type of medical treatment, alone or combined with EBR, still represents a matter for discussion, and among medical treatments, some MTK inhibitors, already approved for iodine refractory differentiated thyroid cancer, have garnered interest. Among these, lenvatinib is known to be directed against FGR 1, 2, 3, 4; VEGFR 1, 2, 3; PDGFRb; RET and c-Kit, and it has been successfully employed in iodine refractory thyroid cancer.3 Lenvatinib has been approved also for treatment of ATC, in Japan in 2015, and there are now several reports regarding this drug.4–9 However, in advanced stages IVB and IVC, as in our cases, the PFS and OS are usually poor. The various published papers have shown a median of PFS and OS ranging, respectively, from 4.0 to 4.2,5 and 7.4 to 10.6 months.5 6 The best results appear to be those of a phase II study.5 6 However, in this study a partial response was seen in only 24% of cases, and only 4 patients out of 17 were able to complete the study, either because they did not show a response, or because they developed severe side effects to the treatment at the initial dose of 24 mg. In this last study, the patients enrolled had as a criterion of inclusion that they were expected to survive at least 8 weeks or more after the first dose of lenvatinib, so we must also suppose that their clinical condition was not so bad. The stage for all patients was between IVA and IVC, but it was not reported which cases were able to finish the study and showed the best results.\n\nOur cases offer interesting points for speculation. In our first case, we had a PFS of 8 months, and the recurrence of disease was in the brain. There are no data regarding the crossing of lenvatinib through the blood–brain barrier, but as regards other MTK inhibitors we can suppose a reduced transfer in the brain, and therefore a reduced concentration and activity at this level.10–13 On the other hand, no locoregional recurrences in other sites of the body were present. Rather, lenvatinib appeared to exert very good locoregional control, inasmuch as CT/PET showed a very remarkable reduction of FDG uptake in the neck. The overall survival was 10.2 months, but it could have been much longer if the patient had not passed away because of bronchopneumonia, due likely to the immunosuppressive treatment, since the neurosurgical intervention removed completely the metastasis. The second case appears even more surprising, considering the stage and the general clinical condition. We had a PFS of 14 months, with an OS of 18 months, and a partial remission which came very near to a complete remission. Both patients tolerated quite well the starting dose of 14 mg, considering the fact that the side effects were related to the dose and to the serum levels.14–16\n\nAn initial speculation could be that in the complex mechanism of the regulation of the various MTK cascades, there could exist a specific, most effective dose, beyond which a hook effect occurs, and the efficacy may decrease. Although data in vitro show that the effects on ATC cells of lenvatinib are dose dependent,17 18 no study, in point of fact, reports if there might exist something like this hook effect for an increasing dose of the drug. If we analyse all the cases reported in the literature, we find only two cases comparable both for advanced stage and for PFS (9.0 and 27.9 months)3; also in these series some patients were treated with 14 mg for a progressive reduction of the drug, but, unfortunately, in that paper it is not specified which dose these two cases were treated with.\n\nWe could also speculate that in our cases we enjoyed such a good response because the dose of lenvatinib was not very high, and was hence well tolerated by the patients, who could continue without important side effects, being that side effects were related to the oral dose.14–16 However, the response was not only long-lasting, but also fast, showing powerful activity of the 14 mg of lenvatinib. Regarding the first hypothesis, that there is the possibility that this intermediate dose might exert some special activity on ATC, studies in vitro will help to show the dose/activity profile of the drug. As already stated, some studies exist showing a dose-dependent activity.17 18 However, higher concentrations will have to be studied, even though we have to keep in mind that studies in vitro on ATC cells cannot represent the reality in vivo, since lenvatinib exerts a fundamental action also on the vessels by Vascular Endothelial Growth Factor.\n\nRegarding molecular analysis, our data do not appear to show any special predictive mutation for a better response.\n\nIn conclusion, in our two consecutive cases treated by lenvatinib, we enjoyed a very good response using 14 mg. Further studies in vitro and clinical trials should be encouraged to test lenvatinib in ATC using lower doses than the standard 24 mg dose. From a practical point of view, we could suggest trying to use this particular dose (14 mg) as a starting dose in such critical patients with ATC, since the drug is effective, the action is fast, and side effects are seen to be less frequent and more manageable.\n\nLearning points\nDiagnosis of anaplastic thyroid cancer (ATC) is usually histological. However, in special cases a cytology examination by an expert pathologist can be sufficient (case 2).\n\nLenvatinib at low-medium dosage (14 mg in our cases) has been demonstrated to be highly effective and quick in controlling the disease. Two possible explanations can be speculated on: simply that this lower dose can allow a better treatment of patients because of the absence of important side effects in such critical patients, or that an especially powerful activity of an intermediate dosage is exerted on the complex balance of multi-tyrosine kinase cascade in ATC.\n\nResearch in vitro and clinical trials could help to elucidate the hypothesis that a lower dosage could be more effective than a full standard dose in this cancer.\n\nLenvatinib can have a neoadjuvant role (case 2).\n\nContributors: DB: writing of the manuscript. PL: references and editing figures. PV: cytology. LT: histology and molecular biology.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Smallridge RC , Ain KB , Asa SL , et al \nAmerican thyroid association guidelines for management of patients with anaplastic thyroid cancer\n. Thyroid \n2012 ;22 :1104 –39\n. 10.1089/thy.2012.0302 23130564 \n2 Ferrari SM , Elia G , Ragusa F , et al \nNovel treatments for anaplastic thyroid carcinoma\n. Gland Surg \n2020 ;9 :S28 –42\n. 10.21037/gs.2019.10.18 32055496 \n3 Schlumberger M , Tahara M , Wirth LJ , et al \nLenvatinib versus placebo in radioiodine-refractory thyroid cancer\n. N Engl J Med \n2015 ;372 :621 –30\n. 10.1056/NEJMoa1406470 25671254 \n4 Iwasaki H , Toda S , Suganuma N , et al \nLenvatinib vs. palliative therapy for stage IVC anaplastic thyroid cancer\n. Mol Clin Oncol \n2020 ;12 :138 –43\n. 10.3892/mco.2019.1964 31929884 \n5 Tahara M , Kiyota N , Yamazaki T , et al \nLenvatinib for anaplastic thyroid cancer\n. Front Oncol \n2017 ;7 :25. 10.3389/fonc.2017.00025 28299283 \n6 Iwasaki H , Yamazaki H , Takasaki H , et al \nLenvatinib as a novel treatment for anaplastic thyroid cancer: a retrospective study\n. Oncol Lett \n2018 ;16 :7271 –7\n. 10.3892/ol.2018.9553 30546466 \n7 Takahashi S , Kiyota N , Yamazaki T , et al \nA Phase II study of the safety and efficacy of lenvatinib in patients with advanced thyroid cancer\n. Future Oncol \n2019 ;15 :717 –26\n. 10.2217/fon-2018-0557 30638399 \n8 Iñiguez-Ariza NM , Ryder MM , Hilger CR , et al \nSalvage lenvatinib therapy in metastatic anaplastic thyroid cancer\n. Thyroid \n2017 ;27 :923 –7\n. 10.1089/thy.2016.0627 28471306 \n9 Oishi K , Takabatake D , Shibuya Y \nEfficacy of lenvatinib in a patient with anaplastic thyroid cancer\n. Endocrinol Diabetes Metab Case Rep \n2017 ;2017 :16 –136\n. 10.1530/EDM-16-0136 \n10 Lagas JS , van Waterschoot RAB , Sparidans RW , et al \nBreast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation\n. Mol Cancer Ther \n2010 ;9 :319 –26\n. 10.1158/1535-7163.MCT-09-0663 20103600 \n11 Thanasupawat T , Natarajan S , Rommel A , et al \nDovitinib enhances temozolomide efficacy in glioblastoma cells\n. Mol Oncol \n2017 ;11 :1078 –98\n. 10.1002/1878-0261.12076 28500786 \n12 Laramy JK , Kim M , Parrish KE , et al \nPharmacokinetic assessment of cooperative efflux of the multitargeted kinase inhibitor ponatinib across the blood-brain barrier\n. J Pharmacol Exp Ther \n2018 ;365 :249 –61\n. 10.1124/jpet.117.246116 29440450 \n13 Kort A , Durmus S , Sparidans RW , et al \nBrain and testis accumulation of regorafenib is restricted by breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1)\n. Pharm Res \n2015 ;32 :2205 –16\n. 10.1007/s11095-014-1609-7 25563977 \n14 Nagahama M , Ozeki T , Suzuki A , et al \nAssociation of lenvatinib Trough plasma concentrations with lenvatinib-induced toxicities in Japanese patients with thyroid cancer\n. Med Oncol \n2019 ;36 :39 . 10.1007/s12032-019-1263-3 30919115 \n15 Hussein Z , Mizuo H , Hayato S , et al \nClinical pharmacokinetic and pharmacodynamic profile of lenvatinib, an orally active, small-molecule, multitargeted tyrosine kinase inhibitor\n. Eur J Drug Metab Pharmacokinet \n2017 ;42 :903 –14\n. 10.1007/s13318-017-0403-4 28236116 \n16 Inoue K , Asai N , Mizuo H , et al \nUnique metabolic pathway of [(14)C]lenvatinib after oral administration to male cynomolgus monkey\n. Drug Metab Dispos \n2012 ;40 :662 –70\n. 10.1124/dmd.111.043281 22207053 \n17 Ferrari SM , La Motta C , Elia G , et al \nAntineoplastic effect of lenvatinib and vandetanib in primary anaplastic thyroid cancer cells obtained from biopsy or fine needle aspiration\n. Front Endocrinol \n2018 ;18 :764 .\n18 Ferrari SM , Bocci G , Di Desidero T , et al \nLenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo\n. Oncol Rep \n2018 ;39 :2225 –34\n. 10.3892/or.2018.6306 29517103\n\n",
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"issue": "13(12)",
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"keywords": "endocrine cancer; thyroid disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D017024:Chemotherapy, Adjuvant; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D010671:Phenylurea Compounds; D000072078:Positron Emission Tomography Computed Tomography; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D065646:Thyroid Carcinoma, Anaplastic; D013961:Thyroid Gland; D013964:Thyroid Neoplasms; D013965:Thyroidectomy; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
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"title": "Low-intermediate dose of lenvatinib in anaplastic thyroid cancer is highly effective and safe.",
"title_normalized": "low intermediate dose of lenvatinib in anaplastic thyroid cancer is highly effective and safe"
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"abstract": "Is to develop a method for determining amlodipine in the tissues of organs and blood, applicable in the practice of forensic chemical analysis. TLC, normal pressure column chromatography, HPLC and GC-MS were considered as methods of analysis. Amlodipine was isolated from the biomaterial by insisting twice with acetone for 30 min using a 2: 1 mass-isolating and biomatrix agent. The purification of recovered analyte was done in a column (150×10 mm) of a 30 µm Silasorb S-18 sorbent, eluting with an acetone - water solvent mixture (8:2). Preliminary identification was carried out in a thin layer of sorbent on «Sorbfil» plates, which was confirmed by HPLC and GC-MS methods. Determination by GC-MS was carried out in a column with a stationary phase of 5% phenyl-95% dimethylpolysiloxane. The fragmentation of molecules was an electron impact with an energy of 70 eV. Methods for the determination of amlodipine using GC-MS in biomatrix have been developed, which meet the criteria of linearity, selectivity, correctness, precision and stability. The limits of detection and quantitative determination of amlodipine in organ tissues (liver) are 0.14 and 0.24 μg/g, in blood - 0.12 and 0.20 μg/g, respectively. The methods were applied in the examination of a case of amlodipine poisoning and made it possible to determine the analyte in some organs and blood of the corpse.",
"affiliations": "Kursk State Medical University, Kursk, Russia.;Kursk State Medical University, Kursk, Russia.;Bureau of Forensic Medicine of the Kursk Region, Kursk, Russia.",
"authors": "Kvachakhia|L L|LL|0000-0001-8872-0691;Shormanov|V K|VK|0000-0001-8872-0691;Banchukova|E A|EA|0000-0003-2767-1544",
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"keywords": "amlodipine; expert material; identification and definition; isolation",
"medline_ta": "Sud Med Ekspert",
"mesh_terms": "D000096:Acetone; D017311:Amlodipine; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D015203:Reproducibility of Results",
"nlm_unique_id": "0404546",
"other_id": null,
"pages": "39-44",
"pmc": null,
"pmid": "33180413",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Forensic chemical study of Amlodipine.",
"title_normalized": "forensic chemical study of amlodipine"
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{
"abstract": "Immune checkpoint inhibitors act to restore T cell-mediated antitumor immunity. By this nature, these cancer immunotherapy drugs are associated with various immune-related adverse events such as thyroid dysfunction. We describe a case of thyrotoxicosis secondary to a programmed cell death 1 (PD-1) immune checkpoint inhibitor, pembrolizumab. A 30-year-old female was started on pembrolizumab immunotherapy for stage III small cell carcinoma of the ovary, hypercalcemic type. Thirteen days after her second cycle of therapy, she presented with symptoms consistent with thyrotoxicosis. A thyroiditis was diagnosed by thyroid function tests and ultrasonography. She was originally treated with prednisone and metoprolol for possible Grave's disease. Pertechnetate thyroid scan was more consistent with thyroiditis secondary to pembrolizumab. She underwent a total thyroidectomy 10 days after initial presentation for refractory thyrotoxicosis despite maximal medical therapy. Her symptoms resolved and thyroid function tests significantly improved. Pathology was consistent with severe thyroiditis. Immune microenvironment may play a role in the expression of programmed cell death protein 1 ligand 1 (PD-L1). Chronic inflammation surrounding tumor upregulates PD-L1 expression on tumor cells by the release of cytokines, which acts to inhibit tumor destruction. We suggest that our patient had an undetected chronic inflammation of the thyroid, specifically Hashimoto's thyroidits, which predisposed her to thyroid destruction when taking pembrolizumab. Understanding that an inflammatory environment impacts thyroid toxicity to PD-1 inhibitor therapy is novel and should be further studied.",
"affiliations": "Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Six Founders Pavilion, Philadelphia, PA, 19104-4283, USA. Brittney.imblum@uphs.upenn.edu.;Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Six Founders Pavilion, Philadelphia, PA, 19104-4283, USA.;Department of Surgery and Division of Endocrine & Oncologic Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, Four Silverstein, Philadelphia, PA, 19104-4283, USA.;Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Six Founders Pavilion, Philadelphia, PA, 19104-4283, USA.",
"authors": "Imblum|Brittney A|BA|;Baloch|Zubair W|ZW|;Fraker|Douglas|D|;LiVolsi|Virginia A|VA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D013956:Antithyroid Agents; D008713:Methimazole; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1007/s12022-019-9579-2",
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"issn_linking": "1046-3976",
"issue": "30(2)",
"journal": "Endocrine pathology",
"keywords": "PD-1 inhibitor; PDL-1 inhibitor; Pembrolizumab; Small cell carcinoma of ovary; Thyroid; Thyroiditis; Thyrotoxicosis",
"medline_ta": "Endocr Pathol",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D013956:Antithyroid Agents; D018288:Carcinoma, Small Cell; D005260:Female; D006111:Graves Disease; D006801:Humans; D008713:Methimazole; D010051:Ovarian Neoplasms; D013961:Thyroid Gland; D013965:Thyroidectomy; D013966:Thyroiditis",
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"pmid": "31111437",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12826640;18981091;21268011;22461641;22548945;23193072;25751110;27086918;27398650;27571185;28609832;28973656;29319130;29610684;30121940",
"title": "Pembrolizumab-Induced Thyroiditis.",
"title_normalized": "pembrolizumab induced thyroiditis"
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"abstract": "Leptomeningeal metastases (LM) are found in approximately 3.8% of non-small cell lung cancer cases with an increased incidence in adenocarcinoma, and approximately one-third of patients will present with concomitant brain metastases. We report the case of a 50-year-old male patient with stage IV exon 19-del-EGFR mutant lung adenocarcinoma who progressed on second-generation TKI therapy with manifestation of symptomatic simultaneous diffuse brain and LM. Whole-brain radiotherapy with concurrent afatinib resulted in an almost complete regression of neurological symptoms as well as good, durable radiological response. Furthermore, treatment was well tolerated with no relevant adverse effects.",
"affiliations": "Department of Radiation Oncology, LMU Munich, Munich, Germany.;Department of Radiation Oncology, LMU Munich, Munich, Germany.;Department of Radiation Oncology, LMU Munich, Munich, Germany.;Department of Radiation Oncology, LMU Munich, Munich, Germany.;Department of Radiation Oncology, LMU Munich, Munich, Germany.",
"authors": "Eze|Chukwuka|C|;Hegemann|Nina-Sophie|NS|;Roengvoraphoj|Olarn|O|;Dantes|Maurice|M|;Manapov|Farkhad|F|",
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"fulltext": "\n==== Front\nFront OncolFront OncolFront. Oncol.Frontiers in Oncology2234-943XFrontiers Media S.A. 10.3389/fonc.2017.00088OncologyCase ReportConcurrent Afatinib and Whole-Brain Radiotherapy in Exon 19-del-EGFR Mutant Lung Adenocarcinoma: A Case Report and Mini Review of the Literature Eze Chukwuka 1*Hegemann Nina-Sophie 1Roengvoraphoj Olarn 1Dantes Maurice 1Manapov Farkhad 11Department of Radiation Oncology, LMU Munich, Munich, GermanyEdited by: Christopher Schultz, Medical College of Wisconsin, USA\n\nReviewed by: Joseph A. Bovi, Medical College of Wisconsin, USA; Joshua Silverman, New York University, USA\n\n*Correspondence: Chukwuka Eze, chukwuka.eze@med.uni-muenchen.deSpecialty section: This article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology\n\n10 5 2017 2017 7 8812 2 2017 20 4 2017 Copyright © 2017 Eze, Hegemann, Roengvoraphoj, Dantes and Manapov.2017Eze, Hegemann, Roengvoraphoj, Dantes and ManapovThis 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) or licensor 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.Leptomeningeal metastases (LM) are found in approximately 3.8% of non-small cell lung cancer cases with an increased incidence in adenocarcinoma, and approximately one-third of patients will present with concomitant brain metastases. We report the case of a 50-year-old male patient with stage IV exon 19-del-EGFR mutant lung adenocarcinoma who progressed on second-generation TKI therapy with manifestation of symptomatic simultaneous diffuse brain and LM. Whole-brain radiotherapy with concurrent afatinib resulted in an almost complete regression of neurological symptoms as well as good, durable radiological response. Furthermore, treatment was well tolerated with no relevant adverse effects.\n\nafatinibbrain and leptomeningeal metastasesnon-small cell lung cancertyrosine-kinase inhibitorwhole-brain radiotherapy\n==== Body\nIntroduction\nLeptomeningeal metastases (LM) represent the infiltration of the leptomeninges by malignant cells (1) and are a readily increasing complication in cancer patients. LM are found in approximately 5% of patients with malignant tumors (1), and in non-small cell lung cancer (NSCLC), the incidence is approximately 3.8% with an increased incidence in adenocarcinoma, and roughly one-third of patients will present with concomitant brain metastases (BM) (2). The incidence is steadily increasing due to improvement in diagnostic tools such as neuroimaging methods as well as availability of improved treatments, consecutively leading to improved survival. However, general prognosis remains poor in the order of 2–4 months (3–7). Currently, no standard treatment exists (8). Occurrence of LM under prolonged tyrosine-kinase inhibitor (TKI) therapy has been previously described (9).\n\nAfatinib is a second-generation irreversible covalent inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinases including ErbB-2 (HER2) and ErbB-4. Subgroup analysis from LUX-LUNG 3 and LUX-LUNG 6 studies demonstrated a significant overall survival benefit for afatinib compared to chemotherapy in UICC stage IIIB/IV lung adenocarcinoma patients with 19del-EGFR mutation (10). Consecutively, in a combined post hoc analysis of both studies, progression free survival was significantly improved with afatinib vs. with chemotherapy in patients with BM (8.2 vs. 5.4 months; HR, 0.50; p = 0.0297) (11). There is a paucity of literature on concurrent radiotherapy and second-generation TKIs. In 2014, Atmaca et al. published a case report of a patient who received concomitant radiotherapy to the mediastinum and primary lung tumor with afatinib. The therapy resulted in partial remission in the irradiated sites without any relevant treatment-associated adverse effects (12). In addition, Li et al. reported in a case series on a 52-year-old male patient with BM from an L858R mutant adenocarcinoma of the lung. Whole-brain radiotherapy (WBRT) was delivered to a total dose of 30.0 Gy in 10 fractions, and afatinib was administered concurrently. Follow-up magnetic resonance imaging (MRI) showed regression of BM (13).\n\nCase\nThe case of a 50-year-old male never smoker with stage IV Exon 19-del-EGFR mutant, ALK- and ROS-1-negative lung adenocarcinoma diagnosed in April 2015 was presented at the multidisciplinary tumor board. At initial diagnosis, the patient presented with malignant pleural effusion and FDG-avid diffuse bone metastasis on 18F-FDG/PET-CT (positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-d-glucose integrated with computed tomography). Due to Exon-19-deletion, afatinib 40 mg/day was prescribed. Follow-up imaging showed good extracranial remission. Approximately 12 months later, the patient presented with cephalalgia, seizures, impaired vision, and hypesthesia. Gadolinium-enhanced multiplanar MRI of the brain and spine showed isolated intraparenchymal and leptomeningeal carcinomatosis of the brain; the findings were conclusive for leptomeningeal spread (see Figures 1–3). Analysis of the cerebrospinal fluid (CSF) confirmed the findings. The patient was started on oral dexamethasone. 18F-FDG-PET/CT confirmed no signs of extracranial tumor progression. The patient underwent WBRT with concurrent afatinib due to fear of extracranial tumor progression in the case afatinib was discontinued. WBRT was applied with 6 MV photon beams once daily; fourteen fractions to a total dose of 35.0 Gy and was well tolerated without any severe cutaneous adverse effects. Three-month follow-up MRI and 18F-FDG-PET/CT showed significant regression of intracranial disease as well as stable extracranial disease. Furthermore, the patient noted an almost complete regression of the above-mentioned neurological symptoms. Approximately nine months following WBRT (see Figures 1–3), contrast-enhanced MRI of the brain showed sustained durable response in the absence of any severe neurological side effects. Furthermore, follow-up 18F-FDG/PET-CT showed stable extracranial disease with multiple FDG non-avid sclerotic bone lesions as a sign of treatment response to afatinib. In addition, although there were no signs of tumor progression on the follow-up scans, after discussion at the multidisciplinary tumor board, precautionary further analysis of the CSF extracted at initial diagnosis of cranial metastases for acquired secondary T790M mutation was recommended.\n\nFigure 1 Axial contrast-enhanced 3D-FAST SPIN ECHO spectral presaturation with inversion recovery [left: pre-whole-brain radiotherapy (WBRT); right: 9-month follow-up]: note decrease in intraparenchymal brain metastases and leptomeningeal enhancement pre- vs. post-WBRT. In addition, note consecutive enlargement of the lateral ventricles on 9-month follow-up scan.\n\nFigure 2 Coronal contrast-enhanced T1-weighted magnetic resonance imaging [left: pre-whole-brain radiotherapy (WBRT); right: 9-month follow-up]: note decrease in leptomeningeal enhancement pre- vs. post-WBRT. In addition, note enlargement of the lateral ventricles on 9-month follow-up scan.\n\nFigure 3 Sagittal contrast-enhanced 3D-FAST SPIN ECHO spectral presaturation with inversion recovery [left: pre-whole-brain radiotherapy (WBRT); right: 9-month follow-up]: note decrease in intraparenchymal brain metastases enhancement pre- vs. post-WBRT. In addition, note enlargement of the ventricles on 9-month follow-up scan.\n\nDiscussion\nBased on the National Comprehensive Cancer Network guidelines, WBRT is a mainstay in the treatment of BM. However, its role in the treatment of LM is yet to be clearly defined. Morris et al. demonstrated in a retrospective study on LM from NSCLC poor survival. In the study, survival was not improved by WBRT (14). In contrast, Soon et al. showed in a systematic review and meta-analysis that there was some evidence that upfront cranial radiotherapy might improve intracranial disease and survival outcomes compared with TKI alone in patients with EGFR mutant NSCLC (15). A recently published study by Jiang et al. demonstrated no overall survival benefit when first-generation TKIs combined with WBRT vs. TKIs alone were administered (16). Hoffknecht et al. showed that patients pretreated with first-generation TKI and new intracranial progression could benefit from treatment conversion to afatinib (17).\n\nIn the present case, simultaneous intraparenchymal brain and LM arose during afatinib therapy despite extracranial tumor control, which can be partially attributed to EGFR mutation heterogeneity (18). There has been no study focusing on the efficacy of WBRT combined with afatinib in LM, but clinical studies on BM have shown that WBRT could increase the permeability of TKI into the CSF (19, 20); hence, in this case, response may also be partially attributed to this phenomenon. In the present case, concomitant afatinib with WBRT was feasible with achievement of rash palliation of symptoms and good, durable radiological response in an Exon19-del EGFR-mutant lung adenocarcinoma patient who progressed during TKI therapy with the manifestation of simultaneous brain and LM. Remarkably, WBRT in combination with afatinib resulted in sustained tumor control going on 9 months following treatment at a stage of disease with dismal prognosis.\n\nEthics Statement\nThis case report was carried out in accordance with the recommendations of the Ethics Committee of the Ludwig Maximilian University of Munich with express written informed consent from the subject, who gave written informed consent in accordance with the Declaration of Helsinki. Treatment was given in palliative intent, hence the exemption from ethics committee approval. This registry does not meet the WHO definition of a clinical trial and is considered exempt from http://clinicaltrials.gov requirements.\n\nAuthor Contributions\nCE drafted, wrote, and edited the manuscript. N-SH edited and critically revised the manuscript. OR edited the manuscript and figures. MD edited the manuscript. FM edited and critically revised the manuscript for valuable intellectual content.\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. The reviewer, JB, and handling editor declared their shared affiliation, and the handling editor states that the process nevertheless met the standards of a fair and objective review.\n\nThe case report has not been previously published and is not under consideration elsewhere. The persons listed as authors have given their approval for the submission of the case report.\n==== Refs\nReferences\n1 Pavlidis N \nThe diagnostic and therapeutic management of leptomeningeal carcinomatosis . Ann Oncol (2004 ) 15 (Suppl 4 ):iv285 –91 .10.1093/annonc/mdh941 15477323 \n2 Liao B-C Lee J-H Lin C-C Chen YF Chang CH Ho CC \nEpidermal growth factor receptor tyrosine kinase inhibitors for non-small-cell lung cancer patients with leptomeningeal carcinomatosis . J Thorac Oncol (2015 ) 10 (12 ):1754 –61 .10.1097/JTO.0000000000000669 26334749 \n3 Chamberlain MC . Leptomeningeal metastasis . Curr Opin Oncol (2010 ) 22 (6 ):627 –35 .10.1097/CCO.0b013e32833de986 20689429 \n4 Wasserstrom WR Glass JP Posner JB . Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients . Cancer (1982 ) 49 (4 ):759 –72 .10.1002/1097-0142(19820215)49:4<759:AID-CNCR2820490427>3.0.CO;2-7 6895713 \n5 Groves MD . New strategies in the management of leptomeningeal metastases . Arch Neurol (2010 ) 67 (3 ):305 –12 .10.1001/archneurol.2010.18 20212228 \n6 Ozdemir Y Yildirim BA Topkan E . Whole brain radiotherapy in management of non-small-cell lung carcinoma associated leptomeningeal carcinomatosis: evaluation of prognostic factors . J Neurooncol (2016 ) 129 (2 ):329 –35 .10.1007/s11060-016-2179-9 27306442 \n7 Brower JV Saha S Rosenberg SA Hullett CR Ian Robins H . Management of leptomeningeal metastases: prognostic factors and associated outcomes . J Clin Neurosci (2016 ) 27 :130 –7 .10.1016/j.jocn.2015.11.012 26778048 \n8 Lee SJ Lee J-I Nam D-H Ahn YC Han JH Sun JM \nLeptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors . J Thorac Oncol (2013 ) 8 (2 ):185 –91 .10.1097/JTO.0b013e3182773f21 23328548 \n9 Li Y-S Jiang B-Y Yang J-J Tu H-Y Zhou Q Guo W-B \nLeptomeningeal metastases in non-small cell lung cancer patients with EGFR mutations . J Thorac Oncol (2016 ) 11 (11 ):1962 –9 .10.1016/j.jtho.2016.06.029 27539328 \n10 Yang JC Wu YL Schuler M Sebastian M Popat S Yamamoto N \nAfatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials . Lancet Oncol (2015 ) 16 (2 ):141 –51 .10.1016/S1470-2045(14)71173-8 25589191 \n11 Schuler M Wu Y-L Hirsh V O’Byrne K Yamamoto N Mok T \nFirst-line afatinib versus chemotherapy in patients with non–small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases . J Thorac Oncol (2016 ) 11 (3 ):380 –90 .10.1016/j.jtho.2015.11.014 26823294 \n12 Atmaca A Al-Batran S-E Allgäuer M Jäger E . Afatinib with concurrent radiotherapy in a patient with metastatic non-small cell lung cancer . Oncol Res Treat (2014 ) 37 (5 ):262 –5 .10.1159/000362488 24853786 \n13 Li S-H Hsieh M-H Fang Y-F . Afatinib in treatment-naive patients with EGFR-mutated lung adenocarcinoma with brain metastasis: a case series . Medicine (Baltimore) (2015 ) 94 (41 ):e1739 .10.1097/MD.0000000000001739 26469914 \n14 Morris PG Reiner AS Szenberg OR Clarke JL Panageas KS Perez HR \nLeptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy . J Thorac Oncol (2012 ) 7 (2 ):382 –5 .10.1097/JTO.0b013e3182398e4f 22089116 \n15 Soon YY Leong CN Koh WY Tham IWK . EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis . Radiother Oncol (2015 ) 114 (2 ):167 –72 .10.1016/j.radonc.2014.12.011 25583566 \n16 Jiang T Su C Li X Zhao C Zhou F Ren S \nEGFR TKIs plus WBRT demonstrated no survival benefit other than that of TKIs alone in patients with NSCLC and EGFR mutation and brain metastases . J Thorac Oncol (2016 ) 11 (10 ):1718 –28 .10.1016/j.jtho.2016.05.013 27237825 \n17 Hoffknecht P Tufman A Wehler T Pelzer T Wiewrodt R Schütz M \nEfficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease . J Thorac Oncol (2015 ) 10 (1 ):156 –63 .10.1097/JTO.0000000000000380 25247337 \n18 Remon J Majem M . EGFR mutation heterogeneity and mixed response to EGFR tyrosine kinase inhibitors of non small cell lung cancer: a clue to overcoming resistance . Transl Lung Cancer Res (2013 ) 2 (6 ):445 –8 .10.3978/j.issn.2218-6751.2013.10.14 25806267 \n19 Zeng YD Liao H Qin T Zhang L Wei WD Liang JZ \nBlood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy . Oncotarget (2015 ) 6 (10 ):8366 –76 .10.18632/oncotarget.3187 25788260 \n20 Zhao J Chen M Zhong W Zhang L Li L Xiao Y \nCerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma . Clin Lung Cancer (2013 ) 14 (2 ):188 –93 .10.1016/j.cllc.2012.06.004 22846582\n\n",
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}
],
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"reaction": [
{
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"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "FERNANDEZ KH, RADY P, TYRING S, STONE MS. ACQUIRED EPIDERMODYSPLASIA VERRUCIFORMIS IN A CHILD WITH ATOPIC DERMATITIS. PEDIATR DERMATOL. 2014;31(3):400-2",
"literaturereference_normalized": "acquired epidermodysplasia verruciformis in a child with atopic dermatitis",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
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"receivedate": "20150206",
"receiver": {
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},
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150721"
},
{
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{
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},
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"medicinalproduct": "CICLOSPORIN"
}
],
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"patientonsetage": "4",
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"reactionoutcome": "1"
}
],
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},
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"literaturereference": "FERNANDEZ KH, RADY P, TYRING S, STONE MS. ACQUIRED EPIDERMODYSPLASIA VERRUCIFORMIS IN A CHILD WITH ATOPIC DERMATITIS. PEDIATR-DERMATOL 2014; 31(3):400-2.",
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"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150130",
"receivedate": "20150130",
"receiver": {
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},
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] |
{
"abstract": "According to national guidelines and statements drugs that can cause or exacerbate heart failure (HF) are considered potentially harmful and should be avoided if possible in patients with a diagnosis of heart failure with reduced ejection fraction (HFREF). To evaluate the prevalence of potentially harmful drug (PHD) prescription among patients with a diagnosis of systolic heart failure we conducted a retrospective cohort study using Truven Health MarketScan Commercial database from 2011 to 2014. Prescription of PHD as defined by American Heart Association Statement was examined among patients with a HFREF diagnosis in: (1) Two outpatient encounters, (2) One inpatient encounter as primary diagnosis and/or (3) one inpatient encounter any position and one outpatient encounter. Among 40,966 patients, 24.2% were prescribed with at least 1 drug with the potential to cause or exacerbate heart failure. Of the 9,954 patients prescribed with PHD, nonsteroidal anti-inflammatory agents were the most frequent category prescribed (67.4%), followed by antihypertensive (24%), diabetes mellitus (23.3%), neurological and psychiatric (21%) and antiarrhythmic medications (12.6%). After multivariable analysis female patients, the presence of a comorbidity associated with a PHD use and polypharmacy were more frequently prescribed a PHD. In conclusion almost ¼ of adult patients with a diagnosis of HFREF have a prescription of a drug with a potential to cause or exacerbate heart failure as defined by current heart failure guidelines.",
"affiliations": "Division of Cardiology, Department of Medicine, University of Iowa, Iowa City, Iowa. Electronic address: paulino-alvarez@uiowa.edu.;Department of Management, Policy and Community, School of Public Health, University of Texas, Houston, Texas.;Division of Cardiology, Department of Medicine, University of Iowa, Iowa City, Iowa.;Department of Management, Policy and Community, School of Public Health, University of Texas, Houston, Texas.",
"authors": "Alvarez|Paulino A|PA|;Truong|Chau N|CN|;Briasoulis|Alexandros|A|;Ganduglia-Cazaban|Cecilia|C|",
"chemical_list": "D002317:Cardiovascular Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjcard.2019.01.052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9149",
"issue": "123(9)",
"journal": "The American journal of cardiology",
"keywords": null,
"medline_ta": "Am J Cardiol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002317:Cardiovascular Agents; D011307:Drug Prescriptions; D005260:Female; D005500:Follow-Up Studies; D054143:Heart Failure, Systolic; D006801:Humans; D008297:Male; D008875:Middle Aged; D019338:Polypharmacy; D012189:Retrospective Studies; D013318:Stroke Volume; D055815:Young Adult",
"nlm_unique_id": "0207277",
"other_id": null,
"pages": "1458-1463",
"pmc": null,
"pmid": "30791999",
"pubdate": "2019-05-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Prescription of Potentially Harmful Drugs in Young Adults With Heart Failure and Reduced Ejection Fraction.",
"title_normalized": "prescription of potentially harmful drugs in young adults with heart failure and reduced ejection fraction"
} | [
{
"companynumb": "US-JNJFOC-20190427393",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
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"drugadministrationroute": "065",
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"drugdosageform": "SUSTAINED RELEASE TABLETS",
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"medicinalproduct": "METHYLPHENIDATE HYDROCHLORIDE."
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Left ventricular failure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "ALVAREZ PA, TRUONG CN, BRIASOULIS A, GANDUGLIA-CAZABAN C. PRESCRIPTION OF POTENTIALLY HARMFUL DRUGS IN YOUNG ADULTS WITH HEART FAILURE AND REDUCED EJECTION FRACTION. AMERICAN JOURNAL OF CARDIOLOGY 01-MAY-2019?123 (9):1458-1463.",
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"qualification": "1",
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},
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},
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}
] |
{
"abstract": "Vancomycin-resistant enterococci (VRE) infections have been increasingly reported in immunosuppressed individuals over the past decade. Emergence of this pathogen in the bone marrow transplantation (BMT) setting, in the form of bacteremia or positive stool cultures, is of concern because of lack of effective antimicrobial therapy. We report episodes of vancomycin-resistant E. faecium bacteremia in two patients undergoing BMT including the first case of VRE meningitis observed in this setting. Since the outcome in these patients undergoing matched unrelated donor BMT was fatal, we believe that routine screening for VRE in high risk patients should be considered. Management of VRE carrier state in BMT candidates is unclear at present.",
"affiliations": "Division of Infectious Diseases, New England Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.",
"authors": "Koc|Y|Y|;Snydman|D R|DR|;Schenkein|D S|DS|;Miller|K B|KB|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.1038/sj.bmt.1701303",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "22(2)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D016026:Bone Marrow Transplantation; D004352:Drug Resistance, Microbial; D016984:Enterococcus faecium; D005260:Female; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D015470:Leukemia, Myeloid, Acute; D014184:Transplantation, Homologous; D014640:Vancomycin",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "207-9",
"pmc": null,
"pmid": "9707033",
"pubdate": "1998-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vancomycin-resistant enterococcal infections in bone marrow transplant recipients.",
"title_normalized": "vancomycin resistant enterococcal infections in bone marrow transplant recipients"
} | [
{
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{
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},
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"medicinalproduct": "DALFOPRISTIN/QUINUPRISTIN"
}
],
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"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "5"
}
],
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},
"primarysource": {
"literaturereference": "KOC, S. VANCOMYCIN-RESISTANT ENTEROCOCCAL INFECTIONS IN BONE MARROW TRANSPLANT RECIPIENTS.. BONE MARROW TRANSPLANT. 1998;22(2):207-209",
"literaturereference_normalized": "vancomycin resistant enterococcal infections in bone marrow transplant recipients",
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},
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},
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},
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},
{
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],
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"reaction": [
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"reactionmeddraversionpt": "21.0",
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},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal impairment",
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}
],
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},
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"literaturereference_normalized": "vancomycin resistant enterococcal infections in bone marrow transplant recipients",
"qualification": "3",
"reportercountry": "US"
},
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"receivedate": "20180913",
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},
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},
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},
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"medicinalproduct": "CEFTAZIDIME."
},
{
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},
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"drugindication": "ACUTE MYELOID LEUKAEMIA",
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{
"abstract": "Sclerema neonatorum is extremely rare in the 21st century. We report a premature infant managed in a neonatal intensive care unit with delayed development of sclerema neonatorum.",
"affiliations": "Division of Dermatology, Department of Internal Medicine, Ohio State University, Columbus, Ohio.;Forefront Dermatology, Cedar Rapids, Iowa.;Department of Dermatology, University of Iowa Carver College of Medicine, Iowa City, Iowa.",
"authors": "Spohn|Gina P|GP|;Pietras|Thomas A|TA|;Stone|Mary Seabury|MS|",
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"country": "United States",
"delete": false,
"doi": "10.1111/pde.12814",
"fulltext": null,
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"issn_linking": "0736-8046",
"issue": "33(2)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D016638:Critical Illness; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases; D012593:Sclerema Neonatorum; D013997:Time Factors",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e168-9",
"pmc": null,
"pmid": "27001336",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed-Onset Sclerema Neonatorum in a Critically Ill Premature Infant.",
"title_normalized": "delayed onset sclerema neonatorum in a critically ill premature infant"
} | [
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{
"abstract": "Haploidentical related donor (HRD) transplantation was performed in 7 recipients with chronic granulomatous disease (CGD) who had no matched-related or unrelated donor.\n\n\n\nPeripheral blood cell (PBC) products were used with a conditioning regimen consisting of low-dose cyclophosphamide, fludarabine, total body irradiation, and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of high-dose post-transplant cyclophosphamide and sirolimus. Recipients were ages 14-26 years, and 3 had severe infections active at transplant.\n\n\n\nAll 7 recipients achieved full engraftment with complete donor chimerism early in the post-transplant period. Acute GVHD occurred in all cases and was grade 3 or steroid refractory in 3. Two patients with steroid-refractory GVHD died. Three patients with severe infectious complications active at transplant, 1 Nocardia pneumonia and 2 extensive invasive fungal infections), survived and were cured of their infection at last follow-up. Bacterial disease occurred post-transplant in all recipients, and viral infections/reactivation were common, including 4 cases of BK virus-associated hemorrhagic cystitis.\n\n\n\nSeven patients with CGD achieved rapid and full-donor engraftment from HRDs utilizing PBCs and a conditioning regimen with PTCy and sirolimus GVHD prophylaxis. However, the incidence of grade 3 and steroid-refractory GVHD was high and led to 2 deaths. Patients with active infections at transplant had successful transplant courses and were cured of their disease. Although there was an initial success with this regimen, the cumulative experience does not support its use in CGD due to an unacceptable rate of severe GVHD.",
"affiliations": "Clinical Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. mark.parta@nih.gov.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA.;National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA.",
"authors": "Parta|Mark|M|;Hilligoss|Dianne|D|;Kelly|Corin|C|;Kwatemaa|Nana|N|;Theobald|Narda|N|;Zerbe|Christa S|CS|;Holland|Steven M|SM|;Malech|Harry L|HL|;Kang|Elizabeth M|EM|",
"chemical_list": "D007166:Immunosuppressive Agents; D003520:Cyclophosphamide",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10875-020-00772-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-9142",
"issue": "40(4)",
"journal": "Journal of clinical immunology",
"keywords": "Chronic granulomatous disease; graft-versus-host disease; haploidentical; post-transplant cyclophosphamide",
"medline_ta": "J Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003520:Cyclophosphamide; D018450:Disease Progression; D005260:Female; D006086:Graft vs Host Disease; D006105:Granulomatous Disease, Chronic; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D011183:Postoperative Complications; D016019:Survival Analysis; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "619-624",
"pmc": null,
"pmid": "32314173",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural",
"references": "27641484;26453586;29373243;29412158;18489989;30770870;24797298;27885760;29746680",
"title": "Failure to Prevent Severe Graft-Versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Chronic Granulomatous Disease.",
"title_normalized": "failure to prevent severe graft versus host disease in haploidentical hematopoietic cell transplantation with post transplant cyclophosphamide in chronic granulomatous disease"
} | [
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{
"abstract": "Lidocaine allergy presents a unique difficulty for both patients and providers who undergo/perform bronchoscopy. We present a case of a 73 yo male with severe lidocaine allergy who successfully underwent bronchoscopy with chloroprocaine topical anesthesia and discuss alternative topical anesthetic agents that may be used in this special situation.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, United States.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, United States.",
"authors": "Hensley|Matthew|M|;Singer|Benjamin H|BH|",
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"country": "England",
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"doi": "10.1016/j.rmcr.2017.12.010",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30373-810.1016/j.rmcr.2017.12.010Case ReportAlternative topical anesthesia for bronchoscopy in a case of severe lidocaine allergy Hensley Matthew mhens5790@gmail.coma∗Singer Benjamin H. aa Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, United States∗ Corresponding author. 3916 Taubman Center, 1500 E Medical Center Dr., Ann Arbor, MI 48103, United States. mhens5790@gmail.com03 1 2018 2018 03 1 2018 23 90 92 25 11 2017 23 12 2017 31 12 2017 © 2018 The Authors. Published by Elsevier Ltd.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Lidocaine allergy presents a unique difficulty for both patients and providers who undergo/perform bronchoscopy. We present a case of a 73 yo male with severe lidocaine allergy who successfully underwent bronchoscopy with chloroprocaine topical anesthesia and discuss alternative topical anesthetic agents that may be used in this special situation.\n==== Body\n1 Introduction\nTopical anesthesia has been a mainstay to provide relief and blunt the cough reflex during bronchoscopy. In the past, topical agents used have included lidocaine, tetracaine, benzocaine, and cocaine; lidocaine being the most popular [1]. The American College of Chest Physicians have released a statement suggesting that lidocaine is the preferred topical anesthetic agent of choice, given its short half-life and favorable side effect profile [2]. The British Thoracic society also recommends lidocaine as the topical anesthetic of choice unless contraindicated [3]. Additional specifications include using 2% nasal lidocaine gel and 1% lidocaine in a spray-as-you-go fashion for optimal blunting of the cough reflex [3]. However, what medication does the bronchoscopist use if a lidocaine allergy is present? We now present a case of a 73-year-old male with severe lidocaine allergy and a need for bronchoscopy.\n\n2 Case presentation\nA 73-year-old male with a history of chronic idiopathic autoimmune disease on chronic steroids presented with dyspnea, productive cough, and fever. The patient was admitted to the hospital two weeks prior with prostatic abscess requiring drainage and outpatient intravenous antibiotics. Three days after discharge, the patient developed fever, cough productive of clear sputum, and worsening dyspnea. He was seen in the outpatient setting and subsequently referred to the emergency department for increased work of breathing and desaturations to <88%.\n\nEmergency department evaluation revealed a temperature of 38.3C, respiratory rate of 32, saturating 94% on 4L supplemental oxygen, with normal heart rate and blood pressure. Exam was significant for tachypnea with crackles bilaterally, without JVD or lower extremity edema. Lab evaluation was notable for a normal white blood cell count (5.8), procalcitonin of 0.32 (0–0.25), negative Streptococcus pneumoniae and Legionalla antigens, negative nasopharyngeal viral PCR swab, negative blood cultures. A Pneumocystis PCR was positive, but the sample was not from the lower respiratory tract. He was unable to provide sputum voluntarily and sputum could not be induced. Imaging with chest radiography and computerized tomography revealed bilateral multifocal infiltrates (Fig. 1, Fig. 2) The patient was started on broad spectrum antibiotics for hospital acquired pneumonia, but was not empirically treated for Pneumocystis due to severe allergy to trimethoprim/sulfamethoxazole. The infectious disease service was consulted and felt the Pneumocystis PCR was falsely positive and the patient required bronchoscopy to obtain an adequate specimen.Fig. 1 Chest radiograph demonstrating multifocal pneumonia.\n\nFig. 1Fig. 2 Representative chest imaging via CT scan.\n\nFig. 2\n\nThe patient had a history of a delayed hypersensitivity reaction, manifested as a severe desquamative rash, to lidocaine used in skin biopsies as well as epinephrine and methylene blue injected mucosally during colonoscopy. This reaction recurred both with preservative-free lidocaine and articaine. He had safely received 2% chloroprocaine during prior skin biopsies. With the patient's consent, we obtained 20ml of injectable paraben-free 2% chloroprocaine for use as topical anesthetic during the bronchoscopy. We subsequently used the spray-as-you-go technique via bronchoscopy with moderate conscious sedation, using midazolam and fentanyl, which the patient had tolerated previously. The patient tolerated the procedure well with minimal coughing. Ultimately, all microbiologic data from the bronchoalveolar lavage was negative, including Pneumocystis PCR, and the patient was treated empirically for hospital acquired pneumonia.\n\n3 Discussion\nLidocaine has been the topical anesthetic of choice for bronchoscopy [1], [2], [3]. There has been debate over the route of delivery and concentration of lidocaine during bronchoscopy [4], [5], [6], [7]. However, when a patient has a lidocaine allergy or allergies to multiple topical anesthetics, the bronchoscopist encounters a unique problem.\n\nHypersensitivity reactions from lidocaine are thought to be related to paraben within the solution [8]. Lidocaine specifically has been thought to have sensitizing properties relative to other amide anesthetics. Past alternatives have included tetracaine and cocaine [1]. In this case, the patient had experienced hypersensitivity reactions to multiple medications applied topically or infiltrated via mucosal or intradermal injection, but had tolerated chloroprocaine.\n\nChloroprocaine is a local anesthetic that was developed for use in spinal anesthesia [9], [10]. It is an ester, while lidocaine or bupivacaine are amides. For this reason its half-life is much shorter than lidocaine [11]. Its use in spinal anesthesia has demonstrated shorter recovery times and less neurotoxicity compared to lidocaine and bupivacaine [12], [13]. Despite a concern of transient neurologic symptoms, there is no conclusive evidence of serious adverse effects from its use [10]. Chloroprocaine has approximately half of the potency of lidocaine when used for local anesthesia (Table 1) [14].Table 1 Agents used in topical/local anesthesia based on type, relative potency, duration and maximum dosages [15].\n\nTable 1Name\tPotency\tType\tMaximum Dose\tDuration\t\nLidocaine\t2\tAmide\t4.5 mg/kg\t120 min\t\nPrilocaine\t2\tAmide\t8 mg/kg\t30 min\t\nBupivacaine\t8\tAmide\t3 mg/kg\t120 min\t\nArticaine\t3\tAmide\t7mg/kg\t60 min\t\n\n\n\t\nProcaine\t1\tEster\t12 mg/kg\t45 min\t\nChloroprocaine\t1\tEster\t12 mg/kg\t30 min\t\nTetracaine\t8\tEster\t3 mg/kg\t180 min\t\nCocaine\t2\tEster\t3 mg/kg\t60 min\t\n\n\nIn this case, we were aware that the patient had tolerated chloroprocaine for intradermal anesthesia. Cross reactivity among multiple amide anesthetics has been described using skin testing [16]. While we speculate that an ester anesthetic is less likely than an alternative amide to provoke a type IV hypersensitivity reaction in a patient sensitized to lidocaine, esters are not intrinsically less allergenic than amides [17]. The safety of alternative ester anesthetics will therefore depend on a patient's prior exposure history to both ester and amide anesthetics [18]. We cannot predict a priori that all patients with a severe reaction to lidocaine or other amides would tolerate chloroprocaine or another ester anesthetic, though the experience of this case suggests that if a particular ester anesthetic is tolerated for one application, its use may be adapted for bronchoscopy.\n\nWe conclude that 2% chloroprocaine, though not previously described in bronchoscopy, was a safe alternative to lidocaine for topical anesthesia in bronchoscopy for a patient with severe hypersensitivity to amide anesthetics. While deep sedation and monitored anesthesia care would also facilitate bronchoscopy in a patient with hypersensitivity to topical anesthetics, those resources are not routinely available during all bronchoscopies at many centers. The use of an alternative agent in this case facilitated safe and expedient completion of the procedure.\n\nConflicts of interest and source of funding\nNone.\n\nAppendix A Supplementary data\nThe following is the supplementary data related to this article:mmc1\nmmc1 \n\nAppendix A Supplementary data related to this article can be found at https://doi.org/10.1016/j.rmcr.2017.12.010.\n==== Refs\nReferences\n1 Perry L.B. Topical anesthesia for bronchoscopy Chest 73 5 Suppl 1978 May 691 693 639577 \n2 Wahidi M.M. Jain P. Jantz M. American College of Chest Physicians consensus statement on the use of topical anesthesia, analgesia, and sedation during flexible bronchoscopy in adult patients Chest 140 5 2011 Nov 1342 1350 22045879 \n3 Du Rand I.A. Blaikley J. Booton R. British Thoracic Society Bronchoscopy Guideline Group British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE Thorax 68 Suppl 1 2013 Aug i1 i44 23860341 \n4 Kaur H. Dhooria S. Aggarwal A.N. A randomized trial of 1% vs 2% lignocaine by the spray-as-you-go technique for topical anesthesia during flexible bronchoscopy Chest 148 3 2015 Sep 739 745 25811287 \n5 Foster W.M. Hurewitz A.N. Aerosolized lidocaine reduces dose of topical anesthetic for bronchoscopy Am. Rev. Respir Dis. 146 2 1992 Aug 520 522 1489150 \n6 Keane D. McNicholas W.T. Comparison of nebulized and sprayed topical anaesthesia for fibreoptic bronchoscopy Eur. Respir. J. 5 9 1992 Oct 1123 1125 1426224 \n7 Charalampidou S. Harris E. Chummun K. Evaluation of the efficacy of nebulised lignocaine as adjunctive local anaesthesia for fibreoptic bronchoscopy: a randomised, placebo-controlled study Ir. Med. J. 99 1 2006 Jan 8 10 16506681 \n8 Saito M. Abe M. Furukawa T. Study on patients who underwent suspected diagnosis of allergy to amide-type local anesthetic agents by the leukocyte migration test Allergol. Int. 63 2 2014 Jun 267 277 24759556 \n9 Veneziano G. Iliev P. Tripi J. Continuous chloroprocaine infusion for thoracic and caudal epidurals as a postoperative analgesia modality in neonates, infants, and children Paediatr. Anaesth. 26 1 2016 Jan 84 91 26530835 \n10 Goldblum E. Atchabahian A. The use of 2-chloroprocaine for spinal anaesthesia Acta Anaesthesiol. Scand. 57 5 2013 May 545 552 23320599 \n11 Kuhnert B.R. Kuhnert P.M. Philipson E.H. The half-life of 2-chloroprocaine Anesth. Analg. 65 3 1986 Mar 273 278 3954093 \n12 Camponovo C. Wulf H. Ghisi D. Intrathecal 1% 2-chloroprocaine vs. 0.5% bupivacaine in ambulatory surgery: a prospective, observer-blinded, randomised, controlled trial Acta Anaesthesiol. Scand. 58 5 2014 May 560 566 24601887 \n13 Teunkens A. Vermeulen K. Van Gerven E. Comparison of 2-chloroprocaine, bupivacaine, and lidocaine for spinal anesthesia in patients undergoing knee arthroscopy in an outpatient setting: a double-blind randomized controlled trial Reg. Anesth. Pain Med. 41 5 2016 Sep-Oct 576 583 27281722 \n14 Yung E. Yarmush J.M. Weinberg J. Comparison of the potency of lidocaine and chloroprocaine in sciatic nerve block in Sprague-Dawley rats Pharmacology 83 6 2009 356 359 19420984 \n15 Open Anesthesia. Local Anesthetics [Open Anesthesia Website]. Available at: https://www.openanesthesia.org/local_anesthetics_systemic_toxicity. Accessed Oct 1, 2017.\n16 Fuzier R. Lapeyre-Mestre M. Mertes P.-M. Nicolas J.-F. Benoit Y. Didier A. Albert N. Montastruc J.-L. French Association of Regional Pharmacovigilance Centers, Immediate- and delayed-type allergic reactions to amide local anesthetics: clinical features and skin testing Pharmacoepidemiol. Drug Saf. 18 2009 595 601 19402039 \n17 Eggleston S.T. Lush L.W. Understanding allergic reactions to local anesthetics Ann. Pharmacother. 30 1996 851 857 8826570 \n18 To D. Kossintseva I. de Gannes G. Lidocaine contact allergy is becoming more prevalent Dermatol. Surg. 40 2014 1367 1372 25380091\n\n",
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"abstract": "Yılmaz-Semerci S, Demirel G, Taştekin A. Wickerhamomyces anomalus blood stream infection in a term newborn with pneumonia. Turk J Pediatr 2017; 59: 349-351. The incidence of invasive candidiasis is high in neonates admitted to neonatal intensive care unit and is associated with significant morbidity and mortality rates. Candida albicans is the most common fungal agent pathogenic to neonates but invasive fungal infections caused by uncommon fungi have increased in recent years. Wickerhamomyces anomalus is a very rare pathogen causing blood stream infection in neonates, which has reportedly caused only few cases in the literature. Here we report a case of blood stream infection caused by a fungal agent Wickerhamomyces anomalus in a term male infant.",
"affiliations": "Division of Neonatology, Department of Pediatrics, İstanbul Kanuni Sultan Süleyman Training and Research Hospital.;Division of Neonatology, Department of Pediatrics, İstanbul Medipol University, İstanbul, Turkey.;Division of Neonatology, Department of Pediatrics, İstanbul Medipol University, İstanbul, Turkey.",
"authors": "Yılmaz-Semerci|Seda|S|;Demirel|Gamze|G|;Taştekin|Ayhan|A|",
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"mesh_terms": "D000935:Antifungal Agents; D016469:Fungemia; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal; D008168:Lung; D008297:Male; D009181:Mycoses; D010843:Pichia; D011014:Pneumonia; D014057:Tomography, X-Ray Computed",
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"title": "Wickerhamomyces anomalus blood stream infection in a term newborn with pneumonia.",
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{
"abstract": "BACKGROUND\nBordetella bronchiseptica is a gram-negative, obligate aerobic coccobacillus known to cause disease in domesticated animals and pets. In humans, B. bronchiseptica commonly leads to respiratory infections like pneumonia or bronchitis, and animal contact usually precedes the onset of symptoms.\n\n\nMETHODS\nWe report a case of post-traumatic B. bronchiseptica meningitis without recent surgery in the setting of immunosuppression with a monoclonal antibody. Our case concerns a 77-year-old male with ulcerative colitis on infliximab who sustained a mechanical fall and developed a traumatic cerebrospinal fluid leak complicated by meningitis. He received meropenem then ceftazidime during his hospital course, and temporary neurosurgical drain placement was required. His clinical condition improved, and he was discharged at his baseline neurological status.\n\n\nCONCLUSIONS\nB. bronchiseptica is an unusual cause of meningitis that may warrant consideration in immunocompromised hosts with known or suspected animal exposures. To better characterize this rare cause of meningitis, we performed a systematic literature review and summarized all previously reported cases.",
"affiliations": "Yale School of Medicine, 15th York Street, LLCI 10th floor, P.O. Box 208018, New Haven, CT, 06520, USA.;Department of Internal Medicine, Section of Infectious Diseases, Yale New Haven Hospital, New Haven, CT, USA.;Yale School of Medicine, 15th York Street, LLCI 10th floor, P.O. Box 208018, New Haven, CT, 06520, USA.;Yale School of Medicine, 15th York Street, LLCI 10th floor, P.O. Box 208018, New Haven, CT, 06520, USA.;Yale School of Medicine, 15th York Street, LLCI 10th floor, P.O. Box 208018, New Haven, CT, 06520, USA. firas.kaddouh@yale.edu.",
"authors": "Radcliffe|Christopher|C|;Lier|Audun|A|;Doilicho|Natnael|N|;Parikh|Sunil|S|;Kaddouh|Firas|F|http://orcid.org/0000-0001-9531-4560",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D002442:Ceftazidime; D000069285:Infliximab; D000077731:Meropenem",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-020-05668-2",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334 BioMed Central London \n\n5668\n10.1186/s12879-020-05668-2\nCase Report\nBordetella bronchiseptica: a rare cause of meningitis\nRadcliffe Christopher 1 Lier Audun 2 Doilicho Natnael 1 Parikh Sunil 12 http://orcid.org/0000-0001-9531-4560Kaddouh Firas firas.kaddouh@yale.edu 13 1 grid.47100.320000000419368710Yale School of Medicine, 15th York Street, LLCI 10th floor, P.O. Box 208018, New Haven, CT 06520 USA \n2 grid.417307.6Department of Internal Medicine, Section of Infectious Diseases, Yale New Haven Hospital, New Haven, CT USA \n3 grid.417307.6Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Yale New Haven Hospital, New Haven, CT USA \n3 12 2020 \n3 12 2020 \n2020 \n20 92212 6 2020 27 11 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nBordetella bronchiseptica is a gram-negative, obligate aerobic coccobacillus known to cause disease in domesticated animals and pets. In humans, B. bronchiseptica commonly leads to respiratory infections like pneumonia or bronchitis, and animal contact usually precedes the onset of symptoms.\n\nCase presentation\nWe report a case of post-traumatic B. bronchiseptica meningitis without recent surgery in the setting of immunosuppression with a monoclonal antibody. Our case concerns a 77-year-old male with ulcerative colitis on infliximab who sustained a mechanical fall and developed a traumatic cerebrospinal fluid leak complicated by meningitis. He received meropenem then ceftazidime during his hospital course, and temporary neurosurgical drain placement was required. His clinical condition improved, and he was discharged at his baseline neurological status.\n\nConclusions\nB. bronchiseptica is an unusual cause of meningitis that may warrant consideration in immunocompromised hosts with known or suspected animal exposures. To better characterize this rare cause of meningitis, we performed a systematic literature review and summarized all previously reported cases.\n\nKeywords\nBordetella bronchisepticaInfliximabMeningitisEmerging infectionsissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nFirst isolated in 1911 as the causative agent behind canine distemper [1], Bordetella bronchiseptica is a gram-negative, obligate aerobe known to cause disease in dogs, pigs, and several other animals [2]. In humans, animal contact is often the source of transmission, and respiratory infections like pneumonia or bronchitis are common clinical syndromes [2]. B. bronchiseptica infections often occur in people with immunocompromising conditions [3–9], and the majority of patients in a recent series had comorbidities which increased their susceptibility to infection [10].\n\nUnlike respiratory infections, B. bronchiseptica meningitis is exceedingly rare [11–13]. We report a case of a 77-year-old male with ulcerative colitis on infliximab who sustained a fall and developed a traumatic cerebrospinal fluid (CSF) leak complicated by B. bronchiseptica meningitis. To our knowledge, this represents the first reported case of post-traumatic B. bronchiseptica meningitis in a patient without recent central nervous system instrumentation. We performed a systematic literature review and summarized all prior reports in order to better characterize this potentially emerging cause of meningitis.\n\nCase presentation\nA 77-year-old male with a past medical history of hypertension, osteoarthritis, and ulcerative colitis on infliximab presented to an outside hospital after an unwitnessed mechanical fall. There was no noted preceding prodrome. He was retired and volunteered frequently at animal shelters with extensive animal contact. On presentation, he endorsed a headache as well as posterior neck pain and was found to be hypertensive (systolic blood pressure 208 mmHg) with leukocytosis (21,100/μL; ref. range 3500-10,000/μL). A head-and-neck computed tomography (CT) scan revealed small subdural hematomas, mild traumatic subarachnoid hemorrhage with small intraventricular component, and a nondisplaced fracture of the sphenoid sinus.\n\nHe was admitted to the intensive care unit (ICU) for management of hypertensive emergency and was treated empirically with a 7-day course of intravenous ampicillin-sulbactam for presumed aspiration pneumonia. Sputum cultures were not obtained. On hospital day 8, he developed serosanguinous nasal drainage, confirmed to be CSF rhinorrhea by beta-2-transferrin testing, which subsequently resolved without intervention. While on the floor, he was ambulating and functioning at baseline per family members, but developed mild dizziness and new headache on hospital day 10. The following morning, he exhibited altered mental status with a temperature of 39.2 °C and blood pressure of 230/110 mmHg. His markedly elevated blood pressure was attributed to agitation, suspected seizure, and poorly-controlled hypertension at baseline. Laboratory studies revealed new leukocytosis (16,000/μL). Blood cultures were drawn and returned negative. A repeat CT scan was stable without findings suggestive of herniation or significant cerebral edema, and CSF cultures were collected via lumbar puncture. Intravenous meropenem was empirically started, and he was readmitted to the ICU for neurological monitoring and blood pressure control. Blood cultures were again drawn on hospital day 12 and returned negative.\n\nB. bronchiseptica eventually grew on CSF culture, and meropenem was continued. Table 1 lists the isolate’s susceptibility profile. On hospital day 17, he had worsening encephalopathy, a repeat CSF analysis showed resolving pleocytosis, and a repeat CT scan showed stable communicating hydrocephalus. He was transferred to Yale New Haven Hospital the following day. On hospital day 19, temporary CSF diversion was achieved by a lumbar drain due to concern for communicating hydrocephalus. CSF cultures were collected at the time of lumbar drain placement and returned negative. Three subsequent CSF cultures were also negative. On hospital day 20, sensitivity data for B. bronchiseptica cultures were received from the outside hospital, and antibiotic therapy was deescalated to intravenous ceftazidime. Three days after its placement, the lumbar drain was removed and replaced with an external ventricular drain since the patient’s neurological exam failed to improve. A CT scan demonstrated persistent ventriculomegaly, and obstructive hydrocephalus was suspected. His mental status dramatically improved over the following days, and the external ventricular drain was removed 7 days after placement. Notably, ventriculomegaly persisted on a repeat CT scan. Guided by CSF profile and culture data, ceftazidime was discontinued at that time. In total, he received 10 days of meropenem and an additional 9 days of ceftazidime. He was at his baseline neurologically when discharged to a rehabilitation facility after a 32-day hospital stay.\nTable 1 Sensitivity data for B. bronchiseptica isolate\n\nSusceptible\tIntermediate\tResistant\t\nceftazidime\tcefepime\taztreonam\t\ngentamicin\tceftriaxone\t\t\nimipenem\t\t\t\npiperacillin-tazobactam\t\t\t\ntobramycin\t\t\t\ntrimethoprim/sulfamethoxazole\t\t\t\nLegend: The isolate’s susceptibility profile was determined using a DxM MicroScan WalkAway (Beckman Coulter) instrument. Bold text represents column titles\n\n\n\nDiscussion and conclusions\nB. bronchiseptica commonly causes respiratory infections when transmitted to humans [2]. To our knowledge, this is the first case of non-surgical B. bronchiseptica meningitis complicating a traumatic CSF leak. Our patient was successfully treated with a 19-day course of antibiotics and temporary CSF diversion. It is presumed that his exposure to B. bronchiseptica occurred during his volunteer activities at local animal shelters, but it is unknown whether he was colonized with B. bronchiseptica, as previous studies support B. bronchiseptica colonization of the human respiratory tract [10, 14]. Both his advanced age and infliximab therapy may have contributed to his immunocompromised status and increased susceptibility to infection. Ultimately, he survived the hospital stay with significant recovery and returned to his baseline neurological status.\n\nTo search PubMed and Ovid databases for B. bronchiseptica meningitis cases, we used the following search operators: (“Bordetella bronchiseptica” OR “Haemophilus bronchiseptica” OR “Brucella bronchiseptica” OR “Bacillus suisepticus” OR “Alcaligenes bronchicanis” OR “Alcaligenes bronchisepticus”) AND (meningitis OR encephalitis OR cerebritis OR “cerebral abscess”). Table 2 summarizes all reported cases and the present case. Two pediatric cases and one adult case have been reported [11–13]. The first report concerned a 9-year-old male who underwent an open reduction for orbital fractures after being kicked in the head by a horse [11], another was a case of a 17-year-old female involving an acoustic neuroma resection 6 weeks before presentation [12], and the only previously reported adult case concerned a 49-year-old male who had a glioblastoma resected 6 weeks before presentation [13]. Treatment was successful for both pediatric cases [11, 12], and the 49-year-old male died after transitioning to palliative care [13].\nTable 2 Summary of reported B. bronchiseptica meningitis cases\n\nAge/Sex\tAnimal Exposure\tRecent Central Nervous System Instrumentation\tRecent Trauma\tInitial Cerebrospinal Fluid Profile\tOutcome\tReference\t\n9-year-old/male\thousehold pets\topen reduction procedure for orbital fractures\thead trauma from horse kick\twhite blood cell count, 2034/mm3; no red blood cells; glucose, 55 mg/dL; protein, 40 mg/dL\ttreatment success\t[11]\t\n17-year-old/female\thousehold pets\tacoustic neuroma resection\tnone\twhite blood cell count, 20/mm3; glucose, 49 mg/dL; protein, 25 mg/dL; Gram-stain negative\ttreatment success\t[12]\t\n49-year-old/male\thousehold pets\tglioblastoma resection\tnone\twhite blood cell count, 28; red blood cell count, 8; glucose, 59 mg/dL; protein, 26 mg/dL; Gram-stain negative\ttransitioned to palliative care due to underlying glioblastoma and died\t[13]\t\n77-year-old/male\tanimal shelters\tnone\tmechanical fall\twhite blood cell count, 1700; red blood cell count, 103; glucose, 95 mg/dL (serum glucose 178 mg/dL); protein, 95 mg/dL; Gram-stain negative\ttreatment success\tour case\t\nLegend: The table summarizes all reported cases identified by searching PubMed and Ovid databases. Bold text represents column titles\n\n\n\nOur case is notable for being the first reported case of B. bronchiseptica meningitis without surgical instrumentation preceding the initial presentation; however, the infection in the 9-year-old male may have been subclinical after sustaining head trauma and only manifested after surgery [11]. All previously reported cases had documented animal exposures [11–13], and our case is consistent with these reports. Interestingly, the household pets and horse involved in the 9-year-old male’s case tested negative for B. bronchiseptica, and the true source of his infection was unknown [11]. Although rare, B. bronchiseptica meningitis has now been reported in several patients with compromised meningeal barriers and immunocompromising comorbidities, all with suspected animal exposures [12, 13]. Furthermore, the increasing use of immunosuppressive agents for the treatment of autoimmune, oncological, or cardiovascular diseases merits increased vigilance for uncommon causes of meningitis or systemic infection [15–17].\n\nAbbreviations\nCSFCerebrospinal fluid\n\nCTComputed tomography\n\nICUIntensive care unit\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nCR wrote the manuscript and contributed to concept/design. AL made critical revisions to the manuscript and contributed to concept/design. ND made critical revisions to the manuscript and contributed to concept/design. SP made critical revisions to the manuscript. FK made critical revisions to the manuscript, contributed to concept/design, and provided supervision. All authors read and approved the final manuscript.\n\nFunding\nThe authors declare that funding was not utilized for the preparation of this manuscript.\n\nAvailability of data and materials\nMaterials in the form of electronic medical records are available but unable to be released due to the Health Insurance Portability and Accountability Act. All relevant, deidentified data has been presented in this case report and further inquiry can be addressed to the corresponding author.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient’s spouse, his medical power of attorney, for publication of this case report. The patient provided verbal assent.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Ferry NS Etiology of canine distemper J Infect Dis 1911 8 399 420 10.1093/infdis/8.4.399 \n2. Woolfrey BF Moody JA Human infections associated with Bordetella bronchiseptica Clin Microbiol Rev 1991 4 3 243 255 10.1128/CMR.4.3.243 1889042 \n3. Dworkin MS Sullivan PS Buskin SE Harrington RD Olliffe J MacArthur RD Bordetella bronchiseptica infection in human immunodeficiency virus-infected patients Clin Infect Dis 1999 28 5 1095 1099 10.1086/514761 10452641 \n4. Woods P Ordemann K Stanecki C Brown J Uzodi A Bordetella bronchiseptica pneumonia in an adolescent: case report and review of the pediatric literature Clin Pediatr (Phila) 2020 59 3 322 328 10.1177/0009922819897355 31876162 \n5. Powers HR, Shah K. Bordetella bronchiseptica bloodstream infection in a renal transplant patient. Transpl Infect Dis. 2017;19(6). 10.1111/tid.12774 Epub 2017 Oct 25.\n6. Mazumder SA Cleveland KO Bordetella bronchiseptica bacteremia in a patient with AIDS South Med J 2010 103 9 934 935 10.1097/SMJ.0b013e3181ebcdbc 20689480 \n7. Redelman-Sidi G Grommes C Papanicolaou G Kitten-transmitted Bordetella bronchiseptica infection in a patient receiving temozolomide for glioblastoma J Neuro-Oncol 2011 102 2 335 339 10.1007/s11060-010-0322-6 \n8. Gisel JJ Brumble LM Johnson MM Bordetella bronchiseptica pneumonia in a kidney-pancreas transplant patient after exposure to recently vaccinated dogs Transpl Infect Dis 2010 12 1 73 76 10.1111/j.1399-3062.2009.00451.x 19874567 \n9. Bauwens JE Spach DH Schacker TW Mustafa MM Bowden RA Bordetella bronchiseptica pneumonia and bacteremia following bone marrow transplantation J Clin Microbiol 1992 30 9 2474 2475 10.1128/JCM.30.9.2474-2475.1992 1401019 \n10. Garcia-de-la-Fuente C Guzman L Cano ME Aguero J Sanjuan C Rodriguez C Microbiological and clinical aspects of respiratory infections associated with Bordetella bronchiseptica Diagn Microbiol Infect Dis 2015 82 1 20 25 10.1016/j.diagmicrobio.2015.01.011 25703895 \n11. Chang KC Zakhein RM Cho CT Montgomery JC Letter: posttraumatic purulent meningitis due to Bordetella bronchiseptica J Pediatr 1975 86 4 639 640 10.1016/S0022-3476(75)80178-8 \n12. Belen O Campos JM Cogen PH Jantausch BA Postsurgical meningitis caused by Bordetella bronchiseptica Pediatr Infect Dis J 2003 22 4 380 381 12712975 \n13. Groner M Rodriguez A Doblecki-Lewis S Bordetella bronchiseptica post-surgical meningitis in an adult Infect Dis Clin Pract 2016 24 6 e56 e57 10.1097/IPC.0000000000000419 \n14. Wernli D Emonet S Schrenzel J Harbarth S Evaluation of eight cases of confirmed Bordetella bronchiseptica infection and colonization over a 15-year period Clin Microbiol Infect 2011 17 2 201 203 10.1111/j.1469-0691.2010.03258.x 20459438 \n15. Cholapranee A Hazlewood GS Kaplan GG Peyrin-Biroulet L Ananthakrishnan AN Systematic review with meta-analysis: comparative efficacy of biologics for induction and maintenance of mucosal healing in Crohn's disease and ulcerative colitis controlled trials Aliment Pharmacol Ther 2017 45 10 1291 1302 10.1111/apt.14030 28326566 \n16. Monaco C Nanchahal J Taylor P Feldmann M Anti-TNF therapy: past, present and future Int Immunol 2015 27 1 55 62 10.1093/intimm/dxu102 25411043 \n17. Salvana EM Salata RA Infectious complications associated with monoclonal antibodies and related small molecules Clin Microbiol Rev 2009 22 2 274,90 10.1128/CMR.00040-08 19366915\n\n",
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"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000368:Aged; D000818:Animals; D000900:Anti-Bacterial Agents; D001885:Bordetella Infections; D016950:Bordetella bronchiseptica; D002442:Ceftazidime; D065634:Cerebrospinal Fluid Leak; D003093:Colitis, Ulcerative; D004322:Drainage; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D008581:Meningitis; D000077731:Meropenem; D019635:Neurosurgical Procedures; D016896:Treatment Outcome",
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"title": "Bordetella bronchiseptica: a rare cause of meningitis.",
"title_normalized": "bordetella bronchiseptica a rare cause of meningitis"
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"abstract": "Brucellosis is being increasingly recognized after solid organ transplantation but has not been reported after orthotopic heart transplantation. We present the case of a 51-year-old farmer who underwent orthotopic heart transplantation and was readmitted after 3 months in a severely immunosuppressed state with significant nonspecific complaints. He posed a diagnostic and management dilemma to all disciplines, but finally turned out to be harboring Brucella infection. He responded well to medical management and was discharged in a stable clinical status. Although rare, brucellosis should be included in the investigative workup for nonspecific symptoms after cardiac transplantation.",
"affiliations": "Department of Cardiovascular and Thoracic Surgery, Government Medical College, Kottayam, India. Electronic address: drvinimuralia@gmail.com.;Department of HPB and Liver Transplant, Caritas Hospital, Kottayam, India.;Department of Pulmonology, Government Medical College, Kottayam, India.;Department of Cardiovascular and Thoracic Surgery, Government Medical College, Kottayam, India.",
"authors": "Nair|Vinitha V|VV|;Appukuttan|Murali|M|;Narayan|Kiran Vishnu|KV|;Nair|Jayakumar Thanathu Krishnan|JTK|",
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"title": "Brucellosis After Cardiac Transplantation.",
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"abstract": "Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of TH1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in TH1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.",
"affiliations": "Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Department of Systems Biology, Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Department of Systems Biology, Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.;Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.;Department of Oncology, Geneva University Hospitals, Geneva, Switzerland.;Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.;Precision Oncology Center, Department of Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland.;Precision Oncology Center, Department of Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland.;Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.;Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland.;Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.;Department of Oncology, Geneva University Hospitals, Geneva, Switzerland.;Precision Oncology Center, Department of Oncology, Lausanne University Hospital CHUV, Lausanne, Switzerland.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA.;Department of Systems Biology, Harvard Medical School, Boston, MA, USA.;Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, USA. mikael.pittet@unige.ch.",
"authors": "Siwicki|Marie|M|0000-0001-6330-8780;Gort-Freitas|Nicolas A|NA|0000-0001-8614-4782;Messemaker|Marius|M|0000-0002-7179-0594;Bill|Ruben|R|0000-0002-4674-2531;Gungabeesoon|Jeremy|J|0000-0002-4505-3160;Engblom|Camilla|C|0000-0001-5090-4161;Zilionis|Rapolas|R|;Garris|Christopher|C|;Gerhard|Genevieve M|GM|0000-0002-4144-3284;Kohl|Anna|A|0000-0002-0040-4967;Lin|Yunkang|Y|0000-0002-9182-8158;Zou|Angela E|AE|0000-0002-9709-3121;Cianciaruso|Chiara|C|0000-0002-5635-5404;Bolli|Evangelia|E|;Pfirschke|Christina|C|0000-0001-9434-4485;Lin|Yi-Jang|YJ|0000-0002-1850-4245;Piot|Cecile|C|0000-0001-7639-3662;Mindur|John E|JE|0000-0002-2212-3904;Talele|Nilesh|N|0000-0003-2758-8599;Kohler|Rainer H|RH|0000-0001-6269-6590;Iwamoto|Yoshiko|Y|;Mino-Kenudson|Mari|M|0000-0002-9092-2265;Pai|Sara I|SI|;deVito|Claudio|C|0000-0002-4966-1278;Koessler|Thibaud|T|0000-0001-9196-9076;Merkler|Doron|D|;Coukos|Alexander|A|;Wicky|Alexandre|A|0000-0003-0967-5787;Fraga|Montserrat|M|;Sempoux|Christine|C|0000-0003-1375-3979;Jain|Rakesh K|RK|0000-0001-7571-3548;Dietrich|Pierre-Yves|PY|0000-0002-7375-6939;Michielin|Olivier|O|;Weissleder|Ralph|R|0000-0003-0828-4143;Klein|Allon M|AM|0000-0001-8913-7879;Pittet|Mikael J|MJ|0000-0002-2060-4691",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1126/sciimmunol.abi7083",
"fulltext": null,
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"issn_linking": "2470-9468",
"issue": "6(61)",
"journal": "Science immunology",
"keywords": null,
"medline_ta": "Sci Immunol",
"mesh_terms": null,
"nlm_unique_id": "101688624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34215680",
"pubdate": "2021-07-02",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.",
"title_normalized": "resident kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy"
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{
"abstract": "Recent reports have shown that excellent survival outcomes can be achieved in adult Burkitt's lymphoma with the use of DA-EPOCH-R regimen. When compared to earlier intense pediatric-type protocols, this regimen is less toxic. There are limited reports available on the use of this regimen outside the context of clinical trials. We analyzed the outcomes of patients who were treated with the DA-EPOCH-R regimen [Burkitt's lymphoma (BL), primary mediastinal B cell lymphoma (PMBCL) and HIV-positive patients with diffuse large B cell lymphoma (DLBCL)] at our center over a 3 year period. Baseline characters, responses, and toxicity data was captured from records. Event-free survival (EFS-from therapy initiation till occurrence of event (non-achievement of complete response or relapse) and overall survival (OS-from therapy initiation till death due to any cause) were estimated using Kaplan-Meier method. Among 41 patients [median age 40 years (18-76)], the following diagnoses were included-HIV negative patients (N = 29): BL (N = 24), PMBCL (N = 5); HIV positive patients (N = 12): BL (N = 8), and DLBCL (N = 4). Among those with BL, majority had stage III/IV disease (N = 21/32, 65%). At the completion of planned therapy, 33 had achieved CR (81%). One patient died due to toxicity. The actuarial EFS and OS at 2 years were 80 and 77% respectively for all patients. The OS at 2 years was 100% for PMBCL, 80% for BL and 50% for HIV-positive DLBCL. Majority of the failures in BL were in patients with advanced disease. DA-EPOCH-R can be used in real-world setting and allows treatment of older patients with BL.",
"affiliations": "1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.;1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.;1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.;1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.;1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.;1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.;1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.;2Department of Pathology, Cancer Institute (WIA), Chennai, Tamilnadu 600020 India.;1Department of Medical Oncology, Cancer Institute (WIA), Adyar, Chennai, 600020 India.",
"authors": "Ganesan|Prasanth|P|0000-0003-2762-6591;Ganesan|Trivadi S|TS|;Atreya|Harshvardhan|H|;Kannan|Krishnarathinam|K|;Radhakrishnan|Venkatraman|V|;Dhanushkodi|Manikandan|M|;Joshua|Thanda Lucy Ann|TLA|;Sundersingh|Shirley|S|;Sagar|Tenali Gnana|TG|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s12288-017-0901-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0971-4502",
"issue": "34(3)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "Burkitt’s lymphoma; DA-EPOCH-R; HIV-positive lymphoma; Primary mediastinal B cell lymphoma",
"medline_ta": "Indian J Hematol Blood Transfus",
"mesh_terms": null,
"nlm_unique_id": "9425818",
"other_id": null,
"pages": "454-459",
"pmc": null,
"pmid": "30127552",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article",
"references": "17242396;23574119;22180164;24146219;20023215;16502413;24224624;25113771;23361927;24397614;25359988;22563152",
"title": "DA-EPOCH-R in Aggressive CD 20 Positive B Cell Lymphomas: Real-World Experience.",
"title_normalized": "da epoch r in aggressive cd 20 positive b cell lymphomas real world experience"
} | [
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{
"abstract": "Loperamide (Imodium®) has been accepted as a safe, effective, over-the-counter anti-diarrheal drug with low potential for abuse. It is a synthetic opioid that lacks central nervous system activity at prescribed doses, rendering it ineffective for abuse. Since 2012, however, the North Carolina Office of the Chief Medical Examiner has seen cases involving loperamide at supratherapeutic levels that indicate abuse. The recommended dose associated with loperamide should not exceed 16 mg per day, although users seeking an opioid-like high reportedly take it in excess of 100 mg per dose. When taken as directed, the laboratory organic base extraction screening method with gas chromatography-mass spectrometry/nitrogen phosphorus detector lacks the sensitivity to detect loperamide. When taken in excess, the screening method identifies loperamide followed by a separate technique to confirm and quantify the drug by liquid chromatography-tandem mass spectrometry. Of the 21 cases involving loperamide, the pathologist implicated the drug as either additive or primary to the cause of death in 19 cases. The mean and median peripheral blood concentrations for the drug overdose cases were 0.27 and 0.23 mg/L, respectively. Furthermore, an extensive review of the pharmacology associated with loperamide and its interaction with P-glycoprotein will be examined as it relates to the mechanism of toxicity.",
"affiliations": "North Carolina Office of the Chief Medical Examiner, Raleigh, NC 27607, USA sandra.bishop@dhhs.nc.gov.;North Carolina Office of the Chief Medical Examiner, Raleigh, NC 27607, USA.;North Carolina Office of the Chief Medical Examiner, Raleigh, NC 27607, USA.;North Carolina Office of the Chief Medical Examiner, Raleigh, NC 27607, USA.;North Carolina Office of the Chief Medical Examiner, Raleigh, NC 27607, USA.;North Carolina Office of the Chief Medical Examiner, Raleigh, NC 27607, USA.;North Carolina Office of the Chief Medical Examiner, Raleigh, NC 27607, USA.",
"authors": "Bishop-Freeman|Sandra C|SC|;Feaster|Marc S|MS|;Beal|Jennifer|J|;Miller|Alison|A|;Hargrove|Robert L|RL|;Brower|Justin O|JO|;Winecker|Ruth E|RE|",
"chemical_list": "D000701:Analgesics, Opioid; D008139:Loperamide",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkw069",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "40(8)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008139:Loperamide; D008297:Male; D009657:North Carolina; D015813:Substance Abuse Detection",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "677-686",
"pmc": null,
"pmid": "27474361",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Loperamide-Related Deaths in North Carolina.",
"title_normalized": "loperamide related deaths in north carolina"
} | [
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"abstract": "Lacosamide enhances slow inactivation of voltage-gated sodium channels and can lead to dose-dependent PR interval prolongation. Previously, lacosamide has been associated with second-degree atrioventricular (AV) heart block in the context of multiple medical comorbidities and/or in the elderly with multimorbidity on other dromotropic agents. We report a case of second-degree AV block occurring in a healthy, athletic young adult. The patient had baseline bradycardia with no known cardiac comorbidities. He was exquisitely sensitive to lacosamide with EKG and telemetry changes developing on the order of hours after receiving intravenous lacosamide. Lacosamide was subsequently stopped, the second-degree AV block was no longer present and EKG returned to baseline. We hypothesize that his sensitivity to lacosamide-induced AV block was possibly secondary to his baseline bradycardia with early repolarization changes. The case underscores the importance of surveillance cardiac monitoring. While medical comorbidities and an older age may portend a greater risk of PR prolongation, routine EKGs should be considered in all patients receiving lacosamide.",
"affiliations": "Northwestern University Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, United States.;Northwestern University Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, United States.;Northwestern University Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, United States.;Northwestern University Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, United States.",
"authors": "Stamm|Brian|B|;Sheikh|Atif|A|;Schuele|Stephan|S|;Templer|Jessica W|JW|",
"chemical_list": null,
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"doi": "10.1016/j.ebr.2020.100372",
"fulltext": "\n==== Front\nEpilepsy Behav Rep\nEpilepsy Behav Rep\nEpilepsy & Behavior Reports\n2589-9864 Elsevier \n\nS2589-9864(20)30020-4\n10.1016/j.ebr.2020.100372\n100372\nArticle\nLacosamide-associated second-degree atrioventricular block in a healthy, young athlete\nStamm Brian brian.stamm@northwestern.edu⁎ Sheikh Atif atif.sheikh@northwestern.edu Schuele Stephan sschuele@nm.org Templer Jessica W. Jessica.Templer@nm.org Northwestern University Feinberg School of Medicine, Department of Neurology, Chicago, IL 60611, United States\n⁎ Corresponding author at: Northwestern Memorial Hospital, 251 E Huron St, Chicago, IL 60611, United States. brian.stamm@northwestern.edu\n02 6 2020 \n2020 \n02 6 2020 \n14 10037215 3 2020 16 5 2020 18 5 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Lacosamide enhances slow inactivation of voltage-gated sodium channels and can lead to dose-dependent PR interval prolongation. Previously, lacosamide has been associated with second-degree atrioventricular (AV) heart block in the context of multiple medical comorbidities and/or in the elderly with multimorbidity on other dromotropic agents. We report a case of second-degree AV block occurring in a healthy, athletic young adult. The patient had baseline bradycardia with no known cardiac comorbidities. He was exquisitely sensitive to lacosamide with EKG and telemetry changes developing on the order of hours after receiving intravenous lacosamide. Lacosamide was subsequently stopped, the second-degree AV block was no longer present and EKG returned to baseline. We hypothesize that his sensitivity to lacosamide-induced AV block was possibly secondary to his baseline bradycardia with early repolarization changes. The case underscores the importance of surveillance cardiac monitoring. While medical comorbidities and an older age may portend a greater risk of PR prolongation, routine EKGs should be considered in all patients receiving lacosamide.\n\nHighlights\n• This is a case of second-degree AV block with lacosamide in a healthy, young adult.\n\n• PR prolongation can be seen with lacosamide irrespective of medical comorbidities.\n\n• Surveillance cardiac monitoring should be considered in patients taking lacosamide.\n\n\n\nKeywords\nEpilepsyPR prolongationLacosamideHeart blockArrhythmia\n==== Body\n1 Introduction\nLacosamide was approved for use in 2008 by the U.S. Food and Drug Administration for adjunctive treatment of focal and secondarily generalized seizures [1]. In part, lacosamide works by enhancing slow inactivation of voltage-gated sodium channels [2]. While pooled studies have evaluated the cardiac safety of lacosamide and shown dose-dependent PR interval prolongation, second-degree atrioventricular (AV) heart block was not observed in these studies [3] and has only been described in a single case report, in a medically complex patient receiving other PR-prolonging agents [4]. Lacosamide-associated complete heart block has also been demonstrated in several cases of elderly patients with multimorbidity on other dromotropic agents [[5], [6], [7]]. In contrast, we report a case of second-degree AV block in a healthy, athletic young adult with drug-resistant epilepsy, baseline bradycardia, lupus profundus, and no other comorbidities. The patient was exquisitely sensitive to lacosamide with EKG and telemetry changes developing on the order of hours after receiving intravenous lacosamide. Once lacosamide was stopped, the patient's EKG returned to baseline.\n\n2 Case report\nThe patient is a 32-year-old healthy right-handed male with a prior history of biopsy-confirmed lupus profundus (but no evidence of systemic lupus erythematosus) and drug-resistant left temporal lobe epilepsy with focal impaired awareness seizures, admitted to the epilepsy monitoring unit (EMU). Neuroimaging was unremarkable. The patient's cardiac history was notable for baseline sinus bradycardia and early repolarization (demonstrated on multiple EKGs in the preceding years). These EKGs had presumably been obtained in the setting of his prior rheumatologic evaluations and because he was previously taking hydroxychloroquine and methotrexate for lupus profundus. At the time of his EMU admission, he had not been taking immunosuppressants for several months. He had never had cardiac symptoms other than occasional, intermittent palpitations. He had no significant cardiac family history and no family history of sudden death.\n\nThe patient's antiseizure regimen upon admission to the EMU was lacosamide three times a day (TID; 100 mg, 200 mg, 100 mg), lamotrigine 100 mg TID, levetiracetam 1000 mg TID, and clonazepam 1 mg TID (TID dosing was preferred by the patient). Lacosamide level on admission was 3.8 mcg/mL (normal range: up to 15.0 mcg/mL; level approximately 3 weeks prior was 6.1 mcg/mL); lamotrigine on admission 2.6 mcg/mL (normal range: 4.0–18.0 mcg/mL; 3 weeks prior 6.0 mcg/mL); and levetiracetam on admission 7.6 mcg/mL (normal range: 12.0–46.0 mcg/mL). His admission labs were within normal limits, including a normal potassium (3.9 mEq/L; normal range: 3.5–5.1 mEq/L).\n\nEKG on admission revealed prolonged PR interval (214 ms; normal PR interval is 120–200 ms) with first-degree AV block, as well as early repolarization with J-point elevations in several leads (Fig. 1A). QRS duration and QT interval were within normal limits. The case was discussed with the cardiology consult team who recommended standard cardiac monitoring but no other acute interventions, and patient was placed on continuous telemetry. On day one, lacosamide and levetiracetam were held as part of his diagnostic EMU evaluation. On day two, lamotrigine was held and clonazepam was reduced to 0.5 mg TID. Day two EKG showed normalized PR interval to 170 ms with sinus bradycardia (Fig. 1B). On day three, after diagnostic evaluation was completed, medications were resumed and lacosamide 150 mg IV, lamotrigine 200 mg PO, and levetiracetam 2 g IV were administered. That evening, he received lacosamide 150 mg, lamotrigine 100 mg, levetiracetam 1000 mg, and clonazepam 0.5 mg. Over the course of the evening, telemetry revealed frequent second degree, Mobitz type 1 AV block (Wenckebach), defined by progressively lengthening PR interval and ultimately, the P wave is not conducted, in contrast to Mobitz type 2 AV block in which dropped beats occur sporadically without antecedent progressive PR prolongation (Fig. 2).Fig. 1 Representative EKGs.\n\nA) Day one EKG with first-degree atrioventricular (AV) block, as well as early repolarization with J-point elevations in several leads. B) Day two EKG with normalized PR interval to 170 ms with sinus bradycardia.\n\nFig. 1Fig. 2 Day four representative telemetry tracing showing second degree, Mobitz type 1 AV block (Wenckebach).\n\nFig. 2\n\nOn day four, repeat EKG again showed prolongation of PR interval to 204 ms. Given these findings, lacosamide was discontinued on day four. Telemetry overnight from day four to day five showed no evidence of second-degree AV block, and EKG obtained on day five showed nearly normal PR interval (200 ms). Unfortunately, the patient never received follow-up EKGs despite our recommendations.\n\n3 Discussion\nDose-dependent PR prolongation is a known side effect of lacosamide and has been demonstrated in pooled data from randomized-controlled trials [3], but AV heart block secondary to the medication is a rare phenomenon demonstrated previously only in case reports. The previously published cases, as summarized in Table 1, are largely confined to older, multimorbid patients taking additional dromotropic medications known to prolong the PR interval [[4], [5], [6], [7], [8]].Table 1 Literature summary of cases of lacosamide-associated atrioventricular block, with the current case listed first.\n\nTable 1Age & gender\tPast or concurrent medical history\tSeizure localization\tLCM dosing, formulation\tNotable other meds\tPR; heart block type\tTime to PR normalization/resolution of EKG abnormalities\tOutcome\t\n32 M\tLupus profundus\tLeft temporal lobe\t400 mg/day PO\tLTG\t2nd degree\t~ 12 h for AV block resolution; 36 h for PR normalization\tComplete recovery\t\n45 M\tCraniopharyngioma s/p craniotomy c/b panhypopituitarism; ALL\tRight frontal lobe\t200 mg/day PO\tCBZ, levothyroxine\t2nd degree\t19 h for AV block resolution; 3 days for PR normalization\tPPM placement; complete recovery [4]\t\n49 F\tHypothyroidism\tFocal, unspecified\t500 mg/day PO\tCBZ, levothyroxine\tSinus pauses; junctional escape rhythm\t4 days for sinus pause normalization\tComplete recovery [8]\t\n71 F\tHTN, development of renal & hepatic failure\tFocal, unspecified\t300 mg/day PO\tMetoprolol\t3rd degree\t2 days for resolution of complete heart block\tTemporary PPM placement [6]\t\n88 F\tHTN\tUnspecified\t100 mg/day PO\tBisoprolol\t3rd degree\tUnknown\tPPM placement [7]\t\n89 F\tHF, HTN, kidney dysfunction, hypothyroidism\tNonconvulsive status\t800 mg IV\tMetoprolol, amlodipine, levothyroxine\t3rd degree\tWithin 24 h for PR normalization\tDeath 2/2 respiratory failure [5]\t\nAbbreviations: LCM, lacosamide; M, male; PO, per orem; LTG, lamotrigine; AV, atrioventricular; s/p, status post; c/b, complicated by; ALL, acute lymphocytic leukemia; CBZ, carbamazepine; PPM, pacemaker; F, female; HTN, hypertension; HF, heart failure; IV, intravenous; 2/2, secondary to.\n\n\n\nWhen compared with these previously published cases, our patient is unique in that he is the youngest, overall healthiest, and was exquisitely sensitive to the medication with respect to time scale of AV nodal changes. While the other cases were complicated by multiple comorbidities, our patient's only notable medical history was lupus profundus, an uncommon form of chronic cutaneous lupus erythematosus (CCLE). While systemic lupus erythematosus (SLE) has a widely recognized association with heart block, and SLE co-occurs in approximately 10% of lupus profundus cases [9,10], our patient had been evaluated by rheumatology and did not meet diagnostic criteria for SLE and notably had a negative antinuclear antibody test during his EMU admission.\n\nAll of the previously reported patients were taking other dromotropic medications in addition to lacosamide. Though our patient was additionally taking lamotrigine—which also acts on sodium channels—this medication has been shown to only slightly prolong the PR interval, namely at high doses. Also, the above-described changes largely occurred while lamotrigine was being held constant.\n\nThe temporal correlation of lacosamide with prolonged PR interval and AV block was particularly striking in this case with AV block resolving within 12 h of lacosamide cessation and PR normalization occurring within 36 h. This time scale is impressive given lacosamide's approximate elimination half-life of 13 h. Whereas many of the prior cases had comorbid renal dysfunction, our patient's preserved renal function may have led to more rapid clearance of the medication and thus quicker resolution of the pathologic EKG findings.\n\nInterestingly, our patient fits the phenotype of a healthy, young athlete with an admission EKG showing J-point elevations consistent with early repolarization changes. Studies have shown that prevalence of J-point elevation in athletes tends to be higher than that of the general population [11], thought to be related to a physiological balance favoring parasympathetic tone [12]. One cross-sectional study found that former National Football League players had, on average, lower resting heart rates and a higher prevalence of first-degree atrioventricular block than healthy controls [13]. Finally, reports of sudden cardiac death in athletes have gained attention in recent years, with some cases attributed to conduction abnormalities, but the more predominant etiology being hypertrophic cardiomyopathy [14]. In summary, in addition to his preserved renal function, our patient's repolarization abnormalities, baseline bradycardia, and overall tendency towards increased parasympathetic tone may have predisposed him to his exquisite sensitivity towards lacosamide.\n\nThis case demonstrates a unique departure from prior reports of lacosamide-associated heart block because this patient was relatively young and had minimal baseline medical complexity compared with prior cases. Awareness of lacosamide-associated heart block is particularly important now given its increasing use in status epilepticus due to the drug's intravenous availability [15]. Especially in status epilepticus, efficient administration of lacosamide is paramount, and recent data suggests IV push has a similar adverse effect rate to IV piggyback preparation, with the same rates of PR prolongation in each group [16]. Regardless of route of administration, this case should serve as a reminder of the importance of cardiac monitoring with new or altered dosing of lacosamide, even—or perhaps particularly—in healthy, young athletes.\n\n4 Conclusion\nWe report a case of lacosamide-associated, second-degree AV block in a healthy, athletic young adult. This case differs from the preexisting literature, as our patient had no major medical comorbidities and was exquisitely sensitive to lacosamide with EKG and telemetry changes developing within hours of administration and rapid resolution with stopping lacosamide. Monitoring of cardiac function is important in all patients taking lacosamide, irrespective of age and medical comorbidities.\n\nContributions\nBrian Stamm: Conceptualization, Investigation, Writing – original draft preparation. Atif Sheikh: Writing – review and editing. Stephan Schuele: Supervision, Writing – review and editing. Jessica Templer: Supervision, Writing – review and editing.\n\nEthical statement\nNo experimentation was conducted on human subjects (our study is a case report) and thus informed consent was not obtained.\n\nDeclaration of competing interest\nDr. Schuele is on the speaker's bureau for Eisai Inc., Sunovion, and Greenwich.\n\nAcknowledgments\nNone.\n==== Refs\nReferences\n1 UCB Pharma Vimpat prescribing information 2009 UCB Pharma \n2 Errington A.C. Stohr T. Heers C. Lees G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels Mol Pharmacol 73 2008 157 169 17940193 \n3 Rudd G.D. Haverkamp W. Mason J.W. Wenger T. Jay G. Hebert D. Lacosamide cardiac safety: clinical trials in patients with partial-onset seizures Acta Neurol Scand 132 2015 355 363 25933358 \n4 Nizam A. Mylavarapu K. Thomas D. Briskin K. Wu B. Saluja D. Lacosamide-induced second-degree atrioventricular block in a patient with partial epilepsy Epilepsia 52 2011 e153 e155 21801173 \n5 Krause L.U. Brodowski K.O. Kellinghaus C. Atrioventricular block following lacosamide intoxication Epilepsy Behav 20 2011 725 727 21411374 \n6 Bhana I.G. Chourasiya M. Desai S.D. Lacosamide associated complete heart block in elderly Ann Indian Acad Neurol 22 4 2019 529 530 31736597 \n7 Lachuer C. Corny J. Bezie Y. Ferchichi S. Durand-Gasselin B. Complete atrioventricular block in an elderly patient treated with low-dose lacosamide Cardiovasc Toxicity 18 2018 579 582 \n8 Chinnasami S. Rathore C. Duncan J. Sinus node dysfunction: an adverse effect of lacosamide Epilepsia 54 6 2013 e90 e93 23360388 \n9 Watanabe T. Tsuchida T. Lupus erythematosus profundus: a cutaneous marker for a distinct clinical subset? Br J Dermatol 134 1 1996 123 8745897 \n10 Martens P.B. Moder K.G. Ahmed I. Lupus panniculitis: clinical perspectives from a case series J Rheumatol 26 1 1999 68 9918242 \n11 Tikkanen J.T. Junttila M.J. Anttonen O. Aro A.L. Luttinen S. Kerola T. Early repolarization: electrocardiographic phenotypes associated with favorable long-term outcome Circulation 123 23 2011 2666 2673 21632493 \n12 Barbosa E.C. Bomfim A.S. Benchimol-Barbosa P.R. Ginefra P. Ionic mechanisms and vectorial model of early repolarization pattern in the surface electrocardiogram of the athlete Ann Noninvasive Electrocardiol 13 3 2008 301 307 18713332 \n13 Aagaard P. Sharma S. McNamara D.A. Joshi P. Ayers C.R. de Lemos J.A. Arrythmias and adaptations of the cardiac conduction system in former National Football League players J Am Heart Assoc 8 2019 e010401 \n14 Ackerman M. Atkins D.L. Triedman J.K. Sudden cardiac death in the young Circulation 133 10 2016 1006 1026 26951821 \n15 Bauer S. Willems L.M. Paule E. Petschow C. Zöllner J.P. Rosenow F. The efficacy of lacosamide as monotherapy and adjunctive therapy in focal epilepsy and its use in status epilepticus: clinical trial evidence and experience Ther Adv Neurol Disord 10 2 2017 103 126 28382109 \n16 Davidson K.E. Newell J. Alsherbini K. Krushinski J. Jones G.M. Safety and efficiency of intravenous push lacosamide administration Neurocrit Care 29 2018 491 495 29949010\n\n",
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},
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},
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] |
{
"abstract": "Postoperative diaphragmatic hernia (PDH) is an increasingly reported complication of esophageal cancer surgery. It occurs more frequently with minimally invasive techniques and very little is known about its pathogenesis. Currently, no consensus exists concerning preventive measures and its management. A 36 years old male underwent minimally invasive esophagectomy and presented with chest pain and dyspnoea in the emergency department 8 months after the procedure. He was started on acute coronary syndrome treatment protocol but was later diagnosed on CT scan to have diaphragmatic hernia through a defect in the oesophageal hiatus. As he was already loaded with dual anti platelet therapy it led to qualitative defect of the platelet which resulted in bleeding post procedure and the patient needed resuscitation with blood products. Dual anti-platelet therapy is an integral component of early management strategy in acute coronary syndrome. Chest X-ray was not helpful, but abdominal or chest computed tomography was useful for accurate diagnosis.",
"affiliations": "Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan.;Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan.;Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan.",
"authors": "Saleem|Huma|H|;Malik|Sara Haider|SH|;Mehdi|Syed Raza|SR|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel",
"country": "Pakistan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1025-9589",
"issue": "30(4)",
"journal": "Journal of Ayub Medical College, Abbottabad : JAMC",
"keywords": "Dual anti platelet\ntherapy; Esophagectomy; Diaphragmatic; Massive haemorrhage; hernia",
"medline_ta": "J Ayub Med Coll Abbottabad",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000328:Adult; D000077144:Clopidogrel; D003951:Diagnostic Errors; D016629:Esophagectomy; D006470:Hemorrhage; D006548:Hernia, Diaphragmatic; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D011183:Postoperative Complications; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8910750",
"other_id": null,
"pages": "611-613",
"pmc": null,
"pmid": "30632349",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Massive Haemorrhage In Patient After Repair Of Post Esophagectomy Diaphragmatic Hernia And A Loading Dose Of Clopidogrel.",
"title_normalized": "massive haemorrhage in patient after repair of post esophagectomy diaphragmatic hernia and a loading dose of clopidogrel"
} | [
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{
"abstract": "Although renal impairment is a rare complication of ulcerative colitis (UC), interstitial nephritis can occur as an idiosyncratic reaction to 5-aminosalicylate (5-ASA) treatment for UC. Monozygotic twins developed UC at ages 49 and 51, and they were separately treated at different medical institutes. They did not know that they had the same disease and were treated with the same drug (5-ASA). During the course of 5-ASA treatment, renal impairment diagnosed as interstitial nephritis occurred in both. Granulocyte/monocyte adsorption was initiated, UC remission was achieved and renal function deterioration subsided in both. Drug or treatment responses may be concordant in monozygotic twins with UC. Careful review is important before treatment to avoid serious adverse events.",
"affiliations": "Department of Internal Medicine, South-Miyagi Medical Center Hospital, Ogawara, Japan.;Department of Gastroenterology, South-Miyagi Medical Center Hospital, Ogawara, Japan.;Division of Nephrology, Department of Internal Medicine, Endocrinology and Vascular Medicine, Tohoku University School of Medicine, Sendai, Japan.;Laboratory of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan.",
"authors": "Sato|Hitoshi|H|;Umemura|Ken|K|;Yamamoto|Tae|T|;Sato|Hiroshi|H|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218346",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D003093:Colitis, Ulcerative; D004200:Diseases in Twins; D005260:Female; D006801:Humans; D019804:Mesalamine; D008875:Middle Aged; D009395:Nephritis, Interstitial; D014430:Twins, Monozygotic",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28183711",
"pubdate": "2017-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11099061;12211531;12806610;15188168;15256311;17243140;18416774;1984188;22537423;24262508;26619893;7839349;8555939;8707121;9576439;957999",
"title": "Interstitial nephritis associated with ulcerative colitis in monozygotic twins.",
"title_normalized": "interstitial nephritis associated with ulcerative colitis in monozygotic twins"
} | [
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}
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},
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],
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"reactionmeddraversionpt": "20.0",
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},
{
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"reactionmeddraversionpt": "20.0",
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}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2016"
}
},
"primarysource": {
"literaturereference": "SATO H, UMEMURA K, YAMAMOTO T, SATO H. INTERSTITIAL NEPHRITIS ASSOCIATED WITH ULCERATIVE COLITIS IN MONOZYGOTIC TWINS. BMJ CASE REPORTS. 2017;.",
"literaturereference_normalized": "interstitial nephritis associated with ulcerative colitis in monozygotic twins",
"qualification": "1",
"reportercountry": "JP"
},
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"receiptdate": "20170517",
"receivedate": "20170517",
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},
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"safetyreportid": 13558103,
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20170830"
},
{
"companynumb": "JP-MEDA-2017030068",
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"occurcountry": "JP",
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{
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}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201410"
}
},
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"literaturereference": "SATO H,UMEMURA K,YAMAMOTO T,SATO H. INTERSTITIAL NEPHRITIS ASSOCIATED WITH ULCERATIVE COLITIS IN MONOZYGOTIC TWINS. BMJ CASE REP 2017; 1-4",
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},
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] |
{
"abstract": "Eruption of lymphocyte recovery (ELR) may occur during bone marrow aplasia after chemotherapies. We reviewed the clinical and pathologic features of 12 patients (male-female ratio, 7:5; median age, 61 years) with an atypical ELR histologically mimicking a primary cutaneous T-cell lymphoma such as Sézary syndrome or CD30+ T-cell lymphoproliferative disorder. All the patients displayed an erythematous maculopapular eruption on the trunk and the limbs associated with fever. All but one had received a polychemotherapy for an acute myeloid leukemia (n=10) or a urothelial carcinoma (n=1) before the occurrence of the skin eruption. One had an autoimmune lymphoproliferative syndrome causing chronic agranulocytosis requiring granulocyte colony-stimulating factor injection. In all patients, the skin eruption was associated with a slight increase of white blood cell count followed by bone marrow recovery within the next weeks. All skin biopsies showed a dermal perivascular lymphocytic infiltrate containing atypical medium- to large-sized CD3+, CD4+ and CD8+, CD25+, ICOS+, PD1- lymphocytes with a strong CD30 expression in most instances (n=10), suggesting the recruitment of strongly activated T cells in the skin. In 6 patients, a diagnosis of CD30+ lymphoproliferative disorder or Sézary syndrome was proposed or suspected histopathologically, and only the clinical context allowed the diagnosis of ELR with a peculiar presentation with atypical lymphocytes. We describe a series of patients with an unusual form of ELR characterized by the presence of atypical activated T cells in the skin. On a practical ground, pathologists should be aware of this distinctive and misleading presentation.",
"affiliations": "Department of Dermatology, Hôpital Henri-Mondor, AP-HP, 94220 Créteil, France.;Department of Dermatology, Hôpital Henri-Mondor, AP-HP, 94220 Créteil, France.;Department of Dermatology, Inselspital Bern University Hospital, University of Bern, 3010 Bern, Switzerland.;Department of Pathology, Lille University Hospital, 59000 Lille, France.;Department of Pathology, Centre Léon Bérard, 69008 Lyon, France.;Department of Pathology, Lyon-Sud University Hospital, 69310 Pierre-Bénite, France.;Department of Pathology, Nantes University Hospital, 44093 Nantes Cedex 1, France.;Department of Biological Hematology and INSERM U955 team 9, AP-HP, Henri-Mondor Hospital, 94220 Créteil, France.;Department of Dermatology, Hôpital Henri-Mondor, AP-HP, 94220 Créteil, France.;Department of Dermatology, Hôpital Henri-Mondor, AP-HP, 94220 Créteil, France.;Department of Hematology, AP-HP, Henri-Mondor Hospital, 94220 Créteil, France.;Department of Hematology, AP-HP, Henri-Mondor Hospital, 94220 Créteil, France.;Department of Hematology, AP-HP, Henri-Mondor Hospital, 94220 Créteil, France.;Department of Pathology and INSERM U955 team 9, AP-HP, Henri-Mondor Hospital, 94220 Créteil, France. Electronic address: nicolas.ortonne@aphp.fr.",
"authors": "Hurabielle|Charlotte|C|;Sbidian|Emilie|E|;Beltraminelli|Helmut|H|;Bouchindhomme|Brigitte|B|;Chassagne-Clément|Catherine|C|;Balme|Brigitte|B|;Bossard|Céline|C|;Delfau-Larue|Marie-Hélène|MH|;Wolkenstein|Pierre|P|;Chosidow|Olivier|O|;Cordonnier|Catherine|C|;Toma|Andrea|A|;Pautas|Cécile|C|;Ortonne|Nicolas|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.humpath.2017.10.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0046-8177",
"issue": "71()",
"journal": "Human pathology",
"keywords": "CD30+ lymphoproliferative disorder; Cutaneous T-cell lymphoma; Eruption of lymphocyte recovery; Maculopapular rash; Pseudolymphoma",
"medline_ta": "Hum Pathol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003937:Diagnosis, Differential; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D016410:Lymphoma, T-Cell, Cutaneous; D008297:Male; D008875:Middle Aged; D012878:Skin Neoplasms; D013601:T-Lymphocytes",
"nlm_unique_id": "9421547",
"other_id": null,
"pages": "100-108",
"pmc": null,
"pmid": "29107664",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Eruption of lymphocyte recovery with atypical lymphocytes mimicking a primary cutaneous T-cell lymphoma: a series of 12 patients.",
"title_normalized": "eruption of lymphocyte recovery with atypical lymphocytes mimicking a primary cutaneous t cell lymphoma a series of 12 patients"
} | [
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"companynumb": "FR-CELGENEUS-FRA-20171211006",
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},
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"medicinalproduct": "CYTARABINE."
}
],
"patientagegroup": null,
"patientonsetage": "48",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "White blood cell count increased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Rash morbilliform",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bone marrow failure",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Rash erythematous",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ORTONNE N, HURABIELLE C, SBIDIAN E, BELTRAMINELLI H, BOUCHINDHOMME B, CHASSAGNE-CLEMENT C. ERUPTION OF LYMPHOCYTE RECOVERY WITH ATYPICAL LYMPHOCYTES MIMICKING A PRIMARY CUTANEOUS T-CELL LYMPHOMA: A SERIES OF 12 PATIENTS. HUM-PATHOL. 2017?71:1-9.",
"literaturereference_normalized": "eruption of lymphocyte recovery with atypical lymphocytes mimicking a primary cutaneous t cell lymphoma a series of 12 patients",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20180321",
"receivedate": "20180212",
"receiver": {
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"receivertype": "6"
},
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"sender": {
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "A Syrian asylum seeker with multidrug-resistant tuberculosis (TB) developed a bronchopleural fistula after pneumonectomy. Although screening tests were negative on admission, carbapenemase-producing Enterobacteriaceae were cultured after a few months of TB treatment. Prevalence of multidrug-resistant organisms is reported to be increased in asylum seekers compared with the general Dutch population. Arduous conditions during transit and interrupted health care delivery in our patient led to multiple-resistant microorganisms that complicated treatment.",
"affiliations": "University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.;Department of Medical Microbiology, Tzaneio General Hospital of Piraeus, Athens, Greece.;Department of Medical Microbiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.;Department of Medical Microbiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.;Department of Microbiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.;Department of Pulmonary Diseases and Tuberculosis, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.;Tuberculosis Center Beatrixoord, University of Groningen, University Medical Center Groningen, Haren, The Netherlands.;University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.;Tuberculosis Center Beatrixoord, University of Groningen, University Medical Center Groningen, Haren, The Netherlands.",
"authors": "Ravensbergen|Sofanne J|SJ|;Louka|Christina|C|;Lokate|Mariëtte|M|;Bathoorn|Erik|E|;Pournaras|Spyros|S|;van der Werf|Tjip S|TS|;de Lange|Wiel C M|WCM|;Stienstra|Ymkje|Y|;Akkerman|Onno W|OW|",
"chemical_list": "D011515:Prothionamide; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000583:Amikacin; D002991:Clofazimine; D000069349:Linezolid; D000077266:Moxifloxacin",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.17-0544",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "98(2)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000328:Adult; D000583:Amikacin; D000073182:Carbapenem-Resistant Enterobacteriaceae; D002991:Clofazimine; D016903:Drug Monitoring; D006801:Humans; D000069349:Linezolid; D008297:Male; D000077266:Moxifloxacin; D009426:Netherlands; D015995:Prevalence; D011515:Prothionamide; D012036:Refugees; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D018088:Tuberculosis, Multidrug-Resistant",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "376-378",
"pmc": null,
"pmid": "29280429",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23241381;27824604;26838714;27009172;19581459;28397262;22945916;27665703;26755567;19776233;19525514;23100498;25859995;27579250;21555768;23870096;26794850",
"title": "Case Report: Carbapenemase-Producing Enterobacteriaceae in an Asylum Seeker with Multidrug-Resistant Tuberculosis.",
"title_normalized": "case report carbapenemase producing enterobacteriaceae in an asylum seeker with multidrug resistant tuberculosis"
} | [
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{
"abstract": "We present a case of paradoxical gas embolism during CO2 insufflation in laparoscopic nephrectomy for a huge renal angiomyolipoma. Paradoxical CO2 embolism in the left heart chambers without demonstrable intracardiac right-to-left shunt was detected by transesophageal echocardiography (TEE). The surgical procedure was stopped immediately, but the patient recovered with mild neurologic deficit. We speculate that rapid pneumoperitoneum introduction pushed CO2 into the abnormal vasculature of the angiomyolipoma, which communicates with the systemic vascular system, causing pseudoaneurysm formation. Follow-up abdominal computed tomography showed a new pseudoaneurysm inside the tumor. If intracardiac right-to-left shunt is excluded for the reason of paradoxical gas existence, there remains extracardiac right-to-left shunt, with transpulmonary passage of the venous emboli being the most likely mechanism. In fact, the cause of paradoxical gas embolism in this case remains unknown. Therefore, laparoscopic surgery for huge angiomyolipoma should be performed with extreme caution; an open procedure may be considered as an alternative.",
"affiliations": "Department of Anesthesiology, Cheng-Hsin Rehabilitation Medical Center, Taipei, Taiwan, R.O.C.",
"authors": "Huang|Yu-Yin|YY|;Wu|Hsin-Lun|HL|;Tsou|Mei-Yung|MY|;Zong|Hsiao-Jen|HJ|;Guo|Wan-You|WY|;Chan|Kwok-Hon|KH|;Ting|Chien-Kun|CK|",
"chemical_list": "D002245:Carbon Dioxide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S1726-4901(08)70107-2",
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"issn_linking": "1726-4901",
"issue": "71(4)",
"journal": "Journal of the Chinese Medical Association : JCMA",
"keywords": null,
"medline_ta": "J Chin Med Assoc",
"mesh_terms": "D000368:Aged; D018207:Angiomyolipoma; D002245:Carbon Dioxide; D017548:Echocardiography, Transesophageal; D004618:Embolism, Air; D019320:Embolism, Paradoxical; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D010535:Laparoscopy; D011028:Pneumoperitoneum, Artificial",
"nlm_unique_id": "101174817",
"other_id": null,
"pages": "214-7",
"pmc": null,
"pmid": "18436506",
"pubdate": "2008-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Paradoxical carbon dioxide embolism during pneumoperitoneum in laparoscopic surgery for a huge renal angiomyolipoma.",
"title_normalized": "paradoxical carbon dioxide embolism during pneumoperitoneum in laparoscopic surgery for a huge renal angiomyolipoma"
} | [
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"receiptdate": "20161123",
"receivedate": "20161123",
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"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportversion": 1,
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"sendertype": "2"
},
"serious": 1,
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{
"abstract": "Dexmedetomidine is a selective alpha-2 adrenergic agonist that is used frequently for short-term sedation in children. It has been noted to cause hypertension, hypotension, bradycardia, and sinus pauses; however, QTc prolongation has not been reported with dexmedetomidine administration. We describe a case of marked QT prolongation with use of dexmedetomidine in a pediatric critical care setting. Clinicians should be vigilant about potential QT prolongation in patients on dexmedetomidine, particularly in those receiving multiple other medications.",
"affiliations": "Children's National Medical Center, Washington, DC, USA.",
"authors": "Burns|Kristin M|KM|;Greene|E Anne|EA|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine",
"country": "United States",
"delete": false,
"doi": "10.1111/chd.12055",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-079X",
"issue": "9(1)",
"journal": "Congenital heart disease",
"keywords": "Dexmedetomidine; Pediatric Cardiology; Pediatric Critical Care; QT Prolongation",
"medline_ta": "Congenit Heart Dis",
"mesh_terms": "D058647:Adrenergic alpha-2 Receptor Agonists; D000889:Anti-Arrhythmia Agents; D020927:Dexmedetomidine; D004562:Electrocardiography; D006801:Humans; D006993:Hypnotics and Sedatives; D007223:Infant; D008133:Long QT Syndrome; D008297:Male; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101256510",
"other_id": null,
"pages": "E11-5",
"pmc": null,
"pmid": "23510360",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long QT syndrome unmasked by dexmedetomidine: a case report.",
"title_normalized": "long qt syndrome unmasked by dexmedetomidine a case report"
} | [
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"reactionmeddrapt": "Electrocardiogram T wave abnormal",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Heart alternation",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Electrocardiogram QT prolonged",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypocalcaemia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Electrocardiogram repolarisation abnormality",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Respiratory acidosis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug administered to patient of inappropriate age",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BURNS KM, GREENE EA.. LONG QT SYNDROME UNMASKED BY DEXMEDETOMIDINE: A CASE REPORT.. CONGENIT HEART DIS. 2013",
"literaturereference_normalized": "long qt syndrome unmasked by dexmedetomidine a case report",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20160929",
"receivedate": "20160929",
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},
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},
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}
] |
{
"abstract": "The presence of anti-John Cunningham Virus (JCV) antibodies is a risk factor for the development of progressive multifocal leukoencephalopathy (PML) in MS patients treated with natalizumab. It has been suggested that an increase in serum anti-JCV antibody index precedes the development of PML. We here describe extensive longitudinal serum anti-JCV antibody indexes of four MS patients who developed PML. Anti-JCV antibodies were measured using the STRATIFY JCV™DxSelect™ test. All four patients had rather stable high anti-JCV antibody indexes in all samples obtained before developing PML. Possibly caused by reaching the saturation level of the assay, no increase in anti-JCV antibody indexes was seen just before the diagnosis of PML. This study confirms that high serum anti-JCV antibody indexes precede natalizumab-associated PML.",
"affiliations": "Department of Neurology, MS Centre Amsterdam, VU Medical Centre, The Netherlands a.vennegoor@vumc.nl.;Department of Neurology, MS Centre Amsterdam, VU Medical Centre, The Netherlands.;Department of Neurology, MS Centre Amsterdam, VU Medical Centre, The Netherlands.;Department of Radiology, MS Centre Amsterdam, VU Medical Centre, The Netherlands.;Department of Neurology, MS Centre Amsterdam, VU Medical Centre, The Netherlands.",
"authors": "Vennegoor|Anke|A|;van Rossum|Johannis A|JA|;Polman|Chris H|CH|;Wattjes|Mike P|MP|;Killestein|Joep|J|",
"chemical_list": "D000914:Antibodies, Viral; D007155:Immunologic Factors; D000069442:Natalizumab",
"country": "England",
"delete": false,
"doi": "10.1177/1352458514567728",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "21(12)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "John Cunningham Virus (JCV); Multiple sclerosis; natalizumab; progressive multifocal leukoencephalopathy (PML)",
"medline_ta": "Mult Scler",
"mesh_terms": "D000328:Adult; D000914:Antibodies, Viral; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007577:JC Virus; D007968:Leukoencephalopathy, Progressive Multifocal; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "1600-3",
"pmc": null,
"pmid": "25662344",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Longitudinal JCV serology in multiple sclerosis patients preceding natalizumab-associated progressive multifocal leukoencephalopathy.",
"title_normalized": "longitudinal jcv serology in multiple sclerosis patients preceding natalizumab associated progressive multifocal leukoencephalopathy"
} | [
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},
{
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"medicinalproduct": "SULFASALAZINE."
}
],
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"reaction": [
{
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Progressive multifocal leukoencephalopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "3"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20130411"
}
},
"primarysource": {
"literaturereference": "VENNEGOOR A, VAN ROSSUM J A, POLMAN C H, WATTJES M P, AND KILLESTEIN J. LONGITUDINAL JCV SEROLOGY IN MULTIPLE SCLEROSIS PATIENTS PRECEDING NATALIZUMAB-ASSOCIATED PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. MULTIPLE SCLEROSIS JOURNAL.",
"literaturereference_normalized": "longitudinal jcv serology in multiple sclerosis patients preceding natalizumab associated progressive multifocal leukoencephalopathy",
"qualification": "3",
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},
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"receivedate": "20130508",
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},
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20150721"
},
{
"companynumb": "NL-BIOGENIDEC-2013BI008198",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
"drugadditional": null,
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"drugdosagetext": null,
"drugenddate": "20130107",
"drugenddateformat": "102",
"drugindication": "MULTIPLE SCLEROSIS",
"drugintervaldosagedefinition": "802",
"drugintervaldosageunitnumb": "1",
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"drugseparatedosagenumb": "1",
"drugstartdate": "20120106",
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"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TYSABRI"
}
],
"patientagegroup": "5",
"patientonsetage": "40",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Immune reconstitution inflammatory syndrome",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Progressive multifocal leukoencephalopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VENNEGOOR A, VAN ROSSUM J A, POLMAN C H, WATTJES M P, AND KILLESTEIN J. LONGITUDINAL JCV SEROLOGY IN MULTIPLE SCLEROSIS PATIENTS PRECEDING NATALIZUMAB-ASSOCIATED PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. MULTIPLE SCLEROSIS JOURNAL. 06 FEB 2015 PII: 1352458514567728. [EPUB AHEAD OF PRINT] DOI: 10.1177/1352458514567728",
"literaturereference_normalized": "longitudinal jcv serology in multiple sclerosis patients preceding natalizumab associated progressive multifocal leukoencephalopathy",
"qualification": "1",
"reportercountry": "NL"
},
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"receiptdate": "20150303",
"receivedate": "20130205",
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"receivertype": "6"
},
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"safetyreportversion": 10,
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"sendertype": "2"
},
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150721"
},
{
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{
"actiondrug": "5",
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"activesubstancename": "NATALIZUMAB"
},
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"drugdosageform": "INTRAVENOUS INFUSION",
"drugdosagetext": null,
"drugenddate": "20130715",
"drugenddateformat": "102",
"drugindication": "MULTIPLE SCLEROSIS",
"drugintervaldosagedefinition": "802",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
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"drugseparatedosagenumb": "1",
"drugstartdate": "20081024",
"drugstartdateformat": "102",
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"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TYSABRI"
}
],
"patientagegroup": null,
"patientonsetage": "41",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Progressive multifocal leukoencephalopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Immune reconstitution inflammatory syndrome",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20130712"
}
},
"primarysource": {
"literaturereference": "VENNEGOOR A, VAN ROSSUM J A, POLMAN C H, WATTJES M P, AND KILLESTEIN J. LONGITUDINAL JCV SEROLOGY IN MULTIPLE SCLEROSIS PATIENTS PRECEDING NATALIZUMAB-ASSOCIATED PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. MULTIPLE SCLEROSIS JOURNAL.",
"literaturereference_normalized": "longitudinal jcv serology in multiple sclerosis patients preceding natalizumab associated progressive multifocal leukoencephalopathy",
"qualification": "3",
"reportercountry": "NL"
},
"primarysourcecountry": "NL",
"receiptdate": "20150304",
"receivedate": "20130801",
"receiver": {
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"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 9433969,
"safetyreportversion": 7,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150721"
},
{
"companynumb": "NL-BIOGENIDEC-2013BI119973",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
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"drugdosagetext": null,
"drugenddate": "20131205",
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"drugintervaldosagedefinition": "802",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TYSABRI"
}
],
"patientagegroup": "5",
"patientonsetage": "42",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": "90",
"reaction": [
{
"reactionmeddrapt": "Progressive multifocal leukoencephalopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Immune reconstitution inflammatory syndrome",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20131209"
}
},
"primarysource": {
"literaturereference": "VENNEGOOR A, VAN ROSSUM J A, POLMAN C H, WATTJES M P, AND KILLESTEIN J. LONGITUDINAL JCV SEROLOGY IN MULTIPLE SCLEROSIS PATIENTS PRECEDING NATALIZUMAB-ASSOCIATED PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. MULTIPLE SCLEROSIS JOURNAL.",
"literaturereference_normalized": "longitudinal jcv serology in multiple sclerosis patients preceding natalizumab associated progressive multifocal leukoencephalopathy",
"qualification": "3",
"reportercountry": "NL"
},
"primarysourcecountry": "NL",
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"receivedate": "20131220",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20150721"
}
] |
{
"abstract": "OBJECTIVE\nTo investigate the therapeutic effectiveness and side effects of decitabine combined with or without cytarabine-based low dose regimen for acute myeloid leukemia in geratic patients.\n\n\nMETHODS\nClinical data of 8 geratic patients (aged over 70 years) suffered from acute myeloid leukemia from September 2009 to March 2012 were analyzed retrospectively, including age, sex, peripheral blood and bone marrow characteristics and so on. These patients were treated by an 1-hour intravenous infusion of decitabine 20 mg/m2 per day for 5 consecutive days every 4 weeks combined with or without low dose regimen dominantly consisting of cytarabine 20 mg per day as subcutaneous injection for seven consecutive days. The therapeutic effectiveness and side-effects were evaluated.\n\n\nRESULTS\nAmong 8 patients, incinding 3 males and 5 females aged between 71-84 years old, their median white blood cell count was 31.2(1.38-179)× 109/L, and median bone marrow blast cell ratio was 42.7(23-94)% at the initial diagnosis.The median treatment courses was 2.5 (1-20).After treatment by this protocol,2 patients achieved complete remission(CR) (25%), 2 patients achieved partial remission (PR)(25%), 3 were not relieved, and 1 died, thus the overall response rate reached to 50% (4/8). The median overall survival time was 9.5 (2-36) months, and the overall survival time of 3 patients reached 1 year or more. The main side-effects of treatment were grade III-IV of myelosuppression (87.5%) and pneumonia (50%).\n\n\nCONCLUSIONS\nDecitabine combined with or without cytarabine-based low dose regimen is promising for the treatment of geriatric acute myeloid leukemia, thus improving the overall response rate, and prolonging overall survival time.",
"affiliations": "Department of Geriatric Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Geriatric Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Geriatric Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Geriatric Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Geriatric Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Radiology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Geriatric Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Geriatric Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China.;Department of Hematology, Chinese PLA General Hospital, Beijing 100853, China. E-mail:jingyu301@126.com.;Department of Geriatric Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China. E-mail:sjunzh07@163.com.",
"authors": "Zhou|Hong-Wei|HW|;Zhou|Min-Hang|MH|;Wang|Zhi-Hong|ZH|;Li|Peng-Fei|PF|;Liu|Mo|M|;DU|Yu|Y|;Yao|Yi-Bing|YB|;Peng|Chao-Jin|CJ|;Jing|Yu|Y|;Sun|Jun-Zhong|JZ|",
"chemical_list": "D003561:Cytarabine; D000077209:Decitabine; D001374:Azacitidine",
"country": "China",
"delete": false,
"doi": "10.7534/j.issn.1009-2137.2018.01.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1009-2137",
"issue": "26(1)",
"journal": "Zhongguo shi yan xue ye xue za zhi",
"keywords": null,
"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine; D003561:Cytarabine; D000077209:Decitabine; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101084424",
"other_id": null,
"pages": "91-96",
"pmc": null,
"pmid": "29397824",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia.",
"title_normalized": "clinical efficacy of decitabine combined with or without cytarabine based low dose regimen for senile patients with acute myeloid leukemia"
} | [
{
"companynumb": "CN-PFIZER INC-2018507841",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OMACETAXINE MEPESUCCINATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
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"drugdosagetext": "UNK, CYCLIC (ONE-THIRD STANDARD-DOSE)",
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"drugindication": "ACUTE MYELOID LEUKAEMIA",
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"medicinalproduct": "HOMOHARRINGTONINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DECITABINE"
},
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"drugdosageform": null,
"drugdosagetext": "20 MG/M2, DAILY (1-HOUR) (FOR 5 CONSECUTIVE DAYS EVERY 4 WEEKS, ON DAYS 1-5)",
"drugenddate": null,
"drugenddateformat": null,
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},
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},
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},
{
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{
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] |
{
"abstract": "Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study.\n\n\n\nPatients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety.\n\n\n\nFrom December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%).\n\n\n\nPanitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC.",
"affiliations": "Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan. Electronic address: dsakai@cfs.med.osaka-u.ac.jp.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan.;Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.;Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan.;Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan.;Department of Gastroetererological Oncology, Hyogo Cancer Center, Akashi, Japan.;Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan.;Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Japan.;Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Fukuoka, Japan.;Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.;Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Toyama, Japan.;Department of Chemotherapy, Tokyo Women's Medical University, Yachiyo Medical Center, Yachiyo, Japan.;Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan.;Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Gastroenterology, National Hospital Organization Mito Medical Center, Mito, Japan.;Department of Clinical Oncology, Kagawa University Faculty of Medicine, Kagawa, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan.;Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Japan.;Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Japan.;Department of Gastroenterology and Hepatology, Ryugasaki Saiseikai Hospital, Ryugasaki, Japan.;Department of Medical Oncology, Kyoto University Hospital, Kyoto, Japan.;Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan.;Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima, Japan.;Department of Surgery, Osaka General Medical Center, Osaka, Japan.;Cancer Chemotherapy Center, Osaka Medical College, Osaka, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.;Department of Clinical Oncology, Jichi Medical University Hospital, Tochigi, Japan.;Internal Medicine III, Wakayama Medical University, Wakayama, Japan.;Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan.;Center for Clinical and Translational Research, Kyushu University Hospital, Japan.;Division of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.;Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.;Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.",
"authors": "Sakai|Daisuke|D|;Taniguchi|Hiroya|H|;Sugimoto|Naotoshi|N|;Tamura|Takao|T|;Nishina|Tomohiro|T|;Hara|Hiroki|H|;Esaki|Taito|T|;Denda|Tadamichi|T|;Sakamoto|Takeshi|T|;Okuda|Hiroyuki|H|;Satoh|Taroh|T|;Tsushima|Takahiro|T|;Makiyama|Akitaka|A|;Tsuda|Takashi|T|;Hosokawa|Ayumu|A|;Kuramochi|Hidekazu|H|;Tokunaga|Shinya|S|;Moriwaki|Toshikazu|T|;Yasui|Hisateru|H|;Ishida|Hiroyasu|H|;Tsuji|Akihito|A|;Otsu|Satoshi|S|;Shimokawa|Hozumi|H|;Baba|Eishi|E|;Sato|Mikio|M|;Matsumoto|Shigemi|S|;Ozaki|Yukinori|Y|;Shinozaki|Katsunori|K|;Tamagawa|Hiroshi|H|;Goto|Masahiro|M|;Kadowaki|Shigenori|S|;Fujii|Hirofumi|H|;Koh|Yasuhiro|Y|;Yamazaki|Kentaro|K|;Hironaka|Shuichi|S|;Kishimoto|Junji|J|;Boku|Narikazu|N|;Hyodo|Ichinosuke|I|;Muro|Kei|K|",
"chemical_list": "D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D000077150:Oxaliplatin; D000077544:Panitumumab; D000077146:Irinotecan; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2020.04.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "135()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Cetuximab; Chemotherapy; Epidermal growth factor receptor; Irinotecan; Metastatic colorectal cancer; Panitumumab",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077150:Oxaliplatin; D000077544:Panitumumab; D000077982:Progression-Free Survival; D016283:Proto-Oncogene Proteins p21(ras); D013997:Time Factors",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "11-21",
"pmc": null,
"pmid": "32526634",
"pubdate": "2020-08",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D000073843:Equivalence Trial; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G).",
"title_normalized": "randomised phase ii study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with kras wild type metastatic colorectal cancer refractory to fluoropyrimidine irinotecan and oxaliplatin wjog 6510g"
} | [
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],
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],
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"literaturereference": "SAKAI, D.. RANDOMISED PHASE II STUDY OF PANITUMUMAB PLUS IRINOTECAN VERSUS CETUXIMAB PLUS IRINOTECAN IN PATIENTS WITH KRAS WILD-TYPE METASTATIC COLORECTAL CANCER REFRACTORY TO FLUOROPYRIMIDINE, IRINOTECAN AND OXALIPLATIN (WJOG 6510G). EUROPEAN JOURNAL OF CANCER. 2020?135:11-21",
"literaturereference_normalized": "randomised phase ii study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with kras wild type metastatic colorectal cancer refractory to fluoropyrimidine irinotecan and oxaliplatin wjog 6510g",
"qualification": "3",
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},
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"transmissiondate": "20200714"
},
{
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"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Paronychia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin toxicity",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dry skin",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haematotoxicity",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypocalcaemia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Leukopenia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "SUGIMOTO N. RANDOMISED PHASE II STUDY OF PANITUMUMAB PLUS IRINOTECAN VERSUS CETUXIMAB PLUS IRINOTECAN IN PATIENTS WITH KRAS WILD?TYPE METASTATIC COLORECTAL CANCER REFRACTORY TO FLUOROPYRIMIDINE, IRINOTECAN AND OXALIPLATIN (WJOG 6510G).. EUROPEAN JOURNAL OF CANCER. 2020?135:11?21",
"literaturereference_normalized": "randomised phase ii study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with kras wild type metastatic colorectal cancer refractory to fluoropyrimidine irinotecan and oxaliplatin wjog 6510g",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200909",
"receivedate": "20200701",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17972073,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20201103"
}
] |
{
"abstract": "Fifty-four patients with advanced breast cancer who had failed prior non-anthracycline combination chemotherapy were randomized to treatment with either epirubicin 85 mg/m2 or doxorubicin 60 mg/m2 intravenously every three weeks. Of 52 evaluable patients, 25% (six of 24) treated with epirubicin, and 25% (seven of 28) treated with doxorubicin experienced major therapeutic responses. The median duration of response to epirubicin was 11.9 months compared to 7.1 months with doxorubicin. Cardiotoxicity was monitored by serial multigated radionuclide cineangiocardiography performed at rest and after exercise. Laboratory evidence of cardiotoxicity was defined as a decrease in resting left ventricular ejection fraction of greater than 10% from the baseline value, or a decrease of 5% or greater with exercise compared with the resting study performed on the same day. Fifteen patients treated with epirubicin and 18 patients treated with doxorubicin had at least two determinations of left ventricular ejection fraction and were evaluable for laboratory cardiotoxicity. Using methods of survival analysis, the median doses to the development of laboratory cardiotoxicity were estimated to be 935 mg/m2 of epirubicin and 468 mg/m2 of doxorubicin. Four patients treated with epirubicin and five treated with doxorubicin developed symptomatic congestive heart failure. The median cumulative dose at which congestive heart failure occurred was 1,134 mg/m2 of epirubicin compared with 492 mg/m2 of doxorubicin. Fewer episodes of nausea and vomiting were observed in patients receiving epirubicin. Epirubicin is a new anthracycline with reduced cardiac toxicity, but preserved efficacy in the treatment of patients with advanced breast cancer.",
"affiliations": null,
"authors": "Jain|K K|KK|;Casper|E S|ES|;Geller|N L|NL|;Hakes|T B|TB|;Kaufman|R J|RJ|;Currie|V|V|;Schwartz|W|W|;Cassidy|C|C|;Petroni|G R|GR|;Young|C W|CW|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D015251:Epirubicin; D013667:Technetium; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.1985.3.6.818",
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"issue": "3(6)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000206:Actuarial Analysis; D000328:Adult; D000368:Aged; D000505:Alopecia; D000903:Antibiotics, Antineoplastic; D001943:Breast Neoplasms; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin; D015251:Epirubicin; D004912:Erythrocytes; D005260:Female; D006331:Heart Diseases; D006402:Hematologic Diseases; D006801:Humans; D008875:Middle Aged; D009325:Nausea; D010808:Physical Examination; D011446:Prospective Studies; D011877:Radionuclide Imaging; D011897:Random Allocation; D013318:Stroke Volume; D013667:Technetium",
"nlm_unique_id": "8309333",
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"pages": "818-26",
"pmc": null,
"pmid": "3859587",
"pubdate": "1985-06",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer.",
"title_normalized": "a prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer"
} | [
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{
"abstract": "Fifteen patients, with a median age of 19 years having severe aplastic anaemia (SAA) underwent human leucocyte antigen (HLA) identical sibling donor hematopoietic stem cell transplantation (HSCT) using conditioning regimens containing cyclophosphamide with antithymocyte globulin (ATG) or a combination of fludarabine and cyclophosphamide with or without ATG during December 2007 to May 2013. Cyclosporine and mini methotrexate were used as graft versus host disease (GVHD) prophylaxis. Graft source included peripheral blood stem cells in 11, bone marrow in 3 and both in 1. One patient had primary graft failure while 14 patients were engrafted with a median neutrophil and platelet engraftment time of 13.5 days. One patient had secondary graft rejection. Acute GVHD occurred in 3 patients and chronic GVHD in 4. One year death rate in engrafted patients was 14.28 %. At a mean follow-up of 21.2 months, 12 (80 %) are alive and well. One of the donors was a patient of haemophilia but the disease did not occur in the recipient. The graft was successful and the recipient is alive till date.",
"affiliations": "Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.;Civil Hospital, GCRI, Room No. 35, P.G. Hostel, GCRI Campus, Ahmedabad, 380016 Gujarat India.",
"authors": "Raut|Shreeniwas S|SS|;Shah|Sandip A|SA|;Patel|Kinnari A|KA|;Shah|Kamlesh M|KM|;Anand|Asha S|AS|;Talati|Shailesh S|SS|;Panchal|Harsha P|HP|;Patel|Apurva A|AA|;Parikh|Sonia K|SK|;Parekh|Bhavesh B|BB|;Shukla|Shilin N|SN|",
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"country": "India",
"delete": false,
"doi": "10.1007/s12288-014-0397-x",
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"issn_linking": "0971-4502",
"issue": "31(1)",
"journal": "Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion",
"keywords": "Allogeneic bone marrow transplantation; Aplastic anaemia; Gujarat; HLA-matched sibling-donor; Peripheral blood stem cell transplantation",
"medline_ta": "Indian J Hematol Blood Transfus",
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"nlm_unique_id": "9425818",
"other_id": null,
"pages": "1-8",
"pmc": null,
"pmid": "25548437",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": "1932758;10961865;17450183;1521089;16778145;10537929;22517900;8124258",
"title": "Improving Outcome of Aplastic Anaemia with HLA-Matched Sibling Donor Hematopoietic Stem Cell Transplantation: An Experience of Gujarat Cancer and Research Institute (GCRI).",
"title_normalized": "improving outcome of aplastic anaemia with hla matched sibling donor hematopoietic stem cell transplantation an experience of gujarat cancer and research institute gcri"
} | [
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"literaturereference": "RAUT, S.. IMPROVING OUTCOME OF APLASTIC ANAEMIA WITH HLA?MATCHED SIBLING DONOR HEMATOPOIETIC STEM CELL TRANSPLANTATION: AN EXPERIENCE OF GUJARAT CANCER AND RESEARCH INSTITUTE (GCRI). INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION. 2015?31 (1):1?8",
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{
"abstract": "Pneumocystis jirovecii pneumonia (PJP) is a common infection among susceptible patients with compromised immune function and can lead to life-threatening complications without prompt recognition and appropriate treatment. Clinicians should be aware that patients can develop severe infection even while receiving approved prophylactic medications for PJP. Furthermore, atypical radiographic findings, such as the cavitary lung lesions found in the patient in this case report, can make the diagnosis even more challenging.",
"affiliations": "Nika Pierre-Louis and Brian Dlugos were critical care physician assistants in the medical ICU at the Cleveland Clinic in Cleveland, Ohio, when this article was written. Ms. Pierre-Louis now works in the ED at CHI/St. Alexius Health in Bismarck, N.D. The authors have disclosed no potential conflicts of interest, financial or otherwise.",
"authors": "Pierre-Louis|Nika|N|;Dlugos|Brian|B|",
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"mesh_terms": "D001992:Bronchoalveolar Lavage Fluid; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D008168:Lung; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D014057:Tomography, X-Ray Computed; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
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"pages": "28-31",
"pmc": null,
"pmid": "28033170",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "A rare cause of cavitary lung lesions.",
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} | [
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{
"abstract": "A 59-year-old male with follicular lymphoma treated by anti-CD20-mediated B-cell depletion and ablative chemotherapy was hospitalized with a COVID-19 infection. Although the patient did not develop specific humoral immunity, he had a mild clinical course overall. The failure of all therapeutic options allowed infection to persist nearly 300 days with active accumulation of SARS-CoV-2 virus mutations. As a rescue therapy, an infusion of REGEN-COV (10933 and 10987) anti-spike monoclonal antibodies was performed 270 days from initial diagnosis. Due to partial clearance after the first dose (2.4 g), a consolidation dose (8 g) was infused six weeks later. Complete virus clearance could then be observed over the following month, after he was vaccinated with the Pfizer-BioNTech anti-COVID-19 vaccination. The successful management of this patient required prolonged enhanced quarantine, monitoring of virus mutations, pioneering clinical decisions based upon close consultation, and the coordination of multidisciplinary experts in virology, immunology, pharmacology, input from REGN, the FDA, the IRB, the health care team, the patient, and the patient's family. Current decisions to take revolve around patient's follicular lymphoma management, and monitoring for virus clearance persistence beyond disappearance of REGEN-COV monoclonal antibodies after anti-SARS-CoV-2 vaccination. Overall, specific guidelines for similar cases should be established.",
"affiliations": "Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA.;Department of Immunology and Microbiology, Tulane University, New Orleans, LA 70118, USA.;Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA.;Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA.;Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA.;The Scripps Research Institute, San Diego, CA 92037, USA.;Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA.;Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA.;Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA.;Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA.;Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA.;Zalgen Labs, Germantown, MD 20876, USA.;Zalgen Labs, Germantown, MD 20876, USA.;The Scripps Research Institute, San Diego, CA 92037, USA.;Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA.;Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA.;Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA.",
"authors": "Drouin|Arnaud C|AC|;Theberge|Marc W|MW|0000-0002-1491-4538;Liu|Sharon Y|SY|;Smither|Allison R|AR|;Flaherty|Shelby M|SM|;Zeller|Mark|M|;Geba|Gregory P|GP|0000-0001-8936-748X;Reynaud|Peter|P|;Rothwell|W Benjamin|WB|;Luk|Alfred P|AP|;Tian|Di|D|;Boisen|Matthew L|ML|;Branco|Luis M|LM|;Andersen|Kristian G|KG|;Robinson|James E|JE|;Garry|Robert F|RF|0000-0002-5683-3250;Fusco|Dahlene N|DN|",
"chemical_list": "D000911:Antibodies, Monoclonal; D064370:Spike Glycoprotein, Coronavirus; D014765:Viral Vaccines; C000657845:spike protein, SARS-CoV-2",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/v13071202",
"fulltext": "\n==== Front\nViruses\nViruses\nviruses\nViruses\n1999-4915\nMDPI\n\n34201591\n10.3390/v13071202\nviruses-13-01202\nArticle\nSuccessful Clearance of 300 Day SARS-CoV-2 Infection in a Subject with B-Cell Depletion Associated Prolonged (B-DEAP) COVID by REGEN-COV Anti-Spike Monoclonal Antibody Cocktail\nDrouin Arnaud C. 1*\nhttps://orcid.org/0000-0002-1491-4538\nTheberge Marc W. 2\nLiu Sharon Y. 1\nSmither Allison R. 3\nFlaherty Shelby M. 1\nZeller Mark 4\nhttps://orcid.org/0000-0001-8936-748X\nGeba Gregory P. 5\nReynaud Peter 1\nRothwell W. Benjamin 1\nLuk Alfred P. 1\nTian Di 6\nBoisen Matthew L. 7\nBranco Luis M. 7\nAndersen Kristian G. 4\nRobinson James E. 8\nhttps://orcid.org/0000-0002-5683-3250\nGarry Robert F. 3\nFusco Dahlene N. 1\nDe Clercq Erik Academic Editor\n1 Department of Medicine, School of Medicine, Tulane University, New Orleans, LA 70112, USA; sliu26@tulane.edu (S.Y.L.); sflaherty@tulane.edu (S.M.F.); preynau@tulane.edu (P.R.); wrothwel@tulane.edu (W.B.R.); aluk@tulane.edu (A.P.L.); dfusco@tulane.edu (D.N.F.)\n2 Department of Immunology and Microbiology, Tulane University, New Orleans, LA 70118, USA; mtheberge@tulane.edu\n3 Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA; asmither@tulane.edu (A.R.S.); rfgarry@tulane.edu (R.F.G.)\n4 The Scripps Research Institute, San Diego, CA 92037, USA; zellerm@scripps.edu (M.Z.); andersen@scripps.edu (K.G.A.)\n5 Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591, USA; gregory.geba@regeneron.com\n6 Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA; dtian2@tulane.edu\n7 Zalgen Labs, Germantown, MD 20876, USA; mboisen@zalgenlabs.com (M.L.B.); lbranco@zalgenlabs.com (L.M.B.)\n8 Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA; jrobinso@tulane.edu\n* Correspondence: adrouin@tulane.edu; Tel.: +1-504-988-9953\n23 6 2021\n7 2021\n13 7 120224 4 2021\n16 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nA 59-year-old male with follicular lymphoma treated by anti-CD20-mediated B-cell depletion and ablative chemotherapy was hospitalized with a COVID-19 infection. Although the patient did not develop specific humoral immunity, he had a mild clinical course overall. The failure of all therapeutic options allowed infection to persist nearly 300 days with active accumulation of SARS-CoV-2 virus mutations. As a rescue therapy, an infusion of REGEN-COV (10933 and 10987) anti-spike monoclonal antibodies was performed 270 days from initial diagnosis. Due to partial clearance after the first dose (2.4 g), a consolidation dose (8 g) was infused six weeks later. Complete virus clearance could then be observed over the following month, after he was vaccinated with the Pfizer-BioNTech anti-COVID-19 vaccination. The successful management of this patient required prolonged enhanced quarantine, monitoring of virus mutations, pioneering clinical decisions based upon close consultation, and the coordination of multidisciplinary experts in virology, immunology, pharmacology, input from REGN, the FDA, the IRB, the health care team, the patient, and the patient’s family. Current decisions to take revolve around patient’s follicular lymphoma management, and monitoring for virus clearance persistence beyond disappearance of REGEN-COV monoclonal antibodies after anti-SARS-CoV-2 vaccination. Overall, specific guidelines for similar cases should be established.\n\nB-DEAP COVID-19\nB-cell depletion associated prolonged COVID-19\nCOVID-19\nSARS-CoV-2 persistence\nvirus mutations\nanti-CD20-mediated B-cell depletion\nobinutuzumab\nREGEN-COV\nREGN10933 and REGN10987\nspike mutation\nanti-COVID-19 vaccine\n==== Body\n1. Introduction\n\nCOVID-19 clinical presentation can vary in severity and duration of infection. Most therapeutic options and clinical trials are focused on subjects early in the course of infection. Patients with prolonged acute infection, often associated with immune depletion, have limited therapeutic options. Here, we present a case of depletion associated prolonged (DEAP) COVID-19 treated with the off-label use of synthetic monoclonal antibody.\n\nCase Report Presentation\n\nA 59-year-old male with obesity (BMI 28.6 kg/m2), hypertension, and hypothyroidism was admitted with COVID-19. The hypertension was mild, and the patient was not being treated with any medications (i.e., no angiotensin-converting enzyme inhibitors, nor angiotensin-receptor blockers). Three years prior to admission, the patient had a classical Hodgkin’s lymphoma, grade IV, followed 18 months later by a follicular lymphoma (FL), grade III. Thirteen months prior to writing he received two of five cycles of G-benda, a combination of obinutuzumab, an anti-CD20 B-cell-depleting monoclonal antibody, and bendamustine, an ablative chemotherapeutic agent. Within weeks of the completion of the second G-benda cycle, the patient was admitted to an outside institution for roughly one week of fever, cough, and shortness of breath. Nasal swab qRT-PCR, abnormal imaging, and oxygen desaturation confirmed symptomatic COVID-19 infection. Throughout the month following admission, the patient required high-flow oxygen, however, the patient did not develop acute respiratory distress syndrome (ARDS) or require intubation. Anti-COVID-19 therapy consisted of hydroxychloroquine (400 mg once day one of admission, then 200 mg twice daily on days 2, 3, 7, and 8 of admission), azithromycin (500 mg once daily for the first five days of admission), lopinavir/ritonavir (200/50 mg tablets, two tablets bid days six through 15 of admission), steroids (solumedrol 80 mg iv bid, then 60 mg iv bid days 11 and 12 of admission, respectively), and two infusions of COVID-19 convalescent plasma, 30 and 50 days after diagnosis. All treatments were unsuccessful in clearing virus, as measured by unchanged nasal SARS-CoV-2 qRT-PCR and persistent symptoms. After 6 weeks, the patient was transferred to our center to receive remdesivir. Remdesivir was administered as 200 mg iv once daily for one dose, then 100 mg iv once daily for nine days. Following remdesivir, the patient exhibited slow clinical improvement. Three and a half months following diagnosis, after an overall mild clinical course and decreased oxygen dependence, patient was discharged home to quarantine for an indefinite period, given persistent detectable SARS-CoV-2 by nasal swab qRT-PCR (Table S1). After 10 weeks at home, he was readmitted for severe consolidated pneumonia, in the context of lympho-neutropenia and persistently low serum IgG (Table S2A,B), the latter prompting treatment with IVIG. During the week following readmission, he tested negative for SARS-CoV-2 on nasal swabs taken over two consecutive days (COVID-19 IDnow (Abbott)). The pneumonia was treated with broad-spectrum antibiotic/antifungal coverage including piperacillin-tazobactam, vancomycin, voriconazole, and steroids (prednisone 60 mg po once daily). However, three weeks from readmission, since no organism could be isolated and both cough and dyspnea persisted, COVID-19-related pneumonia was suspected; a nasal swab was administered (IDnow) and tested positive. COVID-19 was reconfirmed on subsequent nasal swabs, all with a detectable genome of SARS-CoV-2 by both tests (IDnow, cobas (Roche)). In retrospect, all samples collected within a couple of days of enrollment for the research study (nasal swab, saliva, and residual broncho-alveolar lavage (BAL) fluid) had detectable SARS-CoV-2 by TaqPath/CDC qRT-PCR, ruling out a SARS-CoV-2 re-infection, and presenting more consistently with a single prolonged infection with two false-negative nasal swabs upon readmission. During his subsequent prolonged (6 month) hospitalization, the patient experienced an unchanged clinical status with no improvement but no severe worsening, and mild oxygen dependence requiring on average 4 L/min. Weekly SARS-CoV-2 qRT-PCRs either by IDnow or cobas were all positive (Table S1). The patient did not develop anti-SARS-CoV-2 humoral response on serial plasma collected from days 80, 210, and 270 following initial diagnosis, using two independent ELISA platforms, both of which detect antibodies against SARS-CoV-2 nucleocapsid protein (NP) and either trimeric spike or spike receptor-binding domain (RBD) (Zalgen and in-house ELISA test) (Table S3). Sequencing of the virus was possible on nasal swab, saliva, and BAL collected 6 days after re-admission, with sample SARS-CoV-2 Ct values < 14. Sequence analysis of samples collected days 74 to 296 from initial diagnosis showed the persistent accumulation of new mutations over time, resulting in six amino acid changes, some not previously described (Figure 1, GISAID accession numbers: Virus name Accession ID: hCoV-19/USA/LA-ALSR-5820/2020 EPI_ISL_878549, hCoV-19/USA/LA-ALSR-5826/2020 EPI_ISL_878563, hCoV-19/USA/LA-ALSR-6526/2021 EPI_ISL_962812, hCoV-19/USA/LA-ALSR-6528/2021 EPI_ISL_962813, hCoV-19/USA/LA-ALSR-6529/2021 EPI_ISL_962814, hCoV-19/USA/LA-ALSR-6531/2020 EPI_ISL_962815). Eight months following initial symptom onset, alerted by report of variants with increased transmissibility/severity [1], and having concerns regarding the possible accumulation of new mutations, we proposed to attempt to clear virus carriage using an anti-SARS-CoV-2 spike protein monoclonal antibody cocktail, casirivimab/imdevimab (REGEN-COV).\n\n2. Materials and Methods\n\n2.1. Sample Processing Protocols\n\nPlasma prepared from anticoagulated fresh blood draw and residual samples are frozen and stored at −80 °C in aliquots of 200 µL.\n\n2.2. Serology Tests\n\n2.2.1. ReSARS® CoV-2 N-Protein and S-RBD IgG ELISA Kits for RUO, Zalgen Labs, LLC\n\nReSARS® CoV-2 N-protein and S-RBD IgG ELISA kits for RUO, Zalgen Labs, LLC (Germantown, MD, USA) are formatted as direct ELISAs with recombinant antigens coated directly on to 96-well microtiter plates (Nunc) and stabilized with proprietary block solution. The assays are semi-quantitative with convalescent COVID-19 donor plasma (lyophilized) provided to prepare a reference curve. Additional COVID-19 donor plasma (lyophilized) is provided as a positive control and bulk normal human plasma (lyophilized) is provided as a negative control. After reconstituting the reference and controls with purified water, the reference, controls, and human plasma samples (K3EDTA) are diluted 1:101 in sample diluent (10:1000 µL). The reference is further diluted 4-fold to prepare a five-point reference curve. The reference curve, controls, and samples are added to duplicate, designated microwells at 100 µL/well and incubated at ambient temperature (18–30 °C) for 30 min. Two wells of just sample diluent are included as a reagent blank. Following incubation, the plates are washed 4 × 300 µL/well with PBS-Tween wash buffer. For detection of N-protein or S-RBD-specific IgG, affinity purified goat anti-human IgG HRP conjugate reagent is added to the microwells at 100 µL/well and incubated at ambient temperature for 30 min. PBS-Tween wash is repeated to remove conjugate reagent. TMB substrate (Moss) is added to microwells (100 µL/well) for 10 min at ambient temperature. Substrate color development is stopped with the addition of 2% methane sulfonic acid Stopping Solution. Microwell plates are read at 450 nm with 650 nm reference. Gen5 program is used to subtract mean 450–650nm followed by reagent blank subtraction. Specific IgG (units/mL) is calculated from a 4-parameter logistic fit of the reference curve. The valuation of the reference plasma is based on a 0–100 scale with 100 units/mL equivalent to maximum clinical titer. Negative cut-off is equivalent to 2 units/mL based on mean + 2.5× Standard Deviation of +100 pre-COVID US normal plasmas.\n\n2.2.2. SARS-CoV-2 Anti-S (HEXAPRO) ELISA for RUO (Dr Robinson’s Lab)\n\nA plasmid for the expression of stable pre-fusion trimeric SARS-CoV-2 spike protein, similar to that described by Wrapp et al [2], was kindly provided by Kate Hastie (La Jolla Institute for Immunology). Recombinant stabilized spike protein is produced and purified as described by [3] Dan et al. Wells of 96-well ELISA plates (Costar, Easy Wash) are coated for 1 h at room temperature with this SARS-CoV-2 spike protein (500 ng/well in 100 mM sodium bicarbonate buffer). Wells are washed 5× and blocked for 1 h with 0.5%Tween, 5% dry milk, 4% whey, 10%FBS in 1× PBS at 37 °C. Sera or plasma samples diluted to 1:100 in the same buffer are incubated in antigen-coated and uncoated wells for 1 h at room temperature. Bound IgG is detected with peroxidase-conjugated goat anti-IgG (Jackson Immunoresearch, West Grove, PA, USA) and color is developed with TMB-peroxidase as described [4]. Net OD values at 450 nm were calculated by subtracting background OD readings from OD readings with spike protein. A cut off net OD value of 0.451 is calculated based on testing of >100 pre-COVID-19 serum samples.\n\n2.2.3. COVID-19 ACE2 Competition Assay® (V-PLEX SARS-CoV-2 Panel 2), Meso Scale Discovery, for RUO\n\nThis multiplexed solid-phase chemi-luminescence assay allows the simultaneous detection of IgG binding to four SARS-CoV-2 antigens and the quantification of antibody-induced ACE-2 binding inhibition. The latter is an ELISA-based pseudo-neutralization assay, detecting antibodies able to block the binding of angiotensin-converting enzyme 2 (ACE2) to the SARS-CoV-2 spike and S1 RBD antigens. Plates are blocked and washed, serial dilution of assay calibrator (COVID-19-neutralizing antibody; monoclonal antibody against S protein; 200 unit/mL), control and plasma samples (10 μL) diluted 1:100 in assay diluent are added to the plates. Following sample incubation an 0.25 μg/mL solution of MSD SULFO-TAG™ conjugated ACE-2 is added, after which plates are read. The assay is performed with the Meso QuickPlex SQ120 on a 10-spot 96-well microplate. Data is extrapolated from a calibration curve and calculated as percent inhibition normalized by a blank sample or as concentration of neutralizing SARS-CoV/SARS-CoV-2 spike monoclonal antibody. The value of 1 unit/mL of concentration of calibrator corresponds to neutralizing activity of 1 μg/mL monoclonal antibody to SARS-CoV/SARS-Cov-2 spike protein. % inhibition = [(1 − average sample single)/average single of Calibrator 8] × 100\n\n2.3. Molecular Tests\n\n2.3.1. CDC Emergency Use Authorization (EUA) 2019-nCoV Real-Time qRT-PCR Panel Protocol, A. Smither and Dr. Garry’s Lab. for RUO\n\nSamples: Research swabs, saliva samples, and BAL collected prior to REGN infusion are processed with this qRT-PCR protocol. Sample RNA extraction is performed with QIAmp Viral RNA Mini Kit (Qiagen) according to the manufacturer’s instructions. Primers: The presence of SARS-CoV-2 nucleocapsid (NP) is assessed using 2 sets of primers designed to target two portions of the NP gene, and a human gene RNAseP (RP) (Table 1).\n\nReaction mix: 8.5 μL nuclease-free water, 1.5 μL combined primer/probe mix (Integrated DNA Technologies), 5 μL 4× TaqPath 1-Step RT-qPCR Master Mix, CG (Applied Biosystems), and 5 μL of RNA (extract or standard) in a final volume of 20 µL. Each primer/probe set is run as a singlet for a total of three reactions/specimen. Amplification: Cycling parameters programed as 25 °C for 2 min, 50 °C for 15 min, 95 °C for 2 min, and 40 cycles of 95 °C for 3 s and 55 °C for 30 s, in a QuantStudio 3 Real-Time PCR System (Applied Biosystems). Calibrator: Viral load is assessed using an N1-specific ssRNA standard dilution series ranging from 108–101 copies (kind gift of Chris. Monjure). Analysis: A specimen is considered positive if all targets, viral (N1; N2) and human (RP), have a Ct < 35.\n\n2.3.2. Applied Biosystems TaqPath COVID-19 Combo Kit (Dr. Tian’s Lab) for IVD Use\n\nResearch swabs collected immediately prior to and after REGN MoAb infusions were processed in the Molecular Laboratory of the Tulane Department of Pathology (Dr. Tian, MD., PhD. Director). The laboratory is certified under CLIA and accredited by CAP to perform high-complexity testing. The test is approved under FDA Emergency Use Authorization (EUA). RNA extraction is performed using the KingFisher Flex automated extractor. Extraction requires a starting sample volume of 200 µL of the swab initial material and 10 µL of the final 50 µL elution volume is used per RT-PCR reaction. The SARS-CoV-2 RT-PCR is performed with the Thermo-Fisher TaqPath COVID-19 Combo Kit following the manufacturer’s recommendations. For amplification, we use the QS5 QuantStudio Real-time PCR system, with a total of 40 cycles. A cut-off Ct value set at 37 cycles is used to set the detection of the viral genes N, ORF1ab and S.\n\n2.3.3. SARS-CoV-2 Genome Sequencing (Andersen Lab. Scripps Research Institute), for RUO\n\nSamples with an N1 Ct < 30 (correlating to ~500 copies of virus/μL) were selected for amplicon sequencing. Samples’ viral RNA was shipped to Scripps Research Institute. All samples passed the required QC, consisting of RNA concentration measurement (Qubit) and fragment size evaluation (TapeStation) before sequencing. Virus sequencing is performed using NextSeq. For analysis, sequence reads are aligned to a hCoV-19 reference sequence and consensus sequences generated using iVar.\n\n3. Results\n\nThe compassionate use of emergency IND was approved by the FDA and the local IRB. Virus mutation analysis was consistent with persistent infection, and the lack of expected casirivimab/imdevimab escape: 1—one strain of virus, inferring that the virus was of identical strain before and after discharge home/readmission; 2—the constant accumulation of mutations within S and N sequences; 3—the absence of mutations that would decrease the efficiency of anti-S monoclonal antibody (Figure 1).\n\nOn day 270 the patient received the first infusion of REGEN-COV anti-spike monoclonal antibody cocktail at a dose of 2.4 g. Over subsequent weeks, 10 successive nasal swabs and 13 nasopharyngeal swabs were performed to monitor effects on viral persistence (Figure 2 and Figure 3). Tested by IDnow, after two detectable swabs, the virus became undetectable four times. However, all samples tested by cobas remained detectable. Samples tested by TaqPath immediately following infusion had Ct~13, followed by increase of all Ct values to a range of 28 and up to 30 with increased time post-infusion. We concluded that viral clearance was incomplete. Since the mean estimated half-life for both antibodies in casirivimab/imdevimab ranges from 25 to 37 days [5], a consolidation infusion was administered 35 days (~6 weeks) after first infusion, at a higher dose of 8 g (4 g for each of casirivimab and of imdevimab, respectively). Serological testing after infusion confirmed the absence of anti-N antibodies and the presence of anti-S only with neutralizing effect confirmed by Mesoscale discovery COVID-19 ACE2 competition assay, with results ranging from absent at baseline to >100% after first and second infusions (Table S3). After a second monoclonal antibody infusion, the results of all swabs, performed bi-weekly with all three techniques (IDnow, cobas, TaqPath), were non-detectable. Over the period of infusions, days 250–330, the patient underwent a long, well-tolerated, steroid taper (from 60 mg once daily to no steroids, tapered down by 5 mg roughly every week over twelve weeks). After 360 days, the patient was noted to have persistent pancytopenia, despite what appeared to be SARS-CoV-2 virus clearance; therefore, a bone marrow biopsy was performed, revealing no involvement by the patient’s FL. Peripheral blood immunophenotyping (Table S4) showed virtual absence of CD20 B-cells, low CD4 and CD8 T-cells, and persistent low serum IgG levels (Table S2B), all suggesting continued effects of G-benda. Since the expected recovery of some B-cell functionality was reached, allowing more reasonable chances for vaccine success, and in absence of clear contraindication, the patient received a first dose of Pfizer-BioNTech COVID-19 vaccine, 390 days following initial diagnosis. He was then discharged to home, where he would live with one family member (who had received vaccine dose one), with plans for close clinical follow up and regular check-ins from the state department of health.\n\n4. Discussion\n\nConcerns have been raised that patients with cancer, treated with ablative chemotherapy and B-cell depletion mediated by anti-CD20 monoclonal antibody, may experience more severe COVID-19 infection and a decreased efficiency of the anti-SARS-CoV-2 vaccine [6,7]. Since anti-CD20-MoAb-mediated B-cell depletion is prolonged (6–9 months), and normal B-cell levels are only reached after ~12 months [8], concerns related to inadequate humoral immune response are legitimate. In this patient, anti-SARS-CoV-2 antibodies were tested 80, 95, 210, and 220 days after diagnosis, using two independent ELISAs for the detection of the main virus antigens, nucleocapsid, spike protein in its trimeric form, and spike receptor-binding domain. All pre-REGEN-COV plasma showed no reactivity to virus antigens, which is consistent with the absence of neutralizing activity tested at 210 and 220 days (Table S3). More than one year after the last dose of obinutuzumab/bendamustine, our patient had persistent and pronounced lymphopenia, hypogammaglobulinemia (IgG~200 mg/dL), and no CD20/low CD4 T-cells in peripheral blood by flow cytometry. Of note, bendamustine can induce a very delayed T-lymphocyte reconstitution, particularly of CD4+ T cells [9], raising the possibility that benda alone or benda enhanced by COVID-19 was suppressing this patient’s CD4+ T cells. This case report is a striking illustration that anti-CD20-mediated B-cell depletion is not always associated with severe or life-threatening COVID-19 [10], but also with a mild yet prolonged course, as reported [6,11]. In this regard, non-specific immunity and the specific non-B-cell-dependent host defenses adequately contained the infection, or at least prevented the destructive effects of massive virus replication. Consistently, NK-cell function has even been reported as increased upon the anti-CD20 depletion of B-cells [12]. The absence of humoral response may also have prevented its deleterious side effects, such as antibody-dependent cell cytotoxicity or excessive inflammatory response [6,13]. In the absence of specific natural humoral response and after the ineffective immune pressure of multiple convalescent plasma infusions, the acquisition/shedding of variants of increased virulence or with the potential for immune escape was eventually our main concern [1]. Serial sequencing showed that the spike region identified no definitive casirivimab/imdevimab escape mutants, so the specific neutralizing effect of casirivimab/imdevimab toward the patient’s variants was predicted [14]. To optimize patient care, we firstly implemented drastic confinement measures with concern for virus mutation in a patient with active shedding, and secondly, sequenced isolates from respiratory samples over time to monitor strain mutations and predict the efficacy of the anti-spike REGEN-COV antibody cocktail.\n\nOther cases of prolonged COVID following the use of anti-CD20-depleting agents have been reported in the literature, including one case where repeated administration of convalescent plasma was associated with large and dynamic virus population shifts, without virus clearance [15]. Similarly, the current case reports B-DEAP COVID-19 with lack of virus clearance upon treatment with convalescent plasma. In contrast however, this case describes subsequent successful virus clearance using a synthetic anti-SARS-CoV-2 cocktail. It is hoped that the case described here might provide the glimmer of a potential treatment avenue to be pursued more systematically for future B-DEAP-COVID-19 cohorts.\n\nRelated to the performance of diagnostics in this case, in two instances the analytical sensitivity of IDnow appeared to be lower than that of cobas or TaqPath. First, at the time of re-admission for pneumonia, the question of persistent SARS-CoV-2 infection was challenged, as two immediate consecutive swabs were negative by IDnow. In contrast, qRT-PCR in saliva, nasal swab, and BAL had detectable amounts of virus, arguing that the patient had an ongoing, continuous infection. Second, after the first REGEN-COV infusion, testing for SARS-CoV-2 was repeated in nasal swabs by IDnow and cobas (Figure 2). SARS-CoV-2 was reproducibly not detected by IDnow but detected by cobas. The discrepancy has led us to suggest the partial success of the first REGEN-COV infusion, also supported by repeatedly higher Ct values of TaqPath assay performed after the first infusion. Notably, we could not perform a strict correlation of Ct values and viral load in the absence of an internal genomic calibrator in the samples. Altogether, it is important to recall that test sensitivity/specificity and test clinical value are two separate notions, depending primarily upon the clinical question that needs to be answered. In clinical cases such as the one described here, pending clearer guidelines, the authors would suggest that clinicians employ multiple distinct SARS-CoV-2 diagnostic tests when clinical suspicion is high, and sequence the virus/publicly share the diagnostic test and sequence results whenever possible.\n\nAnti-SARS-CoV-2 vaccine was administered in the window where REGEN-COV antibody cocktail levels were expected to decline, and when we could expect an effective vaccine response regarding B-cell-depletion recovery. This usually occurs 11 months after the last anti-CD20 dose, even in the absence of B cells detected in peripheral blood. We are still unable to predict whether our patient will efficiently develop a vaccine response, and we will follow up with serial visits, a complete blood count, serum IgG levels, anti-S Ab titers, neutralization assay, and nasal swabs. It is our hope that future studies can be performed to evaluate for the presence of activated T-cells or SARS-CoV-2-specific T-cells. Persistent pancytopenia and hypo-gamma-globulinemia still observed one year after two cycles of G-benda have not yet been resolved. First, they are likely attributable to G-benda since complete blood count parameters and IgG levels were normal prior to these treatments. Second, they are not associated with relapsed/persistent FL involvement by recent bone marrow biopsy study. Additional marrow-suppressive effects of SARS-CoV-2 cannot be excluded.\n\nObinutuzumab is a second-generation humanized anti-CD20 monoclonal antibody that has been developed to increase complement-dependent cytotoxicity and/or antibody-dependent cellular cytotoxicity by enhancing binding affinity for the Fc-γ receptor III expressed on immune effector cells. Early and late-onset neutropenia have been reported with greater incidence in obinutuzumab compared to rituximab (GAZYVA full Prescribing Information. Genentech, Inc.; 2020). Hypo-gammaglobulinemia was reported as long as 6 years after rituximab anti-CD20 B-cell depleting therapy, a rare phenomenon possibly associated with a polymorphism of the gene coding for FcγR3 [16]. SNPs FCGR2A[1 31H/R] and FCGR3A[158F/V] [17] have both been associated with increased affinity of Fcγ receptors on lymphocytes and neutrophils, and, if present, could explain prolonged cytopenia and hypogammaglobulinemia. Evaluation for these FC-gamma receptor (FCGR) variants has not been performed but should be considered, as should additional immune-function assays. Of note, since obinutuzumab recently received FDA approval, in contrast to rituximab, the drug’s long term side effects on white blood cells and IgG levels remain anecdotal in the literature [18,19]. The patient had a hypothyroidism of autoimmune origin and an exceedingly rare sequence of classical Hodgkin’s lymphoma followed by a high-grade follicular lymphoma [20] within a couple of years, raising concerns for congenital immunodeficiency and autoimmune lymphoproliferative disorder [21]. In this regard, we could rule out common variable immunodeficiency with normal IgG and IgA levels prior to G-benda, and normal complement CH50, C3, and C5.\n\n5. Conclusions\n\nThis is the first case of anti-CD20-mediated B-cell depletion associated prolonged COVID-19 (B-DEAP COVID-19) treated successfully with a clearance of ~300 days of SARS-CoV-2 infection by REGEN-COV monoclonal antibody cocktail infusion. Specific guidelines should be developed on how to manage infection control, monitor virus genetic mutations, and best provide passive (SARS-CoV-2 specific antibody infusions) and active immunizations in the case of B-DEAP COVID-19.\n\nAcknowledgments\n\nThe authors would like to thank the U.S. F.D.A., the Centers for Disease Control and Prevention, Regeneron, as well as the Louisiana State Department of Health and Tulane Medical Center Infection Control, for helpful discussions related to this case. The study team would like to thank the COVID-unit nurses, house staff, the patient’s family, and above all the patient for their persistence and patience during the described course. The patient himself has requested to state that he hopes this information may benefit others as we continue the struggle against COVID-19.\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/v13071202/s1. Table S1: SARS-CoV-2 detection prior to REGEN-COV antibody cocktail infusion. Table S2: Complete blood count results (a) and serum IgG levels from patient with B-cell depletion associated prolonged (B-DEAP) COVID-19. Table S3: Anti-SARS-CoV-2 antibody ELISA and ACE2 competition assay from patient with B-cell depletion associated prolonged (B-DEAP) COVID-19. Table S4: Peripheral blood immunophenotyping flow cytometric and complement studies from patient with B-cell depletion associated prolonged (B-DEAP) COVID-19. Supplementary Methods.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization, A.C.D., D.N.F.; methodology, A.C.D., D.N.F., M.W.T., S.Y.L., A.R.S., S.M.F., M.Z., G.P.G., P.R., W.B.R., A.P.L., D.T., K.G.A., J.E.R., R.F.G., M.L.B., L.M.B.; software, M.W.T., M.Z., K.G.A., R.F.G.; validation, A.R.S., M.W.T., D.N.F., A.C.D., M.L.B., L.M.B., R.F.G.; formal analysis, A.C.D., D.N.F., M.W.T., A.R.S., S.M.F., M.Z., G.P.G., D.T., K.G.A., J.E.R., R.F.G., M.L.B., L.M.B.; investigation, D.N.F., A.C.D.; resources, A.C.D., D.N.F., R.F.G., K.G.A.; data curation, A.C.D., D.N.F., M.W.T., A.R.S., M.Z., K.G.A., M.L.B., R.F.G., D.T., J.E.R.; writing—original draft preparation, A.C.D., D.N.F.; writing—review and editing, A.C.D., D.N.F., G.P.G., M.W.T., S.Y.L., S.M.F., A.R.S., D.T., R.F.G., M.L.B., L.M.B., K.G.A., M.Z., J.E.R.; visualization, A.C.D., R.F.G., M.W.T., G.P.G., D.N.F.; supervision, A.C.D., P.R., W.B.R., K.G.A., R.F.G., D.N.F.; project administration, A.C.D., D.N.F.; funding acquisition, A.C.D., K.G.A., R.F.G., D.N.F. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received the following funding. Compassionate use REGEN-COV antibody cocktail was provided by Regeneron. The ClinSeqSer observational study is supported by a startup fund from Tulane (DNF), a Pilot Award from Tulane (AD), and a contract from the Centers for Disease Control and Prevention (75D30120C08472) (DNF) and an NIH 1U19AI135995-01 (KA, RFG).\n\nInstitutional Review Board Statement\n\nFor REGEN-COV dose one, through IND 148069 REGEN-COV (casirivimab/imdevimab) was administered following written informed consent and IRB acknowledgement. For REGEN-COV dose two, IRB approval and written informed consent were obtained prior to infusion under emergency use of REGEN-COV, with protocol Anti SARS-CoV-2 Antibody Cocktail, Human Research Protection Program, Tulane University, IRB approvals # 2020-2276 and 2021-239. Separate from REGEN-COV treatment, the patient enrolled in the observational study ClinSeqSer (Collection of SARS CoV-2 Secretions and Serum for Countermeasure Development; aka ClinSeqSer, Tulane IRB 2020-396), through informed consent. Following consent into ClinSeqSer, the patient underwent collection of nasal swab, saliva, and residual bronchoalveolar lavage fluid for SARS-CoV-2 qRT-PCR and sequencing, collection of residual blood from clinical laboratory studies for antibody testing, then later collection of fresh blood draw for plasma anti-SARS-CoV-2 antibody studies. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Tulane University School of Medicine.\n\nInformed Consent Statement\n\nInformed consent was obtained from the subject involved in the study. Written informed consent has been obtained from the patients to publish this paper.\n\nData Availability Statement\n\nData supporting the reported results can be obtained by emailing the corresponding author.\n\nConflicts of Interest\n\nDNF and AD have served as site investigators on REGN-2066, 2067, and 2069 clinical trials. RG is Chief Scientific Advisor at Zalgen Labs, and holds an equity interest in Zalgen Labs. Zalgen Labs is directed and co-owned by R.F.G. and L.M.B. G.P.G. is Senior Vice President, Global Development, Regeneron Pharmaceutical Inc. All other authors report no conflicts of interest. The funders had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.\n\nFigure 1 Amino acid mutations detected over time through serial SARS-CoV-2 sequencing during 300 days of virus shedding in patient with B-DEAP (B-cell depletion associated prolonged) COVID-19. (a) X-axis indicates days post-diagnosis. Y-axis indicates amino acid mutations detected through the sequencing of nasal swabs positive for SARS-CoV-2 RNA with Ct value < 30, over time. (b) Structural representation of mutations over time.\n\nFigure 2 SARS-CoV-2 qRT-PCR results following REGEN-COV anti-spike MoAb infusions. (a) TaqPath Ct values. (b) IDnow and cobas Roche results. First dose infusion day 0. TaqPath Ct < 37 detected; Ct > 37 not detected. IDnow and cobas not detected vs. detected.\n\nFigure 3 Clinical course, therapies, virus detection. Chronological presentation of patient’s course, including supplemental oxygen required, therapeutic interventions, anti-SARS-CoV-2 antibody results, and SARS-CoV-2 PCR results. NC = nasal cannula. HCQ = hydroxychloroquine. RDV = remdesivir. L/min = liters per minute. IVIG = intravenous immune globulin.\n\nviruses-13-01202-t001_Table 1 Table 1 Primers.\n\nPrimer/Probe Mix\tSequence\t\n2019-nCoV_N1\tForward\t5′-GACCCCAAAATCAGCGAAAT-3′\t\nReverse\t5′-TCTGGTTACTGCCAGTTGAATCTG-3′\t\nProbe\t5′-FAM-ACCCCGCAT/ZEN/TACGTTTGGTGGACC-3IABkFQ-3′\t\n2019-nCoV_N2\tForward\t5′-TTACAAACATTGGCCGCAAA-3′\t\nReverse\t5′-GCGCGACATTCCGAAGAA-3′\t\nProbe\t5′-FAM-ACAATTTGC/ZEN/CCCCAGCGCTTCAG-3IABkFQ-3′\t\nHu RNAseP\n(RP)\tForward\t5′-AGATTTGGACCTGCGAGCG-3′\t\nReverse\t5′-GAGCGGCTGTCTCCACAAGT-3′\t\nProbe\t5′-FAM-TTC TGA CCT/ZEN/GAA GGC TCT GCG CG-3IABkFQ-3′\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Choi B. Choudhary M.C. Regan J. Sparks J.A. Padera R.F. Qiu X. Solomon I.H. Kuo H.-H. Boucau J. Bowman K. Persistence and evolution of SARS-CoV-2 in an immunocompromised host N. Engl. J. Med. 2020 383 2291 2293 10.1056/NEJMc2031364 33176080\n2. Wrapp D. Wang N. Corbett K.S. Goldsmith J.A. Hsieh C.L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation bioRxiv 2020 10.1126/science.abb2507\n3. Dan J.M. Mateus J. Kato Y. Hastie K.M. Yu E.D. Faliti C.E. Grifoni A. Ramirez S.I. Haupt S. Frazier A. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection Science 2021 371 10.1126/science.abf4063 33408181\n4. Robinson J.E. Hastie K.M. Cross R.W. Yenni R.E. Elliott D.H. Rouelle J.A. Kannadka C.B. Smira A.A. Garry C.E. Bradley B.T. Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits Nat. Commun. 2016 7 11544 10.1038/ncomms11544 27161536\n5. Weinreich D.M. Sivapalasingam S. Perry C. Pan C. Hosain R. Mahmood A. Davis J.D. Turner K.C. Hooper A.T. Hamilton J.D. REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19 N. Engl. J. Med. 2021 384 238 251 10.1056/NEJMoa2035002 33332778\n6. Kos I. Balensiefer B. Roth S. Ahlgrimm M. Sester M. Schmidt T. Thurner L. Bewarder M. Bals R. Lammert F. Prolonged Course of COVID-19-Associated Pneumonia in a B-Cell Depleted Patient After Rituximab Front. Oncol. 2020 10 1578 10.3389/fonc.2020.01578 32984017\n7. Baker D. Roberts C.A.K. Pryce G. Kang A.S. Marta M. Reyes S. Schmierer K. Giovannoni G. Amor S. COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases Clin. Exp. Immunol. 2020 202 149 161 10.1111/cei.13495 32671831\n8. McLaughlin P. Grillo-López A.J. Link B.K. Levy R. Czuczman M.S. Williams M.E. Heyman M.R. Bence-Bruckler I. White C.A. Cabanillas F. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program J. Clin. Oncol. 1998 16 2825 2833 10.1200/JCO.1998.16.8.2825 9704735\n9. Martínez-Calle N. Hartley S. Ahearne M. Kasenda B. Beech A. Knight H. Balotis C. Kennedy B. Wagner S. Dyer M. Kinetics of T-cell subset reconstitution following treatment with bendamustine and rituximab for low-grade lymphoproliferative disease: A population-based analysis Br. J. Haematol. 2018 184 957 968 10.1111/bjh.15722 30548597\n10. Lamure S. Dulery R. Demord M. Di Blasi R. Chauchet A. Hueso T. Rossi C. Drenou B. Deau-Fischer B. Sousain C. High incidence of persistent COVID-19 among patients with lymphoma treated with B-cell depleting immunotherapy AACR 2021 S09-02 10.1158/1557-3265\n11. Yasuda H. Tsukune Y. Watanabe N. Sugimoto K. Uchimura A. Tateyama M. Miyashita Y. Ochi Y. Komatsu N. Persistent COVID-19 pneumonia and failure to develop Anti-SARS-CoV-2 antibodies during Rituximab maintenance therapy for follicular lymphoma Clin. Lymphoma Myeloma Leuk. 2020 20 774 776 10.1016/j.clml.2020.08.017 32933879\n12. Veeramani S. Wang S.-Y. Dahle C. Blackwell S. Jacobus L. Knutson T. Button A. Link B.K. Weiner G.J. 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Severe hypogammaglobulinemia persisting for 6 years after treatment with rituximab combined chemotherapy due to arrest of B lymphocyte differentiation together with alteration of T lymphocyte homeostasis Int. J. Hematol. 2010 91 501 508 10.1007/s12185-010-0528-6 20217285\n17. Sakai H. Tanaka Y. Tazawa H. Shimizu S. Verma S. Ohira M. Tahara H. Ide K. Ishiyama K. Kobayashi T. Effect of Fc-gamma Receptor Polymorphism on Rituximab-Mediated B Cell Depletion in ABO-Incompatible Adult Living Donor Liver Transplantation Transpl. Direct 2017 3 e164 10.1097/TXD.0000000000000683 28620648\n18. Nair R. Tabchi S. Hagemeister F. Obinutuzumab Treatment of Follicular Lymphoma N. Engl. J. Med. 2017 377 2605 2606 10.1056/nejmc1714337 29281573\n19. Grigg A. Dyer M.J. Díaz M.G. Dreyling M. Rule S. Lei G. Knapp A. Wassner-Fritsch E. Marlton P. Safety and efficacy of obinutuzumab with CHOP or bendamustine in previously untreated follicular lymphoma Haematologica 2016 102 765 772 10.3324/haematol.2016.152272 28011903\n20. Niscola P. Palombi M. Fratoni S. Trawinska M.M. Scaramucci L. Giovannini M. Perrotti A. De Fabritiis P. Unusual sequence of lymphoid disorders: Follicular lymphoma subsequent to Hodgkin lymphoma and transformed into diffuse large B-cells non Hodgkin lymphoma Acta Oncol. 2009 48 1073 1074 10.1080/02841860902829213 19308758\n21. Gratzinger D. Jaffe E.S. Chadburn A. Chan J.K.C. de Jong D. Goodland J.R. Said J. Natkunam Y. Primary/Congenital Immunodeficiency: 2015 SH/EAHP Workshop Report-Part 5 Am. J. Clin. Pathol. 2017 147 204 216 10.1093/ajcp/aqw215 28395106\n\n",
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"title": "Successful Clearance of 300 Day SARS-CoV-2 Infection in a Subject with B-Cell Depletion Associated Prolonged (B-DEAP) COVID by REGEN-COV Anti-Spike Monoclonal Antibody Cocktail.",
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{
"abstract": "A 69-year-old man was admitted to our hospital because of dysesthesia in right palm and left upper limb, gait disturbance, and muscle weakness in both lower limbs. At the same time of neurological impairment appeared, he developed pemphigoid. Lumber MRI showed swelling of cauda equina nerve root. We diagnosed as chronic inflammatory demyelinating polyneuropathy based on an electrophysiological examination, and 2 courses of intravenous immunoglobulin therapy (IVIG) were initiated. After the treatments, symptoms improved immediately. However, thrombocytopenia was seen after each treatment which began on the second day of treatment start, reaching the lowest point from about 10 to 14 days, and improved naturally from 10 to 15 days after the end of IVIG. Difficulty in hemostasis was seen during dialysis due to thrombocytopenia. As a cause of thrombocytopenia, formation of IgG-platelet complexes could be considered, and the presence of multiple inflammatory diseases which activated Fcγ receptors play key roles could be a risk for IVIG related thrombocytopenia.",
"affiliations": "Department of Neurology, The Jikei University School of Medicine.;Department of Neurology, The Jikei University School of Medicine.;Department of Neurology, The Jikei University School of Medicine.;Department of Neurology, The Jikei University School of Medicine.;Department of Neurology, The Jikei University School of Medicine.;Department of Neurology, The Jikei University School of Medicine.",
"authors": "Sato|Takeo|T|;Omoto|Shusaku|S|;Onda|Asako|A|;Sakai|Kenichiro|K|;Mitsumura|Hidetaka|H|;Iguchi|Yasuyuki|Y|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "Japan",
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"issue": "60(1)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": "chronic inflammatory demyelinating polyneuropathy; intravenous immunoglobulin therapy; side effect; thrombocytopenia",
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000368:Aged; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D020277:Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; D013921:Thrombocytopenia; D013997:Time Factors",
"nlm_unique_id": "0417466",
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"pages": "57-59",
"pmc": null,
"pmid": "31852869",
"pubdate": "2020-01-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravenous immunoglobulin-induced thrombocytopenia in patient with chronic inflammatory demyelinating polyneuropathy.",
"title_normalized": "intravenous immunoglobulin induced thrombocytopenia in patient with chronic inflammatory demyelinating polyneuropathy"
} | [
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"literaturereference": "SATO T, OMOTO S, ONDA A, SAKAI K, MITSUMURA H, IGUCHI Y. INTRAVENOUS IMMUNOGLOBULIN INDUCED THROMBOCYTOPENIA IN PATIENT WITH CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY. CLINICAL NEUROLOGY. 2020?60(1):57-59",
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{
"abstract": "BACKGROUND\nSudden cardiac arrest following spinal anesthesia is relatively uncommon and a matter of grave concern for any anesthesiologist as well as clinicians in general. There have been, however, several reports of such cases in the literature. Careful patient selection, appropriate dosing of the local anesthetic, volume loading, close monitoring, and prompt intervention at the first sign of cardiovascular instability should improve outcomes. The rarity of occurrence and clinical curiosity of this entity suggest reporting of this unusual and possibly avoidable clinical event.\n\n\nMETHODS\nWe report the occurrence of unanticipated delayed cardiac arrest following spinal anesthesia in a 25-year-old Cameroonian man. Incidentally, the index patient was successfully resuscitated with timely and appropriate cardiopulmonary resuscitative measures. He went ahead to have emergency open appendectomy with good post-operative outcome and recovery.\n\n\nCONCLUSIONS\nThe management of such cardiac arrest under spinal anesthesia is very challenging in resource- limited settings such as ours. Anesthetists and clinicians need to be well informed of this grave complication. A good understanding of the physiologic changes caused by spinal anesthesia and its complications, adequate patient selection, respecting the contraindications of the procedure, adequate monitoring, and constant vigilance are of paramount importance to the eventual outcome.",
"affiliations": "Department of Surgery, Banso Baptist Hospital, P.O Box 9, Nso-Kumbo, Northwestern Region, Cameroon. drbalegbeleye@gmail.com.",
"authors": "Alegbeleye|Bamidele Johnson|BJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-018-1648-5",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n29792218\n1648\n10.1186/s13256-018-1648-5\nCase Report\nRETRACTED ARTICLE: Sudden cardiac arrest under spinal anesthesia in a mission hospital: a case report and review of the literature\nAlegbeleye Bamidele Johnson drbalegbeleye@gmail.com\n\nDepartment of Surgery, Banso Baptist Hospital, P.O Box 9, Nso-Kumbo, Northwestern Region, Cameroon\n24 5 2018\n24 5 2018\n2018\n12 14413 12 2017\n7 3 2018\n© The Author(s). 2018\nhttps://creativecommons.org/licenses/by/4.0/ Open 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.\nissue-copyright-statement© The Author(s) 2018\n==== Body\npmcThe Editor-in-Chief has retracted this case report because of concerns about patient consent to publish. The content of this article is no longer available online to protect the privacy of the patient. The author has not responded to correspondence from the publisher about this retraction.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "Anesthesia-spinal; Cardiac arrest; Intraoperative complications; Resuscitation",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D000775:Anesthesia, Spinal; D001062:Appendectomy; D001064:Appendicitis; D002163:Cameroon; D016887:Cardiopulmonary Resuscitation; D006323:Heart Arrest; D016519:Hospitals, Religious; D006801:Humans; D008297:Male; D008493:Medical Missions",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "144",
"pmc": null,
"pmid": "29792218",
"pubdate": "2018-05-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "12131111;23833864;3337390;11429383;25885243;18467885;21334513;12411815;10669271;564643;2043522;6465566;9316950;23723662;5721838;7189340;9504583;9667342;22837893;2655502;2343727;3902673;1514341;7618723;15220784;11880024;5011415;23878433;1599111;25886115",
"title": "Sudden cardiac arrest under spinal anesthesia in a mission hospital: a case report and review of the literature.",
"title_normalized": "sudden cardiac arrest under spinal anesthesia in a mission hospital a case report and review of the literature"
} | [
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"abstract": "The most common subepidermal blistering disorder, bullous pemphigoid (BP) typically occurs in the elderly without any obvious inciting event. 1 Anti-basement membrane zone antibodies are typically detected on direct and indirect immunofluorescence studies. 2 A flu-like prodromal phase with a non-specific urticarial dermatitis may herald the development of the more characteristic tense bullae. 3 Obtaining a thorough medication history is important as a number of pharmacological agents have been reported to trigger this same phenomenon. We report a case of generalized BP induced by hydrochlorothiazide therapy in a 32-year-old male.",
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"authors": "Warner|Catherine|C|;Kwak|Young|Y|;Glover|Mary H B|MH|;Davis|Loretta S|LS|",
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"mesh_terms": "D000328:Adult; D000906:Antibodies; D000959:Antihypertensive Agents; D001485:Basement Membrane; D006801:Humans; D006852:Hydrochlorothiazide; D008297:Male; D010391:Pemphigoid, Bullous",
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"title": "Bullous pemphigoid induced by hydrochlorothiazide therapy.",
"title_normalized": "bullous pemphigoid induced by hydrochlorothiazide therapy"
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"safetyreportid": 10744741,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150721"
}
] |
{
"abstract": "BACKGROUND\nThe goal of this work was to assess the safety and efficacy of biologics (ie, tumor necrosis factor-α antagonists and tocilizumab) in patients with Takayasu arteritis.\n\n\nRESULTS\nThis was a retrospective, multicenter study of the characteristics and outcomes of 49 patients with Takayasu arteritis (80% female; median age, 42 years [20-55 years] treated by tumor necrosis factor-α antagonists [80%] or tocilizumab [20%]) and fulfilling American College of Rheumatology or Ishikawa criteria. Factors associated with complete response were assessed. Eighty-eight percent of patients with Takayasu arteritis were inadequately controlled with or were intolerant to conventional immunosuppressive therapy (median number, 3 [1-5]). Overall response (ie, complete and partial) to biological-targeted treatments at 6 and 12 months was 75% and 83%, respectively. There were significantly lower C-reactive protein levels at the initiation of biological-targeted treatments (22 mg/L [10-46 mg/L] versus 58 mg/L [26-76 mg/L]; P=0.006) and a trend toward fewer immunosuppressants drugs used before biologics (P=0.054) in responders (ie, complete or partial responders) relative to nonresponders to biological-targeted treatments. C-reactive protein levels and daily prednisone dose significantly decreased after 12 months of biological-targeted treatments (30 versus 6 mg/L [P<0.05] and 15 versus 7.5 mg [P<0.05] at baseline and 12 months, respectively). The 3-year relapse-free survival was 90.9% (83.5%-99%) over the biological treatment period compared with 58.7% (43.3%-79.7%; P=0.0025) with disease-modifying antirheumatic drugs. No difference in efficacy was found between tumor necrosis factor-α antagonists and tocilizumab. After a median follow-up of 24 months (2-95 months), 21% of patients experienced adverse effects, with biological-targeted treatments discontinued in 6.6% of cases.\n\n\nCONCLUSIONS\nThis nationwide study shows a high efficacy of biological-targeted treatments in refractory patients with Takayasu arteritis with an acceptable safety profile.",
"affiliations": "From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi;From AP-HP, Hôpital Saint Antoine, Service de Médecine Interne et Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France (A.M., O.F.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Université Paris 6, Paris, France (C.C., P. Cacoub, D.S.); Unité Epidémiologie et Biostatistiques, INSERM, Hôpital Saint Louis, Paris, France (M.R.-R.); Service de Médecine Vasculaire, Hôpital Européen Georges-Pompidou, Assistance Publique Hôpitaux de Paris-APHP, Université Paris Descartes, Sorbonne Paris Cité, PARCC, Inserm U970, Centre de Référence National Maladies Vasculaires Rares, Paris, France (T.M., E.M.); Service de Médecine Interne, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Versailles, France (J.E.K.); Service de Médecine Interne, CHU Lille, Université Lille II, Lille, France (M.L.); Inserm UMR_1109, Fédération de Médecine Translationnelle, Université de Strasbourg, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France (J.S.); Service de Médecine Interne, CHU Hôtel-Dieu, Nantes, France (A.N., M. Hamidou); Université Paris Descartes, AP-HP, Hôpital Cochin, Centre de Référence Maladies Auto-Immunes et Systémiques Rares, Service de Médecine Interne, Paris, France (P. Cohen, L.G.); Service de Médecine Interne, Hôpital Pitié Salpetrière, Department of Internal Medicine and Clinical Immunology Groupe Hospitalier Pitié-Salpetrière, Université Pierre et Marie Curie, UPMC, Paris, France (M. Hie, Z.A.); Service de Médecine Interne et Immunologie Clinique, Hôpital le Bocage, Dijon, France (S.B.); Service de Médecine Interne, Université Rouen, Rouen, France (I.M.); Service de Médecine Interne et Maladies Vasculaires, Centre de Compétence de Maladies Rares, CHU Angers, Université Angers, Angers, France (C.L.); Service de Médecine Interne, Université Bordeaux, CHU Bordeaux, Bordeaux, France (M.A.V.); Service de Médecine Interne et Immunologie Clinique, Universi",
"authors": "Mekinian|Arsene|A|;Comarmond|Cloé|C|;Resche-Rigon|Mathieu|M|;Mirault|Tristan|T|;Kahn|Jean Emmanuel|JE|;Lambert|Marc|M|;Sibilia|Jean|J|;Néel|Antoine|A|;Cohen|Pascal|P|;Hie|Miguel|M|;Berthier|Sabine|S|;Marie|Isabelle|I|;Lavigne|Christian|C|;Anne Vandenhende|Marie|M|;Muller|Géraldine|G|;Amoura|Zahir|Z|;Devilliers|Hervé|H|;Abad|Sébastien|S|;Hamidou|Mohamed|M|;Guillevin|Loïc|L|;Dhote|Robin|R|;Godeau|Bertrand|B|;Messas|Emmanuel|E|;Cacoub|Patrice|P|;Fain|Olivier|O|;Saadoun|David|D|;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D000069285:Infliximab; D000068879:Adalimumab; C502936:tocilizumab; D000068800:Etanercept; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCULATIONAHA.114.014321",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-7322",
"issue": "132(18)",
"journal": "Circulation",
"keywords": "Takayasu arteritis; biological therapy; treatment outcome; vasculitis",
"medline_ta": "Circulation",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000792:Angiography; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001799:Blood Sedimentation; D002097:C-Reactive Protein; D018572:Disease-Free Survival; D004341:Drug Evaluation; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011241:Prednisone; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D013625:Takayasu Arteritis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "0147763",
"other_id": null,
"pages": "1693-700",
"pmc": null,
"pmid": "26354797",
"pubdate": "2015-11-03",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Efficacy of Biological-Targeted Treatments in Takayasu Arteritis: Multicenter, Retrospective Study of 49 Patients.",
"title_normalized": "efficacy of biological targeted treatments in takayasu arteritis multicenter retrospective study of 49 patients"
} | [
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},
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"drugindication": "TAKAYASU^S ARTERITIS",
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}
],
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{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infusion related reaction",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Herpes zoster",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug intolerance",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tuberculosis",
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},
{
"reactionmeddrapt": "Erysipelas",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use issue",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lung neoplasm malignant",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pharyngitis",
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"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "MEKINIAN A, COMARMOND C, RESCHE-RIGON M, MIRAULT T, KAHN JE, LAMBERT M, ET AL. EFFICACY OF BIOLOGICAL-TARGETED TREATMENTS IN TAKAYASU ARTERITIS: MULTICENTER, RETROSPECTIVE STUDY OF 49 PATIENTS. CONGENITAL HEART DISEASE 03-NOV-2015;132 (18):1693-1700.",
"literaturereference_normalized": "efficacy of biological targeted treatments in takayasu arteritis multicenter retrospective study of 49 patients",
"qualification": "1",
"reportercountry": "FR"
},
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"receiptdate": "20160530",
"receivedate": "20151209",
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},
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"sendertype": "2"
},
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"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
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}
] |
{
"abstract": "BACKGROUND\nThe aim of this study was to establish a new pathologic sub-classification of drug-induced liver injury (DILI) in combination with serum chemistry parameters and clinical observations.\n\n\nMETHODS\nFrom 777 DILI cases diagnosed in China-Japan Friendship Hospital from 2003 to 2014, 590 cases without other concomitant liver diseases were selected for the study. Pathological classification was established. Pathology and serum biochemical correlation analyses in 208 acute cases with complete biochemical data and prognostic information were conducted.\n\n\nRESULTS\nWe established a pathological classification of DILI according to the target cells of the liver (hepatocytes, bile duct epithelial cells, liver vascular and sinusoidal endothelial cells). In the 590 cases of DILI analyzed, hepatocyte injury accounted for 67.0%, bile duct epithelial injury (including cholestasis and mixed type of injury) 23.9%, and vascular injury 8.8%; about half of them were caused by the administration of traditional Chinese herbal medicines. Acute hepatocyte injury (lobular hepatitis) is further divided into mild, moderate and severe subtypes, while the mixed type of injury is categorized as cholestatic hepatitis and mixed hepatitis. The dynamic liver enzyme curves were established between lobular hepatitis and mixed-type hepatitis based on the combined consideration of histopathology and serum chemistry data. We proved that R value > 5 with cholestasis is a special feature of mixed hepatitis, which clarified the suspicion of the previous clinical classification of R value. Greater attention should be paid to drug-induced bile duct vanishing syndrome and drug-induced vascular injury.\n\n\nCONCLUSIONS\nThe pathological classification is simple to adopt and practically useful, which demonstrates the consistency between clinical features and liver pathology. The correlation between pathology and clinical biochemistry is an important way to acquire further understanding of DILI.",
"affiliations": "Department of Pathology, China Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Beijing, 100029, China. wang_tailing@126.com.;Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Xicheng District, Beijing, 100050, China.;Department of Pathology, China Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Beijing, 100029, China.;Department of Pathology, China Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Beijing, 100029, China.;Department of Pathology, China Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Beijing, 100029, China.;Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Xicheng District, Beijing, 100050, China.;Department of Pathology, China Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Beijing, 100029, China.;Department of Pathology, China Japan Friendship Hospital, 2 Yinghuayuan Dongjie, Beijing, 100029, China.;Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Xicheng District, Beijing, 100050, China.;Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Xicheng District, Beijing, 100050, China. youhong30@sina.com.;Liver Research Center, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Xicheng District, Beijing, 100050, China. Jia_jd@ccmu.edu.cn.",
"authors": "Wang|Tailing|T|http://orcid.org/0000-0003-2006-0978;Zhao|Xinyan|X|;Shao|Chen|C|;Ye|Lihong|L|;Guo|Jing|J|;Peng|Na|N|;Zhang|Honglei|H|;Li|Jian|J|;Kong|Yuanyuan|Y|;You|Hong|H|;Jia|Jidong|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12072-019-09940-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1936-0533",
"issue": "13(3)",
"journal": "Hepatology international",
"keywords": "Drug-induced liver injury; Herb-induced liver injury; Histological injury pattern; Liver histology; Pathological classification",
"medline_ta": "Hepatol Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001774:Blood Chemical Analysis; D056486:Chemical and Drug Induced Liver Injury; D002681:China; D003663:Decision Trees; D005260:Female; D022781:Hepatocytes; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D062606:Tertiary Care Centers; D055815:Young Adult",
"nlm_unique_id": "101304009",
"other_id": null,
"pages": "339-351",
"pmc": null,
"pmid": "30977034",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "11261820;11928077;12890847;14331990;17524273;19826970;21480339;22188914;2254635;22629579;24704526;24879977;26517184;27960237;28930128;29502198;30992915;9138126",
"title": "A proposed pathologic sub-classification of drug-induced liver injury.",
"title_normalized": "a proposed pathologic sub classification of drug induced liver injury"
} | [
{
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{
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"activesubstancename": "METRONIDAZOLE"
},
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}
],
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"patientonsetage": "45",
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"reaction": [
{
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "WANG T, ZHAO X, SHAO C, YE L, GUO J, PENG N ET AL.. A PROPOSED PATHOLOGIC SUB-CLASSIFICATION OF DRUG-INDUCED LIVER INJURY.. HEPATOLOGY INTERNATIONAL. 2019?13:339-51",
"literaturereference_normalized": "a proposed pathologic sub classification of drug induced liver injury",
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},
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"transmissiondate": "20191005"
},
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
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"abstract": "Fifty-four consecutive persons with HIV co-infected with hepatitis C virus (HCV) and liver decompensation were treated with direct-acting antivirals (DAA). The HCV treatment was delivered using a multidisciplinary HIV-coinfection model of care integrating sub-specialty services in 3 countries. Of those treated, 91% (95% confidence interval, 80.1 to 95.9) achieved sustained viral response, and only one person died during treatment. Our study provides evidence that HIV providers achieve excellent outcomes when treating patients with histories of decompensated liver disease, with characteristics similar to those studied using a multidisciplinary HIV-centered approach.",
"affiliations": "Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, CA, USA.;U Enfermedades Infecciosas, S Medicina Interna, University Hospital of La Coruña, Spain.;Unit of Infectious Diseases, University Hospital Álvaro Cunqueiro; Vigo, Spain.;Puerta de Hierro Research Institute and University Hospital, Madrid, Spain.;Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy.;Puerta de Hierro Research Institute and University Hospital, Madrid, Spain.;Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, CA, USA.;Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, CA, USA.;UNIR Health Sciences School & Medical Center, Madrid, Spain.;Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, CA, USA.",
"authors": "Cachay|Edward R|ER|0000-0002-2452-7558;Mena|Alvaro|A|;Morano|Luis|L|0000-0002-0560-3260;Benitez|Laura|L|;Maida|Ivana|I|0000-0003-4895-7576;Mendoza|Carmen DE|C|;Hill|Lucas|L|;Torriani|Francesca|F|;Soriano|Vincente|V|;Mathews|W C|WC|;|||",
"chemical_list": "D000998:Antiviral Agents",
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"doi": "10.1177/23259582211024771",
"fulltext": "\n==== Front\nJ Int Assoc Provid AIDS Care\nJ Int Assoc Provid AIDS Care\nJIA\nspjia\nJournal of the International Association of Providers of AIDS Care\n2325-9574\n2325-9582\nSAGE Publications Sage CA: Los Angeles, CA\n\n10.1177/23259582211024771\n10.1177_23259582211024771\nOriginal Research Article\nHepatitis C Treatment Outcomes in Persons With HIV and Decompensated Cirrhosis Using a Collaborative Multidisciplinary HIV-Centered Approach\nhttps://orcid.org/0000-0002-2452-7558\nCachay Edward R. MD 1\nMena Alvaro MD, PhD 2\nhttps://orcid.org/0000-0002-0560-3260\nMorano Luis MD 3\nBenitez Laura MD 4\nhttps://orcid.org/0000-0003-4895-7576\nMaida Ivana MD 5\nMendoza Carmen DE PhD 4\nHill Lucas PharmD 6\nTorriani Francesca MD 1\nSoriano Vincente MD, PhD 7\nMathews W. C. MD, MSPH 1\nfor the HCV-HIV Transatlantic Research Network (HCV-TREN)\n1 Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, CA, USA\n2 U Enfermedades Infecciosas, S Medicina Interna, University Hospital of La Coruña, Spain\n3 Unit of Infectious Diseases, University Hospital Álvaro Cunqueiro; Vigo, Spain\n4 Puerta de Hierro Research Institute and University Hospital, Madrid, Spain\n5 Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy\n6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, CA, USA\n7 UNIR Health Sciences School & Medical Center, Madrid, Spain\nEdward Cachay, MAS, 200 west arbor drive, San Diego, CA 92103, USA. Email: ecachay@health.ucsd.edu\n16 6 2021\nJan-Dec 2021\n20 232595822110247719 2 2021\n18 5 2021\n24 5 2021\n© The Author(s) 2021\n2021\nSAGE Publications Inc. unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nFifty-four consecutive persons with HIV co-infected with hepatitis C virus (HCV) and liver decompensation were treated with direct-acting antivirals (DAA). The HCV treatment was delivered using a multidisciplinary HIV-coinfection model of care integrating sub-specialty services in 3 countries. Of those treated, 91% (95% confidence interval, 80.1 to 95.9) achieved sustained viral response, and only one person died during treatment. Our study provides evidence that HIV providers achieve excellent outcomes when treating patients with histories of decompensated liver disease, with characteristics similar to those studied using a multidisciplinary HIV-centered approach.\n\nHIV\nHCV\nliver decompensation\nDAA\nmultidisciplinary\nPacific AIDS Education and Training Center (PAETC) P30 AI036214 cover-dateJanuary-December 2021\ntypesetterts3\n==== Body\nBackground\n\nWith the advent of Direct-acting antivirals (DAA), HIV medical providers routinely treat hepatitis C (HCV) in persons with HIV (PWH) who do not have cirrhosis or have cirrhosis without decompensation. 1\n\nWorldwide, liver transplantation is not an option for most PWH in need. Yet, many PWH co-infected with HCV and decompensated cirrhosis remain untreated due to health-system and personal barriers to access sub-specialty services. 2 The delay in HCV treatment often leads to frequent hospitalizations, increases resource health care utilization, and death. 3\n\nHIV care is increasingly delivered within integrated HIV-primary care multidisciplinary care models, including but not limited to HIV medical providers, clinical pharmacists, social workers, substance counselors, and psychiatrists. 4 These models allow the real-time interaction of HIV physicians with sub-specialty services and a tandem approach to managing complex PWH, such as those with liver decompensation. HIV physicians implement the medical hepatology recommendations while managing multiple concurrent medical comorbidities. The HIV team addresses potential medical interactions while also supporting services to overcome PWH competing barriers to care, such as drug use, unstable housing, and mental illness. 5 Herein, we report the sustained viral response (SVR) and safety outcomes when HIV teams treated HCV in PWH with liver decompensation, integrating sub-specialty services in 3 different countries.\n\nWhat Do We Already Know About This Topic?\n\nTreatment of hepatitis C using direct-acting antivirals (DAA) in persons with HIV (PWH) is well-tolerated and highly effective. Yet access to hepatitis C treatment sub-specialty services, especially among PWH with liver decompensation, remains suboptimal in many parts of the world, and this is detrimental to their quality of life and survival.\n\nHow Does Your Research Contribute to the Field?\n\nThis work provides evidence that the specialty care that PWH with decompensated cirrhosis needed during DAA treatment can be accomplished in a multidisciplinary HIV-centered model of care lead by trained HIV providers.\n\nWhat Are Your Research’s Implications Toward Theory, Practice, or Policy?\n\nTo accomplish the goal of HCV eradication, the pool of providers treating HCV needs to be expanded, and systems that facilitate HCV treatment of PWH with advanced liver disease need to be augmented.\n\nMethods\n\nWe conducted a retrospective cohort analysis of consecutive PWH co-infected with HCV who had decompensated cirrhosis and were treated with DAA in the HCV-HIV Transatlantic Research Network (HCV-TREN). The cohort comprises 5 academically affiliated HIV clinics in 3 different countries. Using de-identified electronic medical records (EMR) information, we collect data on demographics; HIV regimen, CD4 counts, and viral load; HCV-genotype, prior HCV treatment history, DAA regimen, Child-Turcotte-Pugh (CPT) class, Model for End-Stage Liver Disease (MELD) scores; and Charlson comorbidity index. We also collected patient-reported outcomes relative to current alcohol, illicit drug use, unstable housing, and active psychiatric illness as previously described. 6 Each participating site obtained approval from their designated research Ethics committees: The University of California at San Diego Human Research Protection Program (approval no. 171749X), the Research Ethics Committee of the University of Sassari, Italy (approval no. 2424/CE), the Ethics Committee of Health Department and Social Services and Equity of Spain (approval no. CAC-HCV-2016-01). For this observational retrospective study, all ethics committed waived the requirement for written informed consent as it was a retrospective review of existing medical records.\n\nWe included PWH who were 18 years of age or older with a detectable HCV viral load and a Child-Turcotte-Pugh (CPT) score B or higher treated for HCV between January 2014 and July 2018. In each clinic, there was an HIV clinician experienced in HCV treatment who led team efforts. We followed 4 principles in the management of HCV among PWH: (1) evaluation of HIV control and medical interactions; (2) liver fibrosis staging and prevention of cirrhosis-related complications; (3) addressing concurrent medical comorbidities; and (4) management of ongoing barriers to care. 6\n\nHIV providers used electronic messaging to coordinate all aspects of cirrhosis staging before DAA initiation. The hepatology team completed the required esophagogastroduodenoscopy (EGD) for esophageal varices screening. PWH also completed abdominal ultrasound examination to rule out hepatocellular carcinoma (HCC). In coordination with hepatology teams, HIV teams followed standard of care protocols to manage portal hypertension, hepatic encephalopathy, and spontaneous bacterial peritonitis prophylaxis. HIV pharmacists reviewed the safety of combining different DAA with antiretrovirals and collaborated with HIV providers on any needed ART changes to allow HCV treatment. Depending on each site’s resources, HIV clinical pharmacists, social workers, substance counselors, and psychiatrists provided counseling on avoiding liver-related hepatotoxic medications and alcohol while offering harm reduction counseling to prevent HCV reinfection.\n\nThe primary study endpoint was the proportion of patients who achieved SVR defined as having an undetectable serum HCV RNA 12 weeks after the estimated DAA treatment completion date. The secondary endpoint was the proportion of patients who died after receiving at least one dose of DAA at the estimated date of SVR.\n\nDescriptive statistics were presented using medians with ranges and frequencies with percentages. Bivariate analyses with pairwise comparisons were conducted to investigate factors associated with lack of HCV SVR. We used χ2 test for comparison of categorical variables and the Wilcoxon rank-sum test for numerical variables. Analyses were performed using Stata Statistical Software (Release 14.2. College Station, TX).\n\nResults\n\nDuring the study period, 54 PWH with decompensated cirrhosis were treated for HCV using different DAA regimens. Of them, 18 (33%) had failed prior HCV treatments, and 41 (76%) had HCV genotype 1. Treated patients had a median age of 52 years and a CD4 cell count of 312/mm3, with most (90%) having an undetectable HIV viral load. Forty-six patients (85%) were males, and 35 of them had had as their main HIV risk factor being heterosexual with intravenous drug use history. We were required to change ART in 22 PWH (41%) to allow DAA initiation. All of them had complex HIV resistance history. The prevalence of current alcohol, drug use, and psychiatric illness was 26%, 20%, and 28%, respectively. At the time of HCV treatment initiation, and according to CPT score distribution, 63% of patients had class B7, 15% B8, 11% B9, 5% C10, and 4% C11, with the median baseline MELD score was 11 (range, 8 to 20). Twenty-two patients (41%) had at least 2 decompensated cirrhosis manifestations. Seven (13%) had ascites plus esophageal varices, and hepatic encephalopathy (Table 1).\n\nTable 1. Characteristics of PWH and liver decompensation co-infected with hepatitis C treated with DAA.\n\n\tTOTAL N = 54\tSVR: YES N = 49\tSVR: NO N = 5\t\nAge: median (range), y\t52.5 (41–65)\t53 (41–65)\t53 (47–56)\t\nMale gender: No. (%)\t46 (85.2)\t41 (83.4)\t5 (100.0)\t\nHCV genotype, No. (%)\t\t\t\t\n1/1a/1b\t41 (75.9)\t37 (75.4)\t4 (80.0)\t\n2\t1 (1.9)\t1 (2.0)\t0 (0.0)\t\n3\t6 (11.1)\t6 (12.5)\t0 (0.0)\t\n4\t6 (11.1)\t5 (10.1)\t1 (20.0)\t\nPrior HCV treatment failure: No. (%)\t18 (33.3)\t16 (32.7)\t2 (40)\t\nHCV viral load: median (range), Log10 IU/L\t5.95 (4.20–7.22)\t5.97 (4.28–7.22)\t5.84 (4.20–6.63)\t\nChild-Turcotte-Pugh score, No. (%)\t\t\t\t\nB7\t34 (63.0)\t32 (65.3)\t2 (40.0)\t\nB8\t8 (14.8)\t7 (14.3)\t1 (20.0)\t\nB9\t6 (11.1)\t5 (10.2)\t1 (20.0)\t\nC10/11\t6 (11.1)\t5 (10.2)\t1 (20.0)\t\nMELD score: median (range)\t11 (8–20)\t11 (8–19)\t14 (10–20)\t\nDecompensation events per patient, No. (%)\t\t**\t**\t\nAscites ± leg edema\t26 (48.2)\t25 (51.0)\t1 (20.0)\t\nOnly bleeding esophageal varices (EV)\t2 (3.7)\t2 (4.1)\t0 (0.0)\t\nOnly hepatic encephalopathy (HE)\t4 (7.4)\t4 (8.2)\t0 (0.0)\t\nAscites and spontaneous bacterial peritonitis (SBP)\t5 (9.3)\t5 (10.2)\t0 (0.0)\t\nAscites and bleeding EV\t3 (5.6)\t3 (6.1)\t0 (0.0)\t\nAscites and HE\t5 (9.3)\t4 (8.2)\t1 (20.0)\t\nAscites, HE, and bleeding EV\t7 (12.9)\t6 (12.2)\t1 (20.0)\t\nAscites, SBP, and HE\t1 (1.8)\t0 (0.0)\t1 (20.0)\t\nAscites, SBP, HE, and bleeding EV\t1 (1.8)\t0 (0.0)\t1 (20.0)\t\nHIV risk factor, No. (%)\t\t\t\t\nMen who have sex with men (MSM)\t2 (3.7)\t1 (2.0)\t1 (20.0)\t\nHeterosexual\t12 (22.2)\t12 (24.5)\t0 (0.0)\t\nHemophilia\t1 (1.9)\t1 (2.0)\t0 (0.0)\t\nMSM and intravenous drug use\t2 (3.7)\t2 (4.1)\t0 (0.0)\t\nHeterosexual and intravenous drug use\t35 (64.8)\t32 (65.4)\t3 (60.0)\t\nother\t2 (3.7)\t1 (2.0)\t1 (20.0)\t\nCD4+ count: median (range), cells/mm3\t312.5 (75–1279)\t319 (75–1279)\t417 (256–682)\t\nDetectable HIV viral load (≥20 copies/ml): No. (%)\t5 (9.3)\t5 (10.2)\t0 (0.0)\t\nHIV viral load: median (range)\t0 (0–19,000)\t9 (0-19,000)\t0 (0)\t\nCharlson comorbidity score, median (range)\t7 (2–12)\t6 (2–12)*\t10 (7–12)*\t\nCurrent hazardous alcohol use: No. (%)\t14 (25.9)\t14 (28.6)\t0 (0.0)\t\nCurrent illegal drugs: No. (%)\t11 (20.4)\t8 (16.3)*\t3 (60)*\t\nCurrent unstable housing: No. (%)\t4 (7.4)\t4 (8.2)\t0 (0.0)\t\nActive psychiatric illness: No. (%)\t15 (27.8)\t14 (28.6)\t1 (5)\t\nDirect Acting Antiviral regimen, No. (%)\t\t**\t **\t\nSofosbuvir plus simeprevir– 12weeks\t7 (12.9)\t4 (8.2)\t3 (60.0)\t\nSofosbuvir plus simeprevir and ribavirin– 12weeks\t7 (12.9)\t7 (14.2)\t0 (0.0)\t\nSofosbuvir plus ledipasvir– 24weeks\t13 (24.2)\t12 (24.5)\t1 (20.0)\t\nSofosbuvir plus ledipasvir and ribavirin – 12weeks\t10 (18.5)\t10 (20.4)\t0 (0.0)\t\nSofosbuvir plus ledipasvir and ribavirin – 24weeks\t1 (1.8)\t0 (0.0)\t1 (20.0)\t\nSofosbuvir plus daclatasvir – 24weeks\t5 (9.3)\t5 (10.2)\t0 (0.0)\t\nSofosbuvir plus daclatasvir and ribavirin – 24weeks\t4 (7.4)\t4 (8.2)\t0 (0.0)\t\nSofosbuvir plus velpatasvir and ribavirin – 12weeks\t5 (9.3)\t5 (10.2)\t0 (0.0)\t\nSofosbuvir plus velpatasvir – 24weeks\t2 (3.7)\t2 (4.1)\t0 (0.0)\t\nAntiretorviral therapy: No. (%)\t\t\t\t\nabacavir/lamivudine & dolutegravir\t11 (20.4)\t9 (18.5)\t2 (40.0)\t\nabacavir/lamivudine & raltegravir\t3 (5.5)\t3 (6.1)\t0 (0.0)\t\nabacavir/lamivudine, dolutegravir & rilpivirine\t3 (5.5)\t2 (4.1)\t1 (20.0)\t\nabacavir/lamivudine & ritonavir-boosted darunavir\t3 (5.5)\t3 (6.1)\t0 (0.0)\t\ntenofovir/emtricitabine & raltegravir\t10 (18.5)\t9 (18.5)\t1 (20.0)\t\ntenofovir/emtricitabine & dolutegravir\t8 (14.8)\t8 (16.3)\t0 (0.0)\t\ntenofovir/emtricitabine & rilpivirine\t2 (3.7)\t2 (4.1)\t0 (0.0)\t\ntenofovir/emtricitabine & ritonavir-boosted darunavir\t6 (11.0)\t6 (12.2)\t0 (0.0)\t\ntenofovir/emtricitabine, ritonavir-boosted darunavir & etravirine\t2 (3.7)\t2 (4.1)\t0 (0.0)\t\ntenofovir/emtricitabine, rilpivirine & maraviroc\t1 (1.9)\t1 (2.0)\t0 (0.0)\t\ntenofovir/emtricitabine, rilpivirine & dolutegravir\t1 (1.9)\t1 (2.0)\t0 (0.0)\t\nrilpivirine, ritonavir-boosted darunavir & raltegravir\t1 (1.9)\t1 (2.0)\t1 (20.0)\t\nrilpivirine & ritonavir-boosted darunavir\t1 (1.9)\t1 (2.0)\t0 (0.0)\t\nrilpivirine, maraviroc, & raltegravir\t1 (1.9)\t1 (2.0)\t0 (0.0)\t\ntenofovir/emtricitabine, ritonavir-boosted darunavir, dolutegravir & maraviroc\t1 (1.9)\t0 (2.0)\t1 (20.0)\t\nSVR: sustained viral response, MELD: Model for End-Stage Liver Disease.\n\nBivariate comparison between the groups based on SVR status: *p < 0.05, **p < 0.01.\n\nA total of 49 patients (91%, 95% confidence interval [CI], 80.1 to 95.9) achieved SVR: 94% (95% CI:80.1 to 98.4) among those with CPT B7, 88% (95% CI: 52.9 to 97.8) among those with CPT B8, 83% (95% CI; 43.7 to 96.9) among those with CPT B9, and 83% (36.5 to 99.1) among those with CPT C10/11. The mortality proportion during HCV treatment was 1.9% (95% CI: 0.3 to 9.7). Of the 5 patients who failed HCV treatment, 3 relapsed, 1 was lost to follow up, and one died (Table 2). The death was attributed to the patient’s noncompliance with his secondary antibiotic prophylaxis to prevent recurrent spontaneous bacterial peritonitis. Unlike those who achieved SVR, PWH who failed DAA treatment had more frequent current drug use, multiple comorbidities, and signs of liver decompensation (Table 1). After a median of 2.1 years of follow-up, all PWH who achieved initial SVR remain alive.\n\nTable 2. Clinical characteristics of the 5 patients who failed hepatitis C treatment.\n\n\tRelapse #1\tRelapse #2\tRelapse #3\tDied\tLost to follow-up\t\nAge in years\t54\t56\t50\t47\t51\t\nGender\tmale\tmale\tmale\tmale\tmale\t\nHCV genotype\t1a\t1a\t4\t1a\t1a\t\nPrior HCV treatment failure\tNo\tYes\tYes\tNo\tNo\t\nHCV viral load: Log IU/L\t4296194\t3088341\t697000\t50600\t15888\t\nChild-Turcotte-Pugh score\tC10\tB7\tB7\tB8\tB9\t\nMELD score\t20\t14\t15\t10\t13\t\nDecompensation events\tAscites, HE, bleeding EV\tAscites\tAscites, HE\tAscites, SBP, HE\tAscites, SBP, HE, bleeding EV\t\nHIV risk factor\tHemophilia\tHetero & IDU\tHetero & IDU\tHetero & IDU\tHetero\t\nCD4+ count, cells/mm3\t251\t230\t499\t387\t256\t\nHIV viral load\tUD\tUD\tUD\tUD\tUD\t\nCharlson comorbidity score\t12\t12\t7\t8\t10\t\nCurrent hazardous alcohol use\tNo\tNo\tNo\tNo\tNo\t\nCurrent illegal drugs\tYes\tYes\tNo\tYes\tNo\t\nCurrent unstable housing\tNo\tNo\tNo\tNo\tNo\t\nActive psychiatric illness\tNo\tNo\tYes\tNo\tNo\t\nDirect Acting Antiviral regimen\tsof/smv for 12 weeks\tsof/smv for 12 weeks\tsof/ldv + rbv for 24 weeks\tsof/ldv for 24 weeks\tSof/smv for 12 weeks\t\nAntiretroviral therapy\tabc/3tc+dtg\tabc/3tc+rpv+dtg\ttdf/ftc+etv+ dtg+ mvc+ drv/r\tabc/3tc+dtg\ttdf/ftc+ral\t\nHE: hepatic encephalopathy, EV: esophageal varices, IDU: intravenous drug use, hetero: heterosexual, UD: undetectable\n\nsof: sofosbuvir, smv; simeprevir, ldv: ledipasvir, rbv: ribavirin.\n\nabc: abacavir, 3tc; lamivudine, tdf: tenofovir disoproxil, ftc: emtricitabine, rpv: rilpivirine, etv; etravirine, mvc: maraviroc, dtg: dolutegravir, ral: raltegravir, drv/r: ritonavir-boosted darunavir, sbp: spontaneous bacterial peritonitis.\n\nDiscussion\n\nIn this international cohort of PWH with decompensated cirrhosis treated with DAAs, we observed high HCV cure rates (91% overall) when following treatment models led by HIV physicians using a multidisciplinary care model adjusted to regional resource availability. HCV treatment success was possible despite the high prevalence of ongoing barriers to care in our cohort and the presence of complex advanced liver disease manifestations.\n\nThe role of hepatology is vital for the management of persons with decompensated cirrhosis. For example, hepatologists decide the timing of DAA treatment relative to the patient’s candidacy for liver transplantation. Unfortunately, a liver transplant is not a viable option for most PWH in need, and many with advanced liver disease fail to link to HCV sub-specialty care. 7 Challenges to this conventional approach include the need for a sub-specialty referral and insurance approval in non-universal healthcare systems and long waiting times for a hepatology intake appointment. 8 The combination of PWH with ongoing barriers to care, internalized stigma, and low HCV knowledge also accentuate the lack of HCV linkage to care of some PWH with advanced liver disease to hepatology services. 9\n\nOur success in developing effective cures for HCV requires us to find ways to treat PWH who have traditionally been challenging to treat. To accomplish the goal of HCV eradication, the pool of providers treating HCV needs to be expanded, and systems that facilitate HCV treatment of patients with advanced liver disease need to be created. 5 Our results suggest that the special care that PWH with decompensated cirrhosis needed during DAA treatment can be accomplished in a collaborative, multidisciplinary HIV-centered model of care. Collaboration between hepatology and HIV teams is essential to create concurrent strategies to address the medical, personal, and social needs of PWH to facilitate their access to HCV treatment. Indeed, our study SVR rates and safety outcomes were comparable to those of registrational clinical trials of PWH and decompensated cirrhosis and other hepatology-based studies. 10 Noteworthy, successful HCV treatment in PWH with liver decompensation does not eliminate the risk of HCC or liver disease progression. 11 Thus, PWH with liver decompensation require ongoing follow-up with hepatology services after SVR. Finally, HIV physicians who treat HCV need to be aware that HCV protease inhibitors should not be given to patients with decompensated cirrhosis because of the potential for worsening hepatic decompensation. 12\n\nOur study has limitations. Our sample size was small (N = 54) and thus may not be generalizable. Notwithstanding, our goal is to report a successful approach to treat HCV in PWH with liver decompensation who are also burdened by complex social and medical needs commonly encountered in clinical practice. Our models rely on collaboration with sub-specialty services while maintaining HIV primary care coordination. We recognize that there are multiple strategies to treat HCV in PWH with advanced liver disease. When providers participate in a weekly telehealth-based didactic and clinical case discussion using the ECHO model, successful HCV therapy can be accomplished in patients with advanced liver disease. 13 Regardless of the implemented model tailored to geographic and structural health system needs, we believe that to close the gaps on HCV elimination in our communities, we need to foster inclusion and collaboration among multiple providers caring for PWH with decompensated cirrhosis.\n\nIn conclusion, HCV cure was achieved in 91% of PWH with liver decompensation in 3 different countries using a multidisciplinary HIV-centered treatment approach.\n\nAcknowledgments\n\nWe want to thank our patients, whose resilience and perseverance continue to inspire us to improve our clinical services.\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\nORCID iDs: Edward R. Cachay https://orcid.org/0000-0002-2452-7558\n\nLuis Morano https://orcid.org/0000-0002-0560-3260\n\nIvana Maida https://orcid.org/0000-0003-4895-7576\n==== Refs\nReferences\n\n1 Rizk C Miceli J Shiferaw B , et al. Implementing a comprehensive HCV clinic within an HIV clinic: a model of care for HCV Micro-elimination. Open Forum Infect Dis. 2019;6 (10 ):ofz361.\n2 Sacks-Davis R Doyle JS Rauch A , et al. Linkage and retention in HCV care for HIV-infected populations: early data from the DAA era. J Int AIDS Soc. 2018;21 Suppl 2 (suppl suppl 2 ):e25051.29633559\n3 Hirode G Saab S Wong RJ . Trends in the Burden of Chronic Liver Disease Among Hospitalized US Adults. JAMA Netw Open. 2020;3 (4 ):e201997.32239220\n4 U.S. Department of Health and Human Services. Integrating HIV care, treatment & prevention services into primary care – A toolkit for health centers. July 2018. Accessed on 23 December 2020. https://bphc.hrsa.gov/sites/default/files/bphc/qualityimprovement/pdf/p4c-toolkit-2018.pdf\n5 Cachay ER Hill L Ballard C Colwell B , et al. Increasing hepatitis C treatment uptake among HIV-infected patients using an HIV primary care model. AIDS Res Ther. 2013;10 (1 ):9. doi:10.1186/1742-6405-10-9.23537147\n6 Cachay ER Mena A Morano L , et al. Predictors of hepatitis C Treatment failure after using direct-acting antivirals in people living with human immunodeficiency virus. Open Forum Infect Dis. 2019;6 (3 ):ofz070.30949524\n7 Grottenthaler JM Werner CR Steurer M , et al. Successful direct-acting antiviral (DAA) treatment of HCV/HIV-coinfected patients before and after liver transplantation. PLoS One. 2018;13 (6 ):e0197544.29874250\n8 Reddy K Patrick C Liaquat H , et al. Differences in referral access to care between gastrointestinal subspecialty patients: barriers and opportunities. Health Equity. 2018;2 (1 ):103–108.30283855\n9 Cachay ER Hill L Torriani F , et al. Predictors of missed hepatitis C intake appointments and failure to establish hepatitis C care among patients living with HIV. Open Forum Infect Dis. 2018;5 (7 ):ofy173.30090840\n10 Curry MP O’Leary JG Bzowej N , et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015;373 (27 ):2618–2628.26569658\n11 Ghany MG Morgan TR AASLD-IDSA Hepatitis C. Guidance panel. hepatitis C guidance 2019 update: American Association for the study of liver diseases-infectious diseases society of America recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology. 2020;71 (2 ):686–721.31816111\n12 Available at: FDA warns about rare occurrence of serious liver injury with use of hepatitis C medicines Mavyret, Zepatier, and Vosevi in some patients with advanced liver disease | FDA. Accessed on 19 December 2020.\n13 Barocas JA Beiser M Leon C , et al. A national strategy to combat HCV infection requires approaches to reaching and treating HMH [homeless/marginally housed] adults. Conference on Retroviruses and Opportunistic Infections (CROI); Seattle, WA; February 13-16, 2017; Abstract 557.\n\n",
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"abstract": "Insect damage to, and sub-optimal harvesting practices of the Papaver somniferum poppy are associated with contamination of its seeds with opium alkaloids. Consumption of poppy seeds has been linked to opium-like overdose symptoms, such as reduced consciousness and respiratory depression. However, acute cardiotoxicity secondary to ingestion of contaminated poppy seeds has not been reported previously. We report a case of a 21-year-old man who presented with severe biventricular dysfunction and cardiogenic shock following consumption of homemade poppy seed tea. We highlight the importance of prompt recognition of the myocardial effects of opiates along with the more common respiratory and neurological effects. In this case, the acute cardiotoxicity was fully reversed with high-dose naloxone, milrinone and noradrenaline. In addition, we recommend offering high-level care due to the possibility that specialist cardiac services may be required. Ergo, early transfer to an appropriate centre is recommended.",
"affiliations": "Department of Anaesthesia and Intensive Care Medicine Wythenshawe Hospital Manchester University NHS Foundation Trust Manchester UK.;Department of Anaesthesia and Intensive Care Medicine Wythenshawe Hospital Manchester University NHS Foundation Trust Manchester UK.;Department of Anaesthesia Stepping Hill Hospital Stockport NHS Foundation Trust Stockport UK.",
"authors": "Tan|Y P A|YPA|;Alexander|P D G|PDG|;Knowles|S|S|",
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"title": "Acute cardiotoxicity following 'poppy seed tea' consumption.",
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{
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"reactionoutcome": "2"
}
],
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},
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},
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"medicinalproduct": "SERTRALINE"
}
],
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"reaction": [
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{
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],
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"literaturereference": "Tan YPA, Alexander PDG, Knowles S. Acute cardiotoxicity following ^^poppy seed tea^^ consumption. Anaesthesia Reports. 2021;9:1-4",
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"qualification": "1",
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},
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},
"serious": 1,
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"seriousnessother": 1,
"transmissiondate": "20220423"
}
] |
{
"abstract": "Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.",
"affiliations": "Duke University Medical Center, Rm. 047 Baker House, Trent Drive, DUMC 3624, Durham, NC, 27710, USA, vlaho001@mc.duke.edu.",
"authors": "Vlahovic|Gordana|G|;Karantza|Vassiliki|V|;Wang|Ding|D|;Cosgrove|David|D|;Rudersdorf|Nikita|N|;Yang|Jianning|J|;Xiong|Hao|H|;Busman|Todd|T|;Mabry|Mack|M|",
"chemical_list": "D000814:Aniline Compounds; D013449:Sulfonamides; D016190:Carboplatin; D017239:Paclitaxel; C528561:navitoclax",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-014-0116-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "32(5)",
"journal": "Investigational new drugs",
"keywords": null,
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000814:Aniline Compounds; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D017239:Paclitaxel; D013449:Sulfonamides; D016896:Treatment Outcome",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "976-84",
"pmc": null,
"pmid": "24894650",
"pubdate": "2014-10",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": "19097774;21206976;20182539;20609056;18451170;19228717;10655437;15057285;19003982;7165009;20190564;22496272;21094089;21914853;18767026;20593091;21282543;22184378;18437895;20099064;21934338;22302098",
"title": "A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors.",
"title_normalized": "a phase i safety and pharmacokinetic study of abt 263 in combination with carboplatin paclitaxel in the treatment of patients with solid tumors"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US01525",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
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"medicinalproduct": "CARBOPLATIN."
},
{
"actiondrug": "1",
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"activesubstancename": "PACLITAXEL"
},
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"medicinalproduct": "PACLITAXEL."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NAVITOCLAX"
},
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"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "150 MG, FOR 3 OR 5 CONSECUTIVE DAYS IN A",
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"drugindication": "NEOPLASM",
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"medicinalproduct": "NAVITOCLAX"
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Pulmonary embolism",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GORDANA VLAHOVIC, VASSILIKI KARANTZA, DING WANG, DAVID COSGROVE, NIKITA RUDERSDORF, JIANNING YANG, HAO XIONG, TODD BUSMAN, MACK MABRY. A PHASE I SAFETY AND PHARMACOKINETIC STUDY OF ABT-263 IN COMBINATION WITH CARBOPLATIN/PACLITAXEL IN THE TREATMENT OF PATIENTS WITH SOLID TUMORS. INVEST NEW DRUGS. 2014;32:976-984",
"literaturereference_normalized": "a phase i safety and pharmacokinetic study of abt 263 in combination with carboplatin paclitaxel in the treatment of patients with solid tumors",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20141013",
"receivedate": "20141013",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10513200,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150528"
}
] |
{
"abstract": "BACKGROUND\nHidradenitis suppurativa (HS) is a chronic, disabling skin disease. The estimated prevalence is 1-4 % worldwide. HS is a systemic inflammatory disease and can cause AA amyloidosis. The first report of HS-related amyloidosis dates back to 1966; since then, sporadic cases have been reported. Our work will be the first case series on HS and AA amyloidosis.\n\n\nMETHODS\nWe report eight HS cases complicated with amyloidosis. Six patients were male. The median age was 44 years, and the median disease duration before the amyloidosis diagnosis was 15.5 years. In a mean follow-up of 18 ± 6 months, we achieved favorable renal responses in four of the eight cases (50 %). All cases had a dermatologic response, with four complete and four partial remissions.\n\n\nCONCLUSIONS\nHS is a systemic inflammatory disorder that may cause AA amyloidosis. Aggressive treatment of HS may halt the progression of amyloidosis. HIPPOKRATIA 2020, 24(1): 33-37.",
"affiliations": "Department of Nephrology, Yıldırım Beyazıt University, Yenimahalle Training and Research Hospital, Ankara, Turkey.;Department of Internal Medicine, , Faculty of Medicine, Gazi University, Ankara, Turkey.;Department of Dermatology, Faculty of Medicine, Gazi University, Ankara, Turkey.;Department of Nephrology, Numune Training and Research Hospital, Ankara, Turkey.;Department of Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey.",
"authors": "Helvacı|Ö|Ö|;Güz|G|G|;Adışen|E|E|;Cevher|S K|SK|;Güz|G|G|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1108-4189",
"issue": "24(1)",
"journal": "Hippokratia",
"keywords": "AA amyloidosis; Hidradenitis suppurativa; amyloidosis; end-stage renal disease",
"medline_ta": "Hippokratia",
"mesh_terms": null,
"nlm_unique_id": "101296613",
"other_id": null,
"pages": "33-37",
"pmc": null,
"pmid": "33364737",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "29447652;27238193;25387054;27862787;29355905;23247938;5953172;31166401;31989656;23371008;30488432;29578360;26831295;31049382;29094346;28285782;29660301;26409501;19406505;19293006",
"title": "Hidradenitis Suppurativa: a lesser-known cause of AA amyloidosis.",
"title_normalized": "hidradenitis suppurativa a lesser known cause of aa amyloidosis"
} | [
{
"companynumb": "TR-CELLTRION INC.-2020TR034335",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
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"drugdosageform": "POWDER FOR SOLUTION FOR INFUSION",
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"drugindication": "HIDRADENITIS",
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"medicinalproduct": "INFLIXIMAB (UNKNOWN)"
},
{
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"activesubstancename": "ANAKINRA"
},
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"medicinalproduct": "ANAKINRA"
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Drug hypersensitivity",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "End stage renal disease",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HELVACI O, GUZ G, ADISEN E, CEVHER SK, GUZ G.. HIDRADENITIS SUPPURATIVA: A LESSER-KNOWN CAUSE OF AA AMYLOIDOSIS. HIPPOKRATIA. 2020?24 (1):33-37",
"literaturereference_normalized": "hidradenitis suppurativa a lesser known cause of aa amyloidosis",
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},
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"receiptdate": "20201223",
"receivedate": "20201223",
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},
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"safetyreportversion": 1,
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210114"
},
{
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"drugdosageform": "POWDER FOR SOLUTION FOR INFUSION",
"drugdosagetext": "UNK",
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"medicinalproduct": "INFLIXIMAB (UNKNOWN)"
},
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},
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"drugdosageform": "POWDER FOR SOLUTION FOR INFUSION",
"drugdosagetext": "UNK",
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"drugindication": "HIDRADENITIS",
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"medicinalproduct": "INFLIXIMAB (UNKNOWN)"
}
],
"patientagegroup": null,
"patientonsetage": null,
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"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Bladder cancer",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug effective for unapproved indication",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HELVACI O, GUZ G, ADISEN E, CEVHER SK, GUZ G. HIDRADENITIS SUPPURATIVA: A LESSER-KNOWN CAUSE OF AA AMYLOIDOSIS. HIPPOKRATIA. 2020?24 (1):33-37",
"literaturereference_normalized": "hidradenitis suppurativa a lesser known cause of aa amyloidosis",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20201229",
"receivedate": "20201223",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
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"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210114"
}
] |
{
"abstract": "OBJECTIVE\nTo investigate possible associations between remifentanil and the appearance of sinusoidal heart rate patterns in fetuses, and neonatal outcomes.\n\n\nMETHODS\nThe present retrospective cohort study included data from patients at over 37 weeks of singleton or multiple pregnancies attending Zuyderland Medical Center, Sittard, the Netherlands, in labor between June 1, and August 31, 2015. Patient data were stratified by whether remifentanil was administered during delivery (remifentanil group) or not (control group), and fetal heart rate tracings were reviewed to identify sinusoidal heart rate patterns. The neonatal outcomes compared were 5-minute Apgar scores and umbilical artery pH.\n\n\nRESULTS\nThere were 119 patients included in the study; 60 in the remifentanil group and 59 in the control group. Tracings from 20 (33%) patients in the remifentanil group exhibited a sinusoidal heart rate pattern after remifentanil administration, compared with 5 (8%) patients in the control group (P=0.001). The median time before the onset of sinusoidal patterns after remifentanil administration was 12 minutes. No adverse neonatal outcomes were recorded in either group.\n\n\nCONCLUSIONS\nRemifentanil use during labor was associated with the occurrence of sinusoidal heart rate patterns in the fetus; this was not associated with adverse neonatal outcomes.",
"affiliations": "Department of Obstetrics and Gynecology, Zuyderland Medical Center, Geleen, Netherlands.;Department of Obstetrics and Gynecology, Zuyderland Medical Center, Geleen, Netherlands.;Department of Obstetrics and Gynecology, University Medical Center Utrecht, Utrecht, Netherlands.;Department of Obstetrics and Gynecology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands.",
"authors": "Boterenbrood|Danne|D|;Wassen|Martine M|MM|;Visser|Gerard H A|GHA|;Nijhuis|Jan G|JG|",
"chemical_list": "D006993:Hypnotics and Sedatives; D010880:Piperidines; D000077208:Remifentanil",
"country": "United States",
"delete": false,
"doi": "10.1002/ijgo.12344",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7292",
"issue": "140(1)",
"journal": "International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics",
"keywords": "Neonatal outcome; Remifentanil; Sinusoidal heart rate pattern",
"medline_ta": "Int J Gynaecol Obstet",
"mesh_terms": "D000328:Adult; D005260:Female; D006340:Heart Rate, Fetal; D006801:Humans; D006993:Hypnotics and Sedatives; D007231:Infant, Newborn; D007743:Labor, Obstetric; D009426:Netherlands; D010880:Piperidines; D011247:Pregnancy; D000077208:Remifentanil; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "0210174",
"other_id": null,
"pages": "60-64",
"pmc": null,
"pmid": "28994111",
"pubdate": "2018-01",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Retrospective study of the effect of remifentanil use during labor on fetal heart rate patterns.",
"title_normalized": "retrospective study of the effect of remifentanil use during labor on fetal heart rate patterns"
} | [
{
"companynumb": "NL-MYLANLABS-2018M1001597",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "REMIFENTANIL"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": "020630",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "INJECTION",
"drugdosagetext": "28MICROG OF REMIFENTANIL (SOLUTION 40 MICROG/ML) BY A PATIENT-CONTROLLED DEVICE",
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"drugindication": "LABOUR PAIN",
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"medicinalproduct": "REMIFENTANIL"
}
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"patientonsetage": null,
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"reaction": [
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Sinusoidal foetal heart rate pattern",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BOTERENBROOD D, WASSEN MM, VISSER GHA, NIJHUIS JG. RETROSPECTIVE STUDY OF THE EFFECT OF REMIFENTANIL USE DURING LABOR ON FETAL HEART RATE PATTERNS. INT-J-GYNAECOL-OBSTET 2018?140(1):60-64.",
"literaturereference_normalized": "retrospective study of the effect of remifentanil use during labor on fetal heart rate patterns",
"qualification": "3",
"reportercountry": "NL"
},
"primarysourcecountry": "NL",
"receiptdate": "20180115",
"receivedate": "20180115",
"receiver": {
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
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] |
{
"abstract": "Older people are increasingly being referred for consideration for pancreas transplantation (PT). We investigated the outcomes after PT in our older recipient cohort. A prospectively maintained database was interrogated. The cohort was analysed for associations between outcome and older recipient age. A total of 444 transplants were performed in patients aged 23-54 years and 83 transplants in patients aged 55-67 years. There was no difference in death-censored pancreas or kidney graft survival between the groups. Patient death was associated with older recipient age (HR 1.63 per 10-year increase). In multivariate Cox regression, risk of mortality was also associated with post-transplant myocardial infarction (HR 7.25, P = 0.006), pancreas failure (HR 1.91, P = 0.003) and kidney failure (HR 3.55, P < 0.001). About 40% of recipients who died in the first year post-transplant suffered early graft loss. Those alive at a year post-transplant had inferior survival if they had lost their kidney graft (P < 0.001). Mortality is higher in older patients and is strongly associated with pancreas and kidney graft failure. This suggests that pancreas transplantation is feasible in older recipients, and careful selection of donor organs is important to optimize survival.",
"affiliations": "Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.;Oxford Transplant Centre, Oxford, UK.",
"authors": "Mittal|Shruti|S|0000-0003-2390-5366;Smilevska|Rumyana|R|;Franklin|Rachel|R|;Hammer|Clare|C|;Knight|Simon|S|0000-0003-4837-9446;Vrakas|Georgios|G|;Reddy|Srikanth|S|;Gilbert|James|J|;Quiroga|Isabel|I|;Sharples|Edward|E|;Ploeg|Rutger|R|;Friend|Peter|P|;Sinha|Sanjay|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/tri.13575",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "33(5)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "outcome; pancreas clinical; surgery",
"medline_ta": "Transpl Int",
"mesh_terms": "D000368:Aged; D006085:Graft Survival; D006801:Humans; D016030:Kidney Transplantation; D010179:Pancreas; D016035:Pancreas Transplantation; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "529-535",
"pmc": null,
"pmid": "31943392",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An analysis of the association between older recipient age and outcomes after whole-organ pancreas transplantation - a single-centre, retrospective study.",
"title_normalized": "an analysis of the association between older recipient age and outcomes after whole organ pancreas transplantation a single centre retrospective study"
} | [
{
"companynumb": "NVSC2020GB036158",
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{
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"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "65379",
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"drugcharacterization": "1",
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"drugdosagetext": "750 MG BD",
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
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"drugadministrationroute": "065",
"drugauthorizationnumb": "65461",
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"drugcharacterization": "1",
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"drugdosagetext": "0.5 MG/KG BD",
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"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
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"medicinalproduct": "TACROLIMUS."
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{
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"drugdosagetext": "UNK (8 AND 10 NG/ML)",
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"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": "5",
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"reaction": [
{
"reactionmeddrapt": "Transplant failure",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MITTAL S, SMILEVSKA R, FRANKLIN R, HAMMER C, KNIGHT S, VRAKAS G, ET AL.. AN ANALYSIS OF THE ASSOCIATION BETWEEN OLDER RECIPIENT AGE AND OUTCOMES AFTER WHOLE-ORGAN PANCREAS TRANSPLANTATION- A SINGLE-CENTRE, RETROSPECTIVE STUDY. TRANSPLANT INTERNATIONAL. 2020?1-7",
"literaturereference_normalized": "an analysis of the association between older recipient age and outcomes after whole organ pancreas transplantation a single centre retrospective study",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20200211",
"receivedate": "20200211",
"receiver": {
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},
"reporttype": "1",
"safetyreportid": 17402209,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200409"
}
] |
{
"abstract": "The mortality of hepatobiliary cancer still stays high around the world, with disappointing treatment status at advanced stage. Genomic analysis has identified the global spectrum of alterations in liver cancer, but the most common mutations are not actionable, meanwhile lacking potent molecular-targeted drugs for specific oncogenic drivers. Multiple-targeted drugs which mainly inhibited tumors' angiogenesis, such as sorafenib and lenvatinib, improved survival time for patients with advanced hepatocellular carcinoma, although the median overall survival remains 1-1.5 years. It is still ambiguous for the precise biomarkers of multiple-targeted drugs utilized in hepatobiliary cancer. Herein, we reported two observational patients who were sequentially treated by various targeted drugs and obtained lasting overall survival time. Both the two patients weekly switched targeted drugs according to the changes of tumor markers. These two cases would get us thinking: what is the underlying mechanism of molecular-targeted drugs in hepatobiliary tumors; and whether a \"drugs screening model\" during real-time treatment could be achieved through the assistance from sensitive and specific tumor markers.",
"affiliations": "Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, People's Republic of China.;Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, People's Republic of China.;Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, People's Republic of China.;Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, People's Republic of China.",
"authors": "Lin|Jianzhen|J|;Yang|Xiaobo|X|;Xie|Yuan|Y|;Zhao|Haitao|H|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S223568",
"fulltext": "\n==== Front\nOnco Targets TherOnco Targets TherOTTottOncoTargets and therapy1178-6930Dove 22356810.2147/OTT.S223568Case SeriesUnleashing The Potential Of Multiple-Targeted Therapies In Hepatobiliary Cancers: Two Cases, Cocktail Therapy With Nine Molecular Targeted Agents And Long-Lasting Survival Lin et alLin et alLin Jianzhen 1Yang Xiaobo 1Xie Yuan 1Zhao Haitao 11 Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, People’s Republic of ChinaCorrespondence: Haitao Zhao Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), #1 Shuaifuyuan, Wangfujing, Beijing100730, People’s Republic of ChinaTel +86-10-69156042Fax +86-10-69156043 Email zhaoht@pumch.cn19 11 2019 2019 12 9941 9945 17 7 2019 02 11 2019 © 2019 Lin et al.2019Lin et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nThe mortality of hepatobiliary cancer still stays high around the world, with disappointing treatment status at advanced stage. Genomic analysis has identified the global spectrum of alterations in liver cancer, but the most common mutations are not actionable, meanwhile lacking potent molecular-targeted drugs for specific oncogenic drivers. Multiple-targeted drugs which mainly inhibited tumors’ angiogenesis, such as sorafenib and lenvatinib, improved survival time for patients with advanced hepatocellular carcinoma, although the median overall survival remains 1–1.5 years. It is still ambiguous for the precise biomarkers of multiple-targeted drugs utilized in hepatobiliary cancer. Herein, we reported two observational patients who were sequentially treated by various targeted drugs and obtained lasting overall survival time. Both the two patients weekly switched targeted drugs according to the changes of tumor markers. These two cases would get us thinking: what is the underlying mechanism of molecular-targeted drugs in hepatobiliary tumors; and whether a “drugs screening model” during real-time treatment could be achieved through the assistance from sensitive and specific tumor markers.\n\nKeywords\nhepatobiliary cancermolecular targeted drugprecision medicineThis work is supported by the International Science and Technology Cooperation Projects (2016YFE0107100 and 2015DFA30650), the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003), the Beijing Natural Science Foundation (L172055), the National Ten-thousand Talent Program, Beijing Science and Technology Cooperation Special Award Subsidy Project and CAMS Initiative for Innovative Medicine (CAMS-2018-I2M-3-001).\n==== Body\nEffective and proven systematic adjuvant chemotherapy regimens for advanced hepatobiliary malignancies remain of limited clinical utility and typically fail to show effective and enduring responses. To this end, advances in cancer genomics and targeted use of molecular-directed agents have brought about new therapeutic options for patients with hepatobiliary tumors.1,2 Previous studies investigating genomic characteristics of cholangiocarcinoma have revealed that actionable alterations mainly included IDH1/2, FGFR fusion and sporadic pathogenic mutations in BRCA1/2 and mismatch repair genes.2 Thus, investigation of numerous pathway-targeted or oncogenic signaling-targeted therapies holds promise for patients with hepatobiliary tumors. We have launched a clinical trial termed “Precise Treatments in Hepatobiliary Cancers (PTHBC, NCT02715089),” in March 2016. Our trial was based on genetic analyses and precise diagnosis of tumors to explore precise treatments in hepatobiliary cancer. Important goals were to evaluate drug safety, progression-free clinical course and finally overall survival.\n\nHere, we retrospectively reported and discussed two illustrative patients, who were diagnosed and observed during this study time course. Each of these two end-stage patients received multiple targeted therapeutic agents (up to nine different drugs, termed “targeted cocktail therapy”).\n\nCase 1\nA 73-year-old male patient was diagnosed with advanced cholangiocarcinoma with extensive and multi lesions in the liver (greatest diameter: 10.7 cm) without liver cirrhosis. He has a history of hepatitis type B infection for 21 years but is negative for schistosomiasis infection. Biopsies confirmed moderately differentiated cholangiocarcinoma positive for CD34 (1+), CK7 (3+) and CK19 (3K). The patient underwent percutaneous transhepatic cholangial drainage for relief of obstructive jaundice. In the absence of effective anti-tumor therapy, however, the tumor progressed after 2 months of initial diagnosis. The cholangiocarcinoma tissue biopsies were sent to proceed molecular expression detection.\n\nMolecular Pathology Results\nImmunohistochemistry in situ indicated high expression of EGFR (2+), VEGFR (3+), C-erbB2 (3+), with 30% positive for Ki-67.\n\nDNA extraction was inadequate for oncogene sequencing so the tumor genetic profiling was uncertain.\n\nTreatment And Clinical Course\nThe hospital multidisciplinary tumor board recommended standard systematic chemotherapy (gemcitabine plus oxaliplatin). The patient refused chemotherapy and then administered the mixed cocktail targeted therapy by himself, with nine molecular-specific agents (Figure 1). The exact therapeutic process and sequential tumor markers (TM, CA19-9 and CA125) are as summarized in Figure 1 and reviewed as follow:Figure 1 Overview of the therapeutic regimens and tumor marker fluctuations in patient case 1, who used up to nine different targeted drugs over a 2 years period. The arrows under the line chart indicate the therapeutic regimen for each time (dash arrow means period of targeted therapy pause). The central curves indicate fluctuations of tumor markers.\n\n\n\nThe patient chose afatinib (40 mg once daily) as the first-line treatment for the high expression of EGFR and C-erbB2. The 39-day treatment achieved stability in clinical disease (radiological assessment referred to RECIST v1.13) but as TM remained elevated, he was then treated with cabozantinib (40 mg twice daily), a low molecular inhibitor of the receptor tyrosine kinases (RTK; e.g. c-Met and VEGFR2) given high expression of the latter receptor in the tumor.\n\nAfter the 10-day treatment, the TM did not sharply decline so he turned to dacomitinib (targeting both EGFR and C-erbB2). This course of dacomitinib (30 mg once daily for 13 days) did not lower TM. However, radiological imaging indicated decreases in tumor size. At that time, therapy was changed to sunitinib (25 mg once daily), a small molecule RTK inhibitor, for 12 days, with dramatical declines in TM. Patient then restarted dacomitinib for 12 days but the CA125 then increased rapidly.\n\nHe then formed anti-VEGFR modalities with cabozantinib and/or sunitinib to control tumor progression. The patient used cabozantinib or sunitinib alternatively every fortnight, interspersing this regimen with anti-EGFR targeted therapy, with the use of osimertinib (80 mg once daily) or erlotinib (100 mg once daily), which was then monitored by TM. Intriguingly, the tumor lesions were stable without evidence for distant metastasis for 17 months. Overall, the adverse events (AEs) induced by the molecular-targeted drugs were tolerable, and no severe AEs were reported by the patient, possibly due to the low dosage and short enduring time of each drug. However, after long-term medication and recurrence of obstructive jaundice, he suspended targeted treatment for 3 months and turned to supportive care.\n\nImaging assessment confirmed progressive disease after 3-month time-out from targeted anti-tumor therapy. He restarted alternative targeted treatment with lenvatinib and cabozantinib, but the cancer still progressed. Finally, he died of cancer progression and survived for 31 months since the first time he received targeted therapy.\n\nCase 2\nA 57-year-old male patient underwent right hepatectomy for multi-focal liver malignancy (main lesion was 2.3 cm). He had had chronic hepatitis virus B infection for 20 years and liver cirrhosis for 10 years. The pathology revealed moderately differentiated hepato-cholangiocarcinoma. He received TACE as postoperative adjuvant therapy on one occasion. At 3 months after surgery, tumor recurred and PET-CT scan indicated that intrahepatic tumors invaded the hilar and right hepatic lobe. There was main portal vein invasion, as well as multiple intra-abdominal metastases. The cancer progressed after adjuvant radiotherapy and he required ERCP and stent placement. His tumor tissue was sent to tumor profiling laboratory.\n\nMolecular Pathology Results\nTumor cells were estimated to constitute around 80% of the total cells in a sample from the previous surgical resection. Immunohistochemistry in situ indicated no expression of PD-1, PD-L1 and VEGFR. Mild positive expression of EGFR (1+), C-erbB2 (1+, 30%) was noted.\n\nCancer genomic sequencing revealed pathogenic somatic mutations in ATM (c.A1561T; p.R521*) and JAK3 (c.C3239G; p.P1080R).\n\nTreatment And Clinical Course\nThe PUMCH multidisciplinary tumor board recommended the patient undergo treatment with standard first-line chemotherapy based on gemcitabine for cholangiocarcinoma, alternatively to receive olaparib based on the presence of a pathogenic serine-threonine kinase ATM mutation. He refused the standard form of chemotherapy.\n\nHe first received afatinib, because of positive expression of EGFR and C-erbB2 in tumor. One-month afatinib (40 mg once daily) decreased CA19-9 (from 121 to 26.1). Because of oral mucosa ulcerations, he changed to another 10-day cabozantinib (80 mg twice daily), with CA19-9 falling from 26.1 to 19.\n\nHowever, imaging assessment indicated progressive disease after 1.5 months of targeted therapy. He then employed olaparib (400 mg twice daily) treatment. One-month olaparib achieved stable disease (SD) in primary lesion, but a new lesion appeared in right adrenal gland and the CA19-9 became elevated to 42.1. Then, he chose to be alternatively treated by cabozantinib (80 mg twice daily) and axitinib (10 mg twice daily) every month. The 3-month post-therapy assessment suggested overall SD with shrinkage of lesions (Figure 2A and B), while at 6.5-month post-therapy, our evaluation confirmed cancer progression with emerging metastases and increase in size of the primary lesions. He was then changed to lenvatinib (12 mg once daily) as salvage anti-cancer treatment, but the one-month single targeted therapy was ineffective. Ultimately, he received immunotherapy with PD-1 inhibitor (pembrolizumab, 200 mg per 3 weeks) for 3 months, and there was no objective evidence of response. He died from cancer cachexia and uncontrolled biliary infection, albeit he survived for 20 months on targeted therapy.Figure 2 Radiological evidence for the shrank target lesions from the patient in case 2, who received alternative cabozantinib and axitinib for 3 months ((A) prior the treatment; (B) post treatment).\n\n\n\nRevelation\nThe characteristics of precision medicine provide MTDs with the advantages of better tolerability with less adverse events. However, precision may often also mean narrow range of efficacy. Cancers, particularly hepatobiliary tumors, possess complicated transduction signaling pathways, exhibit global complementary networks in oncogenic process and show much heterogeneity during clonal evolution.4 Thus, multiple targeted approaches could likely exhibit better therapeutic efficacy in hepatobiliary tumors.\n\nHere, we presented illustrative end-stage patients treated with targeted cocktail therapy, who appeared to have obtained prolonged survival time with good tolerability. We communicate these results to show how drug selection may proceed in the relative absence of clear guidelines and lack of direction as to specific molecular targets in hepatobiliary tumors.\n\nOur questions and perspectives arising from these 2 cases are as follows:\nIs it reasonable to independently guide targeted therapy based merely on cancer-related mutations? The unpredictable outcomes raise questions as to the definition of precise guiding targets for targeted therapy.5\n\nIs imperative to monitor dynamically during targeted therapy by utilizing sensitive and non-invasive tumor biomarkers, which could timely reflect cancer response with ongoing treatment? Traditional tumor markers might be highlighted to direct clinical management. Sensitive tumor markers could also narrow the therapeutic window period between initiation and efficacy evaluation.\n\nMight future standard clinical practice require rapid switch over of next-line treatment options, when progressive disease occurs? Clinical trials have shown that regorafenib can still bring survival benefits for progressive disease, even after sorafenib failure. This is observed despite two of these MTDs target VEGFR, along with other tyrosine kinase receptors. It remains unclear as to whether and how to alternate different and related MTDs during treatment for stable and progressive disease.\n\nIs this therapeutic mode suitable for clinical practice in the real-world? From the perspective of cost-benefit, most patients do not have the economic strength to undertake long-term treatment with multiple targeted drugs.\n\n\n\nConclusion\nOverall, our comprehension of the relative contributions of factors including actual validated targets and defining the essential mechanisms of MTDs responses remain major challenges in precision oncology. We still have a long journey to achieve biomarker-guided targeted therapy in hepatobiliary tumors.\n\nAcknowledgments\nThe authors thank the patients who volunteered to participate in this study and the staff members at the study sites who cared for these patients; the members of the data and safety monitoring committee; representatives of the sponsors who were involved in the data collection and analyses; and technology support. The authors sincerely thank Dr. Simon C. Robson for his help in revising the manuscript.\n\nAbbreviations\nATM, ataxia telangiectasia; CA, cancer antigen; EGFR, epidermal growth factor receptor; ERCP, endoscopic retrograde cholangio-pancreatography; H-ChC, hepato-cholangiocellular carcinoma; JAK, janus kinases; MTDs, molecular targeted drugs; RTK, receptor tyrosine kinase; TACE, transcatheter arterial chemoembolization; TM, tumor markers; SD, stable disease; VEGFR, vascular endothelial growth factor receptor.\n\nEthics Approval And Consent To Participate\nAll patients participated in this observational trial provided written informed consent for medical treatment and collection of tumor biopsies and for comprehensive molecular profiling of tumor and germline samples. All patients were enrolled in institutional protocols approved by the Ethics Review Committee of Peking Union Medical College Hospital (Beijing, China) (reference no. PM-1503).\n\nData Sharing Statement\nThe datasets used and/or analyzed during the current study were available from the corresponding authors on reasonable request.\n\nConsent For Publication\nThe consent forms were signed by every participant and will be provided upon request.\n\nAuthor Contributions\nAll authors contributed to data analysis, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n1. Llovet \nJM , Montal \nR , Sia \nD , Finn \nRS . Molecular therapies and precision medicine for hepatocellular carcinoma . Nat Rev Clin Oncol . 2018 . doi:10.1038/s41571-018-0073-4 \n2. Valle \nJW , Lamarca \nA , Goyal \nL , Barriuso \nJ , Zhu \nAX . New horizons for precision medicine in biliary tract cancers . Cancer Discov . 2017 ;7 :943 –962 . doi:10.1158/2159-8290.CD-17-0245 28818953 \n3. Schwartz \nLH , Seymour \nL , Litiere \nS , et al. RECIST 1.1 – standardisation and disease-specific adaptations: perspectives from the RECIST working group . Eur J Cancer . 2016 ;62 :138 –145 . doi:10.1016/j.ejca.2016.03.082 27237360 \n4. McGranahan \nN , Swanton \nC . Clonal heterogeneity and tumor evolution: past, present, and the future . Cell . 2017 ;168 :613 –628 . doi:10.1016/j.cell.2017.01.018 28187284 \n5. Dagogo-Jack \nI , Shaw \nAT . Tumour heterogeneity and resistance to cancer therapies . Nat Rev Clin Oncol . 2018 ;15 :81 –94 . doi:10.1038/nrclinonc.2017.166 29115304\n\n",
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"title": "Unleashing The Potential Of Multiple-Targeted Therapies In Hepatobiliary Cancers: Two Cases, Cocktail Therapy With Nine Molecular Targeted Agents And Long-Lasting Survival.",
"title_normalized": "unleashing the potential of multiple targeted therapies in hepatobiliary cancers two cases cocktail therapy with nine molecular targeted agents and long lasting survival"
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{
"abstract": "BACKGROUND\nHeart failure during systemic lupus erythematosus has various causes.\n\n\nMETHODS\nA 29-year-old female presented with a systemic lupus flare and a nephrotic syndrome, followed by cardiogenic shock requiring extra-corporeal membranous oxygenation. Ventricular dysfunction was related to massive myocardial infarction due to an anterior interventricular artery thrombosis and an underlying atheroma. The young age and the absence of chest pain were not suggestive of coronary artery disease initially. Coronary thrombosis was probably favored by the nephrotic syndrome, in which the arterial thrombotic risk is increased.\n\n\nCONCLUSIONS\nCoronary artery disease should be systematically evoked in the presence of ventricular dysfunction in patients with systemic lupus, including when they are young and in the absence of chest pain. Nephrotic syndrome should be identified as a risk factor for arterial thrombosis.",
"affiliations": "Service de médecine interne 2, Centre national de référence maladies systémiques rares, lupus et syndrome des anticorps antiphospholipides, hôpital de la Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75013 Paris, France; Service de réanimation médicale, hôpital de la Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 75013 Paris, France.;Service de réanimation médicale, hôpital de la Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 75013 Paris, France.;Service d'urgences néphrologiques et transplantation rénale, hôpital Tenon, Sorbonne université, Assistance publique-Hôpitaux de Paris, 75020 Paris, France.;Service d'anatomo-pathologie, hôpital de la Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 75013 Paris, France.;Service de gynécologie-obstétrique, hôpital de la Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 75013 Paris, France.;Service de médecine interne 2, Centre national de référence maladies systémiques rares, lupus et syndrome des anticorps antiphospholipides, hôpital de la Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75013 Paris, France.;Service de médecine interne 2, Centre national de référence maladies systémiques rares, lupus et syndrome des anticorps antiphospholipides, hôpital de la Pitié-Salpêtrière, Sorbonne université, Assistance publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75013 Paris, France. Electronic address: fleur.cohen@aphp.fr.",
"authors": "Moyon|Q|Q|;Schmidt|M|M|;Hertig|A|A|;Fouret|P|P|;Vauthier-Brouzes|D|D|;Amoura|Z|Z|;Cohen Aubart|F|F|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.revmed.2019.03.001",
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"issue": "40(6)",
"journal": "La Revue de medecine interne",
"keywords": "Acute coronary syndrome; Atherosclerosis; Athérosclérose; Lupus nephritis; Lupus systémique; Nephrotic syndrome; Néphropathie lupique; Syndrome coronarien aigu; Syndrome néphrotique; Systemic lupus erythematosus",
"medline_ta": "Rev Med Interne",
"mesh_terms": "D000328:Adult; D003324:Coronary Artery Disease; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D009404:Nephrotic Syndrome",
"nlm_unique_id": "8101383",
"other_id": null,
"pages": "395-399",
"pmc": null,
"pmid": "30981562",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Coronary involvement and nephrotic syndrome in systemic lupus: A case report.",
"title_normalized": "coronary involvement and nephrotic syndrome in systemic lupus a case report"
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{
"abstract": "OBJECTIVE\nDespite widespread use of vasopressin for the treatment of septic shock, few cases of diabetes insipidus (DI) following its discontinuation have been reported.\n\n\nMETHODS\nA 54-year-old man presented with pneumonia progressing to septic shock, requiring norepinephrine and vasopressin for refractory hypotension. After clinical improvement, the patient on 3 separate occasions developed polyuria and severe hypernatremia upon discontinuation of vasopressin, with prompt recovery upon its resumption.\n\n\nCONCLUSIONS\nOccurrence of DI upon discontinuation of vasopressin infusion appears to be rare, but incidence may be underestimated due to a paucity of published reports. Actual incidence and underlying mechanism of this phenomenon remain to be elucidated.",
"affiliations": "Division of Critical Care Medicine, Montefiore Medical Center, Bronx, NY, USA.;Department of Pharmacy, Montefiore Medical Center, Bronx, NY, USA.;Division of Critical Care Medicine, Montefiore Medical Center, Bronx, NY, USA.",
"authors": "Rana|H|H|;Ferguson|N|N|;Dicpinigaitis|P V|PV|",
"chemical_list": "D014662:Vasoconstrictor Agents; D014667:Vasopressins",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12627",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(2)",
"journal": "Journal of clinical pharmacy and therapeutics",
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"medline_ta": "J Clin Pharm Ther",
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"abstract": "Sidestream dark field (SDF) imaging allows direct visualization of microvascular architecture and function. We examine the role of an SDF imaging device in visualizing the sub-lingual microvasculature as a surrogate for splanchnic microperfusion. We demonstrate good correlation between current monitoring techniques and the SDF imaging device in a rare case of vancomycin-resistant enterococcal (VRE) sepsis along with heparin-induced thrombocytopenia (HIT). To the best of our knowledge, VRE endocarditis with concurrent HIT has not been described in literature. The role of SDF imaging may predict the earlier need for escalation of care, improving morbidity and mortality.",
"affiliations": "Cardiothoracic Unit, Heart and Lung Centre, Wolverhampton, WV10 0QP, United Kingdom.",
"authors": "Bechar|Janak|J|;Polesello|Luigi|L|;Lombrano|Maria|M|;Martinelli|Giampaolo|G|;Luckraz|Heyman|H|",
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"fulltext": "\n==== Front\nAnn Card AnaesthAnn Card AnaesthACAAnnals of Cardiac Anaesthesia0971-97840974-5181Medknow Publications & Media Pvt Ltd India 26750702ACA-19-19710.4103/0971-9784.173048Case ReportThe role of side stream dark field microvasculature imaging in a rare case of vancomycin-resistant enterococcal endocarditis complicated by heparin-induced thrombocytopenia Bechar Janak Polesello Luigi Lombrano Maria Martinelli Giampaolo Luckraz Heyman Cardiothoracic Unit, Heart and Lung Centre, Wolverhampton, WV10 0QP, United KingdomAddress for correspondence: Dr. Janak Bechar, New Queen Elizabeth Hospital, Edgbaston, B15 2WB, United Kingdom. E-mail: janakashwin.bechar@nhs.netJan-Mar 2016 19 1 197 200 22 9 2014 02 11 2015 Copyright: © 2016 Annals of Cardiac Anaesthesia2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Sidestream dark field (SDF) imaging allows direct visualization of microvascular architecture and function. We examine the role of an SDF imaging device in visualizing the sub-lingual microvasculature as a surrogate for splanchnic microperfusion. We demonstrate good correlation between current monitoring techniques and the SDF imaging device in a rare case of vancomycin-resistant enterococcal (VRE) sepsis along with heparin-induced thrombocytopenia (HIT). To the best of our knowledge, VRE endocarditis with concurrent HIT has not been described in literature. The role of SDF imaging may predict the earlier need for escalation of care, improving morbidity and mortality.\n\nAortic valve replacementCoronary artery bypass graftEndocarditisHeparin induced thrombocytopeniaImagingOrthogonal polarisation spectral imagingSide steam dark field\n==== Body\nINTRODUCTION\nAssessment of hemodynamic status is often limited to global parameters and ignores the microvascular perfusion.[1] Sidestream dark field imaging (SDF) allows the direct visualization of the microcirculation.[2] The SDF device (handheld) uses a polarized green light (3 mm penetration), measuring scatter of hemoglobin containing red blood cells to visualize the microvasculature of human organs in real time.[3] Microvessels smaller than 20 μm are detected.\n\nThree video time points of 20 s duration were recorded to map the sub-lingual microvasculature. Using software AVA 3.0, vessel density can be interrogated and perfusion quality averaged over three video samples. Parameters of vessel density are: Total vascular density (TVD), perfused small vessel density (PVD) and the De Backer score which is derived from the SDF device videos to describe the vessel density more reliably.[14] The score is also a function of the flow through the microvasculature and the proportion of perfused vessels. The proportion of perfused small vessels (PPV), microvascular flow index (MFI), and flow heterogeneity index (FHI) describe the perfusion quality of microvasculature. The PPV is simply the percentage of vessels perfused as a function of the total number of vessels. The MFI describes the predominant type of flow in the microvasculature (0 = absent, 1 = intermittent, 2 = sluggish, 3 = normal). The FHI is calculated as the difference between the maximum and the minimum MFI of the different sub-lingual sites examined, divided by the average of all the MFI obtained. The methodology for all indices is detailed in De Backer et al.[1] and Koning et al.[5]\n\nRecent clinical studies have demonstrated that alterations in microcirculation are key in the development of sepsis,[367] needing monitoring and early intervention.[8] We report a rare case of a septic patient with heparin induced thrombocytopenia (HIT), assessing the microcirculation using SDF.\n\nCASE REPORT\nA 63-year-old man was admitted to his local general hospital after feeling unwell for a fortnight. A blood culture confirmed the presence of vancomycin resistant enterococcal (VRE). Transthoracic esophageal echocardiogram confirmed dehiscence of the aortic valve with a root abscess, mitral valve vegetations, patent foramen ovale (PFO), and an inferior vena cava Eustachian valve. On transfer to our institution, he was in liver and renal failure (bilirubin 54 mg/dL, alkaline phosphatase 222 IU/L and alanine aminotransferase 1211IU/L), the latter being managed with continuous veno-venous hemofiltration (CVVHF) with heparin as the anticoagulant. Initial blood tests revealed a platelet count of 179 × 103 per mm.[3] During hospitalization, he developed a significant drop in platelet count to 35 × 103 per mm3 on day 3 of CVVHF and HIT was confirmed by enzyme-linked immunosorbent assay serotonin release assay. Heparin was thus stopped, using Danaparoid as hemofiltration anticoagulation. While being investigated for HIT, platelet counts dropped to 16 × 103 per mm3 having been off heparin for over a week.\n\nThe patient previously underwent an aortic valve replacement for aortic stenosis, 4 months prior to this acute presentation. His regular medication was as follows: Aspirin, bisoprolol, perindopril and atorvastatin. On his acute presentation, the patient underwent redo-aortic valve replacement (size 23 Perimount Magna tissue valve), mitral valve repair (size 28 mm St. Jude Medical saddle ring), closure of the PFO (4/0 Proline), repair of the aortic root abscess and excision of the Eustachian valve (due to possible endocarditis). The patient made slow progress on the Cardiac Intensive Care Unit (CICU) due to his ventilator dependence needing tracheostomy and his renal failure needing renal replacement therapy. In total, the patient was on cardiovascular support for 22 days (maximal of milrinone 10 ml/h, noradrenaline 20 ml/h and vasopressin 2 IU/h). After appropriate weaning, he was discharged after 6 months with further rehabilitation.\n\nDuring his CICU stay, SDF device was used to examine the sub-lingual microvasculature as a surrogate of splanchnic cardiac perfusion at 4 times points postsurgery. There are currently no other means of assessing splanchnic circulation. The time points were early postoperative (48, 60 and 90 h) when the patient was still displaying signs of sepsis (pyrexia, low systemic vascular resistance, increased inflammatory markers, and increased inotropic-vasoconstrictor support) along with HIT being present and later on when sepsis was well-controlled, and his platelet count had recovered (47 days post postoperative). SDF data were not recorded between 90 h and 47 days at the patient was clinically stable. Table 1 displays global cardiovascular data from these time points and the data gathered from the SDF device for vessel density and perfusion quality.\n\nTable 1 Microvascular and global monitoring data\n\nTime point (postsurgery)\tVessel density\tPerfusion quality\tCardiovascular variables\tInotropes and vasopressors\t\n\t\t\t\t\nTVD\tPVD\tDe Backer score\tPPV\tMFI small\tFHI\tCI\tMAP\tSVRI\tpH\tLactate\tNA\tVA\t\n1 (48 h)\t20.35\t17.25\t11.66\t83.69\t1\t0\t3.7\t66\t1038\t7.42\t4.9\t0.3\t1\t\n2 (60 h)\t37.21\t37.21\t21.37\t100\t3.5\t0.28\t2.9\t55\t1178\t7.36\t6.9\t0.2\t1\t\n3 (90 h)\t35.78\t35.78\t22.54\t100\t3\t0\t2.8\t74\t1885\t7.2\t6.6\t0.26\t4\t\n4 (47 days)\t36.86\t36.86\t22.39\t100\t3\t0\t2.8\t52\t1715\t7.45\t1.1\t0.06\tNone\t\nWorking, normal values and further information on the SDF device is described in Koning et al.[5] TVD: Total vascular density, PVD: Perfused small vessel density, PPV: Proportion of perfused small vessels, MFI: Microvascular flow index, FHI: Flow heterogeneity index. Calculated as the difference between the maximum and minimum MFI of different sub-lingual sites, divided by the average of all MFI obtained. CI: Cardiac index (L/min/m2), MAP: Mean arterial pressure (mmHg), SVRI: Systemic vascular resistance index (dynes×s/cm5/m2), NA: Noradrenaline (mcg/kg/min), VA: Vasopressin (UI/h), SDF: Side stream dark field\n\nDISCUSSION\nGilliam et al.[8] reported 18 cases of VRE endocarditis in literature. Clinical studies have shown microcirculatory alterations are key in sepsis development.[36789] However, there are no reports in the literature assessing the microcirculation in a septic environment with the added insult of HIT. The implications of VRE endocarditis and HIT results in very high-risk surgery if undertaken. Our case report as demonstrates that surgery can be done when appropriate measures are taken. The SDF device was used at time points when the patient's condition changed clinically. Figure 1 shows a representative image of the microvasculature seen by the SDF device. Table 1 confirmed that the vessel density (TVD, PVD and De Backer Score) and perfusion quality (PPV, MFI and FHI) were at their lowest at time point 1 (48 h). PPV was very low at time point 1 (83.96), suggesting intermittent microvascular flow, despite a good cardiac index (CI) (3 L/min/m2). CI in this case was, thus, not representative of microvascular perfusion. Furthermore, the microperfusion was intermittent, despite the low systemic vascular resistance index (SVRI) at time point 1 (1038).\n\nFigure 1 A representative image from the side stream dark field device. Capillaries (with red cells) and arterioles visualized\n\nTimepoint 2 (60 h) heralded a peak in the vessel density scores of TVD and PVD, as well as MFI. This, perhaps, suggests a microvascular hyperemia (MFI 3.5). A FHI of 0.28 could also signal patchy and irregular microvasculature, suggesting that some areas may be re-perfused (hyperemic) with persistent areas of ischemia. Moreover, according to Trzeciak et al. a heterogeneous flow (FHI = 0.28) is more often linked with lower mean arterial pressure (MAP) in septic patients compared with controls.[10] These patients have a higher chance of not surviving.\n\nNot surprisingly, lactate was also markedly elevated at time point 2 (6.9 mmol/l), suggesting previous anaerobic respiration and metabolic stress. Interestingly, this time point also shows a decrease in MAP 55 mmHg, which supports the increase in lactic acid. This is also probably due to decreased inotrope and vasopressor administration.\n\nDe Backer score (vessel density) was elevated in comparison to time point 1 (21.37 vs. 11.66) but lower than time points 3 and 4 (22.54 and 22.39 respectively). The fluctuation of this score at time points 3 and 4 may be a hallmark of the vessel density being preserved, but not homogenously. The fall in MAP seen in time point 2 may be due to decreased inotrope and vasopressor administration.\n\nThe perfusion quality (PPV and MFI) plateaus from time point 3 (90 h). CI falls and plateaus at time point 3, inversely to perfusion quality in this instance. Lactate was also high (6.6 mmol/l) and pH low (7.2) despite a reasonable SVRI (1715 dynes × s/cm5/m2) and good microcirculation. This increased metabolic stress may be attributed to the high dose of vasopressin used (4 UI/h), with hypothesized subsequent splanchnic vasoconstriction due to an episode of sepsis requiring increased inotropic support. This, however, was not mirrored in the sub-lingual microcirculation. MAP was much better than other time points at 70 mmHg, once more suggesting that MAP is not a good indicator of microvascular perfusion. This suggests that microvascular monitoring in critically ill patients has benefit and is partially independent of global changes. This has also been demonstrated in literature.[1] While the SDF device did not alter the course of this case (as there is no case for comparison), it provided information about the microcirculation, which could be reflective of the splanchnic circulation. While no gold standard for measuring microperfusion exists, the SDF device shows promise in measuring such parameters.\n\nCONCLUSION\nTo the best of our knowledge, VRE endocarditis with concurrent HIT has not been described in literature. The possible role of SDF imaging in the assessment of microvascular tissue well-being is important, especially when there are fluctuating global cardiovascular characteristics. This technology may prove vital in predicting the earlier need for escalation of care, improving morbidity and mortality in complex cases.\n\nWorking, normal values and further information on the SDF device is described in Koning et al.[5]\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 De Backer D Hollenberg S Boerma C Goedhart P Büchele G Ospina-Tascon G How to evaluate the microcirculation: Report of a round table conference Crit Care 2007 11 R101 17845716 \n2 Slaaf DW Tangelder GJ Reneman RS Jäger K Bollinger A A versatile incident illuminator for intravital microscopy Int J Microcirc Clin Exp 1987 6 391 7 3429145 \n3 Boerma EC Mathura KR van der Voort PH Spronk PE Ince C Quantifying bedside-derived imaging of microcirculatory abnormalities in septic patients: A prospective validation study Crit Care 2005 9 R601 6 16280059 \n4 De Backer D Creteur J Preiser JC Dubois MJ Vincent JL Microvascular blood flow is altered in patients with sepsis Am J Respir Crit Care Med 2002 166 98 104 12091178 \n5 Koning NJ Atasever B Vonk AB Boer C Changes in microcirculatory perfusion and oxygenation during cardiac surgery with or without cardiopulmonary bypass J Cardiothorac Vasc Anesth 2014 28 1331 40 24035060 \n6 Sakr Y Dubois MJ De Backer D Creteur J Vincent JL Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock Crit Care Med 2004 32 1825 31 15343008 \n7 Ince C Microcirculation in distress: A new resuscitation end point? Crit Care Med 2004 32 1963 4 15343029 \n8 Forrest GN Arnold RS Gammie JS Gilliam BL Single center experience of a vancomycin resistant enterococcal endocarditis cohort J Infect 2011 63 420 8 21920382 \n9 McDonald JR Olaison L Anderson DJ Hoen B Miro JM Eykyn S Enterococcal endocarditis: 107 cases from the international collaboration on endocarditis merged database Am J Med 2005 118 759 66 15989910 \n10 Trzeciak S Dellinger RP Parrillo JE Guglielmi M Bajaj J Abate NL Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: Relationship to hemodynamics, oxygen transport, and survival Ann Emerg Med 2007 49 88 98 98.e1-2 17095120\n\n",
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"abstract": "To evaluate whether concurrent neoadjuvant radiation added to standard chemotherapy could increase the pathologic complete response (pCR) to treatment for locally advanced breast cancer (LABC).\n\n\n\nThis prospective phase 2 trial recruited 32 LABC patients from 2009 to 2011. Patients received neoadjuvant every-3-weekly 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) for 3 cycles, followed by weekly docetaxel (35 mg/m2) for 9 cycles. Regional radiation (45 Gy/25 plus 5.4 Gy/5) was delivered concurrently with docetaxel, then modified radical mastectomy. Patients were matched post hoc by a blinded statistician to a concurrent cohort treated with neoadjuvant chemotherapy, modified radical mastectomy, and adjuvant regional radiation.\n\n\n\nThirty of 32 patients completed treatment. Twenty-seven were successfully matched by propensity score to 81 control patients by age, stage, and molecular subtype. The concurrent chemoradiation produced a significant increase in pCR (14% vs 22%, P<.001) but no statistically significant difference in disease-free and overall survival at 3 years (respectively, 69% vs 81%, P=.186, hazard ratio 0.51; and 74% vs 89%, P=.162, hazard ratio 0.46). Toxicity included 25% of patients with grade 3 pneumonitis and 25% of patients with dermatitis, and 1 death.\n\n\n\nConcurrent neoadjuvant radiation added to radiosensitizing chemotherapy significantly improved pCR. A prospective randomized clinical trial is warranted to exploit the improved response seen with concurrent therapy but using another radio-sensitizing taxane, to better minimize treatment-related toxicity and determine its impact on overall survival.",
"affiliations": "Department of Oncology, London Regional Cancer Program, London, Ontario, Canada; Department of Surgery, London Health Sciences Centre, London, Ontario, Canada. Electronic address: muriel.brackstone@lhsc.on.ca.;Department of Oncology, London Regional Cancer Program, London, Ontario, Canada.;Department of Pathology, London Health Sciences Centre, London, Ontario, Canada.;Department of Surgery, London Health Sciences Centre, London, Ontario, Canada.;Department of Oncology, London Regional Cancer Program, London, Ontario, Canada.;Department of Oncology, London Regional Cancer Program, London, Ontario, Canada.;Department of Oncology, London Regional Cancer Program, London, Ontario, Canada.;Department of Oncology, London Regional Cancer Program, London, Ontario, Canada.;Department of Medical Imaging, St. Joseph's Healthcare Centre, London, Ontario, Canada.;Department of Medical Imaging, St. Joseph's Healthcare Centre, London, Ontario, Canada.;Department of Medical Imaging, St. Joseph's Healthcare Centre, London, Ontario, Canada.;Department of Oncology, London Regional Cancer Program, London, Ontario, Canada; Department of Pathology, London Health Sciences Centre, London, Ontario, Canada.",
"authors": "Brackstone|Muriel|M|;Palma|David|D|;Tuck|Alan B|AB|;Scott|Leslie|L|;Potvin|Kylea|K|;Vandenberg|Theodore|T|;Perera|Francisco|F|;D'Souza|David|D|;Taves|Donald|D|;Kornecki|Anat|A|;Muscedere|Giulio|G|;Chambers|Ann F|AF|",
"chemical_list": "D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D000077143:Docetaxel; D015251:Epirubicin; D003907:Dexamethasone; D003520:Cyclophosphamide; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2017.06.005",
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"issn_linking": "0360-3016",
"issue": "99(4)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D059248:Chemoradiotherapy; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D003907:Dexamethasone; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D015411:Mastectomy, Modified Radical; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D057216:Propensity Score; D011446:Prospective Studies; D011838:Radiation-Sensitizing Agents; D043823:Taxoids",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "769-776",
"pmc": null,
"pmid": "28870785",
"pubdate": "2017-11-15",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "Concurrent Neoadjuvant Chemotherapy and Radiation Therapy in Locally Advanced Breast Cancer.",
"title_normalized": "concurrent neoadjuvant chemotherapy and radiation therapy in locally advanced breast cancer"
} | [
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"abstract": "Patients with an indwelling tunneled dialysis catheter (TDC) for hemodialysis access are at a high risk of developing methicillin-resistant Staphylococcus aureus (MRSA) infection. MRSA bacteremia complications rarely include infected aneurysm. Here, we report the first case of an infected thoracic aneurysm associated with TDC-related MRSA bacteremia. An 86-year-old Japanese male with a TDC for hemodialysis access developed TDC-related MRSA bacteremia. Intravenous vancomycin was initiated, and the TDC was removed on day 3. Despite removal of the catheter and initiation of vancomycin treatment, MRSA bacteremia persisted. Chest computed tomography (CT) showed no aneurysm; however, calcification of the thoracic aorta was detected on admission. The patient subsequently developed hemosputum. CT revealed a thoracic aneurysm, which turned out to be caused by MRSA bacteremia. The patient eventually died because of the rupture of the infected aneurysm, as confirmed by autopsy. This report demonstrates TDC management in a patient with TDC-related MRSA bacteremia and the importance of investigating a metastatic infection to a calcified artery if bacteremia persists.",
"affiliations": "Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Pathology, Graduate School of Medical Sciences, Kyorin University, Mitaka, Japan.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. snaito.kid@tmd.ac.jp.;Department of Pathology, Yokosuka Kyosai Hospital, Yokosuka, Kanagawa, Japan.;Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Nephrology, Yokosuka Kyosai Hospital, 1-16 Yonegahamadori, Yokosuka, Kanagawa, 238-8558, Japan.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.",
"authors": "Katsuragawa|Fumiko|F|;Nagahama|Kiyotaka|K|;Naito|Shotaro|S|0000-0001-9774-1638;Tsuura|Yukio|Y|;Otani|Megumi|M|;Koide|Takaaki|T|;Nishiyama|Sakino|S|;Yanagi|Tomoki|T|;Nanamatsu|Azuma|A|;Aki|Shota|S|;Aoyagi|Makoto|M|;Tanaka|Hiroyuki|H|;Rai|Tatemitsu|T|;Uchida|Shinichi|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
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"issue": "7(2)",
"journal": "CEN case reports",
"keywords": "Hemodialysis; Infected aneurysm; MRSA bacteremia; Tunneled dialysis catheter",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D061605:Administration, Intravenous; D000369:Aged, 80 and over; D000785:Aneurysm, Infected; D000900:Anti-Bacterial Agents; D001013:Aorta, Thoracic; D044466:Asians; D016470:Bacteremia; D002408:Catheters, Indwelling; D062905:Central Venous Catheters; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D006435:Renal Dialysis; D012421:Rupture; D013203:Staphylococcal Infections; D014057:Tomography, X-Ray Computed; D014640:Vancomycin",
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"pages": "325-329",
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"references": "21272261;19743492;19793317;10816154;21620670;2545622;15980618;17347644;23429353;27236094;15492943;17905558;15218459;9844145;26965815",
"title": "Ruptured infected aneurysm of the thoracic aorta associated with tunneled dialysis catheter-related methicillin-resistant Staphylococcus aureus bacteremia in a hemodialysis patient.",
"title_normalized": "ruptured infected aneurysm of the thoracic aorta associated with tunneled dialysis catheter related methicillin resistant staphylococcus aureus bacteremia in a hemodialysis patient"
} | [
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"literaturereference": "NAITO S. RUPTURED INFECTED ANEURYSM OF THE THORACIC AORTA ASSOCIATED WITH TUNNELED DIALYSIS CATHETER-RELATED METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS BACTEREMIA IN A HEMODIALYSIS PATIENT. CEN-CASE-REP. 2018?325-329.",
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"abstract": "A 69-year-old man visited our hospital due to an abnormal shadow on a chest X-ray. Chest CT showed a mass shadow in his left lower lobe accompanied by an infiltrative shadow in the right upper lobe. Thorough examination led to a diagnosis of pulmonary squamous cell lung carcinoma, stage IIIB (T3N2M0). Combination treatment with chemotherapy and programmed cell death receptor 1 (PD-1) inhibitor was started, leading to a partial response. However, his pre-existing pulmonary infiltrative shadow progressed during the maintenance treatment with PD-1 inhibitor, and sputum culture revealed Mycobacterium abscessus infection. Thus, exacerbation of pre-existing nontuberculous mycobacterial pulmonary disease (NTM-PD) resulting from treatment with PD-1 inhibitor was suspected. Then, treatment with PD-1 inhibitor was discontinued, and he underwent pulmonary resection after antibiotic therapy against Mycobacterium abscessus infection. Recently, special attention has been paid to the association of Mycobacterium tuberculosis (TB) infection and treatment with immune checkpoint inhibitors (ICIs) in TB-endemic areas. This case also emphasizes the importance of realizing the risk of NTM infection when treating patients with ICIs, especially in NTM-endemic areas.",
"affiliations": "Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Surgery, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Surgery, Takatsuki General Hospital, Takatsuki, Osaka, Japan.;Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan.",
"authors": "Okamoto|Mariko|M|;Kim|Young Hak|YH|;Ouchi|Aiko|A|;Yamaoka|Takashi|T|;Iwamoto|Natsuhiko|N|;Iwatsubo|Shigeaki|S|;Matsumura|Kanoko|K|;Nakamura|Miho|M|;Kin|Yasuo|Y|;Shiina|Yoshitaka|Y|;Funada|Yasuhiro|Y|",
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"doi": "10.1016/j.rmcr.2021.101529",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00191-X\n10.1016/j.rmcr.2021.101529\n101529\nCase Report\nExacerbation of nontuberculous mycobacterial pulmonary disease in a patient with advanced non-small-cell lung cancer during treatment with PD-1 inhibitor and chemotherapy\nOkamoto Mariko a\nKim Young Hak ykim.free@gmail.com\na∗\nOuchi Aiko a\nYamaoka Takashi a\nIwamoto Natsuhiko a\nIwatsubo Shigeaki a\nMatsumura Kanoko a\nNakamura Miho a\nKin Yasuo b\nShiina Yoshitaka b\nFunada Yasuhiro a\na Department of Respiratory Medicine, Takatsuki General Hospital, Takatsuki, Osaka, Japan\nb Department of Respiratory Surgery, Takatsuki General Hospital, Takatsuki, Osaka, Japan\n∗ Corresponding author. Department of Respiratory Medicine, Takatsuki General Hospital, 1-3-13 Kosobe-cho, Takatsuki, Osaka, 569-1192, Japan. ykim.free@gmail.com\n21 10 2021\n2021\n21 10 2021\n34 10152925 6 2021\n7 9 2021\n19 10 2021\n© 2021 The Authors\n2021\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/).\nA 69-year-old man visited our hospital due to an abnormal shadow on a chest X-ray. Chest CT showed a mass shadow in his left lower lobe accompanied by an infiltrative shadow in the right upper lobe. Thorough examination led to a diagnosis of pulmonary squamous cell lung carcinoma, stage IIIB (T3N2M0). Combination treatment with chemotherapy and programmed cell death receptor 1 (PD-1) inhibitor was started, leading to a partial response. However, his pre-existing pulmonary infiltrative shadow progressed during the maintenance treatment with PD-1 inhibitor, and sputum culture revealed Mycobacterium abscessus infection. Thus, exacerbation of pre-existing nontuberculous mycobacterial pulmonary disease (NTM-PD) resulting from treatment with PD-1 inhibitor was suspected. Then, treatment with PD-1 inhibitor was discontinued, and he underwent pulmonary resection after antibiotic therapy against Mycobacterium abscessus infection. Recently, special attention has been paid to the association of Mycobacterium tuberculosis (TB) infection and treatment with immune checkpoint inhibitors (ICIs) in TB-endemic areas. This case also emphasizes the importance of realizing the risk of NTM infection when treating patients with ICIs, especially in NTM-endemic areas.\n\nKeywords\n\nNon-small-cell lung cancer\nImmune checkpoint inhibitor\nPD-1 inhibitor\nNontuberculous mycobacterial pulmonary disease\nExacerbation\n==== Body\npmc1 Introduction\n\nThe most recent progress in the treatment of patients with non-small-cell lung cancer (NSCLC) is the development of immune checkpoint inhibitors (ICIs), especially programmed cell death receptor 1 (PD-1) or programmed cell death receptor ligand 1 (PD-L1) inhibitor [1,2]. PD-(L)1 inhibitor with or without chemotherapy is the current standard of care for patients with treatment-naïve advanced NSCLC, raising concerns about increases of infectious diseases [3], and a growing number of reports have suggested the association of Mycobacterium tuberculosis (TB) infection with PD-(L)1 inhibitors [[4], [5], [6]]. Here, we report a patient with NSCLC whose pre-existing nontuberculous mycobacteria pulmonary disease (NTM-PD) exacerbated during treatment with PD-1 inhibitor and chemotherapy.\n\n2 Case report\n\nA 69-year-old man was referred to our hospital due to an abnormal shadow on a chest X-ray (Fig. 1A). Computed tomography (CT) showed a lung mass, 3.3 × 3.0 cm, in the left lower lobe (Fig. 2A) accompanied by an infiltrative shadow in the right upper lobe (Fig. 2B). Transbronchial tumor biopsy demonstrated squamous cell carcinoma. Positron emission tomography (PET) revealed mediastinal lymph node metastases, whereas no distant metastases were detected. There were no apparent brain metastases on magnetic resonance imaging (MRI). Hence, he was diagnosed with squamous cell lung carcinoma, stage IIIB (T3N2M0). Immunohistochemistry for PD-L1 revealed that his tumor proportion score (TPS) was 100%. Since curative radiation therapy was inappropriate because of the large radiation field, combination treatment with chemotherapy (nab-paclitaxel + carboplatin) and PD-1 inhibitor (pembrolizumab) was started. After four cycles of the treatment, he achieved a partial response (Fig. 2C); however, after two cycles of maintenance treatment with pembrolizumab, he developed a cough, and chest X-ray revealed progression of his pre-existing infiltrative shadow in the right upper lung field (Fig. 1B). His sputum culture was positive for Mycobacterium abscessus. Thus, exacerbation of pre-existing NTM-PD due to treatment with PD-1 inhibitor was suspected. Therefore, pembrolizumab was discontinued and antibiotic therapy with imipenem, amikacin, and clarithromycin was started. He then underwent right upper lobectomy and after that pembrolizumab was resumed concurrently with antibiotic therapy. However, disease progression was confirmed after three additional cycles of pembrolizumab. Thereafter, pembrolizumab was terminated and he is now receiving cytotoxic chemotherapy without recurrence of Mycobacterium abscessus.Fig. 1 Chest radiographic examination. (A) A mass shadow in the left lower lung field (arrow) accompanied by an infiltrative shadow in the right upper lobe (arrowhead). (B) Shrinking of the mass shadow (arrow) with the progression of the pre-existing infiltrative shadow (arrowhead).\n\nFig. 1\n\nFig. 2 Chest computed tomography. (A) A lung mass in the left lower lobe (arrow). (B) An infiltrative shadow in the right upper lobe (arrowhead). (C) Shrinking of the mass shadow in the left lower lobe (arrow).\n\nFig. 2\n\n3 Discussion\n\nSince the first publication of a case suggesting the association of TB infection and treatment with PD-(L)1 inhibitors in 2016, special attention has been paid to the association, especially in TB-endemic areas [7]. Although the precise mechanisms are not fully understood, it is postulated that PD-(L)1 inhibitors might unmask latent TB infection by overexpressing TB-specific T cells [8].\n\nTo our knowledge, only one case series (including 3 patients) has been reported regarding the association of NTM infection and treatment with PD-(L)1 inhibitors [9]; however, according to a retrospective review using the US Food and Drug Administration Adverse Events Reporting System (FAERS), there were 72 cases of TB infection and 13 cases of NTM infection resulting from treatment with PD-(L)1 inhibitors between January 2015 and March 2020. The reporting odds ratio (ROR) was measured to compare the risk of the infection between PD-(L)1 inhibitors and other drugs, and it was 1.79 (95% CI: 1.42–2.26, p < 0.0001) for TB infection and 5.49 (95% CI: 3.15–9.55, p < 0.0001) for NTM infection [10]. Therefore, it is clear that PD-(L)1 inhibitors increase the risk of NTM infection.\n\nA recent Japanese nationwide hospital-based survey demonstrated that the incidence rate for NTM-PD was 14.7 cases per 100,000 person-years in 2014, which was approximately three times higher than that in 2007 [11]. In another international survey, the annual prevalence of NTM-PD was estimated at 24.9 cases per 100,000 persons in Japan, but only 6.2 cases per 100,000 persons in Europe [12]. Physicians, especially in NTM-endemic areas such as Japan, should be aware of the risk of pre-existing NTM-PD exacerbation due to PD-(L)1 inhibitors. Furthermore, considering the expected high prevalence of latent NTM infection without NTM-PD in NTM-endemic areas, potential risk of NTM infection should be paid close attention in every patient receiving PD-(L)1 inhibitor in those areas. In fact, the aforementioned case series were from Japan, and none of the three patients had NTM-PD at the baseline but newly developed it during treatment with PD-(L)1 inhibitors [9].\n\nRecently, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, another ICI, was introduced for the treatment of NSCLC [13,14], and the incidence of immune-related adverse events (irAEs) is expected to increase. Accordingly, more patients will receive steroids, which may also increase the risk of infectious disease including NTM.\n\n4 Conclusion\n\nWe encountered an NSCLC patient whose pre-existing NTM-PD exacerbated during treatment with PD-1 inhibitor and chemotherapy. Physicians in endemic areas should be aware of the risk of NTM infection when treating patients with ICI.\n\nFunding source\n\nNone declared.\n\nAuthors’ disclosures of potential conflicts of interest\n\nNone declared.\n==== Refs\nReferences\n\n1 Topalian S.L. Hodi F.S. Brahmer J.R. Gettinger S.N. Smith D.C. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N. Engl. J. Med. 366 2012 2443 2454 22658127\n2 Brahmer J.R. Tykodi S.S. Chow L.Q. Hwu W.J. Topalian S.L. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer N. Engl. J. Med. 366 2012 2455 2465 22658128\n3 Fujita K. Kim Y.H. Kanai K. Yoshida H. Mio T. Emerging concerns of infectious diseases in lung cancer patients receiving immune checkpoint inhibitor therapy Respir. Med. 146 2019 66 70 30665520\n4 Fujita K. Terashima T. Mio T. Anti-PD1 antibody treatment and the development of acute pulmonary tuberculosis J. Thorac. Oncol. 11 2016 2238 2240 27423391\n5 Jensen K.H. Persson G. Bongaard A.-L. Pohl M. Development of pulmonary tuberculosis following treatment with anti-PD-1 for non-small cell lung cancer Acta Oncol. 57 2018 1127 1128 29384034\n6 van Eeden R. Rapoport B.L. Smit T. Anderson R. Tuberculosis infection in a patient treated with nivolumab for non-small cell lung cancer: case report and literature review Front. Oncol. 9 2019 10.3389/fonc.2019.00659\n7 Reungwetwattana T. Adjei A.A. Anti-PD-1 antibody treatment and the development of acute pulmonary tuberculosis J. Thorac. Oncol. 11 2016 2048 2050 27866633\n8 Picchi H. Mateus C. Chouaid C. Besse B. Marabelle A. Infectious complications associated with the use of immune checkpoint inhibitors in oncology: reactivation of tuberculosis after anti PD-1 treatment Clin. Microbiol. Infect. 24 2018 216 218 29269089\n9 Fujita K. Yamamoto Y. Kanai O. Okamura M. Nakatani K. Development of Mycobacterium avium complex lung disease in patients with lung cancer on immune checkpoint inhibitors, open Forum. Infect. Dis. 7 2020 ofaa067\n10 Anand K. Sahu G. Burns E. Ensor A. Ensor J. Mycobacterial infections due to PD-1 and PD-L1 checkpoint inhibitors ESMO. Open. 5 2020 e000866\n11 Namkoong Ho Kurashima A. Morimoto K. Hoshino Y. Hasegawa N. Epidemiology of pulmonary nontuberculous mycobacterial disease, Japan, emerg Infect. Dis 22 2016 1116 1117\n12 Schildkraut J.A. Gallagher J. Morimoto K. Lange C. Haworth C. Epidemiology of nontuberculous mycobacterial pulmonary disease in Europe and Japan by Delphi estimation Respir. Med. 173 2020 106164 32992265\n13 Hellmann M.D. Paz-Ares L. Bernabe Caro R. Zurawski B. Kim S.W. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer N. Engl. J. Med. 381 2019 2020 2031 31562796\n14 Paz-Ares L. Ciuleanu T.E. Cobo M. Schenker M. Zurawski B. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial Lancet Oncol. 22 2021 198 211 33476593\n\n",
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"title": "Exacerbation of nontuberculous mycobacterial pulmonary disease in a patient with advanced non-small-cell lung cancer during treatment with PD-1 inhibitor and chemotherapy.",
"title_normalized": "exacerbation of nontuberculous mycobacterial pulmonary disease in a patient with advanced non small cell lung cancer during treatment with pd 1 inhibitor and chemotherapy"
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"abstract": "•Cure rates are high for choriocarcinoma, however chemoresistant disease often leads to death.•High expression of PD-L1 suggests a role for checkpoint inhibitors in choriocarcinoma.•Pembrolizumab should be considered for salvage therapy for chemoresistant choriocarcinoma.",
"affiliations": "Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California Irvine Medical Center, Orange, CA, United States.;Department of Pathology, University of California Irvine Medical Center, Orange, CA, United States.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California Irvine Medical Center, Orange, CA, United States.",
"authors": "Clair|Kiran H|KH|;Gallegos|Nicolas|N|;Bristow|Robert E|RE|",
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"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789 Elsevier \n\nS2352-5789(20)30091-6\n10.1016/j.gore.2020.100625\n100625\nCase Report\nSuccessful treatment of metastatic refractory gestational choriocarcinoma with pembrolizumab: A case for immune checkpoint salvage therapy in trophoblastic tumors\nClair Kiran H. jclair@uci.edua⁎ Gallegos Nicolas b Bristow Robert E. a a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of California Irvine Medical Center, Orange, CA, United States\nb Department of Pathology, University of California Irvine Medical Center, Orange, CA, United States\n⁎ Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of California, Irvine Medical Center, 333 City Blvd. West, Suite 1400, Orange, CA 92868, United States. jclair@uci.edu\n01 9 2020 \n11 2020 \n01 9 2020 \n34 10062522 5 2020 13 8 2020 16 8 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Cure rates are high for choriocarcinoma, however chemoresistant disease often leads to death.\n\n• High expression of PD-L1 suggests a role for checkpoint inhibitors in choriocarcinoma.\n\n• Pembrolizumab should be considered for salvage therapy for chemoresistant choriocarcinoma.\n\n\n\nKeywords\nGestational trophoblastic neoplasiaChoriocarcinomaChemotherapy resistanceImmunotherapy\n==== Body\n1 Introduction\nChoriocarcinoma is a highly malignant form of gestational trophoblastic neoplasia. Given its rarity, incidence rates range from 3.3 per 40,000 pregnancies in Southeast Asia to 1 in 40,000 pregnancies in North America and Europe (Goldstein et al., n.d.). Management of these tumors is primarily based on its high sensitivity to chemotherapy and its unique production of hCG (Seckl et al., 2010). While variations in treatment schedules exist, complete remission has been observed following single-agent therapy in 85% of low-risk patients (Alazzam et al., 2009). If resistance to single therapy is observed, approximately 15–20% of patients will respond to second-line combination therapy (Powles et al., 2007). There are limited studies evaluating combination salvage therapies in unresectable drug-resistant patients.\n\nWe propose a biologic basis for immune checkpoint therapy in refractory trophoblastic tumors. To facilitate an environment where the developing fetus evades the maternal immune response, placental tissue expresses programmed death-ligand 1 (PD-L1) which binds programmed-death-1 receptor (PD-1) on lymphocytes via immune checkpoint activity. This is the first report of a lasting clinical response in a patient treated with anti-PD1 therapy with over 30 months of disease remission (Huang et al., 2017, Ghorani et al., 2017).\n\n2 Case presentation\nA 30-year-old woman presented with a 15-week twin pregnancy consisting of a normal fetus and a suspected molar gestation. Dilation and evacuation was performed with karyotype 46XX and pathology confirming choriocarcinoma. The patient underwent chest imaging which demonstrated several nodules concerning for metastatic disease. The patient had low-risk disease based on World Health Organization’s (WHO) score of 1 and was stage III by Federation of Gynecologic and Oncology (FIGO) criteria. The patient received single agent methotrexate (50 mg/m2), however this was changed to actinomycin-D (1.25 mg/m2) due to plateauing hCG levels. Within 6 weeks of stopping treatment, hCG levels increased and she received 4 cycles of etoposide, methotrexate, actinomycin-D, cyclophosphamide, and vincristine (EMA/CO).\n\nTwo years later, the patient’s hCG remained undetectable and she underwent intrauterine inseminations which resulted in an inappropriate rise in her hCG level. A dilation and curettage was performed without products of conception heightening the concern for recurrent choriocarcinoma. Her hCG was 3849 mIU/mL and CT imaging, magnetic resonance imaging (MRI), and positron emission tomography-computerized tomography (PET-CT) were all negative. The hCG level continued to rise and due to high clinical suspicion, she completed nine cycles of methotrexate (50 mg/m2) with an hCG plateau followed by four cycles of single agent actinomycin-D. The patient’s hCG remained elevated and a PET/CT confirmed increased FDG-avidity in the uterine fundus and pulmonary lesions. She completed six cycles of EMA/CO with PET/CT confirming complete response. Despite this, her hCG rapidly rose again to 369 mIU/mL within one month of completing therapy and proceeded with third-line multi-agent chemotherapy.\n\nAfter completion of five cycles of EMA/EP, her hCG normalized and she desired a pause in treatment and pursued holistic modalities at this time. Within three months, her hCG increased to 766 mIU/mL. A CT of the chest demonstrated an enlarging isolated right anterior lung nodule and she underwent a video-assisted thoracoscopic wedge resection of a 1.5 cm tumor confirming metastatic disease. Following the confirmation of pulmonary metastasis, the patient strongly desired oocyte preservation and underwent ovulation induction with a Reproductive Endocrinologist. Her hCG increased from 12,000 mIU/ML to 96,952 mIU/mL. Given evidence of chemotherapy resistance, she was started on cisplatin (60 mg/m2), etoposide (150 mg/m2), and paclitaxel (135 mg/m2), despite 6 cycles her hCG continued to increase. Imaging studies at this time demonstrated a uterine mass and 2 small pulmonary nodules (0.5 × 0.3 cm, 0.6 × 0.2 cm). The pulmonary nodules were thought to be amenable to stereotactic radiotherapy and she underwent a robotic-assisted total laparoscopic hysterectomy and bilateral salpingo-oophorectomy. Surgical pathology of the uterus demonstrated a 3.2 cm tumor consistent with recurrent choriocarcinoma involving the endometrium and superficial myometrium, the cervix and bilateral fallopian tubes showed no evidence of malignancy. At the patient’s post-operative visit however, she reported intermittent headaches and an MRI confirmed two metastatic lesions. The patient did not receive the planned stereotactic radiotherapy directed to the pulmonary lesions however did receive whole brain radiation in 15 fractions of 37.5 Gy (Fig. 1) and her hCG continued to rise from 569 mI/mL to 4527 mIU/mL.Fig. 1 Magnetic resonance imaging (MRI) demonstrates a right cerebellar hemisphere lesion (A) with interval resolution of perilesional edema following 37.5 Gy whole brain radiation in 15 fractions, with corresponding hemosiderin/blood products (B).\n\n\n\nThe patient’s disease was refractory to ifosfamide (904 mg/m2), carboplatin (AUC of 4), etoposide (55 mg/m2) (ICE) and single agent bevacizumab (15 mg/kg). Molecular profiling was performed with findings of PD-L1 and TOP2A biomarker expression. Her immunohistochemical results can be seen in Fig. 2. Given high PD-L1 expression, the patient was started on pembrolizumab dosed at 200 mg intravenous over 30 min every three weeks. After ten cycles her hCG was undetectable at <5mIU/mL, Table 1. Her serum hCG has remained undetectable 31 months after initiating pembrolizumab. Recent CT imaging of the head, chest, abdomen, and pelvis showed several pulmonary nodules continuing to decrease in size and no evidence of disease progression, as seen in Fig. 3.Fig. 2 Immunohistochemical studies (panel of three IHCs) demonstrate that tumor cells of pulmonary metastasis are (A) diffusely positive for beta hCG, (B) Ki67 confirms a high proliferative index (65%) compatible with choriocarcinoma, and (C) PD-L1 shows strong membranous and cytoplasmic positivity.\n\nTable 1 Trend of serum hCG levels measured during treatment and maintenance periods. The shaded boxes represent treatment regimens (a) methotrexate, (b) actinomycin-D, (c), EMA-CO, (d) EMA-EP, (e) Cis/Taxol/Etoposide, (f) Ifosfomide/Etoposide, (1) video-assisted thorascopic wedge resection, (2) robotic-assisted total laparoscopic hysterectomy, bilateral salpingectomy, and now on maintenance treatment with pembrolizumab.\n\n\t\nFig. 3 Computed tomography (CT) imaging demonstrates an interval decrease in the size of pulmonary metastatic nodules following treatment with 25 cycles of pembrolizumab (A, pre-treatment; B, pembrolizumab therapy).\n\n\n\n3 Discussion\nAs high as 20–30% of high-risk GTD patients will have an incomplete response to first-line chemotherapy and will require salvage therapy (Matsui et al., 2004). Additional treatment for resistant GTN include paclitaxel, cisplatin, etoposide (TP/TE), bleomycin, etoposide, cisplatin (BEP), paclitaxel, ifosfamide, cisplatin (TIP), etoposide, ifosfamide, and cisplatin (VIP), or ifosfamide, carboplatin, and etoposide (ICE) that can lead to remission (Lurain, 2002). The combination of gemcitabine and cisplatin has also been described in achieving remission after in heavily treated patients (Pandian et al., 2004). Given the highly resistant nature of this disease, these varying combinations of chemotherapy can result in significant toxicity and morbidity to the patient.\n\nSeveral recent studies have confirmed high expression of programmed death-ligand 1 (PD-L1) expression in normal and trophoblastic tumors suggesting a potential role for immune checkpoint inhibitors to limit evasion from immune regulation (Veras et al., 2017, Hajri et al., 2017, Tumors, 2016). Currently, there are only two other published cases of patients with metastatic GTN having received immune checkpoint inhibitors as salvage therapy (Ghorani et al., 2017, Huang et al., 2017). There are five cumulative patients included in these published reports, all of who received treatment for approximately six months with undetectable serum hCG levels. In contrast, our patient remains in remission at over 31 months on pembrolizumab treatment and continues to have undetectable serum hCG levels.\n\nIt has been postulated that normal trophoblastic cells behave similarly to malignant cells in their ability to evade the immune system and invade normal tissue. Veras et al. have demonstrated high PD-L1 expression in trophoblastic cells of both normal placentas in addition to gestational trophoblastic tumors (Veras et al., 2017). Binding of PD-1 to its ligand, PD-L1, can initiate a downstream signal inhibition of T-cell activation. The presence of the PD-L1 protein can be detected using immunohistochemistry and this is reported as a percentage of total cells showing protein expression, with a higher percentage representing a higher degree of immune-reactivity. Within normal placental tissue, there was high expression of PD-L1 in syncytiotrophoblasts as compared to cytotrophoblasts. This expression pattern was mimicked in choriocarcinoma with high PD-L1 expression among trophoblastic tumors (Tumors, 2016). The high expression of PD-L1 in syncytiotrophoblasts of both term placentas and choriocarcinomas suggests a mechanism for the immunosuppressive environment necessary for the formation of a fetal-maternal interface. Given paternal antigen expression during pregnancy, PD-L1 expression allows for fetal tolerance to evade maternal immune recognition. The significance of the PD-1/PD-L1 pathway in achieving a fetal-maternal interface has also been demonstrated in mouse models. Guleria et al. showed that PD-L1 deficient mice or mice treated with PD-L1 inhibitors had decreased rates of fetal survival and smaller litter sizes suggesting a role in the development of fetal-maternal immune tolerance (Guleria et al., 2005).\n\nWith the findings of high PD-L1 expression among trophoblastic tumors, it becomes necessary to evaluate the clinical implications of expression patterns. Bolze et al. sought to assess the significance of PD-L1 expression among patients with pre-malignant and malignant trophoblastic disease. Expression of PD-L1 was high in all trophoblastic subtypes and 80% of choriocarcinoma specimens analyzed, again suggesting a role for the PD-L1/PD-1 pathway inhibition.\n\nPembrolizumab is a highly sensitive monoclonal IgG antibody against PD-1 that prevents the engagement with its ligand PD-L1, leading to downstream inhibition of T-cell activity. This immune inhibition results in tumor-specific antigen recognition by cytotoxic T-cells, triggering increased immune response and tumor death. Currently, the US Food and Drug Administration (FDA) has approved pembrolizumab for use in unresectable melanoma, non-small cell lung cancer, recurrent or metastatic head and neck squamous cell cancers, classical Hodgkins lymphoma, in any solid tumor with microsatellite instability, and in PD-L1 positive cervical cancer (FDA’s label for pembrolizumab, 2017). It has an excellent safety profile with discontinuation rates of only 8–20% due to toxicity, however, the question of optimal treatment duration is one that has not yet been answered in regards to immunotherapy (FDA’s label for pembrolizumab, 2017). Given the known serologic marker of hCG for GTN, the longevity of action after discontinuation of immunotherapy may be better understood in these patients compared to other disease sites.\n\n4 Conclusion\nWhile the majority of patients with choriocarcinoma will achieve a complete response from single-agent chemotherapy alone, limited treatment options are available for those who develop unresectable disease or resistance to chemotherapy. The high expression of PD-L1 by normal trophoblasts and trophoblastic tumors such as choriocarcinoma provide a potential mechanism for immune evasion and increased survival of tumor cells. It becomes imperative that further investigation of PD-L1 and PD-1 inhibitors as potential therapeutic in trophoblastic tumors be pursued.\n\nCRediT authorship contribution statement\nKiran H. Clair: Investigation, Writing - original draft. Nicolas Gallegos: Formal analysis, Investigation, Immunohistochemistry and pathology review. Robert E. Bristow: Supervision, Writing - review & editing.\n\nDeclaration of Competing Interest\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n==== Refs\nReferences\nAlazzam, M., Tidy, J., Bw, H., Osborne, R., 2009.First line chemotherapy in low risk gestational trophoblastic neoplasia (Review).\nFDA’s label for pembrolizumab, 2017.\nGhorani E. Kaur B. Fisher R.A. Short D. Joneborg U. Carlson J.W. Akarca A. Marafioti T. Quezada S.A. Sarwar N. Seckl M.J. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia Lancet 390 2017 2343 2345 10.1016/S0140-6736(17)32894-5 29185430 \nGoldstein, R., Donald, P. Berkowitz, n.d. Current management of gestational trophoblastic neoplasia.\nGuleria I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. Noelle R.J. Coyle A. Mellor A.L. Khoury S.J. Sayegh M.H. A critical role for the programmed death ligand 1 in fetomaternal tolerance Brief Definit. Rep. 202 2005 231 237 10.1084/jem.20050019 \nHajri Þ.T. Bolze P. Patrier Þ.S. Abbas F. Schott Þ.A.M. Allias Þ.F. Devouassoux-shisheboran M. Freyer Þ.G. Þþ Þ. PD-L1 Expression in premalignant and malignant trophoblasts from gestational trophoblastic diseases is ubiquitous and independent of clinical outcomes Int J Gynecol Cancer 27 2017 554 561 10.1097/IGC.0000000000000892 28060141 \nHuang M. Pinto A. Castillo R.P. Slomovitz B.M. Complete serologic response to pembrolizumab in a woman with chemoresistant metastatic choriocarcinoma J. Clin. Oncol. 35 2017 3172 3174 10.1200/JCO.2017.74.4052 28742453 \nLurain J.R. Advances in management of high-risk gestational trophoblastic tumors J. Reprod. Med. 47 2002 451 459 12092013 \nMatsui H. Iitsuka Y. Suzuka K. Yamazawa K. Mitsuhashi A. Sekiya S. Salvage chemotherapy for high-risk gestational trophoblastic tumor J. Reprod. Med. 49 2004 438 442 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15283050 15283050 \nPandian Z. Seckl M.J. Smith R. Lees D.A.R. Gestational choriocarcinoma: an unusual presentation with response to gemcitabine and surgery Int. J. Obstetr. Gynecol. 111 2004 382 384 \nPowles, T., Stebbing, J., Short, D., Young, A., Bower, M., Pappin, C., Schmid, P., 2007. A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia, 732–737. doi: 10.1038/sj.bjc.6603608.\nSeckl M.J. Sebire N.J. Berkowitz R.S. Gestational trophoblastic disease Lancet 376 2010 717 729 10.1016/S0140-6736(10)60280-2 20673583 \nTumors, T., 2016. Comprehensive immunohistochemical study of, 40 1133–1142.\nVeras E. Kurman R.J. Wang T. Shih I. Ph D. PD-L1 Expression in human placentas and gestational trophoblastic diseases Int. J. Gynecol. Pathol. 2017 146 153 10.1097/PGP.0000000000000305 27362903\n\n",
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"keywords": "Chemotherapy resistance; Choriocarcinoma; Gestational trophoblastic neoplasia; Immunotherapy",
"medline_ta": "Gynecol Oncol Rep",
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"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": "16027236;27362903;28060141;15008778;15283050;12092013;20673583;29185430;27158757;17299394;28742453;19160319;22244665",
"title": "Successful treatment of metastatic refractory gestational choriocarcinoma with pembrolizumab: A case for immune checkpoint salvage therapy in trophoblastic tumors.",
"title_normalized": "successful treatment of metastatic refractory gestational choriocarcinoma with pembrolizumab a case for immune checkpoint salvage therapy in trophoblastic tumors"
} | [
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] |
{
"abstract": "Complications of IV mannitol administration resulting in compartment syndrome may warrant surgical intervention. Compartment syndrome is difficult to diagnose in the anesthetized patient. Infusing mannitol in an observed IV site permits discontinuation of mannitol before complications ensue. Early recognition and surgical intervention averted potential impairment in our patient.",
"affiliations": "Department of Anesthesiology, University of South Florida College of Medicine, Tampa 33612, USA. jjedwards@pol.net",
"authors": "Edwards|Johnathan J|JJ|;Samuels|David|D|;Fu|Eugene S|ES|",
"chemical_list": "D004234:Diuretics, Osmotic; D008353:Mannitol",
"country": "United States",
"delete": false,
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"mesh_terms": "D000768:Anesthesia, General; D003161:Compartment Syndromes; D004234:Diuretics, Osmotic; D004487:Edema; D005260:Female; D005542:Forearm; D006801:Humans; D002532:Intracranial Aneurysm; D008353:Mannitol; D008875:Middle Aged; D012039:Regional Blood Flow",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "245-6, table of contents",
"pmc": null,
"pmid": "12505960",
"pubdate": "2003-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Forearm compartment syndrome from intravenous mannitol extravasation during general anesthesia.",
"title_normalized": "forearm compartment syndrome from intravenous mannitol extravasation during general anesthesia"
} | [
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},
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"medicinalproduct": "LIDOCAINE."
}
],
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"reactionmeddraversionpt": "22.0",
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}
],
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},
"primarysource": {
"literaturereference": "EDWARDS JJ, SAMUELS D, FU ES. FOREARM COMPARTMENT SYNDROME FROM INTRAVENOUS MANNITOL EXTRAVASATION DURING GENERAL ANESTHESIA. ANESTHESIA + ANALGESIA. 2003 JAN?96(1):245-6.",
"literaturereference_normalized": "forearm compartment syndrome from intravenous mannitol extravasation during general anesthesia",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190904",
"receivedate": "20190904",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "3",
"safetyreportid": 16773034,
"safetyreportversion": 1,
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},
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] |
{
"abstract": "BACKGROUND\nDopaminergic medications relieve symptoms of the restless legs syndrome (RLS) but have the potential to cause iatrogenic worsening (augmentation) of RLS with long-term treatment. Pregabalin may be an effective alternative.\n\n\nMETHODS\nIn this 52-week, randomized, double-blind trial, we assessed efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole. Patients were randomly assigned to receive 52 weeks of treatment with pregabalin at a dose of 300 mg per day or pramipexole at a dose of 0.25 mg or 0.5 mg per day or 12 weeks of placebo followed by 40 weeks of randomly assigned active treatment. The primary analyses involved a comparison of pregabalin and placebo over a period of 12 weeks with use of the International RLS (IRLS) Study Group Rating Scale (on which the score ranges from 0 to 40, with a higher score indicating more severe symptoms), the Clinical Global Impression of Improvement scale (which was used to assess the proportion of patients with symptoms that were \"very much improved\" or \"much improved\"), and a comparison of rates of augmentation with pregabalin and pramipexole over a period of 40 or 52 weeks of treatment.\n\n\nRESULTS\nA total of 719 participants received daily treatment, 182 with 300 mg of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole, and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in mean scores on the IRLS scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (P<0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%, P<0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1% vs. 7.7%, P=0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P=0.08). There were six cases of suicidal ideation in the group receiving pregabalin, three in the group receiving 0.25 mg of pramipexole, and two in the group receiving 0.5 mg of pramipexole.\n\n\nCONCLUSIONS\nPregabalin provided significantly improved treatment outcomes as compared with placebo, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole. (Funded by Pfizer; ClinicalTrials.gov number, NCT00806026.).",
"affiliations": "From the Department of Neurology, Johns Hopkins University, Baltimore (R.P.A.); Pfizer Global Research and Development, Groton, CT (C.C., S.D., J.M., L.K.); Sleep Research Institute, Madrid (D.G.-B.); the Department of Pulmonary Medicine, Tampere University Hospital, Tampere, Finland (O.P.); and Massachusetts General Hospital, Boston (J.W.W.).",
"authors": "Allen|Richard P|RP|;Chen|Crystal|C|;Garcia-Borreguero|Diego|D|;Polo|Olli|O|;DuBrava|Sarah|S|;Miceli|Jeffrey|J|;Knapp|Lloyd|L|;Winkelman|John W|JW|",
"chemical_list": "D000927:Anticonvulsants; D052160:Benzothiazoles; D018491:Dopamine Agonists; D000069583:Pregabalin; D005680:gamma-Aminobutyric Acid; D000077487:Pramipexole",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1303646",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "370(7)",
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"abstract": "Triple-negative breast cancers are often characterized by aggressive behavior and short clinical course once they become chemotherapy-resistant. We describe below a patient who has shown a response to combination of chemotherapy with Elenagen, a plasmid encoding p62. Elenagen was tested in a previous phase I/II study in patients with refractory solid tumors and shown to be safe. Also, plasmid ability to halt tumor progression and restore sensitivity to chemotherapy was found. Preclinical data supports effects on tumor grade and change the tumor's microenvironment in spontaneous canine breast cancers. We describe here a 48-year old female with triple-negative and BRCA1/2-negative breast cancer who had a primary resistance to chemotherapy and negative dynamics despite the use of multiple lines of treatments. Elenagen was applied intramuscularly at a dose of 1 mg weekly in combination with standard chemotherapy scheme CMF (cyclophosphamide, methotrexate, fluorouracil). In this patient we observed partial tumor regression (by 33%) and 19 weeks of progression-free survival. This first observed objective response to a combination of Elenagen with chemotherapy demonstrates that even in heavily pretreated chemo-resistant triple-negative tumor, the addition of Elenagen to a chemotherapy regimen can cause an objective response and increase in progression-free survival. Such a regimen is worthy of further study in a larger number of patients.",
"affiliations": "Irkutsk State Medical Academy of Postgraduate Education, Irkutsk Regional Cancer Dispensary, Irkutsk, Russian Federation.;CureLab Oncology, Inc, Dedham, MA, USA.;Federal Center of Neurosurgery, Tyumen, Russian Federation.;Russian Academy of Sciences, Moscow, Russian Federation.;CureLab Oncology, Inc, Dedham, MA, USA.",
"authors": "Ponomarenko|Dmitry M|DM|;Gabai|Vladimir L|VL|;Sufianov|Albert A|AA|;Kolesnikov|Sergey I|SI|;Shneider|Alexander M|AM|",
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"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 2732310.18632/oncotarget.27323Research PaperResponse of a chemo-resistant triple-negative breast cancer patient to a combination of p62-encoding plasmid, Elenagen, and CMF chemotherapy Ponomarenko Dmitry M. 1Gabai Vladimir L. 23*Sufianov Albert A. 45Kolesnikov Sergey I. 678Shneider Alexander M. 259*1Irkutsk State Medical Academy of Postgraduate Education, Irkutsk Regional Cancer Dispensary, Irkutsk, Russian Federation2CureLab Oncology, Inc, Dedham, MA, USA3Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA4Federal Center of Neurosurgery, Tyumen, Russian Federation5Sechenov First Moscow State Medical University, Moscow, Russian Federation6Russian Academy of Sciences, Moscow, Russian Federation7Lomonosov Moscow State University, Moscow, Russian Federation8Research Center of Family Health and Reproduct ion Problems, Irkutsk, Russian Federation9Department of Molecular Biology, Ariel University, Ariel, IsraelCorrespondence to:Alexander M. Shneider, ashneider@curelab.com* These authors have contributed equally to this work\n\n21 1 2020 21 1 2020 11 3 294 299 14 9 2019 19 10 2019 Copyright: © 2019 Ponomarenko et al.2019This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Triple-negative breast cancers are often characterized by aggressive behavior and short clinical course once they become chemotherapy-resistant. We describe below a patient who has shown a response to combination of chemotherapy with Elenagen, a plasmid encoding p62. Elenagen was tested in a previous phase I/II study in patients with refractory solid tumors and shown to be safe. Also, plasmid ability to halt tumor progression and restore sensitivity to chemotherapy was found. Preclinical data supports effects on tumor grade and change the tumor’s microenvironment in spontaneous canine breast cancers. We describe here a 48-year old female with triple-negative and BRCA1/2-negative breast cancer who had a primary resistance to chemotherapy and negative dynamics despite the use of multiple lines of treatments. Elenagen was applied intramuscularly at a dose of 1 mg weekly in combination with standard chemotherapy scheme CMF (cyclophosphamide, methotrexate, fluorouracil). In this patient we observed partial tumor regression (by 33%) and 19 weeks of progression-free survival. This first observed objective response to a combination of Elenagen with chemotherapy demonstrates that even in heavily pretreated chemo-resistant triple-negative tumor, the addition of Elenagen to a chemotherapy regimen can cause an objective response and increase in progression-free survival. Such a regimen is worthy of further study in a larger number of patients.\n\ncancer immunotherapycancer chemotherapyp62 plasmidcancer vaccine\n==== Body\nINTRODUCTION\nBreast cancer is one of the most common tumors, and every year more than two million women in the world are diagnosed with it (https://www.wcrf.org/dietandcancer/cancer-trends/breast-cancer-statistics). Most breast cancers are not hereditary: frequency of hereditary predisposition of breast cancer is about 25% of all cases. Among the subtypes of breast cancer, triple-negative breast cancers (TNBC) which does not express estrogen, progesterone and HER2 receptors account for 15% of cases and are characterized by low levels of differentiation of tumor cells and rapid aggressive growth [1, 2].\n\nFor such receptor-negative cancers, chemotherapy is the method of choice, but there is no single standard approach [3]. Poly-chemotherapy is characterized by an increase in the number of objective responses and time to progression, while mono-chemotherapy is associated with lower toxicity [4, 5]. Given that the results of overall survival are comparable when using mono - or poly-chemotherapy, in patients without rapid progression, preference should be given to mono-chemotherapy. With TNBC, the greatest efficiency is demonstrated by taxanes and anthracyclines [6, 7].\n\nImmunotherapy of cancer has become one of the leading new methods of treatment. In anti-tumor immunotherapy there are two main approaches. The first is the creation of adaptive antitumor immunity against tumor-specific antigens, i.e. stimulating in patient's body more T-and B-lymphocytes against targets mainly represented in cancer cells, but not in other parts of the body. This direction, in particular, includes DNA vaccines [8, 9]. Another approach is to change the intra-tumor environment and reduce its immunosuppressive properties, and for this the Nobel Prize was awarded in 2018 [10, 11]. In addition, it became clear that the classical chemotherapy regimens, originally created in the paradigm of selectively killing of rapidly dividing cells, also significantly act through stimulation and/or modulation of the immune response [12, 13] and therefore can be considered as some sort of immunotherapy as well. It can be expected that the increasing role of the immune mechanism in the action of chemotherapy regimens will be revealed in the coming years.\n\nElenagen is a plasmid DNA encoding protein p62/SQSTM. p62 is directly involved in tumor transformation as a regulator of autophagy, an inducer of anti-oxidant proteins, and a modulator of mitotic transit and genomic stability [14, 15, 16]. Initially, the use of the p62 encoding vector was proposed as a classical DNA vaccine, based on the fact that p62 is overexpressed in a wide range of cancers in humans and mouse models [17, 18]. However, it soon became clear that the effect of Elenagen may also be based on its ability to reduce chronic inflammation, manifested in animal models of osteoporosis, metabolic syndrome, and age-related macular degeneration [19–21].\n\nRecent data obtained on spontaneous breast cancer in dogs demonstrates that the use of Elenagen can drastically change the internal structure of the tumor, which can make the tumor more susceptible to therapeutic effects of anticancer treatment (Venanzi, submitted).\n\nElenagen shows antitumor activity in rodent cancer models and spontaneous tumors in dogs [17, 22], as well as in the phase I/IIa study in patients with disseminated solid tumors that have exhausted standard therapies. Elenagen demonstrated a good safety profile and the ability to stop tumor growth [23].\n\nWe present here a case of a robust response to Elenagen in a patient with metastatic TNBC who has been steadily progressing after multiple lines of chemotherapy.\n\nCLINICAL CASE\nA 46-year old female was diagnosed with breast cancer in September 2016. The same month, a radical resection of the right breast with lymphadenectomy was performed. The immuno-morphological study identified invasive unspecified breast cancer G3, with negative status of ER, PR and HER2. Ki67 proliferation index was very high, about 80%. The tumor was staged as pT1pN1M0. Molecular genetic testing of BRCA1 and BRCA2 genes revealed no mutations.\n\nThe first course of adjuvant chemotherapy was performed from Nov 2016 to Apr 2017 (Table 1), however, immediately after its completion, a relapse in the remaining part of the breast was diagnosed. A right-sided mastectomy was performed in May 2017 followed by a biopsy of supraclavicular lymph nodes in June 2017; the progression of triple-negative breast cancer was established according to the results of morphological studies. Afterwards, 5 additional rounds of chemotherapy using different drugs and their combinations were performed, but the cancer was unresponsive and progressing (Table 1).\n\nTable 1 Lines of chemotherapy applied for treatment of the patient\n\tDates\tDrug scheme\tResult\t\n1\tNov 2016- Apr 2017\tAdryamicin+cyclophosphamide (x4), paclitaxel+carbloplatin (x4)\tLocal recurrence\t\n2\tJune-Aug 2017\tBevacizumab+capetacibine\tProgression\t\n3\tSept-Oct 2017\tEribulin (x2)\tProgression\t\n4\tNov-Dec 2017\tGemcitabine+cisplatinum\tProgression\t\n5\tJan-Feb 2018\tDocetaxel (x2)\tProgression\t\n6\tFeb-Apr 2018\tVinorelbin+capetacebin\tProgression\t\n7\tApr-Aug 2018\tElenagen+cyclophosphamide+methotrexate+fluorouracil\tPartial response\t\nThe last chemotherapy regimen before Elenagen treatment, the combination of capecitabine and vinorelbine, was started on Feb 2018 (Table 1). According to the results of the clinical evaluation and MSCT (multi-slice computer tomography) in April 2018, there was a progression of the tumor with multiple lesions of the lymph nodes of the upper mediastinum, right and left axillary, parasternal, supra - and subclavian. Also, there was a soft tissue formation of the chest wall with dimensions of 65,7x42,5 mm and multiple skin metastases and infiltrative lesions of the skin with tumor lymphangitis (Figure 1, Supplementary Figure 1). Due to its inefficiency, this chemotherapy with capecitabine and vinorelbine was cancelled.\n\nFigure 1 MSCT before the treatment with Elenagen and CMF chemotherapy (the lesion in chest soft tissue in upper left end is marked)\nElenagen was started on Apr 2018 along with a standard CMF chemotherapy regimen: cyclophosphamide 600 mg/m2 i.v., methotrexate 40 mg/m2 i.v., fluorouracil 600 mg/m2 i.v., days 1st and 8th, 2-wk interval between courses. Elenagen was injected intramuscularly at a dose of 1 mg weekly, regardless of the timing of the chemotherapy administered. In general, there was a satisfactory tolerability of therapy. Reported adverse effects were: nausea grade 1-2 CTCE, which is usual for courses of the chemotherapy; leucopenia and neutropenia up to grades 2-3, occasionally requiring a postponement of the administration of the chemotherapy; some short-term pain in the projection of the affected lymph nodes (grade 2) 7 weeks from the start of therapy.\n\nA positive dynamic was recorded in June 2018 after two months of Elenagen-CMF treatment. It included improving clinical symptoms, reducing skin itching in places of skin lesions, reducing the area of the wound surface and the number of wound discharge, and reducing the size of visual formations and hyperemia of the affected skin (Supplementary Figure 1). According to MSCT data, there was a decrease in the size of the sum of the diameters of targeted foci by 33%, and there were no new manifestations of the tumor, thus the tumor response is regarded as a partial regression (Figure 2, Supplementary Figure 1). Therefore, it was decided to continue CMF in combination with Elenagen immunotherapy.\n\nFigure 2 MSCT two months after Elenagen and CMF chemotherapy treatment\nThe lesion in chest soft tissue in upper left end is decreased in size.\n\nAfter two more months (Aug, 2019), control examination revealed tumor progression due to the resumption of growth of previously existing tumor foci (not shown). Based on this, it was decided to change the chemotherapy regimen to palitaxel/carboplatin with weekly administration of Elenagen, however, with examination in October 2018, the progression of the tumor, the growth of existing foci, and the emergence of a new liver metastasis were revealed. The patient was transferred to symptomatic palliative care and died 3 months later.\n\nDISCUSSION\nWe describe a clinical case of using plasmid DNA, encoding р62/SQSTM1 protein, Elenagen, in a patient with metastatic TNBC, whose tumor was progressing after treatment with multiple lines of chemotherapy. The patient didn’t react to any “classicalˮ cytotoxic therapy, but when Elenagen was added she achieved a partial regression of the tumor and progression-free survival for 19 weeks.\n\nFor triple-negative cancers, chemotherapy is the method of choice, but there is no single standard approach [3]. During chemotherapy, resistance inevitably develops over time. Feasibility of further use of cytostatics is questionable if a disease is progressing after 2-3 consecutive lines of chemotherapy including taxanes and anthracyclines. In the absence of a standard, the optimal tactics for further management of the patient is selected individually, taking into account the general conditions, manifestations of toxicity and preferences of the patient. Thus, new approaches, drugs, and therapeutic regimens are urgently needed.\n\nGermline mutations in BRCA1 or BRCA2 (BRCA1/2) are present in approximately 10% of patients with TNBC which make them sensitive to alkylating agents (e.g. platinum) or PARP inhibitors [1]. In our case, the TNBC patient had no BRCA1/2 mutations, and there was primary resistance to all types of chemotherapy tested. The effect of Elenagen on tumor regression was observed when combined with CMF chemotherapy although CMF by itself cannot be considered today as an option for a highly effective treatment. However, we observed an objective response (partial tumor regression), and the progression-free survival of 19 weeks. This result was achieved after the patient’s history of different treatment options using monotherapy and combinations of anthracyclines, cyclophosphamide, taxanes, platinum, bevacizumab, eribulin, vinorelbin and capecitabine (Table 1). At the same time, with all the previous therapies, there was no objective response and there was a continuous progression of the tumor. Thus, apparently Elenagen may restore/increase tumor sensitivity to chemotherapy.\n\nThere may be at least two mechanisms to explain the observed effect of Elenagen with CMF. The first is that chemotherapy, killing immune-suppressor cells, increases the immune response to Elenagen as a cancer vaccine encoding p62 as a tumor-specific antigen. Because of this, it seems promising to combine the known chemotherapy with drugs that reduce intra-tumor immunosuppression [24]. The second is that Elenagen treatment, via changing the microenviroment (e.g. decreasing inflammation), increases the cytotoxic response to anticancer drugs (e.g., by increasing their delivery [25]. The degree of effectiveness of such combinatory schemes can be quite synergistic.\n\nThis case demonstrates the feasibility of further studying, in a larger number of patients, the application of Elenagen concomitantly with chemotherapy to treat heavily pretreated chemo-resistant triple-negative breast cancer patients.\n\nSUPPLEMENTARY MATERIALS AND FIGURES\n \nAuthor contributions\n\n\nD.M.P collected, analyzed data and wrote the draft of the paper; VLG analyzed the data and wrote the paper; AAS and SIK discussed the data and edited the paper; AMS designed the study, analyzed the data and edited the paper. All authors read and approved the final manuscript.\n\n\nCONFLICTS OF INTEREST\n\n\nV.L.G and A.M.S are employees of CureLab Oncology Inc. Other authors have no competing interests.\n\n\nDECLARATION\n\n\n\nEthics approval and consent to participate\n\n\nThe clinical trial of Elenagen followed Declaration of Helsinki and Good Clinical Practice Guidelines. It was approved by Ethics Committee and registered by Russian Ministry of Health on 09.09.2014 (Clinical trial #506, Protocol E001).\n\nWritten informed consent for participation in the study was obtained from the patient.\n\n\nConsent for publication\n\n\nWritten informed consent was obtained from the patient’s family for publication of this case report and any accompanying images.\n\n\nFUNDING\n\n\nNo funding was obtained for this study.\n\nAbbreviations\nMSCTmultispiral computed tomography\n\nTNBCtriple-negative breast cancer\n==== Refs\nREFERENCES\n1. \n\nGarrido-Castro \nAC \n, \nLin \nNU \n, \nPolyak \nK \n. 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Trial Watch: DNA vaccines for cancer therapy .\nOncoImmunology . 2014 ; 3 : e28185 . 10.4161/onci.28185 .\n24800178 \n10. \n\nHoos \nA \n. Development of immuno-oncology drugs — from CTLA4 to PD1 to the next generations .\nNature Reviews Drug Discovery . 2016 ; 15 : 235 . 10.1038/nrd.2015.35 .\n26965203 \n11. \n\nShin \nDS \n, \nRibas \nA \n. The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? \nCurrent Opinion in Immunology . 2015 ; 33 : 23– \n35 . 10.1016/j.coi.2015.01.006 .\n25621841 \n12. \n\nBloy \nN \n, \nBuqué \nA \n, \nAranda \nF \n, \nCastoldi \nF \n, \nEggermont \nA \n, \nCremer \nI \n, \nSautès-Fridman \nC \n, \nFucikova \nJ \n, \nGalon \nJ \n, \nSpisek \nR \n, \nTartour \nE \n, \nZitvogel \nL \n, \nKroemer \nG \n, et al. Trial watch: Naked and vectored DNA-based anticancer vaccines .\nOncoImmunology . 2015 ; 4 : e1026531 . 10.1080/2162402x.2015.1026531 .\n26155408 \n13. \n\nSwart \nM \n, \nVerbrugge \nI \n, \nBeltman \nJB \n. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy .\nFront Oncol . 2016 ; 6 : 233 . 10.3389/fonc.2016.00233 .\n27847783 \n14. \n\nKatsuragi \nY \n, \nIchimura \nY \n, \nKomatsu \nM \n. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor .\nFEBS Journal . 2015 ; 282 : 4672 –8 . 10.1111/febs.13540 .\n26432171 \n15. \n\nMoscat \nJ \n, \nKarin \nM \n, \nDiaz-Meco \nMT \n. p62 in Cancer: Signaling Adaptor Beyond Autophagy .\nCell . 2016 ; 167 :606 –9 . 10.1016/j.cell.2016.09.030 .\n27768885 \n16. \n\nSánchez-Martín \nP \n, \nSaito \nT \n, \nKomatsu \nM \n. p62/SQSTM1: ‘Jack of all trades’ in health and cancer .\nThe FEBS Journal . 2019 ; 286 : 8 –23 . 10.1111/febs.14712 .\n30499183 \n17. \n\nVenanzi \nF \n, \nShifrin \nV \n, \nSherman \nMY \n, \nGabai \nV \n, \nKisilev \nO \n, \nKomissarov \nA \n, \nGrudinin \nM \n, \nShartakova \nM \n, \nRomanovskaya-Romanko \nE \n, \nKudryavets \nY \n, \nBezdenezhnykh \nN \n, \nLykhova \nO \n, \nSemesyuk \nN \n, et al. Broad-spectrum anti-tumor and anti-metastatic DNA vaccine based on p62-encoding vector .\nOncotarget . 2013 ; 4 : 1829 –35 . 10.18632/oncotarget.1397 .\n24121124 \n18. \n\nGabai \nVL \n, \nShifrin \nVI \n. Feasibility analysis of p62 (SQSTM1) – encoding DNA vaccine as a novel cancer immunotherapy .\nInternational Reviews of Immunology . 2014 ; 33 : 375 –82 . 10.3109/08830185.2014.954699 .\n25277339 \n19. \n\nHalenova \nT \n, \nSavchuk \nO \n, \nOstapchenko \nL \n, \nChursov \nA \n, \nFridlyand \nN \n, \nKomissarov \nAB \n, \nVenanzi \nF \n, \nKolesnikov \nSI \n, \nSufianov \nAA \n, \nSherman \nMY \n, \nGabai \nVL \n, \nShneider \nAM \n. P62 plasmid can alleviate diet-induced obesity and metabolic dysfunctions .\nOncotarget . 2017 ; 8 : 56030 –40 . 10.18632/oncotarget.19840 .\n28915571 \n20. \n\nKolosova \nNG \n, \nKozhevnikova \nOS \n, \nTelegina \nDV \n, \nFursova \nAZ \n, \nStefanova \nNA \n, \nMuraleva \nNA \n, \nVenanzi \nF \n, \nSherman \nMY \n, \nKolesnikov \nSI \n, \nSufianov \nAA \n, \nGabai \nVL \n, \nShneider \nAM \n. p62 /SQSTM1 coding plasmid prevents age related macular degeneration in a rat model .\nAging (Albany NY) . 2018 ; 10 : 2136 –47 . 10.18632/aging.101537 .\n30153656 \n21. \n\nSabbieti \nMG \n, \nAgas \nD \n, \nCapitani \nM \n, \nMarchetti \nL \n, \nConcetti \nA \n, \nVullo \nC \n, \nCatone \nG \n, \nGabai \nV \n, \nShifrin \nV \n, \nSherman \nMY \n, \nShneider \nA \n, \nVenanzi \nFM \n. Plasmid DNA-coding p62 as a bone effective anti-inflammatory/anabolic agent .\nOncotarget . 2015 ; 6 : 3590 –9 . 10.18632/oncotarget.2884 .\n25668818 \n22. \n\nGabai \nV \n, \nVenanzi \nFM \n, \nBagashova \nE \n, \nRud \nO \n, \nMariotti \nF \n, \nVullo \nC \n, \nCatone \nG \n, \nSherman \nMY \n, \nConcetti \nA \n, \nChursov \nA \n, \nLatanova \nA \n, \nShcherbinina \nV \n, \nShifrin \nV \n, et al. Pilot study of p62 DNA vaccine in dogs with mammary tumors .\nOncotarget . 2014 ; 5 : 12803 –10 . 10.18632/oncotarget.2516 .\n25296974 \n23. \n\nPonomarenko \nDM \n, \nKlimova \nID \n, \nChapygina \nYA \n, \nDvornichenko \nVV \n, \nZhukova \nNV \n, \nOrlova \nRV \n, \nManikhas \nGM \n, \nZyryanov \nAV \n, \nBurkhanova \nLA \n, \nBadrtdinova \nII \n, \nOshchepkov \nBN \n, \nFilippova \nEV \n, \nOrlov \nSV \n, et al. Safety and efficacy of p62 DNA vaccine ELENAGEN in a first-in-human trial in patients with advanced solid tumors .\nOncotarget . 2017 ; 8 : 56030– \n40 . 10.18632/oncotarget.16574 .\n28881846 \n24. \n\nGalluzzi \nL \n, \nBuqué \nA \n, \nKepp \nO \n, \nZitvogel \nL \n, \nKroemer \nG \n. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents .\nCancer Cell . 2015 ; 28 : 690 –714 . 10.1016/j.ccell.2015.10.012 .\n26678337 \n25. \n\nGkretsi \nV \n, \nZacharia \nLC \n, \nStylianopoulos \nT \n. Targeting Inflammation to Improve Tumor Drug Delivery .\nTrends Cancer . 2017 ; 3 : 621 –30 . https://doi.org/10.1016/j.trecan.2017.07.006.\n28867166\n\n",
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"keywords": "cancer chemotherapy; cancer immunotherapy; cancer vaccine; p62 plasmid",
"medline_ta": "Oncotarget",
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"nlm_unique_id": "101532965",
"other_id": null,
"pages": "294-299",
"pmc": null,
"pmid": "32076489",
"pubdate": "2020-01-21",
"publication_types": "D016428:Journal Article",
"references": "24800178;24121124;28915571;26432171;27401886;27768885;22997442;26965203;30153656;30499183;18561551;26678337;27847783;21198665;26155408;30679171;25621841;25277339;28881846;25668818;17671126;24717572;28867166;25296974;28643430",
"title": "Response of a chemo-resistant triple-negative breast cancer patient to a combination of p62-encoding plasmid, Elenagen, and CMF chemotherapy.",
"title_normalized": "response of a chemo resistant triple negative breast cancer patient to a combination of p62 encoding plasmid elenagen and cmf chemotherapy"
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{
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}
},
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{
"abstract": "Angiosarcoma is a rare and aggressive type of sarcoma, and primary angiosarcoma of the ovary is extremely rare. We report the case of a 29-year-old woman who was diagnosed with ovarian angiosarcoma and possible bone metastases. We treated this patient with a gemcitabine-based regimen as postoperative adjuvant chemotherapy, after which she achieved at least 7 years of progression-free survival, an extremely long duration given the aggressive features of this tumour. We retrospectively performed immunohistochemical analyses and fluorescence in situ hybridization to make a pathology diagnosis and to investigate the tumour features. MYC amplification and c-Myc protein overexpression were positively detected. It might be possible to correlate the effectiveness of the gemcitabine-based chemotherapeutic regimen with MYC gene amplification and c-Myc protein overexpression.",
"affiliations": "Obstetrics and Gynecology, Shizuoka Saiseikai General Hospital, Shizuoka, Japan.;Cell Biology and Anatomy, Hamamatsu University School of Medicine, Shizuoka, Japan.;Obstetrics and Gynecology, Shizuoka Saiseikai General Hospital, Shizuoka, Japan.;Obstetrics and Gynecology, Shizuoka Saiseikai General Hospital, Shizuoka, Japan.;Obstetrics and Gynecology, Shizuoka Saiseikai General Hospital, Shizuoka, Japan.;Obstetrics and Gynecology, Shizuoka Saiseikai General Hospital, Shizuoka, Japan.;Pathology, Shizuoka Saiseikai General Hospital, Shizuoka, Japan.",
"authors": "Yonezawa|I|I|;Waki|M|M|;Tamura|Y|Y|;Onoda|R|R|;Narushima|M|M|;Ishizuka|T|T|;Tajima|S|S|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3747/co.21.2144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-0052",
"issue": "21(6)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Angiosarcoma; MYC; chemotherapy; gemcitabine; mucinous cystadenoma; surgical resection",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "e782-9",
"pmc": null,
"pmid": "25489268",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": "24371666;9952341;2044784;24457083;10366476;8188092;10609500;12354365;8894742;24520828;15626914;21752298;2651469;25374893;16081151;21447800;24257655;21464156;20823420;19396453;21500201;9421078;22827762;21566149;15830366;9591733;10607929;12574850;20416159;7199374;15943995;11481354;9587937;21151524;21619563;16731607;15117993;19696615;22383169",
"title": "Gemcitabine-based regimen for primary ovarian angiosarcoma with MYC amplification.",
"title_normalized": "gemcitabine based regimen for primary ovarian angiosarcoma with myc amplification"
} | [
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"drugstructuredosagenumb": "70",
"drugstructuredosageunit": "009",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "CISPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infertility female",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YONEZAWA I, WAKI M, TAMURA Y, ONODA R, NARUSHIMA M, ISHIZUKA T, ET AL. GEMCITABINE-BASED REGIMEN FOR PRIMARY OVARIAN ANGIOSARCOMA WITH MYC AMPLIFICATION. CURR-ONCOL 2014; 21(6):E782-E789.",
"literaturereference_normalized": "gemcitabine based regimen for primary ovarian angiosarcoma with myc amplification",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20150623",
"receivedate": "20150604",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11166057,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "OBJECTIVE\nWe assessed the efficacy and safety of combination therapy with glucocorticoids and high-trough level tacrolimus (TAC) for the treatment of acute/subacute interstitial pneumonia (A/SIP) in patients with dermatomyositis (DM).\n\n\nMETHODS\nEleven DM-A/SIP patients were enrolled. The combination therapy with glucocorticoids and TAC was started as early as possible after DM-A/SIP was diagnosed. We monitored the trough concentration of TAC. In the initial 3 months, we maintained the trough concentration of TAC at relatively high levels within a range of 15-20 ng/mL. Then, we decreased the TAC doses stepwise to keep the trough concentration at 10-15 ng/mL in the next 3 months and 5-10 ng/mL as a maintenance dose.\n\n\nRESULTS\nSeven patients had clinically amyopathic DM. Six patients were positive for anti-aminoacyl-tRNA synthetase antibody and two were positive for anti-melanoma differentiation-associated gene 5 antibody. Ten patients survived for the period of the 24-week follow up. One patient died under a tentative diagnosis of viral encephalitis at 4 months after the treatment. In the 10 surviving patients, interstitial pneumonia improved in eight patients and was not worse in two patients. Clinical examinations, including the Krebs von den Lungen-6 levels, % forced vital capacity, and chest computed tomography score, were significantly improved by this combination therapy. Although grade 1 and 2 renal damage occurred in 4 and 2 patients, respectively.\n\n\nCONCLUSIONS\nThe present findings suggest that early therapeutic intervention by a combination with glucocorticoids and initial high-trough level TAC is effective for DM-A/SIP although consideration of the risks of infection and renal damage is required.",
"affiliations": "Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Internal Medicine IV, Osaka Medical College, Takatsuki, Osaka, Japan.",
"authors": "Suzuka|Takayasu|T|;Kotani|Takuya|T|http://orcid.org/0000-0003-2190-0780;Takeuchi|Tohru|T|;Fujiki|Youhei|Y|;Hata|Kenichiro|K|;Yoshida|Shuzo|S|http://orcid.org/0000-0002-7652-9539;Shoda|Takeshi|T|;Makino|Shigeki|S|;Arawaka|Shigeki|S|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1111/1756-185X.13414",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-1841",
"issue": "22(2)",
"journal": "International journal of rheumatic diseases",
"keywords": "dermatomyositis; interstitial pneumonia; tacrolimus; treatment",
"medline_ta": "Int J Rheum Dis",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D003882:Dermatomyositis; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016559:Tacrolimus; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101474930",
"other_id": null,
"pages": "303-313",
"pmc": null,
"pmid": "30398034",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of oral high-trough level tacrolimus in acute/subacute interstitial pneumonia with dermatomyositis.",
"title_normalized": "efficacy and safety of oral high trough level tacrolimus in acute subacute interstitial pneumonia with dermatomyositis"
} | [
{
"companynumb": "JP-ACCORD-093022",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "INITIAL DOSE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DERMATOMYOSITIS",
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"medicinalproduct": "PREDNISOLONE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugdosagetext": "AVERAGE DOSE",
"drugenddate": null,
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"drugindication": "DERMATOMYOSITIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "72",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Encephalitis viral",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SUZUKA T, KOTANI T, TAKEUCHI T, FUJIKI Y, HATA K, YOSHIDA S, ET AL. EFFICACY AND SAFETY OF ORAL HIGH-TROUGH LEVEL TACROLIMUS IN ACUTE/SUBACUTE INTERSTITIAL PNEUMONIA WITH DERMATOMYOSITIS. INT J RHEUM DIS. 2018 NOV 5.",
"literaturereference_normalized": "efficacy and safety of oral high trough level tacrolimus in acute subacute interstitial pneumonia with dermatomyositis",
"qualification": "3",
"reportercountry": "JP"
},
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"receiptdate": "20181124",
"receivedate": "20181124",
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
}
] |
{
"abstract": "A 51-year-old male with untreated hepatitis C infection, cirrhosis, and dilated cardiomyopathy with a HeartMate II LVAD presented with right heart failure and cardiogenic shock, INR of 7, hemolysis, and renal failure. Acute LVAD thrombosis was suspected. Alteplase was injected into the inflow cannula of the LVAD with little effect. Intravenous alteplase was given but failed to restore an adequate pump output, resulting in the need for emergency pump exchange. The patient had an uncomplicated postoperative recovery and was discharged uneventfully. Inspection of the pump identified a thrombus wedged between the spines of the impeller. Our case highlights the challenges in managing pump thrombosis which is often resistant to thrombolysis and may instead rely upon prompt surgical intervention to be resolved.",
"affiliations": "Department of Cardiothoracic Surgery, Mount Sinai Medical Center, New York, New York 10029, USA.",
"authors": "Tang|Gilbert H L|GH|;Kim|Michael C|MC|;Pinney|Sean P|SP|;Anyanwu|Anelechi C|AC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ccd.24523",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-1946",
"issue": "81(6)",
"journal": "Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions",
"keywords": null,
"medline_ta": "Catheter Cardiovasc Interv",
"mesh_terms": "D020878:Device Removal; D017809:Fatal Outcome; D006331:Heart Diseases; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D011474:Prosthesis Design; D011475:Prosthesis Failure; D012770:Shock, Cardiogenic; D015912:Thrombolytic Therapy; D013927:Thrombosis; D017211:Treatment Failure; D016896:Treatment Outcome; D016277:Ventricular Function, Left",
"nlm_unique_id": "100884139",
"other_id": null,
"pages": "1072-4",
"pmc": null,
"pmid": "22718366",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Failed repeated thrombolysis requiring left ventricular assist device pump exchange.",
"title_normalized": "failed repeated thrombolysis requiring left ventricular assist device pump exchange"
} | [
{
"companynumb": "US-ROCHE-1252484",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
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"drugdosageform": "INFUSION",
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"medicinalproduct": "HEPARIN"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MILRINONE"
},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "MILRINONE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "103172",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": "OVER 90 MIN",
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"medicinalproduct": "ACTILYSE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
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"drugadministrationroute": "042",
"drugauthorizationnumb": "103172",
"drugbatchnumb": null,
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"drugdosageform": "SOLUTION FOR INFUSION",
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"drugindication": "THROMBOSIS IN DEVICE",
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"medicinalproduct": "ACTILYSE"
}
],
"patientagegroup": null,
"patientonsetage": "51",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TANG G, KIM M, PINNEY S AND ANYANWU A. FAILED REPEATED THROMBOLYSIS REQUIRING LEFT VENTRICULAR ASSIST DEVICE PUMP EXCHANGE. . CATHET CARDIOVASC INTERVENT 2013 JAN 01;81(6):1072-1074.",
"literaturereference_normalized": "failed repeated thrombolysis requiring left ventricular assist device pump exchange",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170112",
"receivedate": "20170112",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13110100,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170428"
}
] |
{
"abstract": "OBJECTIVE\nTo improve the interpretation of fatal intoxications by establishing fatal and non-fatal reference concentrations of metformin in postmortem femoral blood and to further evaluate risk factors associated with fatal metformin intoxication.\n\n\nMETHODS\nAll forensic autopsies in Sweden where metformin was detected in femoral blood 2011-2016 were identified in the National Board of Forensic Medicine databases (NFMD). The cases were classified as single substance intoxications, A (n = 22), multiple substance intoxications, B (N = 7) and postmortem controls, C (N = 13). The control group consisted of cases where metformin was detected, but the cause of death excluded the incapacitation by metformin or other substances. Strict inclusion criteria were used, and all postmortem cases were assessed by two independent reviewers. All other cases where the inclusion criteria of groups A-C where not met formed group O (N = 78). The forensic findings logged in the NFMD where linked to national registers whereby information on comorbidities, dispensed drugs and clinical data could be obtained.\n\n\nRESULTS\nThe mean age was 66 ± 10 years in the total study population and did not differ between the groups. The proportion of men was 64% in group A, 71% in B, 77% in C and 74% in group O. The median values of metformin in group A (48.5 μg/g; range 13.0-210 μg/g) and B (21.0 μg/g; range 4.40-95.0 μg/g) were significantly (p < 0.001 and p = 0.015 respectively) higher than those of the control group C (2.30 μg/g ; range 0.70-21.0 μg/g). The median concentration of metformin in group A and B was also significantly higher than in group O (4.60 μg/g; range 0.64-54.0 μg/g) (p < 0.001 and p = 0.040 respectively). The results suggest that intoxication with metformin as a cause of death should be considered when the postmortem femoral blood level exceeds about 10 μg/g, although higher levels may be seen in postmortem in cases without incapacitation. The metformin intoxication was confirmed to be intentional in 23% (n = 5) of the single intoxications. Underlying factors identified as important for the remaining fatal metformin intoxications included living alone, any contraindication for the use of metformin, known alcohol abuse and a history of stroke or cardiovascular disease.\n\n\nCONCLUSIONS\nThe reported post mortem femoral blood concentrations of metformin can hopefully contribute to a better interpretation of results in suspected poisonings and obscure cases. Living in a single household, history of cardiovascular disease and contraindications, predominantly alcohol abuse, were associated with fatal metformin intoxication.",
"affiliations": "Forensic Medicine Laboratory, Department of Oncology-Pathology, Karolinska Institutet, SE 171 76 Stockholm, Sweden; MSD, Gävlegatan 22, SE 113 30 Stockholm, Sweden. Electronic address: Lotta.walz@ki.se.;Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, SE 581 85 Linköping, Sweden.;Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, SE 581 85 Linköping, Sweden; Department of Medical and Health Sciences, Linköping University, SE 581 83 Linköping, Sweden.;Department of Medical and Health Sciences, Linköping University, SE 581 83 Linköping, Sweden.;Forensic Medicine Laboratory, Department of Oncology-Pathology, Karolinska Institutet, SE 171 76 Stockholm, Sweden; Department of Forensic Medicine, National Board of Forensic Medicine, SE171 77 Stockholm, Sweden.",
"authors": "Walz|Lotta|L|;Jönsson|Anna K|AK|;Ahlner|Johan|J|;Östgren|Carl Johan|CJ|;Druid|Henrik|H|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2019.109935",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "303()",
"journal": "Forensic science international",
"keywords": "Contraindications; Diabetes; Forensic; Intoxication; Metformin; Risk factors",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000059:Accidents; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism; D002318:Cardiovascular Diseases; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D012042:Registries; D012189:Retrospective Studies; D012307:Risk Factors; D012934:Social Isolation; D020521:Stroke; D013405:Suicide; D013548:Sweden",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "109935",
"pmc": null,
"pmid": "31491622",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Metformin - Postmortem fatal and non-fatal reference concentrations in femoral blood and risk factors associated with fatal intoxications.",
"title_normalized": "metformin postmortem fatal and non fatal reference concentrations in femoral blood and risk factors associated with fatal intoxications"
} | [
{
"companynumb": "SE-TEVA-2019-SE-1121984",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "075979",
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"drugcharacterization": "1",
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"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "DIABETES MELLITUS",
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"medicinalproduct": "METFORMIN"
}
],
"patientagegroup": null,
"patientonsetage": "80",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WALZ L, JONSSON AK, AHLNER J, OSTGREN CJ, DRUID H. METFORMIN - POSTMORTEM FATAL AND NON-FATAL REFERENCE CONCENTRATIONS IN FEMORAL BLOOD AND RISK FACTORS ASSOCIATED WITH FATAL INTOXICATIONS. FORENSIC-SCI-INT 2019?:.",
"literaturereference_normalized": "metformin postmortem fatal and non fatal reference concentrations in femoral blood and risk factors associated with fatal intoxications",
"qualification": "3",
"reportercountry": "SE"
},
"primarysourcecountry": "SE",
"receiptdate": "20191015",
"receivedate": "20191015",
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200122"
},
{
"companynumb": "SE-BAUSCH-BL-2019-054680",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALCOHOL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "3",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "ALCOHOL."
},
{
"actiondrug": "5",
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
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{
"abstract": "Children with acute myelogenous leukemia (AML) have a high risk of infectious complications that might be reduced by prophylactic granulocyte colony-stimulating factor (G-CSF). However, G-CSF could induce AML blast proliferation. The prospective randomized trial AML-BFM 98 investigated the impact of G-CSF on hematopoetic recovery and infectious complications (primary endpoints) and on outcome (secondary endpoint) in children (aged 0-18 years) with de novo AML. Patients with more than 5% blasts in day-15 bone marrow or with FAB M3 were not included. Between 1998 and 2003, 161 children with AML were randomized to receive G-CSF after inductions 1 and 2, whereas 156 patients were assigned to the control group. Time of neutropenia after inductions 1 and 2 was significantly shorter in the G-CSF group (23 vs 18 days and 16 vs 11 days; P=.02 and=.001, respectively). G-CSF did not decrease the incidence of febrile neutropenia (72 and 36 patients vs 78 and 37 patients, respectively), microbiologically documented infections (27 and 25 patients vs 36 and 19 patients, respectively) and infection-associated mortality (5 vs 2 patients). Both groups had similar 5-year event-free survival (EFS; 59%+/-4% vs 58%+/-4%). Since G-CSF does not influence the risk of infectious complications or outcome in children undergoing therapy for AML, one cannot advocate the routine use of G-CSF in this patient group.",
"affiliations": "Pediatric Hematology and Oncology, University of Frankfurt, Germany, and Children's Cancer Research Institute, St Anna Kinderspital, Vienna, Austria. thomas.lehrnbecher@kgu.de",
"authors": "Lehrnbecher|Thomas|T|;Zimmermann|Martin|M|;Reinhardt|Dirk|D|;Dworzak|Michael|M|;Stary|Jan|J|;Creutzig|Ursula|U|",
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"doi": "10.1182/blood-2006-07-035915",
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"issn_linking": "0006-4971",
"issue": "109(3)",
"journal": "Blood",
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"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D016179:Granulocyte Colony-Stimulating Factor; D006410:Hematopoiesis; D006801:Humans; D007223:Infant; D017053:Infection Control; D007239:Infections; D015470:Leukemia, Myeloid, Acute; D009503:Neutropenia; D011292:Premedication; D012074:Remission Induction; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
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"pages": "936-43",
"pmc": null,
"pmid": "17008536",
"pubdate": "2007-02-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia.",
"title_normalized": "prophylactic human granulocyte colony stimulating factor after induction therapy in pediatric acute myeloid leukemia"
} | [
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{
"abstract": "OBJECTIVE\nTo describe the outcomes of limbal stem cell transplantation in eyes with limbal stem cell deficiency related to soft contact lens wear.\n\n\nMETHODS\nRetrospective interventional case series.\n\n\nMETHODS\nInstitutional database search at the Cincinnati Eye Institute revealed 9 patients (14 eyes) who underwent limbal stem cell transplantation with systemic immunosuppression for soft contact lens wear-related limbal stem cell deficiency. Outcome measures included patient demographics, symptoms, best-corrected visual acuity, ocular surface stability, adverse events, and additional surgeries required.\n\n\nRESULTS\nAverage patient age at time of surgery was 46.6 ± 11.1 years (range 20-60 years). Average duration of follow-up was 28 ± 19.1 months (range 12-70 months). Preoperative best-corrected visual acuity (BCVA) was 20/40 or worse in all eyes (average 20/70, range 20/40-20/250) and patient symptoms included foreign body sensation, tearing, redness, and/or pain. Four eyes (29%) underwent living-related conjunctival limbal allograft and 10 eyes (71%) underwent cadaver-donor keratolimbal allograft surgery. Topical and systemic immunosuppression was used in all patients. At final follow-up after limbal stem cell transplantation, there was a stable ocular surface in 12 of 14 eyes (86%) and improvement in BCVA to 20/30 or better and complete resolution of patient symptoms in all except 1 patient who had significant rosacea blepharokeratoconjunctivitis, whose BCVA remained at 20/150 and 20/60, in right and left eyes, respectively. The most common adverse event was an increase in intraocular pressure in 8 of 14 eyes (57%), requiring topical antiglaucoma treatment. Ten of 14 eyes (71%) underwent cataract extraction related to topical steroid use. No eyes required subsequent penetrating keratoplasty.\n\n\nCONCLUSIONS\nLimbal stem cell transplantation is a viable option for the management of soft contact lens wear-related limbal stem cell deficiency in young healthy patients. Early intervention prior to subepithelial fibrosis can lead to good visual outcomes with no need for subsequent cornea transplant. Co-management with a solid organ transplant specialist is helpful for the monitoring and management of systemic adverse events related to patient systemic immunosuppression.",
"affiliations": "University of Toronto Medical School, Toronto, Canada.;Cincinnati Eye Institute, Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio. Electronic address: clarachanmd@gmail.com.;Cincinnati Eye Institute, Department of Ophthalmology, University of Cincinnati, Cincinnati, Ohio.",
"authors": "Shen|Carl|C|;Chan|Clara C|CC|;Holland|Edward J|EJ|",
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"country": "United States",
"delete": false,
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"issn_linking": "0002-9394",
"issue": "160(6)",
"journal": "American journal of ophthalmology",
"keywords": null,
"medline_ta": "Am J Ophthalmol",
"mesh_terms": "D000328:Adult; D003263:Contact Lenses, Hydrophilic; D003316:Corneal Diseases; D016039:Corneal Transplantation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016850:Limbus Corneae; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D013997:Time Factors; D014184:Transplantation, Homologous; D014792:Visual Acuity; D055815:Young Adult",
"nlm_unique_id": "0370500",
"other_id": null,
"pages": "1142-1149.e1",
"pmc": null,
"pmid": "26299533",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Limbal Stem Cell Transplantation for Soft Contact Lens Wear-Related Limbal Stem Cell Deficiency.",
"title_normalized": "limbal stem cell transplantation for soft contact lens wear related limbal stem cell deficiency"
} | [
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"drugintervaldosagedefinition": "804",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Hyperbilirubinaemia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHEN C, CHAN CC, HOLLAND EJ. LIMBAL STEM CELL TRANSPLANTATION FOR SOFT CONTACT LENS WEAR-RELATED LIMBAL STEM CELL DEFICIENCY. AM-J-OPHTHALMOL 2015;160(6):1142-1149.",
"literaturereference_normalized": "limbal stem cell transplantation for soft contact lens wear related limbal stem cell deficiency",
"qualification": "3",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20160606",
"receivedate": "20160606",
"receiver": {
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},
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},
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"seriousnessdeath": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160815"
}
] |
{
"abstract": "A previously healthy girl, without heart disease, who ingested 2400 mg of verapamil developed hypotension, trifasicular block pattern, mental confusion, mild metabolic acidosis, and hyperglycemia. She recovered with symptomatic and supportive therapy. A discussion is presented about the action mechanism of the drug.",
"affiliations": null,
"authors": "da Silva|O A|OA|;de Melo|R A|RA|;Jorge Filho|J P|JP|",
"chemical_list": "D014700:Verapamil",
"country": "United States",
"delete": false,
"doi": "10.3109/15563657909010597",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9309",
"issue": "14(4)",
"journal": "Clinical toxicology",
"keywords": null,
"medline_ta": "Clin Toxicol",
"mesh_terms": "D000293:Adolescent; D004562:Electrocardiography; D005260:Female; D006327:Heart Block; D006801:Humans; D013406:Suicide, Attempted; D014700:Verapamil",
"nlm_unique_id": "0205535",
"other_id": null,
"pages": "361-7",
"pmc": null,
"pmid": "466977",
"pubdate": "1979-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Verapamil acute self-poisoning.",
"title_normalized": "verapamil acute self poisoning"
} | [
{
"companynumb": "BR-PFIZER INC-2016014684",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugcumulativedosagenumb": null,
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"drugdosageform": "TABLET",
"drugdosagetext": "2400 MG (60TABLETS), UNK",
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"drugstartdate": "19780129",
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"medicinalproduct": "DILACORON"
}
],
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"patientonsetage": "14",
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"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Atrioventricular block complete",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Metabolic acidosis",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Poisoning deliberate",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hyperglycaemia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Confusional state",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DASILVA, O.. VERAPAMIL ACUTE SELF POISONING. CLINICAL TOXICOLOGY. 1979?14( 4):361-367",
"literaturereference_normalized": "verapamil acute self poisoning",
"qualification": "1",
"reportercountry": "BR"
},
"primarysourcecountry": "BR",
"receiptdate": "20160216",
"receivedate": "20160119",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11928497,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160526"
}
] |
{
"abstract": "Objective:Ovarian cancer (OC) is often diagnosed at an advanced stage with two thirds of patients experiencing recurrent disease with a poor prognosis. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has shown curative potential in malignant melanoma, but has only been investigated scarcely in other cancers. In this pilot study, we tested TIL based ACT in patients with metastatic OC. Methods:Six patients with progressive platinum-resistant metastatic OC were treated with an infusion of TIL preceded by standard lymphodepleting chemotherapy and followed by decrescendo intravenous interleukin-2 (IL-2). Primarily, the feasibility and tolerability of the treatment was assessed. Secondarily, disease control rate was described and immune responses against tumor cells were monitored. Results:Treatment was well tolerated with manageable toxicities. Four patients had stable disease for three months and two patients for five months with five patients having a decrease in target lesions. Progression was primarily due to new lesions while target lesions in general remained stable or in regression. Antitumor reactivity was observed in TIL infusion products from five patients but no antitumor reactivity was detectable in peripheral blood lymphocytes collected after treatment. High numbers of infused TIL expressed exhaustion markers including LAG3 and PD-1, and immunostaining of tumor tissue demonstrated substantial MHCII and PD-L1 expression. Conclusions:ACT with TIL in combination with decrescendo IL-2 is feasible in patients with metastatic OC. Early indications of clinical activity were found. However, TIL ACT efficacy was incomplete with possible involvement of the inhibitory immune checkpoint pathways LAG3/MHCII and PD1/PD-L1.",
"affiliations": "Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Deeley Research Centre, BC Cancer, Victoria, Canada.;Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Department of Gynecology and Obstetrics, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Department of Clinical Physiology and Nuclear Medicine, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Deeley Research Centre, BC Cancer, Victoria, Canada.;Deeley Research Centre, BC Cancer, Victoria, Canada.;Deeley Research Centre, BC Cancer, Victoria, Canada.;Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.;Department of Clinical Immunology and Stem Cell Facility, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Department of Pathology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Deeley Research Centre, BC Cancer, Victoria, Canada.;Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.;Center for Cancer Immune Therapy, Department of Hematology, Herlev Hospital, University of Copenhagen, Herlev, Denmark.",
"authors": "Pedersen|Magnus|M|;Westergaard|Marie Christine Wulff|MCW|;Milne|Katy|K|;Nielsen|Morten|M|0000-0002-1250-4885;Borch|Troels Holz|TH|0000-0002-4402-9281;Poulsen|Lars Grønlund|LG|;Hendel|Helle Westergren|HW|;Kennedy|Mia|M|;Briggs|Gillian|G|;Ledoux|Stacey|S|;Nøttrup|Trine Jakobi|TJ|;Andersen|Pernille|P|;Hasselager|Thomas|T|;Met|Özcan|Ö|0000-0002-3256-7592;Nelson|Brad H|BH|;Donia|Marco|M|;Svane|Inge Marie|IM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/2162402X.2018.1502905",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2162-4011",
"issue": "7(12)",
"journal": "Oncoimmunology",
"keywords": "Adoptive cell therapy; T-cell therapy; TIL therapy; immune therapy; immunotherapy; metastatic ovarian cancer; tumor-infiltrating lymphocytes",
"medline_ta": "Oncoimmunology",
"mesh_terms": null,
"nlm_unique_id": "101570526",
"other_id": null,
"pages": "e1502905",
"pmc": null,
"pmid": "30524900",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12529460;22909342;2451882;22996367;23032743;26069281;20385810;10793106;23690483;2004379;2420446;26351349;7834119;24812403;21498393;25538264;19403881;22722450;24831841;23633484;20491527;17080178;25087573;25823737;18287062;25651787;23770567;19097774;21586688;7494563;15800326;9215828;25838374;12682289;18779745;23381004;23890059;15032595;27006492",
"title": "Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study.",
"title_normalized": "adoptive cell therapy with tumor infiltrating lymphocytes in patients with metastatic ovarian cancer a pilot study"
} | [
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{
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},
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},
{
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},
{
"actiondrug": "5",
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"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "3",
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"drugdosageform": "INJECTION",
"drugdosagetext": "25 MG/M 2 ON DAY -5 TO -1",
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}
],
"patientagegroup": null,
"patientonsetage": "59",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypophosphataemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Lymphopenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hyponatraemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypokalaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PEDERSEN M, WESTERGAARD MCW, MILNE K, NIELSEN M, BORCH TH, POULSEN LG, ET AL. ADOPTIVE CELL THERAPY WITH TUMOR-INFILTRATING LYMPHOCYTES IN PATIENTS WITH METASTATIC OVARIAN CANCER: A PILOT STUDY. ONCOIMM 2018?7(12):E1502905.",
"literaturereference_normalized": "adoptive cell therapy with tumor infiltrating lymphocytes in patients with metastatic ovarian cancer a pilot study",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20190108",
"receivedate": "20190108",
"receiver": {
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"receivertype": "6"
},
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"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "DK-MYLANLABS-2019M1000366",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
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"drugdosagetext": "60 MG/KG ON DAY -7 AND -6",
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"drugindication": "OVARIAN CANCER METASTATIC",
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"medicinalproduct": "CYCLOPHOSPHAMIDE."
},
{
"actiondrug": "5",
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"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "3",
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"drugdosageform": "INJECTION",
"drugdosagetext": "25 MG/M 2 ON DAY -5 TO -1",
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"drugstructuredosageunit": "009",
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"medicinalproduct": "FLUDARABINE"
},
{
"actiondrug": "5",
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"activesubstancename": "FILGRASTIM"
},
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"medicinalproduct": "FILGRASTIM"
},
{
"actiondrug": "5",
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"activesubstancename": "ALDESLEUKIN"
},
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"drugdosagetext": "18 MIU/M 2 FOR 6, 12 AND 24 HOURS FOLLOWED BY 4.5 MIU/M2 FOR 24 HOURS FOR UP TO THREE DAYS",
"drugenddate": null,
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"drugindication": "OVARIAN CANCER METASTATIC",
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}
],
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"patientonsetageunit": "801",
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Hypokalaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hyponatraemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypophosphataemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Lymphopenia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PEDERSEN M, WESTERGAARD MCW, MILNE K, NIELSEN M, BORCH TH, POULSEN LG, ET AL. ADOPTIVE CELL THERAPY WITH TUMOR-INFILTRATING LYMPHOCYTES IN PATIENTS WITH METASTATIC OVARIAN CANCER: A PILOT STUDY. ONCOIMM 2018?7(12):E1502905.",
"literaturereference_normalized": "adoptive cell therapy with tumor infiltrating lymphocytes in patients with metastatic ovarian cancer a pilot study",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20190108",
"receivedate": "20190108",
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"receivertype": "6"
},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "DK-MYLANLABS-2019M1000344",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
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},
"drugadditional": "3",
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"drugauthorizationnumb": null,
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"abstract": "BACKGROUND\nSjogren syndrome (SS) is a common autoimmune disease characterized by lymphocytic infiltration of the exocrine glands with neurological involvement in about 20% of patients. The neurological manifestations in the central nervous system CNS may vary and include a multiple sclerosis (MS)-like disease, and the treatments with immunosuppressive drugs have been undertaken.\n\n\nMETHODS\nWe describe a case of 40-year-old woman with clinical and instrumental evidence of an MS characterized by numerous relapses and demyelinating lesions prevailing in the infratentorial and spinal cord. Immunological analysis showed biological data that were consistent with an SS. The treatment with fingolimod showed not only an optimal response to the demyelinating events but also biological parameters.\n\n\nCONCLUSIONS\nThese data allow us to hypothesize possible combined efficacy of treatment with fingolimod in SS associated with definite MS.",
"affiliations": "Multiple Sclerosis Center, II Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy.",
"authors": "Signoriello|E|E|;Sagliocchi|A|A|;Fratta|M|M|;Lus|G|G|",
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"abstract": "The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose ((18)F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial.",
"affiliations": "Departments of Medical Oncology, University of Würzburg, Würzburg, Germany.;Departments of Nuclear Medicine, University of Würzburg, Würzburg, Germany.;Departments of Nuclear Medicine, University of Würzburg, Würzburg, Germany.;Departments of Medical Oncology, University of Würzburg, Würzburg, Germany.;Departments of Medical Oncology, University of Würzburg, Würzburg, Germany.;Departments of Surgery, University of Würzburg, Würzburg, Germany.",
"authors": "Kunzmann|Volker|V|;Herrmann|Ken|K|;Bluemel|Christina|C|;Kapp|Markus|M|;Hartlapp|Ingo|I|;Steger|Ulrich|U|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000367966cro-0007-0648Published online: September, 2014Intensified Neoadjuvant Chemotherapy with Nab-Paclitaxel plus Gemcitabine Followed by FOLFIRINOX in a Patient with Locally Advanced Unresectable Pancreatic Cancer Kunzmann Volker a*Herrmann Ken bBluemel Christina bKapp Markus aHartlapp Ingo aSteger Ulrich caDepartments of Medical Oncology, University of Würzburg, Würzburg, GermanybDepartments of Nuclear Medicine, University of Würzburg, Würzburg, GermanycDepartments of Surgery, University of Würzburg, Würzburg, Germany*Prof. Dr. med. Volker Kunzmann, Department of Medical Oncology, Medizinische Klinik und Poliklinik II, University of Würzburg, Oberdürrbacher Strasse 6, DE-97080 Würzburg (Germany) E-Mail Kunzmann_V@ukw.deSep-Dec 2014 18 9 2014 18 9 2014 7 3 648 655 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. 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.The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose (18F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial.\n\nKey Words\nPancreatic cancerLocally advanced diseaseNeoadjuvant chemotherapyNab-paclitaxelGemcitabine5-FluorouracilFolinic acidOxaliplatinIrinotecan\n==== Body\nIntroduction\nRoughly 30–40% of patients with pancreatic ductal adenocarcinoma (PDAC) have locally advanced disease. Their prognosis is not really different from that of patients with metastatic PDAC [1]. In about one third of the patients, resectability can be achieved with neoadjuvant chemotherapy and/or chemoradiotherapy. If complete (R0) resection is possible, patients have a similar overall survival (OS) as those with an initially resectable PDAC. These are the results of a meta-analysis of 111 trials with a total of 4,394 patients and mainly 5-fluorouracil- or gemcitabine-based neoadjuvant chemoradiotherapy. Initially nonresectable patients reached an estimated median OS of 20.5 months (range 9–62 months) following resection [1].\n\nRecently, 2 large phase III trials in patients with metastatic PDAC demonstrated encouraging improvements in clinical benefit for 2 combination therapies over single-agent gemcitabine [2, 3]. In one trial, the combination of oxaliplatin, 5-fluorouracil, leucovorin and irinotecan (FOLFIRINOX) significantly improved median OS to 11.1 months as compared to 6.8 months for gemcitabine [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.45–0.73, p < 0.001] and median progression-free survival to 6.4 versus 3.3 months (HR 0.47; 95% CI 0.37–0.59, p < 0.001), respectively. The overall response rate with the combination was 31.6 as compared to 9.4% with gemcitabine alone. There was 1 (0.6%) reported complete response with this combination. The treatment with FOLFIRINOX resulted in significantly more adverse events of grade ≥3 in terms of neutropenia (45.7% for FOLFIRINOX vs. 21.0% for gemcitabine), febrile neutropenia (5.4 vs. 1.2%), thrombocytopenia (9.1 vs. 3.6%), diarrhea (12.7 vs. 1.8%) and peripheral neuropathy (9.0 vs. 0%), while the incidence of alanine aminotransferase elevation was decreased (7.3 vs. 20.8%) [2].\n\nThe combination of nab-paclitaxel plus gemcitabine was studied in the pivotal phase III trial MPACT. A total of 861 patients with metastatic PDAC received first-line chemotherapy either with the combination of nab-paclitaxel at 125 mg/m2 and gemcitabine at 1,000 mg/m2, both administered on days 1, 8, 15, 29, 36, and 43 of a 56-day cycle with subsequent cycles on days 1, 8, and 15 of a 28-day cycle, or with gemcitabine monotherapy at 1,000 mg/m2 weekly for 7 out of 8 weeks in the first cycle and in subsequent cycles on days 1, 8, and 15 of a 28-day cycle. Median OS significantly increased to 8.7 months (95% CI 7.89–9.69) as compared to 6.6 months (95% CI 6.01–7.20) with gemcitabine alone (HR 0.72; 95% CI 0.620–0.825, p < 0.0001) and median progression-free survival was 5.5 versus 3.7 months (HR 0.69; 95% CI 0.58–0.82, p < 0.001), respectively. The combination of nab-paclitaxel plus gemcitabine resulted in an overall response rate of 23 versus 7% with gemcitabine monotherapy (p < 0.001) [3, 4]. There was 1 (0.2%) reported complete response with this combination. The most frequently observed adverse events of grade ≥3 were neutropenia (38% for nab-paclitaxel and gemcitabine vs. 27% for gemcitabine alone), leukopenia (31 vs. 16%), fatigue (17 vs. 7%) and neuropathy (17 vs. 1%) [3]. The results of this trial led to the approval of the combination of nab-paclitaxel and gemcitabine in the European Union as the first-line treatment for patients with metastatic pancreatic adenocarcinoma in January 2014 [5].\n\nThus, both combinations offer a markedly increased efficacy compared to prior standard systemic therapy in the metastatic setting of PDAC. Based on these encouraging data we treated a patient with an initially unresectable, locally advanced PDAC with a novel neoadjuvant chemotherapy consisting of a sequence of these combination regimens, i.e. nab-paclitaxel plus gemcitabine followed by FOLFIRINOX.\n\nCase Presentation\nIn December 2012, a 46-year-old female patient presented to our center with jaundice. She was otherwise asymptomatic and in an excellent performance status. She reported no comorbidities and neither alcohol nor nicotine abuse nor prior diabetes mellitus. Family history concerning malignancies was also negative. Laboratory findings were typical of cholestasis with an elevated concentration of total serum bilirubin to 8.4 mg/dl. The level of the tumor marker CA 19-9 was increased to 171 U/ml. Abdominal ultrasound revealed a dilation of the ductus hepatocholedochus (DHC) but no detectable tumor mass. Endoscopic retrograde cholangiopancreatography showed a malignant stenosis of the DHC. A stent was placed into the DHC to allow biliary drainage, and as a result total serum bilirubin decreased to a normal value within a few days. Endosonography revealed a hypoechoic lesion in the pancreatic head between DHC and the portal vein in the vicinity of the celiac trunk as well as suspicious locoregional lymph nodes. There were, however, no tumor cells in the bioptic material gained repeatedly during this session. Integrated fludeoxyglucose (18F) positron emission tomography (PET)-computed tomography (CT) found a PET-avid tumor in the pancreatic head largely adjacent to the celiac trunk and a PET-avid regional lymph node metastasis (fig. 1). There were no signs of peritoneal carcinomatosis or distant metastasis. An exploratory laparotomy confirmed the diagnosis of PDAC by intraoperatively frozen sections and the suspected unresectability which was due to an encasement of the celiac trunk (>180°) by the pancreatic tumor. Histology detected a moderately differentiated pancreatic adenocarcinoma surrounded by stromal desmoplasia. Thus, the locally advanced PDAC could be classified as pT4 Nx cM0 G2. During surgery, the patient received a biliodigestive anastomosis using Roux-en-Y anastomosis and a central venous port system.\n\nThree weeks after surgery, intensified neoadjuvant chemotherapy was started with the objective to achieve secondary resectability. The patient was given 2 cycles of a combination of nab-paclitaxel plus gemcitabine. Nab-paclitaxel was given at a dose of 125 mg/m2 on days 1, 8 and 15, gemcitabine at a dose of 1,000 mg/m2 on days 1, 8 and 15, both repeated on day 29. Chemotherapy was tolerated well. The patient developed grade 2 neutropenia and grade 1 fatigue. Treatment resulted in a complete metabolic remission. The follow-up PET-CT showed no more PET-avid lesions (fig. 2).\n\nChemotherapy was continued with 4 cycles of FOLFIRINOX. Oxaliplatin was administered at a dose of 85 mg/m2 on day 1, leucovorin at a dose of 400 mg/m2 on day 1, and irinotecan at a dose of 180 mg/m2 on day 1 followed by continuous infusion of 5-fluorouracil over 46 h at a dose of 2,400 mg/m2. Cycles were repeated every 2 weeks. Side effects were grade 1 neutropenia, grade 2 fatigue, grade 1 diarrhea and grade 1 peripheral neuropathy.\n\nThe follow-up PET-CT confirmed the complete metabolic remission; yet, it also showed a persistent tumor abutment of the celiac trunk, formally still unresectable according to NCCN guidelines (fig. 3).\n\nIn June 2013, a second laparotomy was performed. No vital tumor cells were found in the biopsies taken intraoperatively (frozen sections) of the tissue surrounding the celiac trunk and the DHC stump. Thus, a pylorus-preserving resection of the pancreatic head, regional lymphadenectomy, pancreaticojejunostomy and antecolic duodenojejunostomy were performed.\n\nSurgery resulted in resection-free margins (R0 resection). The pancreatic tumor was 2.2 cm in diameter. Of the 33 lymph nodes that were resected, 2 showed micrometastases. Thus, the postoperative pathology result was ypT3 (2.2 cm) ypN1 (2/33; 1 mm) L0 V0 Pn1, local R0. Less than 10% vital tumor cells were found in the resection specimen, corresponding to Evans Regression Score grade III [6].\n\nSubsequently, the patient was given 2 cycles of adjuvant chemotherapy with gemcitabine from July to September 2013. The patient was alive 18 months after the primary diagnosis at the last follow-up visit in April 2014. She showed a good performance status and had no signs of recurrent disease.\n\nDiscussion\nOur case shows that secondary R0 resection can be achieved with neoadjuvant chemotherapy utilizing modern combination regimens. This is relevant as patients with an initially unresectable locally advanced PDAC have a similar prognosis to patients with a primarily resectable pancreatic cancer if R0 resection can be achieved [1]. However, it needs to be stressed that the concept of neoadjuvant therapy in locally advanced unresectable PDAC and its actual clinical benefits still have to be proven, since evidence from prospective, randomized trials is still lacking.\n\nAfter a follow-up of 18 months, our patient was still progression free. The neoadjuvant chemotherapy we chose was actually a sequence of the 2 most active regimens for metastatic PDAC known today. The patient tolerated this intensified chemotherapy well. However, she already showed complete metabolic remission after 2 cycles of nab-paclitaxel plus gemcitabine. In the pivotal trial in metastatic PDAC, patients with a biochemical response after nab-paclitaxel plus gemcitabine had a better outcome than patients without a PET-response [7]. There are also data suggesting that a metabolic PET response may be of predictive value for patients with locally advanced pancreatic carcinoma treated with definitive concurrent chemoradiotherapy [8].\n\nIt is unclear to what extent the sequential treatment with FOLFIRINOX improved clinical outcome or whether neoadjuvant chemotherapy with the combination of nab-paclitaxel plus gemcitabine alone would have sufficed. This will be the objective of the randomized phase II trial NEOLAP that will start in September 2014. In this trial, patients with locally advanced, initially unresectable or borderline-resectable PDAC will either receive neoadjuvant chemotherapy with 4 cycles of nab-paclitaxel plus gemcitabine or 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. The R0 resection rate will be the primary endpoint.\n\nThe primary tumor of our patient showed extensive stromal desmoplasia which is a typical feature of PDAC. The concept of stromal depletion has been identified as a promising therapeutic route in the treatment of pancreatic cancer [9]. Preclinical data show that the treatment with nab-paclitaxel results in depleting desmoplastic stroma and reducing stromal density of pancreatic tumor tissue [10, 11]. The effect of stromal depletion was highest with the combination of nab-paclitaxel and gemcitabine [11]. There is also clinical evidence from a neoadjuvant trial in 16 patients with resectable pancreatic cancer treated with 2 cycles of nab-paclitaxel plus gemcitabine before surgical resection. Of the 12 patients who completed treatment, 7 were R0 resected with major pathological regressions. A significant decrement in tumor stiffness was measured by endoscopic ultrasound elastography. Histology showed a change in the architecture of the tumor stroma as indicated by markedly disorganized collagen and a very low density of cancer-associated fibroblasts, which was not observed in the untreated or conventionally treated control groups. A preclinical, co-clinical study in a mouse model showed that these effects were specific of nab-paclitaxel and not of gemcitabine [12]. The precise mechanism of stroma depletion by nab-paclitaxel is currently not known and has to be defined in further preclinical and clinical studies. Among the multitude of stromal components, the matricellular glycoprotein secreted protein acidic and rich in cysteine (SPARC) has attracted particular interest. However, despite encouraging data from previous phase I/II trials, extensive SPARC analysis within a phase III trial (MPACT trial) failed to demonstrate any prognostic or predictive role of stromal and/or tumor SPARC expression in the metastastic setting [13].\n\nIn conclusion, chemotherapy with nab-paclitaxel plus gemcitabine followed by FOLFIRINOX was an effective and well-tolerated neoadjuvant treatment in a patient with initially irrresectable, locally advanced PDAC which resulted in secondary resectability (R0 resection). Not only the clinical benefit of sequencing both combination regimens as neoadjuvant therapy for patients with locally advanced PDAC, but also the general concept of neoadjuvant treatment in locally advanced pancreatic cancer needs to be assessed in future prospective clinical trials.\n\nDisclosure Statement\nThe authors received editorial support in the preparation of this paper from Dr. Susanne Hell, funded by Celgene GmbH. Theyare fully responsible for the entire content and all editorial decisions relating to this paper.\n\nFig. 1 January 2013. Tumor lesions in the primary tumor and lymph nodes prior to chemotherapy. a Fused PET-CT and PET of the primary tumor. b Fused PET-CT and PET of the regional lymph node metastases.\n\nFig. 2 March 2013. Tumor lesions in the primary tumor and lymph nodes after 2 cycles of nab-paclitaxel plus gemcitabine. a Fused PET-CT and PET of the primary tumor. b Fused PET-CT and PET of the regional lymph node metastases.\n\nFig. 3 June 2013. Tumor lesions in the primary tumor and lymph nodes after 4 cycles of FOLFIRINOX. a Fused PET-CT and PET of the primary tumor. b Fused PET-CT and PET of the regional lymph node metastases.\n==== Refs\nReferences\n1 Gillen S Schuster T Meyer Zum Büschenfelde C Friess H Kleeff J Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages PLoS Med 2010 7 1000267 \n2 Conroy T Desseigne F Ychou M FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 364 1817 1825 21561347 \n3 Von Hoff DD Ervin T Arena F Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine N Engl J Med 2013 369 1691 1703 24131140 \n4 Goldstein D El-Maraghi RH Hammel P Analyses of updated overall survival (OS) and prognostic effect of neutrophil-to-lymphocyte ratio (NLR) and CA 19-9 from the phase III MPACT study of nab -paclitaxel (nab -P) plus gemcitabine (Gem) versus Gem for patients (pts) with metastatic pancreatic cancer (PC) (abstract 4027) J Clin Oncol 2014 32 suppl 5s \n5 Abraxane® prescribing information October 2013 http://abraxane.com/ \n6 Evans DB Rich TA Byrd DR Cleary KR Connelly JH Levin B Charnsangavej C Fenoglio CJ Ames FC Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas Arch Surg 1992 127 1335 1339 1359851 \n7 Von Hoff DD Ervin TJ Arena FP Results of a randomized phase III trial (MPACT) of weekly nab -paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19–9 correlates (abstract 4005) J Clin Oncol 2013 31 suppl \n8 Topkan E Parlak C Kotek A Yapar AF Pehlivan B Predictive value of metabolic 18FDG-PET response on outcomes in patients with locally advanced pancreatic carcinoma treated with definitive concurrent chemoradiotherapy BMC Gastroenterol 2011 11 123 22074002 \n9 Heinemann V Reni M Ychou M Richel DJ Macarulla T Ducreux M Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies Cancer Treat Rev 2014 40 118 128 23849556 \n10 Von Hoff DD Ramanathan RK Borad MJ Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial J Clin Oncol 2011 29 4548 4554 21969517 \n11 Awasthi N Zhang C Schwarz AM Hinz S Wang C Williams NS Schwarz MA Schwarz RE Comparative benefits of nab-paclitaxel over gemcitabine or polysorbate-based docetaxel in experimental pancreatic cancer Carcinogenesis 2013 34 2361 2369 23803690 \n12 Alvarez R Musteanu M Garcia-Garcia E Stromal disrupting effects of nab-paclitaxel in pancreatic cancer Br J Cancer 2013 109 926 933 23907428 \n13 Hidalgo M Plaza C Illei PB SPARC analysis in the phase III MPACT trial of nab-paclitaxel plus gemcitabine vs. Gem alone for patients with metastatic pancreatic cancer (abstract O-0004) 2014 16th World Congress on Gastrointestinal Cancer, Barcelona\n\n",
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"keywords": "5-Fluorouracil; Folinic acid; Gemcitabine; Irinotecan; Locally advanced disease; Nab-paclitaxel; Neoadjuvant chemotherapy; Oxaliplatin; Pancreatic cancer",
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"abstract": "A case of monocular postoperative hemorrhagic occlusive retinal vasculitis (HORV) after uncomplicated bilateral cataract surgery is described. HORV is a severe syndrome that leads to painless visual loss after uncomplicated cataract surgery. The same surgical procedure was adopted in both eyes except for the use of intracameral vancomycin, which was injected only in the eye that developed HORV. Diffuse retinal ischemia with vascular sheathing and intraretinal hemorrhages were detected during the fourth postoperative day. Despite treatment, the patient developed severe neovascular glaucoma. This case supports the causative role of vancomycin in the pathogenesis of HORV and suggests avoiding it for chemoprophylaxis. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:764-766.].",
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"authors": "Balducci|Nicole|N|;Savini|Giacomo|G|;Barboni|Piero|P|;Ducoli|Pietro|P|;Ciardella|Antonio|A|",
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"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D002387:Cataract Extraction; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D008297:Male; D008875:Middle Aged; D009885:Ophthalmology; D011183:Postoperative Complications; D012160:Retina; D012166:Retinal Hemorrhage; D031300:Retinal Vasculitis; D041623:Tomography, Optical Coherence; D014792:Visual Acuity",
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"pubdate": "2016-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Hemorrhagic Occlusive Retinal Vasculitis After First Eye Cataract Surgery Without Subsequent Second Eye Involvement.",
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] |
{
"abstract": "Osteosarcoma can rarely occur as a subsequent malignant neoplasm after cancer therapy. Children who underwent treatment for cancer and received an allogeneic hematopoietic cell transplant are at a higher risk to develop secondary malignancies. Radiation is also a known risk factor, but estimating the quantitative risk is difficult due to the rarity of the condition and long latency period between primary and secondary cancer. In this report, we present 3 patients diagnosed with leukemia as young children who received hematopoietic cell transplants with total body irradiation as part of the conditioning regimen, and later went on to develop secondary osteosarcoma.",
"affiliations": "Department of Pediatrics.;Department of Pediatrics.;Department of Pediatrics.",
"authors": "Scheuermann|Amanda|A|;Phelan|Rachel|R|;Browning|Meghen|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001442",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(2)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D016026:Bone Marrow Transplantation; D001859:Bone Neoplasms; D002675:Child, Preschool; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D016609:Neoplasms, Second Primary; D012516:Osteosarcoma; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e100-e103",
"pmc": null,
"pmid": "30807391",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Development of Secondary Osteosarcoma After TBI and Allogeneic Bone Marrow Transplant: A Case Series of 3 Patients.",
"title_normalized": "development of secondary osteosarcoma after tbi and allogeneic bone marrow transplant a case series of 3 patients"
} | [
{
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],
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