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"abstract": "OBJECTIVE\nThe aim of this study was to explore the clinical characteristics and outcomes of patients with recurrent chronic hepatitis B meeting the cessation criteria outlined by the 2008 Asian Pacific Association for the Study of the Liver guidelines.\n\n\nMETHODS\nIn total, 223 chronic hepatitis B patients who met the cessation criteria and discontinued nucleos(t)ide analog therapy were prospectively included. They were monitored monthly during the first 4 months and every 3-6 months thereafter. Early relapse was defined as viral relapse (serum hepatitis B virus [HBV] DNA >104 copies/mL) confirmed within 3 months after cessation.\n\n\nRESULTS\nOf the 38 hepatitis B e antigen (HBeAg)-positive relapse cases, 44.7%, 65.8%, 76.3% and 89.5% occurred within 3 months, 6 months, 12 months, and 48 months, respectively; in the 49 HBeAg-negative relapse cases, 44.9%, 51.0%, 77.6% and 91.8% occurred within 3, 6, 12 and 36 months, respectively. Time to undetectable HBV DNA was a predictive factor of early relapse. Viral relapses were accompanied by elevated alanine aminotransferase in 70 (80.5%) patients. A peak alanine aminotransferase 10 times over the upper limit of normal after relapse was observed in 15.8% of the HBeAg-positive and 22.4% of the HBeAg-negative patients. Hepatic decompensation and liver failure were not observed.\n\n\nCONCLUSIONS\nFor HBeAg-positive and HBeAg-negative patients meeting stringent cessation criteria, at least 4 years and 3 years of close follow-up are necessary. For those with a longer time to undetectable HBV DNA, more attention should be paid to the early stages after cessation. Nucleos(t)ide analog withdrawal in selected non-cirrhotic patients is generally safe, although close monitoring and timely intervention are needed.",
"affiliations": "Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan, China.;Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan, China.;Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan, China.;Yantai Infectious Disease Hospital, Yantai, China.;Jinan Infectious Disease Hospital, Shandong University School of Medicine, Jinan, China.;Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan, China.",
"authors": "Liu|Zhirong|Z|;Liu|Feng|F|;Wang|Lei|L|;Liu|Youde|Y|;Zhang|Meng|M|;Li|Tao|T|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.12836",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "47(10)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "hepatitis B; nucleos(t)ide analogs; outcome; relapse/recurrence; safety",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "1000-1007",
"pmc": null,
"pmid": "27917568",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical characteristics and outcomes of patients with recurrent chronic hepatitis B after nucleos(t)ide analog withdrawal with stringent cessation criteria: A prospective cohort study.",
"title_normalized": "clinical characteristics and outcomes of patients with recurrent chronic hepatitis b after nucleos t ide analog withdrawal with stringent cessation criteria a prospective cohort study"
} | [
{
"companynumb": "CN-GILEAD-2017-0294159",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ADEFOVIR DIPIVOXIL"
},
"drugadditional": null,
... |
{
"abstract": "Among neuroeosinophilic syndromes, neuromuscular disorders are considered as a special group, including perimyosistis, polymyositis and fasciitis. These three disorders are considered as a continuum. They usually without a recognized cause, and are considered to be spontaneous or exercise-induced. We report the case of a 43 year-old woman who experienced angioedema followed by an histologically proven-fasciitis with eosinophilia after Ramipril (Triatec) use. Causal attribution to Ramipril was considered \"plausible\". To our knowledge this side effect has never been reported with this drug.",
"affiliations": "Service de Médecine Interne, CHU Timone, Marseille. jserratrice@ap-hm.fr",
"authors": "Serratrice|J|J|;Pellissier|J F|JF|;Champsaur|P|P|;Weiller|P J|PJ|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors; D017257:Ramipril",
"country": "France",
"delete": false,
"doi": "10.1016/s0035-3787(07)90397-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0035-3787",
"issue": "163(2)",
"journal": "Revue neurologique",
"keywords": null,
"medline_ta": "Rev Neurol (Paris)",
"mesh_terms": "D000328:Adult; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D003875:Drug Eruptions; D004802:Eosinophilia; D005208:Fasciitis; D005260:Female; D006801:Humans; D006973:Hypertension; D009765:Obesity; D017257:Ramipril",
"nlm_unique_id": "2984779R",
"other_id": null,
"pages": "241-3",
"pmc": null,
"pmid": "17351545",
"pubdate": "2007-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Fasciitis with eosinophilia: a possible causal role of angiotensin converting enzyme inhibitor.",
"title_normalized": "fasciitis with eosinophilia a possible causal role of angiotensin converting enzyme inhibitor"
} | [
{
"companynumb": "FR-AUROBINDO-AUR-APL-2021-002618",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RAMIPRIL"
},
"drugadditional": "3",
... |
{
"abstract": "A 33-year-old African-American woman was bridged to heart transplantation with a left ventricular assist device. She had a 14-month history of heart failure secondary to viral cardiomyopathy. The patient's refractory ventricular tachycardia was treated with intravenous procainamide owing to the patient's history of amiodarone-induced thyroiditis. After orthotopic cardiac transplant, she experienced prolonged respiratory failure. Serial computed tomography evaluation of the lung revealed diffuse bilateral ground-glass opacities and septal thickening. Bronchoscopies with tissue biopsies were performed with no conclusive results. Specimen samples displayed septal fibrosis with loose fibromyxoid tissue and some hobnail nodularities with no indication of granulomas, neutrophilic infiltration, malignancy, or fungal, viral, or bacterial growth. Histopathological evaluation of the lung wedge biopsy supported a diagnosis of pulmonary fibrosis and noted interstitial fibrosis with areas of focal alveolar hemorrhage and increased macrophage infiltration. Antinuclear body was found to be negative. After in-depth evaluation of the patient's medication history, procainamide was identified as the cause of the toxicity. As procainamide-induced lung fibrosis is relatively uncommon, we present this case to highlight procainamide's potential harm and the need for careful monitoring in postsurgical patients.",
"affiliations": "Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital - Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA.;Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital - Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA.;Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital - Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA.;Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital - Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA.;Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital - Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA.;Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital - Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA.;Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston/Memorial Hermann Hospital - Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA.;Center for Advanced Heart Failure, University of Texas Health Science Center at Houston/Memorial Hermann Hospital - Texas Medical Center, 6400 Fannin Street, Suite 2350, Houston, TX 77030, USA. Electronic address: Francine.Cummings@uth.tmc.edu.",
"authors": "Thangam|Manoj|M|;Nathan|Sriram|S|;Petrovica|Marija|M|;Kar|Biswajit|B|;Patel|Manish|M|;Loyalka|Pranav|P|;Buja|L Maximilian|LM|;Gregoric|Igor D|ID|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D011342:Procainamide",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1054-8807",
"issue": "24(4)",
"journal": "Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology",
"keywords": "Heart transplantation; Procainamide; Pulmonary fibrosis",
"medline_ta": "Cardiovasc Pathol",
"mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D015415:Biomarkers; D001706:Biopsy; D001999:Bronchoscopy; D005260:Female; D006333:Heart Failure; D016027:Heart Transplantation; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung; D011342:Procainamide; D011658:Pulmonary Fibrosis; D017180:Tachycardia, Ventricular; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9212060",
"other_id": null,
"pages": "250-3",
"pmc": null,
"pmid": "25770749",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Procainamide-induced pulmonary fibrosis after orthotopic heart transplantation: a case report and literature review.",
"title_normalized": "procainamide induced pulmonary fibrosis after orthotopic heart transplantation a case report and literature review"
} | [
{
"companynumb": "US-HOSPIRA-2948102",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROCAINAMIDE HYDROCHLORIDE"
},
"drugadditional": nul... |
{
"abstract": "OBJECTIVE\nTo comprehensively evaluate the safety and effectiveness of bleomycin/pingyangmycin-containing chemotherapy for female patients with malignant germ cell tumors in their genital system; to assess the diagnostic value of pulmonary function tests for bleomycin-induced pulmonary toxicity.\n\n\nMETHODS\nData from a cohort of 120 patients, collected across 25 years, was reviewed. Chemotherapy-related adverse events were routinely monitored. Pulmonary toxicity was diagnosed and graded according to serial pulmonary function testing results, and potential impact factors were explored. Short-term remission probability and long-term prognosis were evaluated.\n\n\nRESULTS\nOverall, 49.2% of the patients had pulmonary dysfunction, and the majority manifested as diffusion function impairment. A moderate reduction of carbon monoxide diffusion capacity was detected in 45.0% of all patients, and was severe in 3 patients. Thrombocytopenia, renal dysfunction, and accumulating dose of bleomycin/pingyangmycin significantly increased the risk of lung injury (P<0.05). Thorough surgical removal of tumors enhanced both remission and survival rate. Full-dose delivery of bleomycin/pingyangmycin and patients' sensitivity to chemotherapy also improved long-term survival (P<0.05).\n\n\nCONCLUSIONS\nBPT could be sensitively detected and elaborately graded by PFTs, but the appropriate cut-off value for diagnosis needs further investigations. Timely recognition and control of renal dysfunction and thrombocytopenia could avail the patients of the opportunity to complete curative antineopalstic treatment. Prescriptive bleomycin/pingyangmycin-containing chemotherapy after optimal surgical resection could benefit MGCT patients maximally by improving both remission and survival rate.",
"affiliations": "Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.;Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.",
"authors": "Zhao|Qianying|Q|;Cao|Dongyan|D|;Yu|Mei|M|;Yang|Jiaxin|J|;Liu|Yongjian|Y|;Xiang|Yang|Y|;Wu|Ming|M|;Pan|Lingya|L|;Lang|Jinghe|J|;Xu|Kaifeng|K|;Han|Jiangna|J|;Shen|Keng|K|",
"chemical_list": "D001761:Bleomycin; C025703:bleomycetin",
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.15021",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 1502110.18632/oncotarget.15021Clinical Research PaperSafety and efficacy of bleomycin/pingyangmycin-containing chemotherapy regimens for malignant germ cell tumor patients in the female genital system Zhao Qianying 1Cao Dongyan 1Yu Mei 1Yang Jiaxin 1Liu Yongjian 2Xiang Yang 1Wu Ming 1Pan Lingya 1Lang Jinghe 1Xu Kaifeng 2Han Jiangna 2Shen Keng 11 Department of Gynecology and Obstetrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China2 Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, ChinaCorrespondence to:Keng Shen,shenkeng@pumch.cnJiangna Han,13520053104@139.comQianying Zhao,ofeizhaoqy@163.com28 2 2017 2 2 2017 8 9 15952 15960 15 10 2016 9 1 2017 Copyright: © 2017 Zhao et al.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objectives\nTo comprehensively evaluate the safety and effectiveness of bleomycin/pingyangmycin-containing chemotherapy for female patients with malignant germ cell tumors in their genital system; to assess the diagnostic value of pulmonary function tests for bleomycin-induced pulmonary toxicity.\n\nMethods\nData from a cohort of 120 patients, collected across 25 years, was reviewed. Chemotherapy-related adverse events were routinely monitored. Pulmonary toxicity was diagnosed and graded according to serial pulmonary function testing results, and potential impact factors were explored. Short-term remission probability and long-term prognosis were evaluated.\n\nResults\nOverall, 49.2% of the patients had pulmonary dysfunction, and the majority manifested as diffusion function impairment. A moderate reduction of carbon monoxide diffusion capacity was detected in 45.0% of all patients, and was severe in 3 patients. Thrombocytopenia, renal dysfunction, and accumulating dose of bleomycin/pingyangmycin significantly increased the risk of lung injury (P<0.05). Thorough surgical removal of tumors enhanced both remission and survival rate. Full-dose delivery of bleomycin/pingyangmycin and patients sensitivity to chemotherapy also improved long-term survival (P<0.05).\n\nConclusions\nBPT could be sensitively detected and elaborately graded by PFTs, but the appropriate cut-off value for diagnosis needs further investigations. Timely recognition and control of renal dysfunction and thrombocytopenia could avail the patients of the opportunity to complete curative antineopalstic treatment. Prescriptive bleomycin/pingyangmycin-containing chemotherapy after optimal surgical resection could benefit MGCT patients maximally by improving both remission and survival rate.\n\nbleomycinmedication safetytreatment efficacypulmonary toxicitymalignant germ cell tumor\n==== Body\nINTRODUCTION\nMalignant germ cell tumor (MGCT) is a rare entity in the female genital system and has a peak incidence in women under the age of 20 [1]. Due to cisplatin-based chemotherapy, the 5-year survival rate for patients with MGCTs exceeds 90% [2]. Given that 85% of metastatic GCTs are also cured and that the majority of patients are young adults, treatment-related complications become a core determinant for therapeutic plans [3].\n\nBleomycin is an attractive addition to combination chemotherapy regimens because of its broad activity and low myelotoxicity. The drug has been the mainstay for years in the treatment of MGCTs [4]. Meanwhile, bleomycin-induced pulmonary toxicity (BPT) has been commonly recognized since its clinical application from the early 1970s [5]. BPT may have immediate fatal effects or long-term clinical consequences for survivors with a long life expectancy [6].\n\nHowever, consistent diagnostic criteria have yet to be developed. The incidence of BPT ranges from 2% to 46% due to diverse examination strategies that range from non-specific respiratory symptoms and less-sensitive radiographs to invasive lung biopsy. A number of potential risk factors for BPT have been revealed, including increasing age, underlying lung disease, smoking history, a cumulative bleomycin dose, renal insufficiency, radiation, supplemental oxygen exposure, and granulocyte colony-stimulating factor (G-CSF) support [3, 6, 7].\n\nIn addition, other therapeutic side effects (e.g., myelosuppression and renal dysfunction) might influence BPT severity as well as oncologists’ clinical decisions. Therefore, we reviewed the records from a continuous cohort of female MGCTs in the genital system and prospectively followed these patients. The aim of this study was to assess both the safety and efficacy of PEB (cisplatin, etoposide, and bleomycin/pingyangmycin) or PVB (cisplatin, vincristine, and bleomycin/pingyangmycin) chemotherapy with an emphasis on exploring the incidence and influential factors of BPT measured by serial pulmonary function test (PFT) results.\n\nPATIENTS AND METHODS\nThe Patients’ Record Database was searched for eligible patients between 1998 and 2014. Our final study group included all female patients with MGCTs in their genital system who were treated with a bleomycin/pingyangmycin-containing regimen at our institution. Pingyangmycin, isolated from actinomycetes in Pingyang County (China), has a similar structure to the composition A5 of bleomycin compound and presents equal antineoplastic effect. MGCT diagnoses were confirmed by the pathological review of all specimens in our hospital, and all histological subtypes were eligible for this study.\n\nPatients with FIGO (International Federation of Gynecology and Obstetrics) stage-I dysgerminoma and immature teratoma (grade 1) could be followed, together with those who did not receive a bleomycin/pingyangmycin-containing regimen, were excluded. Standard front-line chemotherapy was either 3 or 4 cycles of PEB or PVB every 3 weeks (cisplatin 30-35 mg/m2/d on days 1-3, etoposide 100 mg/m2/d on days 1-3, or vincristine 1.0-1.5 mg/m2/d on days 1-2, bleomycin/pingyangmycin 15 mg/m2/d on days 1-2 or 20 mg/m2/d day 2/weekly). The actual cycles that were applied might be flexible based on disease condition and therapeutic response. Usually, two courses were consolidated after serum tumor makers (e.g., CA125, AFP and HCG) declined to a normal level. Bleomycin/pingyangmycin was discontinued if (1) the patient's carbon monoxide diffusion capacity corrected for hemoglobin (DLCO) dropped below 70% of the predicted value; or (2) decreased > 20% from baseline level during treatment; and if (3) the lifetime dose limit of 250 mg/m2 was exceeded. A regimen with bleomycin/pingyangmycin omitted (e.g. cisplatin and etoposide, with or without vincristine) was subsequently substituted if necessary. The initial treatment was considered to be effective if the neoplasm was optimally excised and if the surveillance indicators (tumor markers, imaging and physical examinations) were all negative for at least 4 weeks after the completion of treatment. Side effects were under surveillance: complete blood count, liver and renal function, chest X-ray, PFT, glomerular filtration rate (GFR) or creatinine clearance rate (CCr), and tumor markers were monitored. Patients who did not receive all their antineoplastic medications at our institution were omitted for inadequate records.\n\nWith PFTs we assessed the patients’ forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FVC ratio, total lung capacity (TLC,) and DLCO. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria [8], obstructive pulmonary function impairment was defined as an FEV1/FVC ratio < 0.70 and FEV1 < 80% of the predicted value. Restrictive pulmonary function impairment and diffusion capacity impairment were defined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 [9, 10]. Specifically, restrictive dysfunction was defined as TLC < 75% of the predicted value. Diffusion impairment was measured using the DLCO and the disease severity was graded from 0 to 5: (0) no impairment, DLCO > 90% of the predicted value; (1) mild impairment, 90% ≥ DLCO > 75% of the predicted value; (2) moderate impairment, 75% ≥ DLCO > 50% of the predicted value; (3) severe and undesirable impairment, 50% ≥ DLCO > 25% of the predicted value; (4) life-threatening or disabling impairment, DLCO < 25% of predicted value; and (5) death. By definition, a pulmonary function impairment of grade 2 or higher ( ≤ 75%) can be considered abnormal and reflects physiological impairment [10]. Patients with underlying pulmonary dysfunction before chemotherapy were excluded.\n\nOther treatment toxicities and potential risk factors for BPT were co-recorded, including age, prior lung disease, allergy history, renal function, cumulative bleomycin/pingyangmycin dose and delivery approach (intravenous, intramuscular or both), myelosuppression and the consequent use of G-CSF or blood transfusion and supplemental oxygen exposure. Tobacco and alcohol consumption information was not available for evaluation in our young female cohort. The lowest GFR or CCr was recorded and split by 80 ml/min for renal dysfunction diagnosis [3]. Aside from the total dose of bleomycin/pingyangmycin, the time when BPT initially occurred was also documented. Bone marrow toxicity was graded for each cycle according to CTCAE [9], and the worst degree of each myelosuppression subtype was applied for assessment. G-CSF and component blood transfusion (erythrocytes or thrombocytes) was prescribed accordingly. History of major surgery following chemotherapy was used as a surrogate identifier of supplemental oxygen use, which had been previously cited as a risk factor for BPT [3, 11].\n\nThe majority of patients admitted in the last decade are regularly followed-up at our Outpatient Department or local referral hospitals, and long-term prognosis was analyzed in this cohort. The overall survival (OS) and disease-free survival (DFS) were estimated with an emphasis on the association with BPT. Age was dichotomized by the median age of the study cohort, and the total dosage was categorized based on whether the course number of the bleomycin/pingyangmycin-containing regimen exceeded the guideline recommendations.\n\nInfluential factors for BPT severity were evaluated univariately by log-rank tests or Fisher's exact tests with 95% confidence interval (CI). Multivariate analysis was performed with the logistic regression method. Because of small event numbers, it was not possible to evaluate the effects of risk factors for obstructive and restrictive pulmonary function impairments. The observation time for OS ranged from the date of diagnosis to the date of death or the study end date, whichever occurred first. While the endpoint for DFS was either the date of first recurrence or the last follow-up starting from the completion of the first effective treatment. Potential clinical parameters for survival were analyzed univariately using the Kaplan-Meier method. A P-value < 0.05 (two-sided) was considered to be statistically significant. Statistical analyses were performed using Statistical Product and Service Solutions (SPSS) Statistics 20.0 (IBM Corporation, Armonk, New York, USA).\n\nThis study was approved by the institutional review board at Peking Union Medical College Hospital (PUMCH), Beijing, China, and the data of all patients were analyzed anonymously.\n\nRESULTS\nStudy population\nA review of the database revealed 308 female patients with MGCTs in their genital system who were treated at PUMCH during the specified study period. Eventually, 120 cases met the criteria of our study, and the selection process and reasons for the exclusion of patients are summarized in Figure 1.\n\nFigure 1 Process of patients’ enrollment for this study\nClinical characteristics\nTable 1 shows the clinical features of the patients enrolled in the study, including four DSD (disorder of sex development) females (social gender). BPT incidence was similar in DSD and other patients (P = 1.000). The majority of the patients were Han Chinese who were diagnosed between age 10 and 30. Excluding 12 tumors with mix histologies, approximately 70% of the MGCTs were non-dysgerminomas: embryonal carcinoma (1), endodermal sinus tumor (32), gonadoblastoma (1), and immature teratoma (43), with dysgerminomas in the remaining 30%. Overall, 103 (85.8%) patients merely had a neoplasm confined within the pelvis (i.e., FIGO stage I/II). The majority (83.3%) of patients only received PEB regimen, and domestic pingyangmycin was chose for most patients (75.0%) because of economic reasons. Moreover, there were no significant differences found between the BPT and non-BPT group in terms of age, ethnic group, prior lung disease, allergic history, histology and stage (P > 0.05).\n\nTable 1 Clinical characteristics of enrolled patients\nClinical features\tAll patients\tBPT patients\tNon-BPT patients\tP-value\t\n\tNo.\t%\tNo.\t%\tNo.\t%\t\t\nTotal\t120\t100.0\t59\t100.0\t61\t100.0\t-\t\nAge, years\t\t\t\t\t\t\t\t\nMedian (Range)\t20.7 (6-45)\t21.2 (7-38)\t20.3 (6-45)\t0.984\t\nEthnic group\t\t\t\t\t\t\t1.000\t\nHan\t111\t92.5\t55\t93.2\t56\t91.8\t\t\nMinority\t9\t7.5\t4\t6.8\t5\t8.2\t\t\nPrior lung disease\t\t\t\t\t\t\t1.000\t\nAbsent\t119\t99.2\t59\t100.0\t60\t98.4\t\t\nPresent\t1\t0.8\t0\t0.0\t1\t1.6\t\t\nAllergic history\t\t\t\t\t\t\t0.645\t\nAbsent\t97\t80.8\t49\t83.1\t48\t78.7\t\t\nPresent\t23\t19.2\t10\t16.9\t13\t21.3\t\t\nHistology\t\t\t\t\t\t\t0.302\t\nDysgerminoma\t31\t25.8\t12\t20.3\t19\t31.1\t\t\nNon-dysgerminoma\t77\t64.2\t42\t71.2\t35\t57.4\t\t\nMixed MGCT\t12\t10.0\t5\t8.5\t7\t11.5\t\t\nStage\t\t\t\t\t\t\t1.000\t\nFIGO I/II\t103\t85.8\t51\t86.4\t52\t85.2\t\t\nFIGO III/IV\t17\t14.2\t8\t13.6\t9\t14.8\t\t\nRegimen\t\t\t\t\t\t\t0.051\t\nPEB\t100\t83.3\t48\t81.3\t52\t85.3\t\t\nPVB\t12\t10.0\t4\t6.8\t8\t13.1\t\t\nBoth\t8\t6.7\t7\t11.9\t1\t1.6\t\t\nAgent\t\t\t\t\t\t\t0.555\t\nBleomycin\t24\t20.0\t13\t22.0\t11\t18.0\t\t\nPingyangmycin\t90\t75.0\t42\t71.2\t48\t78.7\t\t\nBoth\t6\t5.0\t4\t6.8\t2\t3.3\t\t\nRoute\t\t\t\t\t\t\t0.026\t\nIntravenous\t27\t22.5\t12\t20.3\t15\t24.6\t\t\nIntramuscular\t83\t69.2\t38\t64.4\t45\t73.8\t\t\nBoth\t10\t8.3\t9\t15.3\t1\t1.6\t\t\nSchedule\t\t\t\t\t\t\t0.018\t\nWeekly\t60\t50.0\t24\t40.7\t36\t59.0\t\t\n21-day\t48\t40.0\t25\t42.4\t23\t37.7\t\t\nBoth\t12\t10.0\t10\t16.9\t2\t3.3\t\t\nAbbreviations: BPT, bleomycin induced pulmonary toxicity; FIGO, International Federation of Gynecology and Obstetrics; MGCT, malignant germ cell tumor; PEB/PVB, cisplatin, etoposide/ vincristine and bleomycin/ pingyangmycin\n\nBleomycin/pingyangmycin induced pulmonary toxicity\nBased on the worst PFT result of each patient from their first to the last administration of bleomycin/pingyangmycin, only one case had mild and transient obstructive dysfunction, which was accompanied by diffusion impairment. Another 2 patients merely had TLC that dropped below 75% of the predicted value with normal FEV1, FEV1/FVC and DLCO. Diffusion impairment was present in 57 patients, and the severity was moderate (grade 2) in 54 patients and severe (grade 3) in 3 patients. None had a diffusion capacity impairment of grade 4 or 5. In total, 59 patients (49.2%) out of the 120 in the cohort had BPT defined as obstructive or restrictive dysfunction, or decreased DLCO (grade 2 or higher). Only three BPT (grade 2) patients had symptoms (e.g., cough, expectoration or thoracalgia), whereas two from the non-BPT group also complained of similar discomfort. Among the BPT group, 21 patients had an abnormal chest X-ray or computed tomography (CT) images, including two patients with symptoms. However, the manifestation was diverse and non-specific, such as nodules, bands, effusion or bulla. A typical image of BPT as fibrosis and organization was found in only one patient through high resolution CT. This patient had grade 2 DLCO reduction and cough. Furthermore, three patients had hypersensitive BPT (grade 2-3), which was characterized by a prompt DLCO reduction with less than 60 mg/m2 of bleomycin/pingyangmycin administration. Usually, DLCO would immediately drop more than 15% from the baseline, and their pulmonary function would not recover, even after drug withdrawal. Taking no account of this unique reaction type, the average cumulative doses of bleomycin/pingyangmycin in the BPT and non-BPT group were significantly different (P < 0.05). The average accumulated dosages for BPT patients were 200.4 mg/m2 and 120 mg/m2 through the intramuscular and intravenous administration route, respectively, and both dosages were significantly higher than those of the non-BPT group. In addition, PFTs from 55.9% of BPT patients would present abnormality right after the first course, whereas 54.2% of these patients had their worst pulmonary function after four or more courses of PEB/PVB (Figure 2). The incidence of BPT was similar between groups applied distinct route of bleomycin/pingyangmycin administration (i.e. intravenous and intravascular), or either chemotherapeutic schedule (i.e. 3-week and weekly). However, patients who had interchanged regimens would be more likely to develop BPT (P < 0.05, Table 1).\n\nFigure 2 The occurrence time of A. the initial BPT; B. the most severe BPT.\n\nOther common adverse events from treatment\nThe lowest degrees of each bone marrow toxicity subtype for single patient were recorded and the pooled data were listed in Table 2. Myelosuppression in aspects of hemoglobin and thrombocyte was modest for the most part, whereas the worst granulopenia had reached a CTCAE grade 3 or 4 for 79.2% of patients. As a consequence, G-CSF was generally applied to patients with grade 3 or 4 granulopenia for therapeutic use, whereas prophylactic treatment was implemented for grade 4 cases. Patients with renal function impairment were 33.9% and 8.2% of the BPT and non-BPT groups, respectively. Abundant hydration was arranged due to cisplatin, and the urine volume should be no less than 2500 ml on the day cisplatin was administrated. Three patients suffered serious renal impairments (GFR < 60ml/min), and one of them had cisplatin dose induced, when the worst renal function was detected in the last chemotherapy cycle for the other two patients. Specifically, anemia and thrombocytopenia severity, together with renal insufficiency, significantly increased the risk of BPT by univariate evaluation (P < 0.05).\n\nTable 2 Common chemotherapy-related adverse events\n\tAll Patients\tBPT Patients\tNon-BPT Patients\tP-value\t\n\tNo.\t%\tNo.\t%\tNo.\t%\t\t\nTotal\t120\t100.0\t59\t100.0\t61\t100.0\t-\t\nBone Marrow toxicity (CTCAE grade)\t\nHemoglobin\t\t\t\t\t\t\t0.000\t\n≤1\t77\t64.2\t33\t55.9\t44\t72.1\t\t\n2\t22\t18.3\t11\t18.6\t11\t18.0\t\t\n3\t13\t10.8\t8\t13.6\t5\t8.3\t\t\n4\t8\t6.7\t7\t11.9\t1\t1.6\t\t\nLeukocyte\t\t\t\t\t\t\t0.295\t\n≤1\t9\t7.5\t5\t8.5\t4\t6.6\t\t\n2\t16\t13.3\t10\t16.9\t6\t9.8\t\t\n3\t48\t40.0\t15\t25.4\t33\t54.1\t\t\n4\t47\t39.2\t29\t49.2\t18\t29.5\t\t\nThrombocyte\t\t\t\t\t\t\t0.020\t\n≤1\t90\t75.0\t36\t61.0\t54\t88.5\t\t\n2\t14\t11.7\t10\t16.9\t4\t6.6\t\t\n3\t10\t8.3\t8\t13.6\t2\t3.3\t\t\n4\t6\t5.0\t5\t8.5\t1\t1.6\t\t\nRenal dysfunction (GFR or CCr)\t0.001\t\n>80\t95\t79.2\t39\t66.1\t56\t91.8\t\t\n≤80\t25\t20.8\t20\t33.9\t5\t8.2\t\t\nAbbreviations: BPT, bleomycin/pingyangmycin induced pulmonary toxicity; CTCAE, common terminology criteria for adverse events; GFR, glomerular filtration rate; CCr, creatinine clearance rate\n\nImpact factors for BPT severity\nBPT severity was graded based on the degree of DLCO decline. Risk factors were explored in regards to epidemiologic information, individual history, chemotherapy details, concomitant side effects and combined treatments. Table 3 depicts the results of univariate analyses for each potential hazard, excluding three hypersensitive BPT cases. The cumulative dose of bleomycin/pingyangmycin, the patients’ renal function, hemoglobin and thrombocyte value, platelet transfusion, and chemotherapy regimen (PEB or PVB, weekly or monthly), and the administration route of bleomycin/pingyangmycin were significantly associated with the degree of BPT (p < 0.05). However, multivariate analysis revealed that only increasing dosage, renal insufficiency and serious thrombocytopenia independently aggravated BPT after adjusting for other potential impact factors (P < 0.05).\n\nTable 3 Univariate analysis of influential factors for BPT severity\nImpact factors\tP-value\tImpact factors\tP-value\t\nEpidemiologic information\t\tChemotherapy detail\t\t\nAge at diagnosis\t0.335\tPEB/PVB\t0.043\t\nEthnic group\t0.856\tBleomycin/pingyangmycin\t0.755\t\nIndividual history\t\tWeekly/monthly\t0.031\t\nPrior lung disease\t1.000\tRoute of administration\t0.041\t\nAllergic history\t0.603\tCumulative dose\t0.000\t\nDisease state\t\tAverage course interval\t0.256\t\nStage of disease\t0.081\tCombined treatment\t\t\nHistological subtype\t0.741\tG-CSF\t0.331\t\nSide effects of treatment\t\tAntibiotics\t0.904\t\nRenal dysfunction\t0.001\tBlood transfusion\t-\t\nDrug allergy\t0.332\tErythrocyte\t0.116\t\nGranulopenia\t0.176\tThrombocyte\t0.035\t\nAnemia\t0.041\tChalybeate\t0.067\t\nThrombocytopenia\t0.000\tPost-chemotherapy surgery\t0.072\t\nAbbreviations: BPT, bleomycin-induced pulmonary toxicity; PEB/PVB, cisplatin, etoposide/ vincristine and bleomycin; G-CSF, granulocyte colony stimulating factor\n\nEighty percent of the patients with impaired renal eliminating ability had pathological DLCO reduction, whereas the proportion was merely 41.1% among patients with normal renal function. Moreover, all the three patients with severe BPT (grade 3) had a platelet level dropped below 75*109/L. Specifically, patients who had a grade 2 or higher degree of thrombocytopenia had an odds ratio (OR) of 4.93 for BPT occurrence compared to the combined normal and grade 1 group (P < 0.05).\n\nRemission probability and long-term prognosis\nWith a satisfactory surgical resection of solid tumors and standard frontline chemotherapy, most patients (94.2%) achieved remission immediately. However, the disease persisted for 7 remaining patients (5.8%). Potential impact factors for remission probability detected univariately are listed in Table 4. However, multivariate analysis demonstrated that only surgery thoroughness was an independent predictor for short-term response (P < 0.05). Specifically, the remission probability for patients who had an optimal cytoreductive surgery was 9.9 times higher compared to patients whose tumors were not completely removed. In addition, BPT altered the oncologists’ clinical decision: bleomycin/pingyangmycin dosage had been reduced in 42.3% among the BPT group (20-60 mg/m2 intramuscularly and 10-30 mg/m2 intravenously), whereas the remaining BPT patients had completed full-dose administration. More importantly, the latter group was more likely to remit with a curative remedy (OR 1.190, 95% CI 1.003-1.413) without the exacerbation of BPT.\n\nTable 4 Impact factors for remission and prognosis\nImpact factors\tP-value\t\n\tRemission probability\tOverall survival\tDisease-free survival\t\nAge at diagnosis\t0.544\t0.827\t0.287\t\nEthnic group\t0.429\t0.610\t0.211\t\nStage\t0.258\t0.247\t0.384\t\nHistological subtype\t0.721\t0.318\t0.180\t\nThoroughness of surgery\t0.039\t0.009\t0.711\t\nPEB/PVB\t0.487\t0.956\t0.093\t\nBleomycin/pingyangmycin\t0.043\t0.420\t0.197\t\nRoute of administration\t0.649\t0.744\t0.645\t\nWeekly/monthly\t0.334\t0.238\t0.660\t\nCourse interval\t0.369\t0.911\t0.242\t\nCumulative dose\t0.069\t0.003\t0.393\t\nRenal dysfunction\t0.034\t0.294\t0.384\t\nBPT severity\t0.370\t0.214\t0.806\t\nGranulopenia\t0.343\t0.610\t0.464\t\nAnemia\t0.003\t0.130\t0.127\t\nThrombocytopenia\t1.000\t0.378\t0.339\t\nRemission\t-\t0.000\t-\t\nAbbreviations: BPT, bleomycin-induced pulmonary toxicity; PEB/PVB, cisplatin, etoposide/ vincristine and bleomycin\n\nAfter a median observation time of 53.2 months (range, 2.1 to 139.7 months), two patients died due to ovarian cancer. The 5-year OS rate was predicted to be 97.3% with an estimated median OS period of 11.2 years. Table 4 depicts the results of prognostic factors for OS investigated univariately. It indicated that optimal cytoreduction, sufficient delivery of bleomycin/pingyangmycin and the initial response to therapy significantly improved survival (P < 0.05). Specifically, both deceased patients failed to achieve remission after the initial treatment. Until the end of the study, three patients had recurring diseases with a median relapse interval of 2.7 years. However, no prognostic factors that influenced recurrence were discovered, which probably occurred due to current limited events.\n\nDISCUSSION\nDiagnosed by PFTs, approximately half of the patients have developed pathological pulmonary dysfunction at our institution. In particular, diffusion capacity impairment was prevalent, whereas obstructive and restrictive function impairments were observed in only a few cases. BPT has been recognized ever since its early clinical trials, the diagnostic criteria have not yet been unified. Due to the diversity of examination strategies and enrolled populations, the incidence in prior studies ranged from 2% to 46% in various studies [12]. Compared to respiratory symptoms and chest radiographs, PFT showed higher sensitivity. However, some researchers blamed PFT for vast false positive results [13]. Though life-threatening BPT and cause-specific deaths were prevented from happening, the remission probability was decreased for our BPT patients who had a reduced-dose of bleomycin/pingyangmycin administration. We thus posited that grade 2 DLCO reduction ( > 25%) would better be merely a warning sign, rather than an indicator for immediate drug cessation. On the other hand, a more precise grading of BPT severity might help determine a more appropriate cut-off value for clinical intervention. Specifically, consultation with specialists in respiratory medicine is valuable.\n\nOther common chemotherapy-related complications were routinely monitored to maintain a safe level of medication. The most frequent and prominent myelosuppression was granulopenia, and G-CSF was prescribed when WBC dropped too much or too soon, or without timely recovery. Severe anemia and thrombocytopenia also deserve attention, and component blood transfusion should be supplemented accordingly. Renal function was seriously impaired in three patients, probably due to cisplatin. Urine volume is supposed to be monitored, and adequate hydration should be applied. Carboplatin may be a substitute when cisplatin had to be ceased.\n\nIn this study, we focused on the relationship between BPT and other side effects, which has seldom been assessed in other studies. To the best of our knowledge, hand-in-hand aggravation of thrombocytopenia and BPT was revealed for the first time. However, the mechanism underlying this interaction is unknown. Lung fibrosis and inflammatory reaction might lead to platelet consumption, or disordered coagulation and fibrinolysis may be important for the pathogenesis of pulmonary fibrosis [14, 15]. We suggest timely management of severe thrombocytopenia, which might bring both circulatory and respiratory adverse events under better control. However, the definite clinical value of this relationship needs further investigation and validation. Between 50% and 70% of bleomycin is excreted unchanged by the kidneys. The half-life is 2-5 h in patients with normal renal function, which can increase to 30 hours in patients with reduced GFRs [16], and lead to longer lung exposure to the drug. In accordance with other studies [3, 12], our results demonstrated that decreased GFR or CCr was a predictor for BPT. Renal function can be compromised in a number of ways, especially by cisplatin, or by a secondary obstruction due to the abdominal tumor. In addition, our study confirmed there were dose-dependent effects for BPT severity detected by other studies [3, 12, 17].\n\nWe also investigated other potential impact factors for BPT [2, 3, 6, 7, 12, 17–19], yet none of these factors were validated by our data. In particular, Gerson et al demonstrated that patients who received bleomycin in a continuous infusion did not have DLCO alterations, and other studies showed that continuous infusion might have less toxicity than bolus administration [12, 19]. We failed to find a significant difference in BPT severity between single intravenous and intramuscular routes. However, lung injury might be worse when patients received both administration methods successively. Therefore, we suggest a consistent single delivery pattern of bleomycin/pingyangmycin for each patient.\n\nAfter all, the therapeutic efficacy is the primary concern, especially for a malignant disease with a good prognosis. Under standard guidelines, both the short-term remission and long-term survival rates were relatively high in our patients. Martin et al demonstrated that BPT resulted in a significant decrease in 5-year OS in patients with Hodgkin's lymphoma [6]. However, none of the treatment complications could explain the deaths in our study, which agreed with the results from Thomsen et al [2]. It is worth mentioning that the reduction of bleomycin/pingyangmycin administration did have a reversed impact on remission probability in the BPT group, whereas the dosages within lifetime limit generally would not lead to lethal BPT. Moreover, sufficient delivery of bleomycin/pingyangmycin improved OS. Collectively, a full-dose standard PEB/PVB regimen is recommended, and a more practicable BPT diagnostic model should be established using prospective controlled diagnostic trials.\n\nWe acknowledge that our study has several limitations. For the sake of accuracy, a large number of transferred patients without systematic records of side reactions were excluded. The cohort effects might influence the estimates, and factors underlying non-prescriptive chemotherapy might affect the drug-induced toxicities. Secondly, even though BPT was monitored while bleomycin/pingyangmycin was given, the impact factors were simultaneously collected. Therefore, the causal relationship could hardly be confirmed in a chronological manner. In addition, long-term complications need more intensive observation.\n\nIn conclusion, BPT could be sensitively detected and elaborately graded by PFTs, but the testing specificity needs to be enhanced. Concomitant thrombocytopenia, renal dysfunction, and an excessive dose of bleomycin/pingyangmycin significantly aggravate BPT. Therefore, simple and minimally invasive tests, such as a routine blood test, GFR and PFT should be monitored. With timely recognition and definitive control of treatment complications, patients would have more opportunities to be cured by integral PEB/PVB chemotherapy. Eventually, precision medicine could be achieved from a clinical perspective with treatment efficacy and safety comprehensively balanced for each patient.\n\nCONFLICTS OF INTEREST\n\nThe authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n1 Arora RS Alston RD Eden TO Geraci M Birch JM Comparative incidence patterns and trends of gonadal and extragonadal germ cell tumors in England, 1979 to 2003 Cancer 2012 118 4290 7 \n2 Thomsen FB Bandak M Thomsen MF Lauritsen J Christensen IJ Daugaard G Survival and toxicity in patients with disseminated germ cell cancer aged 40 years and older Cancer 2014 120 43 51 \n3 O’Sullivan JM Huddart RA Norman AR Nicholls J Dearnaley DP Horwich A Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours Ann Oncol 2003 14 91 6 \n4 Gatta G Zigon G Capocaccia R Coebergh JW Desandes E Kaatsch P Pastore G Peris-Bonet R CA; Stiller EUROCARE Working Group Survival of European children and young adults with cancer diagnosed 1995-2002 Eur J Cancer 2009 45 992 1005 \n5 Liles A Blatt J Morris D Wardrop R 3rd Sharma A Sznewajs A R; Goldsby Children's Oncology Group Monitoring pulmonary complications in long-term childhood cancer survivors: guidelines for the primary care physician Cleve Clin J Med 2008 75 531 9 \n6 Martin WG Ristow KM Habermann TM Colgan JP Witzig TE Ansell SM Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's lymphoma J Clin Oncol 2005 23 7614 20 16186594 \n7 Sleijfer S Bleomycin-induced pneumonitis Chest 2001 120 617 24 \n8 Global Initiative for Chronic Obstructive Lung Disease (GOLD) From the Global Strategy for the Diagnosis, Management and Prevention of COPD 2008 http://www.goldcopd.org/ \n9 National Cancer Institute CTEP. CTCAE v3.0. NCI, 2009 \n10 Mulder RL Thönissen NM van der Pal HJ Bresser P Hanselaar W Koning CC Oldenburger F Heij HA Caron HN Kremer LC Pulmonary function impairment measured by pulmonary function tests in long-term survivors of childhood cancer Thorax 2011 66 1065 71 \n11 Ingrassia TS 3rd Ryu JH Trastek VF Rosenow EC 3rd Oxygen-exacerbated bleomycin pulmonary toxicity Mayo Clin Proc 1991 66 173 8 \n12 Azambuja E Fleck JF Batista RG Menna Barreto SS Bleomycin lung toxicity: who are the patients with increased risk? Pulm Pharmacol Ther 2005 18 363 6 \n13 Ng AK Li S Neuberg D Chi R Fisher DC Silver B Mauch PM A prospective study of pulmonary function in Hodgkin's lymphoma patients Ann Oncol 2008 19 1754 \n14 Noth I Anstrom KJ Calvert SB de Andrade J Flaherty KR Glazer C Kaner RJ MA; Olman Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis Am J Respir Crit Care Med 2012 186 88 \n15 Kimura M Tani K Miyata J Sato K Hayashi A Otsuka S Urata T Sone S The significance of cathepsins, thrombin and aminopeptidase in diffuse interstitial lung diseases J Med Invest 2005 52 93 \n16 Alberts DS Chen HS Liu R Himmelstein KJ Mayersohn M Perrier D Gross J Moon T Broughton A Salmon SE Bleomycin pharmacokinetics in man. I. Intravenous administration Cancer Chemother Pharmacol 1978 1 177 81 \n17 Chaudhary UB Haldas JR Long-term complications of chemotherapy for germ cell tumours Drugs 2003 63 1565 77 \n18 Saxman SB Nichols CR Einhorn LH Pulmonary toxicity in patients with advanced-stage germ cell tumors receiving bleomycin with and without granulocyte colony stimulating factor Chest 1997 111 657 60 \n19 Gerson R E Tellez Bernal M Lazaro Leon E Sanchez Forgach C Garcia Irigoyen F Gutierrez Godinez Garcia Gonzalez H Low toxicity with continuous infusion of high-dose bleomycin in poor prognostic testicular cancer Am J Clin Oncol 1993 16 323 6\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(9)",
"journal": "Oncotarget",
"keywords": "bleomycin; malignant germ cell tumor; medication safety; pulmonary toxicity; treatment efficacy",
"medline_ta": "Oncotarget",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001761:Bleomycin; D002648:Child; D015331:Cohort Studies; D005260:Female; D005833:Genital Neoplasms, Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal; D055815:Young Adult",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "15952-15960",
"pmc": null,
"pmid": "28160575",
"pubdate": "2017-02-28",
"publication_types": "D016428:Journal Article",
"references": "11316667;11502668;12488299;12887263;15751279;15939315;16186594;1704473;18467315;18646589;19231160;21803931;22252431;22561965;24108413;7687091;86392;9118704",
"title": "Safety and efficacy of bleomycin/pingyangmycin-containing chemotherapy regimens for malignant germ cell tumor patients in the female genital system.",
"title_normalized": "safety and efficacy of bleomycin pingyangmycin containing chemotherapy regimens for malignant germ cell tumor patients in the female genital system"
} | [
{
"companynumb": "CN-MYLANLABS-2017M1030552",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "The role of hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is debated. Melphalan as a perfusion agent has also demonstrated survival benefit in other recurrent and chemoresistant malignancies. Thus, we hypothesize that melphalan as a HIPEC agent may improve overall survival (OS) and progression-free survival (PFS) in patients with PC from CRC.\nA retrospective review of a prospective database of 48 patients who underwent optimal CRS (CC-0/1) and HIPEC from 2001-2016 was performed. Nineteen had CRS/HIPEC with melphalan (group I) and 29 with mitomycin-C (group II). Survival was estimated using the Kaplan-Meier method. Cox regression was used for multivariate analysis. Perioperative variables were compared.\nMean age at CRS/HIPEC was 53±10 years. Median peritoneal cancer index (PCI) was 17 vs 13 in groups I and II, respectively (p=0.86). PCI≥20 occurred in 9 (47%) and 13 (45%) patients in groups I and II, respectively. Positive lymph nodes were identified in 8/19 (42%) vs 12/29 (41%) in groups I and II, respectively (p=0.73). Multivariate analysis identified PCI≥20 as a predictive factor of survival (HR: 7.5). Median OS in groups I and II was 36 and 28 months, respectively (p=0.54). Median PFS in groups I and II was 10 and 20 months, respectively (p=0.05).\nCRS/HIPEC with MMC had longer median PFS in PC from CRC. PCI≥20 was the only independent predictive factor for survival. Until longer follow-up is available, we recommend using MMC in CRS/HIPEC for PC from CRC. Further prospective randomized studies are necessary.",
"affiliations": "Surgical Oncology Department, Mercy Medical Center, Baltimore, Maryland, 21202, USA.;Surgical Oncology Department, Mercy Medical Center, Baltimore, Maryland, 21202, USA.;Surgical Oncology Department, Mercy Medical Center, Baltimore, Maryland, 21202, USA.;Surgical Oncology Department, Mercy Medical Center, Baltimore, Maryland, 21202, USA.;Surgical Oncology Department, Mercy Medical Center, Baltimore, Maryland, 21202, USA.;Surgical Oncology Department, Mercy Medical Center, Baltimore, Maryland, 21202, USA.",
"authors": "Sipok|Arkadii|A|;Sardi|Armando|A|0000-0003-4132-9489;Nieroda|Carol|C|;King|Mary Caitlin|MC|;Sittig|Michelle|M|0000-0003-2641-1564;Gushchin|Vadim|V|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D016685:Mitomycin; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1155/2018/1920276",
"fulltext": "\n==== Front\nInt J Surg OncolInt J Surg OncolIJSOInternational Journal of Surgical Oncology2090-14022090-1410Hindawi 10.1155/2018/1920276Clinical StudyComparison of Survival in Patients with Isolated Peritoneal Carcinomatosis from Colorectal Cancer Treated with Cytoreduction and Melphalan or Mitomycin-C as Hyperthermic Intraperitoneal Chemotherapy Agent Sipok Arkadii http://orcid.org/0000-0003-4132-9489Sardi Armando asardi@mdmercy.comNieroda Carol King Mary Caitlin http://orcid.org/0000-0003-2641-1564Sittig Michelle Gushchin Vadim Surgical Oncology Department, Mercy Medical Center, Baltimore, Maryland, 21202, USAAcademic Editor: Steven Curley\n\n2018 13 12 2018 2018 19202766 8 2018 5 10 2018 19 11 2018 Copyright © 2018 Arkadii Sipok et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n The role of hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is debated. Melphalan as a perfusion agent has also demonstrated survival benefit in other recurrent and chemoresistant malignancies. Thus, we hypothesize that melphalan as a HIPEC agent may improve overall survival (OS) and progression-free survival (PFS) in patients with PC from CRC.\n\n Methods\n A retrospective review of a prospective database of 48 patients who underwent optimal CRS (CC-0/1) and HIPEC from 2001-2016 was performed. Nineteen had CRS/HIPEC with melphalan (group I) and 29 with mitomycin-C (group II). Survival was estimated using the Kaplan-Meier method. Cox regression was used for multivariate analysis. Perioperative variables were compared.\n\n Results\n Mean age at CRS/HIPEC was 53±10 years. Median peritoneal cancer index (PCI) was 17 vs 13 in groups I and II, respectively (p=0.86). PCI≥20 occurred in 9 (47%) and 13 (45%) patients in groups I and II, respectively. Positive lymph nodes were identified in 8/19 (42%) vs 12/29 (41%) in groups I and II, respectively (p=0.73). Multivariate analysis identified PCI≥20 as a predictive factor of survival (HR: 7.5). Median OS in groups I and II was 36 and 28 months, respectively (p=0.54). Median PFS in groups I and II was 10 and 20 months, respectively (p=0.05).\n\n Conclusions\n CRS/HIPEC with MMC had longer median PFS in PC from CRC. PCI≥20 was the only independent predictive factor for survival. Until longer follow-up is available, we recommend using MMC in CRS/HIPEC for PC from CRC. Further prospective randomized studies are necessary.\n==== Body\n1. Introduction\nCytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has well established predictors, described techniques, and indications for the treatment of peritoneal surface malignancies; however, the HIPEC portion of the treatment is not standardized by methods or chemotherapeutic agents. This is especially true in the treatment of peritoneal carcinomatosis (PC) from colorectal cancer (CRC).\n\nMitomycin-C (MMC) is currently the most common and standard perfusion agent in the United States. In 2013, the American Society of Peritoneal Surface Malignancies (ASPSM) published standardized guidelines for the use of HIPEC in CRC in the United States [1]. These guidelines require (1) a closed method of HIPEC using (2) mitomycin-C (MMC) at a (3) total dose of 40mg (4) initially delivered at 30mg for 60 minutes and adding 10mg for the last 30 minutes, (5) diluted in 3L of perfusion solution, and (6) heated to 42°C (7) for a total perfusion time of 90 minutes [1]. Although a variety of other chemotherapeutic agents have been used, including cisplatin, carboplatin, oxaliplatin, doxorubicin, 5-fluorouracil, and irinotecan [2, 3], there is no clear best choice among them. Therefore, the search is ongoing.\n\nMelphalan may be a good HIPEC perfusion agent due to its several advantages, including better potentiation of the drug by hyperthermia with lower absorption from the abdominal and pelvic regions to blood during the procedure, resulting in lower toxicity potential [4, 5]. The clinical efficacy of melphalan as a second-line HIPEC agent has been demonstrated by our center in patients with various primaries who failed previous CRS/HIPEC treatment with MMC, MMC/doxorubicin, MMC/cisplatin, and doxorubicin/cisplatin [6].\n\nWe hypothesize that if melphalan is an effective HIPEC agent option for recurrent PC after previous CRS/HIPEC, it may offer survival benefit if used at the time of initial CRS/HIPEC. We compared overall survival (OS) and progression-free survival (PFS) in patients with PC from CRC undergoing initial CRS/HIPEC using either MMC or melphalan as the HIPEC agent.\n\n2. Materials and Methods\nA retrospective review of a prospective database of 65 patients who underwent CRS/HIPEC for CRC with PC in a single medical center from February 2001 to January 2016 was performed. Inclusion criteria were (1) use of melphalan or mitomycin-C as a HIPEC agent (2) optimal CRS (CC-0/1) and (3) absence of distant metastases at the time of HIPEC. Forty-eight patients were identified for analysis: 19 patients treated with melphalan (group I) and 29 patients treated with MMC (group II). Radiographic imaging and/or biopsies along with clinical presentation supported the preoperative PC diagnosis. From 2001-2012, mitomycin-C was the primary perfusion agent used for PC from CRC at our center. In 2012, one surgeon empirically began perfusing with melphalan because of the drug's success in recurrent and resistant malignancies and dissatisfaction with MMC results in CRC. The other surgeon continued to primarily use mitomycin-c until 2014 when melphalan became the perfusion agent of choice for PC from CRC, at our institution. Both surgeons consistently used the same selection criteria for CRS/HIPEC throughout the study period.\n\n2.1. Patient Selection\nImaging studies, such as computed tomography (CT), magnetic resonance imaging (MRI), or fluorodeoxyglucose positron emission tomography (FDG-PET), and diagnostic laparoscopy (when necessary) were performed to estimate the feasibility of complete cytoreduction (CC-0/1). Extensive involvement of small bowel, its mesentery, or the porta hepaticus were contraindications for the procedure. In case of extensive, but potentially resectable disease, or a recent extensive incomplete debulking, patients underwent neoadjuvant chemotherapy and were then reevaluated for the feasibility of achieving a complete cytoreduction.\n\n2.2. Surgical Technique and Patient Care\nA xiphopubic incision was made under general anesthesia. The peritoneal cavity was inspected and the peritoneal carcinomatosis index (PCI) score was recorded as previously described by Jacquet et al [7]. Patients with presumed PCI ≥20 underwent diagnostic laparoscopy to estimate the feasibility of achievement of complete cytoreduction (CC). The extent of CRS performed was determined by the specific involvement of organs and structures at the time of surgery with the goal to achieve complete (CC-0) or optimal (CC-1) cytoreductions. Only those involved with disease were removed. Common resections included: previous scar and port sites of the anterior abdominal wall, extensive peritonectomies, including parietal, diaphragmatic, abdominal wall, pelvic, as well as visceral, and peritoneal stripping of the omental bursa and porta hepatis. If tumor lesions were impossible to remove from the surface of solid organs, the organ was resected. Commonly resected organs include bowel and liver segments, uterus, ovaries, and gallbladder. After CRS, completeness of cytoreduction (CC) score was estimated and defined as CC-0 if no visible tumor remained within the abdomen or CC-1 if there were residual tumor nodules <2.5mm. Patients with ≥2.5mm of residual tumor (CC-2/3) were excluded from analysis.\n\nThen, HIPEC perfusion was performed using a closed technique with either melphalan (50mg/m2) or MMC (40mg) at 42-43°C for 90 minutes. The target temperature of the intraperitoneal chemotherapy solution was 41-42°C, which was achieved by inflow temperatures of 41-43°C. After completion of HIPEC, anastomoses were created and the incision was closed [8].\n\nFollowing CRS/HIPEC, patients were observed in the intensive care unit for the first 24 hours or until stable and then were transferred to the surgical oncology unit for further observation. Postoperative surgical complications were analyzed using the Clavien-Dindo classification [9].\n\nClinical follow-up occurred at 3 weeks, 3 months, every 6 months after CRS/HIPEC for 5 years, and yearly after 5 years. OS was defined as the time from CRS/HIPEC to the date of the last contact (censored) or date of death (event). PFS was defined as the time from CRS/HIPEC and the date of the last contact (censored) or date of recurrence (event). Disease recurrence was identified by imaging studies (CT-scan, PET-scan or MRI), elevated biochemical markers (CEA, CA 125, or CA 19-9), and/or clinical presentation (i.e. bowel obstruction). Patients with more than one CRS/HIPEC were included only in PFS analysis from the time of initial CRS/HIPEC to first recurrence.\n\nIBM SPSS 23.0 software package was used (IBM Corp., Armonk, NY USA) for statistical analysis of clinical data. OS and PFS were analyzed using the Kaplan-Meier method. The Log-rank test was used to determine differences between groups and for univariate analysis. Multivariate analysis using Cox regression was performed to exclude confounding variables. Categorical variables were analyzed with the Chi-square test, while continuous variables were analyzed with the Mann-Whitney or t-test. Differences were considered statistically significant if p≤0.05.\n\n3. Results\n3.1. Patient Characteristics\nNineteen patients were treated with melphalan (group I) and 29 patients were treated with MMC (group II). There were 14 (74%) female patients in group I and 13 (54%) in group II (p=0.049). Mean age at the time of CRS/HIPEC was 53±10 years: 52±11 and 51±9 years in groups I and II, respectively (p=0.73). Forty-two (88%) patients had prior surgery for curative intent: 17 (90%) in group I and 25 (86%) in group II. All of these patients received chemotherapy after prior surgery in groups I and II, respectively (p=0.9). Table 1 shows preoperative patient characteristics.\n\nThe primary tumor site was the right colon in 6 (32%) and 8 (28%) patients in groups I and II, respectively (p=0.88). Well, moderately, and poorly differentiated tumors were observed in 2 (11%), 16 (84%), and 1 (5%) patients vs 3 (10%), 17 (59%), and 8 (28%) in groups I and II, respectively (p=0.98).\n\nSynchronous PC was diagnosed in 8 (42%) and 11 (38%) patients in group I and group II, respectively (p=0.43). Six patients underwent CRS/HIPEC as initial treatment [group 1: 2 (11%); group 2: 4 (14%)]. Of these, 3 received neoadjuvant chemotherapy [group I: 1 (5%); group II: 2 (7%)] (p=1). A total of 52 CRS/HIPEC procedures were performed in all patients: 1 patient in group I underwent 2 procedures and 2 patients in group II underwent 2 and 3 procedures, respectively.\n\n3.2. Treatment and Outcomes\nMedian length of CRS/HIPEC was 9 hours (range: 5-14) in both groups. The median preoperative PCI was 17 (range: 3-35) and 13 (range: 3-39) in groups I and II, respectively (p=0.86). All patients had optimal cytoreductions (CC-0/1). Fourteen (74%) patients in group I and 25 (86%) patients in group II had CC-0 cytoreductions (p=0.28).\n\nSixteen (84%) patients in group I and 22 (76%) patients in group II had lymph node (LN) metastases (p=0.72). Median number of LN resected during CRS/HIPEC was 26 (range: 6-119) and 17 (range: 1-53) in groups I and II, respectively (p=0.043). LN metastases identified at CRS/HIPEC were identified in 8 (42%) patients in group I and 12 (46%) patients in group II (p=0.73).\n\nMedian hospital stay was 11 days (range: 9-17) in group I and 10 days (range: 5-59) in group II (p=0.89). Grade II/III/IV postoperative complications occurred in 7/6/0 patients in group I and in 4/1/3 patients in group II, respectively (p<0.01). Grade IV postoperative complications occurred in 3 (10%) patients in group II. One patient had a myocardial infarction, gastro-jejunostomy anastomic failure requiring reoperation, and a left upper quadrant abscess. The second patient had a small bowel fistula with peritonitis complicated by sepsis and respiratory failure, which required complex treatment including antibacterial therapy, intubation, and reoperation. The third patient underwent reoperation for a left gastric artery hemorrhage. Bone marrow toxicity was observed in 10 (53%) patients in group I and 3 (10%) in group II (p<0.01). There was no 30-day postoperative mortality.\n\n3.3. Survival\nAt the time of the analysis, 7/19 (37%) patients in group I were alive: 5 alive with disease and 2 with no evidence of disease. In group II, 6/29 (21%) patients were alive, all without evidence of disease. The mean follow-up was 38±13 months in group I and 57±11 months in group II (p=0.02). Median OS was 36 (95% CI: 17-55) and 28 months (95% CI: 8-47) in groups I and II, respectively. OS at 1, 3 and 5 years is 89%, 54%, and 18% in group I and 89%, 48%, and 28% in group II, respectively (p=0.54) (Figure 1).\n\nSeventeen (89%) patients in group I and 22 (75%) patients in group II had disease recurrence. Median PFS was 10 (95% CI: 6-13) and 20 months (95% CI: 9-39) in groups I and II, respectively. PFS at 1, 3 and 5 years is 32%, 10%, and 10% in group I and 64%, 26%, and 18% in group II, respectively (p=0.05) (Figure 2).\n\nIn the univariate analysis, CC-0 (vs CC-1) and preoperative PCI<20 were identified as variables associated with better PFS and OS; however, in the multivariate analysis only preoperative PCI <20/≥20 was an independent factor for progression and survival (Table 2) (Table 3).\n\n4. Discussion\nMelphalan was never compared to MMC as HIPEC agent in regards of survival outcomes in patients with PC from CRC. HIPEC agents for PC from CRC vary with the institution and/or surgical group performing the procedure, making the analysis of outcomes difficult. In the United States, the most common drug for these patients is MMC. However, the use of MMC has also varied in doses (15-60mg/m2), temperature (40-43°C), and duration of exposure (30-120 minutes) depending on the institution [1]. Recently, the American Society of Peritoneal Surface Malignancies (ASPSM) released guidelines for HIPEC in patients with PC from CRC which established MMC (40mg at 42°C for 90 minutes) as the standard intraperitoneal perfusion agent and drug of choice for PC from CRC [1]. We followed these recommendations when MMC was used.\n\nIt is important to note that the American Society of Peritoneal Surface Malignancies did not publish consensus guidelines for HIPEC in PC from CRC until 2014 and there is very limited data testing these guidelines, which recommend MMC for 90 minutes. Initially, we consistently used MMC as the primary HIPEC perfusion agent for PC from CRC. Empirically, we noticed that MMC outcomes were not as good as we expected, with seemingly quick time to progression. Therefore, based on the pharmacologic and clinical properties, as well as its success in aggressive and resistant malignancies, one surgeon began using melphalan in 2012, while the other HIPEC surgeon at our center continued to use mitomycin-C. At the 2013 regional meeting of the Mid-Atlantic Chapter of the American Society of Peritoneal Surface Malignancies, the use of melphalan as an alternative to MMC was discussed and agreed upon by the physicians as a valid method to try and improve outcomes in PC from CRC. Thus, in 2014, melphalan became the primary perfusion agent for PC from CRC at our center for both surgeons. Melphalan was chosen based on its proven success in recurrent, resistant, and aggressive tumors, such as melanoma and sarcoma with only one time applications [16, 17]. Our group has also demonstrated melphalan to be effective in subsequent HIPEC procedures in patients who recurred after previous CRS/HIPEC procedures with MMC, MMC/doxorubicin, MMC/cisplatin, or doxorubicin/cisplatin, we demonstrated [6]. Pharmacologically, as an alkylating agent, along with ifosfamide and cyclophosphamide, it has the highest potentiation by heat [5]. Melphalan was the most appropriate choice since ifosfamide and cyclophosphamide are prodrugs which require activation by liver microsomal enzymes and, thus, might be less cytotoxic to tumor cells if used in intraperitoneal solution. Moreover, when used for intraperitoneal perfusion, melphalan demonstrates a favorable peritoneal fluid to plasma AUC ratio of 35±13 [4]. Therefore, it achieves higher local concentrations of chemotherapy and lower systemic concentrations [6]. Hence, we used melphalan due to its theoretical and empirical benefit for survival.\n\nThere are also several pitfalls to using melphalan as a HIPEC agent related to its pharmacokinetic and pharmacodynamic properties. A serious disadvantage is its rapid spontaneous degradation by hydrolysis. Thus, a minimum delivery time of only 20-30 minutes from the pharmacy to the operating room and perfusion into the peritoneal cavity is imperative. Maintaining the proper temperature (<42°C) is critical for the same reason [18]. According to studies by Urano et al., melphalan achieves its highest efficacy at 41.5°C [19]. In our study, melphalan was perfused intra-abdominally with median in-port temperature control of 43.3°C (range: 42.4-46.6). Although melphalan was sometimes perfused at a higher median temperature than recommended which may have effected the efficacy of the drug, it appears that our patients still received an therapeutic dose since 10/19 (53%) experienced complications related to bone marrow toxicity. Therefore, to achieve better results using melphalan as a HIPEC agent, proper planning to minimize delivery time and tight temperature control is necessary. Selecting a proper dosage of melphalan is also important to limit toxicity. Bijelic et al. showed that in patients who underwent CRS/HIPEC with melphalan, grade IV complications were associated with a higher dose of the drug (70mg/m2). The authors recommended the use of melphalan at a dose of 60 mg/m2 for 60 minutes [4]. We used a dose of 50 mg/m2 perfused for 90 minutes, which may explain the absence of grade IV complications in our study. Thus, using melphalan at a lower dose may be safe and reduce the number of postoperative complications attributed to drug toxicity, however; further studies on the dosage and duration of the perfusion agent(s) are necessary to determine the most effective combination to treat PC from CRC.\n\nFew studies are available reporting the surgical and hematological complications associated with melphalan as a HIPEC agent. In our study, melphalan demonstrated a higher hematologic toxicity and lower grade III/IV surgical complications compared to MMC. We observed grade III surgical complications in 6 (32%) patients and no (0%) grade IV complications. Hematologic complications occurred in 10 (53%) patients perfused with melphalan of which 5 (26%) developed neutropenia. All cases of neutropenia were successfully managed with filgrastim. These findings validate our previous study in which grade III/IV surgical complications occurred in 7 of 31 cases (23%), while neutropenia was observed in 9 of 31 cases (29%) after CRS/HIPEC with melphalan in patients with PC from various primaries [6]. In a recent study, Hakeam et al compared hematologic complications after CRS/HIPEC with either melphalan (60 mg/m2) or MMC+cisplatin (30 mg/m2 and 100 mg/m2, respectively) for 60 minutes. Leukopenia was observed in 26% and 17% of patients perfused with melphalan and MMC, respectively (p=0.36). Leukopenia occurred earlier in patients perfused with melphalan vs MMC+cisplatin (p=0.033), however; neutropenia did not occur in study patients, which was suggested by the authors to be a result of using an open technique [20]. More studies are needed to evaluate variables involved in the drug effectiveness and toxicity in patients with PC from CRC.\n\nThe role of HIPEC in PC from CRC is debated and only one prospective randomized phase III study comparing CRS/HIPEC with oxaliplatin for 30 minutes + systemic chemotherapy (fluorouracil + leucovorin) vs CRS + systemic chemotherapy (fluorouracil + leucovorin) alone was conducted in France (NCT00769405). The first results of this trial presented at the 2018 American Society of Clinical Oncology meeting showed no statistically significant difference between the groups with median survival of 41.2 months vs 41.7 months in patients treated with CRS/HIPEC + adjuvant systemic chemotherapy versus CRS + adjuvant systemic chemotherapy, respectively (p=1). However, there are many different ways to adjust the HIPEC procedure to achieve superior outcomes, i.e. drug, dosage, time of perfusion, temperature, and surgical technique. Thus, the search of the optimal combination HIPEC technique, including drug choice, continues.\n\nSeveral studies have reported outcomes for CRS/HIPEC with MMC for PC from CRC with median OS ranging from 13-30 months and up to 48 months with optimal cytoreduction (Table 4). In the 2014 ASPSM study, CRS/HIPEC with MMC demonstrated a significantly positive impact on survival in the multivariate analysis of all patients (HR: 1.40 [95% CI: 1.01-1.94]) over oxaliplatin, but failed to show significant difference in patients with CC-0/1 cytoreductions (HR: 1.24 [95% CI: 0.87-1.76]) [15]. This may suggest MMC is more cytotoxic to CRC tumor cells. Similarly, in our study, no statistically significant difference was observed in OS between MMC and melphalan. However, MMC had a longer PFS than melphalan (median: 20 vs 11 months, p=0.05). We did not observe a difference in survival by perfusion drug in either uni- or multivariate analysis. Other studies have identified PCI, CC score, LN metastases, and adjuvant chemotherapy as predictive factors for survival [12, 21]; however, our multivariate analysis only found PCI (<20 or ≥20) to be a predictive factor. Although some studies identified PCI as a prognostic factor for long term survival and it is often used as a criterion for patient selection, there is no firm consensus on patient selection for CRS/HIPEC in PC from CRC based on PCI score [22]. The key prognostic factor is the completeness of cytoreduction [12, 22], lending to the importance of referrals to high-volume, specialized centers [10, 11]. Patients in our study were selected for CRS/HIPEC if a complete cytoreduction was deemed feasible, based on imaging studies and confirmed by exploratory laparoscopy when needed. The effect of HIPEC is on the residual disease after cytoreduction. Although higher PCI scores (>20) can make achieving a CC score of 0 or 1 more challenging, a complete cytoreduction was achieved in 100% of the patients in our study, including those with PCI>20. In addition, the number of patients with PCI>20 in each group was statistically equal (45% MMC vs 47% melphalan, p=1) and the majority of patients had PCI<20 (median PCI: 17 MMC vs 13 melphalan, p=0.86). Preoperative tumor burden plays an important role in patient survival outcomes, however; if a complete cytoreduction is feasible, PCI should not be considered a contraindication to proceed with CRS/HIPEC.\n\nThere are several possible explanations why we did not find any difference in survival outcomes between melphalan and MMC groups in this study. It is a retrospective study with relatively small number of patients and low statistical power to detect clinically relevant difference. In addition, the melphalan was perfused at a higher median perfusion temperature than indicated for this drug. Also, the melphalan group had a significantly shorter mean follow-up (38±13 months) compared to the MMC group (57±11 months). Therefore, further studies with better temperature control and a larger sample size with longer follow-up are needed.\n\nThe interest of using melphalan as a perfusion agent in patients with PC from CRC is strong. A phase II randomized trial, entitled “Comparing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC) Using Mitomycin-C versus Melphalan for Colorectal Peritoneal Carcinomatosis” (NCT03073694), was recently registered in 2017 by the University of Kansas Medical Center. An objective of the trial is to compare the toxicity profiles of these drugs. No results have been published yet.\n\n5. Conclusions\nAlthough OS was not statistically different between patients with PC from CRC treated with CRS/HIPEC with either melphalan or MMC, PFS was statistically longer in patients perfused with MMC. PCI was the only independent predictive factor for survival in multivariate analysis. Therefore, we have discontinued melphalan as a primary HIPEC agent for PC from CRC. Until further studies are available, we recommend using mitomycin-C. Further prospective studies on the role of melphalan are needed.\n\nAcknowledgments\nResearch and publication is funded by internal research fund supported by patient donations.\n\nData Availability\nThe retrospective data used to support the findings of this study may be released upon application to the Mercy Medical Center Institutional Review Board, who can be contacted at IRB Chair: Ralph Lebron, MD (rlebron@mdmercy.com).\n\nDisclosure\nThe abstract from this manuscript was presented at the Society of Surgical Oncology Annual Meeting in Chicago, Illinois, March 21-24, 2018, and at the Maryland Chapter, American College of Surgeons 2018 Annual Spring Meeting, Baltimore, Maryland, April 28, 2018.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Kaplan-Meier curves demonstrate overall survival of patients with PC from CRC treated with CRS/HIPEC. OS was calculated in 45 patients (patients with >1 CRS/HIPEC were excluded).\n\nFigure 2 Progression-free survival of patients with PC from CRC treated with CRS/HIPEC.\n\nTable 1 Patient characteristics.\n\n\tMelphalan (n=19)\tMitomycin-C (n=29)\tp-value\t\n\nGender \n\t \t \t\n0.048\n\t\n Male, n (%)\t5 (26)\t16 (55)\t \t\n Female, n (%)\t14 (74)\t13 (45)\t \t\nNumber of previous surgeries with curative intent\t \t \t0.99\t\n 0 (%)\t2 (10)\t4 (14)\t \t\n 1 (%)\t15 (80)\t21 (72)\t \t\n >1 (%)\t2 (10)\t4 (14)\t \t\nMedian LN resected from previous surgery, (range)\t15 (0-43)\t14 (0-145)\t0.87\t\nLN metastases at the time of previous surgery, n (%)\t12 (71)\t18 (67)\t1\t\nAdjuvant chemotherapy after previous surgery, n (%)\t17 (90)\t25 (86)\t0.9\t\nLocation of tumor origin\t \t \t0.88\t\n Right, n (%)\t6 (32)\t8 (28)\t \t\n Left, n (%)\t13 (68)\t21 (72)\t \t\nPeritoneal carcinomatosis occurrence\t \t \t0.63\t\n Synchronous, n (%)\t8 (42)\t11 (38)\t \t\n Metachronous, n (%)\t13 (58)\t18 (62)\t \t\n\n\n\t\n\nAt the time of CRS/HIPEC\n\t \t\n\n\n\t\nNACT (before HIPEC), n (%)\t1 (5)\t2 (7)\t1\t\nMean age at the time of CRS/HIPEC, years (SD)\t52±11\t51±9\t0.73\t\nMedian time from diagnosis to CRS/HIPEC, months (range)\t22 (0-82)\t16 (0-97)\t0.89\t\nMedian preoperative PCI (range)\t17 (3-35)\t13 (3-39)\t0.86\t\nPCI≥20, (%)\t9 (47)\t13 (45)\t1\t\nMedian LOS, minutes\t569\t580\t0.78\t\nMedian LN resected from CRS/HIPEC, n (range)\t26 (6-119)\t17 (1-53)\t0.07\t\nLymph nodes metastases, n (%)\t8 (42)\t12 (46)†\t0.73\t\nMedian length of stay in hospital, days (range)\t11 (7-17)\t10 (5-59)\t0.89\t\nHistopathology\t \t \t0.98\t\n Well differentiated, n (%)\t2 (11)\t3 (10)\t \t\n Moderately differentiated, n (%)\t16 (84)\t17 (59)\t \t\n Poorly differentiated, n (%)\t1(5)\t8 (28)\t \t\n Not reported, n (%)\t0 (0)\t1 (3)\t \t\nNACT: neoadjuvant chemotherapy; LOS: length of surgery; †calculated in 26 patients (not reported in 3 patients).\n\nTable 2 Univariate and multivariate analysis of survival in patients with colorectal cancer, treated with melphalan or mitomycin-C as a HIPEC agent.\n\n\t \t Univariate\t Multivariate\t\nCharacteristics\tn\tMedian survival months (95%CI)\tp-value\tHR\n(95%CI)\tp-value\t\nAgent\t \t \t0.54\t \t0.24\t\n Melphalan\t18\t36 (17-55)\t \t1.66 (0.7-3.95)\t \t\n Mitomycin-C∗\t27\t28 (8-47)\t \t \t \t\nAge\t \t \t0.42\t \t0.24\t\n ≤53∗\t31\t37 (23-51)\t \t \t \t\n >53\t14\t30 (11-49)\t \t1.62 (0.72-3.64)\t \t\nCC score\t \t \t0.026\t \t0.69\t\n CC-0∗\t37\t36 (24-49)\t \t \t \t\n CC-1\t8\t24 (3-47)\t \t1.25 (0.43-3.64)\t \t\n\nPCI\n\t \t \t\n<0.001\n\t \t\n<0.001\n\t\n ≤20∗\t24\t46 (29-64)\t \t \t \t\n >20\t20\t18 (12-24)\t \t7.5 (2.76-20.4)\t \t\nLN status\t \t \t0.49\t \t1\t\n no LN metastases∗\t22\t37 (35-39)\t \t \t \t\n LN metastases\t19\t27 (18-35)\t \t1 (0.44-2.27)\t \t\nHR: hazard ratio; CI: confidence interval; PCI: peritoneal carcinomatosis index; LN: lymph nodes; ∗used as reference; patients with >1 CRS/HIPEC were excluded from the analysis.\n\nTable 3 Univariate and multivariate analysis of progression free survival in patients with colorectal cancer, treated with melphalan or mitomycin-C as a HIPEC agent.\n\n \t \t Univariate\t Multivariate\t\nCharacteristics\tN\tMedial PFS months\n(95% CI)\tp-value\tHR\n(95% CI)\tp-value\t\nAgent\t \t \t0.05\t \t0.17\t\n Melphalan\t18\t10 (6-13)\t \t1.62 (0.81-3.27)\t \t\n Mitomycin-C∗\t28\t24 (9-39)\t \t \t \t\nAge\t \t \t0.36\t \t0.89\t\n ≤53 years∗\t32\t13 (3-23)\t \t \t \t\n >53years\t14\t11 (9-11)\t \t0.95 (0.47-1.96)\t \t\nCC score\t \t \t0.11\t \t0.67\t\n CC-0∗\t38\t13 (3-23)\t \t \t \t\n CC-1\t8\t12 (10-16)\t \t1.22 (0.49-3.08)\t \t\n\nPCI\n\t \t \t\n<0.001\n\t \t\n<0.001\n\t\n ≤20∗\t25\t28 (18-38)\t \t \t \t\n >20\t20\t10 (4-16)\t \t4.52 (2.05-9.95)\t \t\nLN status\t \t \t0.64\t \t0.97\t\n LN metastases\t19\t10 (9-12)\t \t1.01 (0.5-2.07)\t \t\n no LN metastases∗\t23\t12 (9-15)\t \t \t \t\nHR: hazard ratio; PCI: peritoneal carcinomatosis index; LN: lymph nodes; PFS: progression-free survival; ∗was used as reference in multivariate analysis; Median age of all patients was 53 years.\n\nTable 4 Outcomes in patients with PC from CRC treated with CRS and HIPEC or Early Postoperative Intraperitoneal Chemotherapy.\n\nStudy\tYear\tNo of patients\tPerfusion agent, dose, length, t°\tMedian OS (months),\n(resection status)\t\nGlehen et al. [10]\t2004\t53\n23\tMMC: 40-60 mg at 46-48°C for 90 min\t13 (all patients)\n33 (CC-0)\t\nGlehen et al. [11]\t2004\t506\n271\n106\n\t(1) MMC (30/50 mg/m2) ± cisplatin (50-100 mg/m2) at 41-42.5 °C for 60-120 min\n(2) oxaliplatin (360-460 mg/m2) ± irinoteacan (100-200 mg/m2) ± IV 5-FU + leucovorin at 43 °C for 30 min\t19 (all patients)\n32 (CC-0)\n24 (CC-1)\n\t\nElias et al. [12]\t2010\n\t523\n439\n\t(1) MMC (30/50 mg/m2) ± cisplatin (50-100 mg/m2) at 41°C for 60-120 min\n(2) oxaliplatin (360-460 mg/m2) ± irinoteacan (200 mg/m2) ± IV 5-FU + leucovorin at 43 °C for 30 min\t30 (all patients)\n33 (CC-0)\n\t\nVerwaal et al. [13]\t2008\n\t54\n\tMMC: initial dose of 17.5 mg/m2 with additional 8.8 mg/m2 every 30 min (maximal dose in total 70 mg/m2)at 41-42 °C for 90 min\t22 (all patients)\n48 (R-1)\n\t\nFranko et al. [14]\t2010\n\t67\n\tMMC: initial dose of 30 mg for 60 min with additional 10 mg after for 40 min\t35 (all patients)\t\nASPSM study [15]\t2014\n\t392\n\tMMC: initial dose of 30 mg with additional 10 mg in 60 min at 42°C for 90 minutes\t33 (CC-0/1)\n\t\nThis study\t2018\t19\n29\tMelphalan\nMMC\t36 (CC-0/1)\n28 (CC-0/1)\t\n\nMMC: mitomycin-C; OS: overall survival; R-0: no gross disease with negative resection margins, R-1: no gross disease with positive resection margins; CC-0: no visible residual disease; CC-1: residual disease <2mm;\n==== Refs\n1 Turaga K. Levine E. Barone R. Consensus guidelines from the American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States Annals of Surgical Oncology 2014 21 5 1501 1505 2-s2.0-84898852205 10.1245/s10434-013-3061-z 23793364 \n2 Nadler A. McCart J. A. Govindarajan A. Peritoneal Carcinomatosis from Colon Cancer: A Systematic Review of the Data for Cytoreduction and Intraperitoneal Chemotherapy Clinics in Colon and Rectal Surgery 2015 28 4 234 246 2-s2.0-84947931670 10.1055/s-0035-1564431 26648794 \n3 Murono K. Kawai K. Hata K. Regimens of intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal cancer Anticancer Reseach 2018 38 1 15 22 2-s2.0-85039793564 \n4 Bijelic L. Sugarbaker P. H. Stuart O. A. Hyperthermic Intraperitoneal Chemotherapy with Melphalan: A Summary of Clinical and Pharmacological Data in 34 Patients Gastroenterology Research and Practice 2012 2012 5 827534 10.1155/2012/827534 \n5 Takemoto M. Kuroda M. Urano M. The effect of various chemotherapeutic agents given with mild hyperthermia on different types of tumours International Journal of Hyperthermia 2003 19 2 193 203 2-s2.0-0037335525 10.1080/0265673021000035235 12623641 \n6 Sardi A. Jimenez W. Nieroda C. Sittig M. Shankar S. Gushchin V. Melphalan: A promising agent in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy Annals of Surgical Oncology 2014 21 3 908 914 2-s2.0-84896724794 10.1245/s10434-013-3407-6 24276642 \n7 Jacquet P. Sugarbaker P. H. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis Cancer Treatment and Research 1996 82 359 374 10.1007/978-1-4613-1247-5_23 2-s2.0-0029680270 8849962 \n8 Sugarbaker P. H. Intraperitoneal chemotherapy for treatment and prevention of peritoneal carcinomatosis and sarcomatosis Diseases of the Colon & Rectum 1994 37 2 S115 S122 2-s2.0-0028331939 10.1007/BF02048443 8313782 \n9 Dindo D. Demartines N. Clavien P. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey Annals of Surgery 2004 240 2 205 213 10.1097/01.sla.0000133083.54934.ae 2-s2.0-3242713145 15273542 \n10 Glehen O. Cotte E. Schreiber V. Sayag-Beaujard A. C. Vignal J. Gilly F. N. Intraperitoneal chemohyperthermia and attempted cytoreductive surgery in patients with peritoneal carcinomatosis of colorectal origin British Journal of Surgery 2004 91 6 747 754 2-s2.0-2942514375 10.1002/bjs.4473 15164446 \n11 Glehen O. Kwiatkowski F. Sugarbaker P. H. Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study Journal of Clinical Oncology 2004 22 16 3284 3292 10.1200/jco.2004.10.012 2-s2.0-4344619216 15310771 \n12 Elias D. Gilly F. Boutitie F. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study Journal of Clinical Oncology 2009 28 1 63 68 10.1200/jco.2009.23.9285 19917863 \n13 Verwaal V. J. Bruin S. Boot H. Van Slooten G. Van Tinteren H. 8-Year follow-up of randomized trial: cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer Annals of Surgical Oncology 2008 15 9 2426 2432 10.1245/s10434-008-9966-2 2-s2.0-50049095308 18521686 \n14 Franko J. Ibrahim Z. Gusani N. J. Holtzman M. P. Bartlett D. L. Zeh H. J. III Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis Cancer 2010 116 16 3756 3762 10.1002/cncr.25116 2-s2.0-77956847600 20564081 \n15 Prada-Villaverde A. Esquivel J. Lowy A. M. The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery Journal of Surgical Oncology 2014 110 7 779 785 2-s2.0-84922329818 10.1002/jso.23728 25088304 \n16 Rastrelli M. Mocellin S. Stramare R. Isolated limb perfusion for the management limb threatening soft tissue sarcomas: The role of histological type on clinical outcomes European Journal of Surgical Oncology 2017 43 2 401 406 2-s2.0-85007228653 10.1016/j.ejso.2016.09.021 27890347 \n17 Nieweg O. E. Kroon B. B. R. Isolated limb perfusion with melphalan for melanoma Journal of Surgical Oncology 2014 109 4 332 337 2-s2.0-84893914823 10.1002/jso.23558 24421252 \n18 Sugarbaker P. H. Mora J. T. Carmignani P. Stuart O. A. Yoo D. Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy The Oncologist 2005 10 2 112 122 2-s2.0-13844311027 10.1634/theoncologist.10-2-112 15709213 \n19 Urano M. Ling C. C. Thermal enhancement of melphalan and oxaliplatin cytotoxicity in vitro International Journal of Hyperthermia 2002 18 4 307 315 2-s2.0-0036280888 10.1080/02656730210123534 12079586 \n20 Hakeam H. A. Arab A. Azzam A. Alyahya Z. Eldali A. M. Amin T. Incidence of leukopenia and thrombocytopenia with cisplatin plus mitomycin-c versus melphalan in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) Cancer Chemotherapy and Pharmacology 2018 81 4 697 704 2-s2.0-85041928645 10.1007/s00280-018-3537-4 29429054 \n21 Verwaal V. J. van Ruth S. de Bree E. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer Journal of Clinical Oncology 2003 21 20 3737 3743 10.1200/jco.2003.04.187 2-s2.0-0142087625 14551293 \n22 Esquivel J. Piso P. Verwaal V. American Society of peritoneal surface malignancies opinion statement on defining expectations from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer Journal of Surgical Oncology 2014 110 7 777 778 2-s2.0-84922333922 10.1002/jso.23722 25043759\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-1402",
"issue": "2018()",
"journal": "International journal of surgical oncology",
"keywords": null,
"medline_ta": "Int J Surg Oncol",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D016685:Mitomycin; D010534:Peritoneal Neoplasms; D012189:Retrospective Studies; D015996:Survival Rate; D014481:United States",
"nlm_unique_id": "101566285",
"other_id": null,
"pages": "1920276",
"pmc": null,
"pmid": "30643644",
"pubdate": "2018",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "12079586;12623641;14551293;15164446;15273542;15310771;15709213;18521686;19917863;20564081;22811702;23793364;24276642;24421252;25043759;25088304;26648794;27890347;29277751;29429054;8313782;8849962",
"title": "Comparison of Survival in Patients with Isolated Peritoneal Carcinomatosis from Colorectal Cancer Treated with Cytoreduction and Melphalan or Mitomycin-C as Hyperthermic Intraperitoneal Chemotherapy Agent.",
"title_normalized": "comparison of survival in patients with isolated peritoneal carcinomatosis from colorectal cancer treated with cytoreduction and melphalan or mitomycin c as hyperthermic intraperitoneal chemotherapy agent"
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"abstract": "A 58-year-old woman developed agraphia and mild right hemiparesis approximately one month after undergoing coil embolization of an unruptured left internal carotid artery aneurysm. MRI performed on day 39 post-coil embolization showed multiple lesions in the white matter with signal hyperintensity on T2-weighted and FLAIR images in the left middle cerebral artery territory. The patient's cerebrospinal fluid exhibited an elevated protein level at 46 mg/dL; however, no other findings suggested another underlying disease. Corticosteroids were administered, and, by day 50 post-coil embolization, the clinical findings and abnormal features on MRI had improved. The patient was therefore diagnosed with contrast-induced encephalopathy after coil embolization.",
"affiliations": "Department of Neurology, Saitama Medical University International Medical Center, Japan.",
"authors": "Nagamine|Yuito|Y|;Hayashi|Takeshi|T|;Kakehi|Yoshiaki|Y|;Yamane|Fumitaka|F|;Ishihara|Shoichiro|S|;Uchino|Akira|A|;Tanahashi|Norio|N|",
"chemical_list": "D003287:Contrast Media",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.53.2380",
"fulltext": null,
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"issn_linking": "0918-2918",
"issue": "53(18)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000783:Aneurysm; D002340:Carotid Artery Diseases; D002343:Carotid Artery, Internal; D002533:Cerebral Angiography; D003287:Contrast Media; D003937:Diagnosis, Differential; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D054038:Posterior Leukoencephalopathy Syndrome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2133-8",
"pmc": null,
"pmid": "25224202",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Contrast-induced encephalopathy after coil embolization of an unruptured internal carotid artery aneurysm.",
"title_normalized": "contrast induced encephalopathy after coil embolization of an unruptured internal carotid artery aneurysm"
} | [
{
"companynumb": "JP-GE HEALTHCARE MEDICAL DIAGNOSTICS-OMPQ-PR-1410L-1275",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "IOHEXOL"
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{
"abstract": "BACKGROUND\nThis phase 2 randomized study evaluated trebananib (AMG 386), a peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction of angiopoietin-1 and -2 with Tie2, in combination with paclitaxel with or without bevacizumab in previously untreated patients with HER2-negative locally recurrent/metastatic breast cancer.\n\n\nMETHODS\nPatients received paclitaxel 90 mg/m(2) once weekly (3-weeks-on/1-week-off) and were randomly assigned 1:1:1:1 to also receive blinded bevacizumab 10 mg/kg once every 2 weeks plus either trebananib 10 mg/kg once weekly (Arm A) or 3 mg/kg once weekly (Arm B), or placebo (Arm C); or open-label trebananib 10 mg/kg once a week (Arm D). Progression-free survival was the primary endpoint.\n\n\nRESULTS\nIn total, 228 patients were randomized. Median estimated progression-free survival for Arms A, B, C, and D was 11.3, 9.2, 12.2, and 10 months, respectively. Hazard ratios (95% CI) for Arms A, B, and D versus Arm C were 0.98 (0.61-1.59), 1.12 (0.70-1.80), and 1.28 (0.79-2.09), respectively. The objective response rate was 71% in Arm A, 51% in Arm B, 60% in Arm C, and 46% in Arm D. The incidence of grade 3/4/5 adverse events was 71/9/4%, 61/14/5%, 62/16/3%, and 52/4/7% in Arms A/B/C/D. In Arm D, median progression-free survival was 12.8 and 7.4 months for those with high and low trebananib exposure (AUCss ≥ 8.4 versus < 8.4 mg·h/mL), respectively.\n\n\nCONCLUSIONS\nThere was no apparent prolongation of estimated progression-free survival with the addition of trebananib to paclitaxel and bevacizumab at the doses tested. Toxicity was manageable. Exposure-response analyses support evaluation of combinations incorporating trebananib at doses > 10 mg/kg in this setting.\n\n\nBACKGROUND\nClinicalTrials.gov, NCT00511459.",
"affiliations": "Institut Curie, Paris, France. Electronic address: veronique.dieras@curie.net.;University Hospital Leuven, Leuven, Belgium. Electronic address: hans.wildiers@uzleuven.be.;Medical University of Gdańsk, Gdańsk, Poland. Electronic address: jjassem@gumed.edu.pl.;General Hospital Sint-Augustinus, Antwerp, Belgium. Electronic address: Luc.Dirix@gza.be.;Centre Léon Bérard, Lyon, France. Electronic address: GUASTALL@lyon.fnclcc.fr.;Helsinki University Central Hospital, Helsinki, Finland. Electronic address: Petri.Bono@hus.fi.;UCLA School of Medicine, Los Angeles, CA, USA. Electronic address: SHurvitz@mednet.ucla.edu.;Institut Paoli-Calmettes, Marseilles, France. Electronic address: GONCALVESA@marseille.fnclcc.fr.;C.R.L.C. Val D'Aurelle, Montpellier, France. Electronic address: gilles@romieu.info.;Levine Cancer Institute, Charlotte, NC, USA. Electronic address: Steven.Limentani@carolinashealthcare.org.;CHU Sart Tilman, Liege, Belgium. Electronic address: g.jerusalem@chu.ulg.ac.be.;Kidwai Memorial Institute of Oncology, Bangalore, India. Electronic address: kcluck@gmail.com.;Institut Claudius Régaud, Toulouse, France. Electronic address: Roche.Henri@claudiusregaud.fr.;Complejo Hospitalario de Jaén, Jaén, Spain. Electronic address: oncojaen@telefonica.net.;European Health Centre Otwock, Warszawa, Poland. Electronic address: tadeusz.pienkowski@gmail.com.;Corporació Sanitària Parc Taulí, Sabadell, Spain. Electronic address: MSegui@tauli.cat.;Amgen Inc., Thousand Oaks, CA, USA. Electronic address: ail@amgen.com.;Amgen Inc., Thousand Oaks, CA, USA. Electronic address: yus@amgen.com.;Amgen Inc., Thousand Oaks, CA, USA. Electronic address: cpickett@amgen.com.;UCLA School of Medicine, Los Angeles, CA, USA. Electronic address: DSlamon@mednet.ucla.edu.",
"authors": "Diéras|Véronique|V|;Wildiers|Hans|H|;Jassem|Jacek|J|;Dirix|Luc Y|LY|;Guastalla|Jean-Paul|JP|;Bono|Petri|P|;Hurvitz|Sara A|SA|;Gonçalves|Anthony|A|;Romieu|Gilles|G|;Limentani|Steven A|SA|;Jerusalem|Guy|G|;Lakshmaiah|K C|KC|;Roché|Henri|H|;Sánchez-Rovira|Pedro|P|;Pienkowski|Tadeusz|T|;Seguí Palmer|Miguel Ángel|MÁ|;Li|Ai|A|;Sun|Yu-Nien|YN|;Pickett|Cheryl A|CA|;Slamon|Dennis J|DJ|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D011993:Recombinant Fusion Proteins; D000068258:Bevacizumab; D017239:Paclitaxel; C551398:trebananib",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-9776",
"issue": "24(3)",
"journal": "Breast (Edinburgh, Scotland)",
"keywords": "AMG 386; HER2-negative; bevacizumab; paclitaxel; trebananib",
"medline_ta": "Breast",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D011993:Recombinant Fusion Proteins",
"nlm_unique_id": "9213011",
"other_id": null,
"pages": "182-90",
"pmc": null,
"pmid": "25747197",
"pubdate": "2015-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Trebananib (AMG 386) plus weekly paclitaxel with or without bevacizumab as first-line therapy for HER2-negative locally recurrent or metastatic breast cancer: A phase 2 randomized study.",
"title_normalized": "trebananib amg 386 plus weekly paclitaxel with or without bevacizumab as first line therapy for her2 negative locally recurrent or metastatic breast cancer a phase 2 randomized study"
} | [
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"companynumb": "FR-PFIZER INC-2019515966",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
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"drugadditional": "3",
... |
{
"abstract": "Candida meningitis is a rare life-threatening yeast infection mostly involving immunocompromised or paediatric patients undergoing neurosurgical procedures or shunt placement. Due to difficulties in diagnosis because of diverse clinical manifestations, the number of patients affected is most likely underestimated. Therefore, the correct diagnosis may be delayed for months, and accurate species identification is highly recommended for administering appropriate antifungal therapy. We report the first case of fluconazole-resistant Candida auris meningitis in a paediatric patient in Iran. This strain was probably imported, as it genotypically belonged to Clade I from South Asia. Furthermore, we include a literature review of C auris meningitis cases, as the number of cases with C auris meningitis has increased with reports from the United Kingdom, India and Iran. This problem might increase further in the era of COVID-19 due to attrition of experienced healthcare personnel and a high workload of hospital healthcare workers. To understand the precise prevalence of this emerging multidrug resistance pathogen, epidemiological surveillance studies are urgently warranted.",
"affiliations": "Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.;Immunology, Asthma, and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran.;Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.;Pediatric Intensive Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.;Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.;Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.;Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.;Invasive Fungi Research Center, Communicable Diseases Institute, Mazandaran University of Medical Sciences, Sari, Iran.",
"authors": "Mirhendi|Hossein|H|;Charsizadeh|Arezou|A|;Aboutalebian|Shima|S|https://orcid.org/0000-0003-0178-4372;Mohammadpour|Masoud|M|;Nikmanesh|Bahram|B|;de Groot|Theun|T|https://orcid.org/0000-0001-5841-6461;Meis|Jacques F|JF|https://orcid.org/0000-0003-3253-6080;Badali|Hamid|H|https://orcid.org/0000-0002-6010-8414",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1111/myc.13396",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0933-7407",
"issue": null,
"journal": "Mycoses",
"keywords": "\nCandida\n; antifungal susceptibility; candidaemia; meningitis; typing",
"medline_ta": "Mycoses",
"mesh_terms": null,
"nlm_unique_id": "8805008",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34780087",
"pubdate": "2021-11-15",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "South Asian (Clade I) Candida auris meningitis in a paediatric patient in Iran with a review of the literature.",
"title_normalized": "south asian clade i candida auris meningitis in a paediatric patient in iran with a review of the literature"
} | [
{
"companynumb": "IR-LUPIN PHARMACEUTICALS INC.-2022-07667",
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"occurcountry": "IR",
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"activesubstance": {
"activesubstancename": "PHENYTOIN SODIUM"
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{
"abstract": "Tenofovir disoproxil fumarate (TDF) has increasingly been replaced by tenofovir alafenamide (TAF) because of reduced kidney and bone toxicity with TAF. This switch has, however, caused worsening of lipid concentrations in clinical trials, but data from any real-world setting are scarce. The objective of this study was to characterize the effect of TDF to TAF switch on plasma lipid concentrations in a real-world clinic population. This is a retrospective study comparing lipid concentrations and other laboratory parameters between the last visit on TDF and the first visit after at least a 2-month exposure to TAF. A total of 490 HIV-positive subjects were included in the study. The median (interquartile range) increase was 23.2 (0-38.7) mg/dL in total cholesterol (p < 0.001) and 15.5 (0-30.9) mg/dL in low-density lipoprotein (LDL) cholesterol (p < 0.001). The ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol increased by 0.2 (-0.2 to 0.6), p < 0.001. The proportion of patients having optimal LDL cholesterol concentration by National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) decreased from 30.8% to 17.8% and proportion having dyslipidemia or severe dyslipidemia increased from 30.2% to 50.3% after the switch. Demographic characteristics, antiretroviral agents, or comedication did not affect the changes in lipid concentrations. Plasma creatinine decreased by 0.03 (-0.09 to 0.03) mg/dL (p < 0.001) and estimated glomerular filtration rate increased by 0.5 (-2.3 to 3.2) mL/min (p = 0.009). Switching from TDF to TAF caused a statistically significant worsening of the lipid profile that may have clinical relevance. The benefit of the lipid-lowering effect of TDF should be considered in selected patients with low risk for kidney and bone toxicity.",
"affiliations": "Department of Infectious Diseases, Inflammation Center, Helsinki, Finland.;Department of Infectious Diseases, Inflammation Center, Helsinki, Finland.;Department of Infectious Diseases, Inflammation Center, Helsinki, Finland.",
"authors": "Kauppinen|Kai Juhani|KJ|;Kivelä|Pia|P|;Sutinen|Jussi|J|",
"chemical_list": "D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D008055:Lipids; D002784:Cholesterol; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000225:Adenine; D000409:Alanine",
"country": "United States",
"delete": false,
"doi": "10.1089/apc.2019.0236",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2914",
"issue": "33(12)",
"journal": "AIDS patient care and STDs",
"keywords": "HIV; cholesterol; dyslipidemia; lipid-lowering effect; tenofovir alafenamide; tenofovir disoproxil fumarate",
"medline_ta": "AIDS Patient Care STDS",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000409:Alanine; D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D002784:Cholesterol; D008078:Cholesterol, LDL; D050171:Dyslipidemias; D005260:Female; D005919:Glomerular Filtration Rate; D015658:HIV Infections; D006679:HIV Seropositivity; D006801:Humans; D000960:Hypolipidemic Agents; D050356:Lipid Metabolism; D008055:Lipids; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D000068698:Tenofovir; D016896:Treatment Outcome",
"nlm_unique_id": "9607225",
"other_id": null,
"pages": "500-506",
"pmc": null,
"pmid": "31742421",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Switching from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Significantly Worsens the Lipid Profile in a Real-World Setting.",
"title_normalized": "switching from tenofovir disoproxil fumarate to tenofovir alafenamide significantly worsens the lipid profile in a real world setting"
} | [
{
"companynumb": "FI-MYLANLABS-2020M1013059",
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"occurcountry": "FI",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL"
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"drugadditional": nu... |
{
"abstract": "Calcium channel blocker toxicity can be devastating. Initial therapy with fluid, calcium, and adrenoreceptor agonists should be prompt and novel therapies can be added if no response. Determining cardiogenic shock versus vasoplegia with echocardiogram or other hemodynamic monitoring may guide treatment options.",
"affiliations": "University of Louisville Internal Medicine Residency Training Program Louisville, Kentucky, USA.;University of Louisville Internal Medicine Residency Training Program Louisville, Kentucky, USA.",
"authors": "Burkes|Robert|R|;Wendorf|Gregg|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.300",
"fulltext": "\n==== Front\nClin Case RepClin Case Repccr3Clinical Case Reports2050-09042050-0904John Wiley & Sons, Ltd Chichester, UK 10.1002/ccr3.300Case ReportsA multifaceted approach to calcium channel blocker overdose: a case report and literature review Burkes Robert Wendorf Gregg University of Louisville Internal Medicine Residency Training ProgramLouisville, Kentucky, USACorrespondence Robert Burkes, University of Louisville Internal Medicine Residency Training Program, 550 S. Jackson Street, ACB 3rd Floor, Louisville, KY 724-730-3862, USA. Tel: 502-852-5666; Fax: 502-852-8980; E-mail: rmburk02@louisville.eduFunding Information No sources of funding were declared for this study\n\n7 2015 18 5 2015 3 7 566 569 15 12 2014 21 4 2015 23 4 2015 © 2015 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.2015This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Key Clinical Message\nCalcium channel blocker toxicity can be devastating. Initial therapy with fluid, calcium, and adrenoreceptor agonists should be prompt and novel therapies can be added if no response. Determining cardiogenic shock versus vasoplegia with echocardiogram or other hemodynamic monitoring may guide treatment options.\n\nCalcium channel blockerhyperinsulinemia-euglycemia therapylipid emulsionmethylene blueoverdose\n==== Body\nIntroduction\nCalcium channel blockers are widely prescribed cardiovascular medications with potentially dire consequences at toxic doses. Treatment of cardiovascular collapse is complex in the acute setting and data on treatment modalities are minimal. Often, the best course of action is to support the patient’s cardiovascular system with traditional vasopressors and employ any number of novel therapies based on observational evidence.\n\nCase\nWe present a 60-year-old white female with a history of borderline personality disorder, hypertension (outpatient records indicate office readings for systolic blood pressure ranging from 120 to 130 mmHg on treatment), and chronic lumbago who reported to the emergency department with nausea and vomiting for 2 days and intentional amlodipine overdose. She reported taking approximately 300 mg of amlodipine 10 h prior to admission. The patient’s other medications included oxycodone, docusate, ibuprofen, and pantoprazole, all of which she reported taking as prescribed. On presentation, the patient was alert and oriented with a Glascow Coma Score (GCS) of 15. Vital signs showed a noninvasive blood pressure of 90/56 mmHg with no other abnormality. Examination revealed equal and mildly diminished radial pulses, normal heart rate and rhythm, clear lung fields, sluggish bowel sounds, no peripheral edema and no pallor. Initial laboratory results included an unremarkable complete blood count, a basic metabolic panel showing a sodium of 136 mmol/L, potassium of 5.3 mmol/L, chloride of 102 mmol/L, bicarbonate of 17 mmol/L, urea nitrogen of 22 mg/dL and a creatinine of 1.58 mg/dL (baseline 0.44 mg/dL). Further, urinalysis on admission was remarkable for the presence of ketones. Urine and serum toxicology including salicylate and acetaminophen were negative. Procalcitonin was 0.1 ng/mL and lactic acid was 2 mmol/L. Cardiac troponins were trended and were not elevated. Activated charcoal was not administered on admission due to the amount of time that had passed from ingestion to presentation. The patient was admitted to the medical transitional care unit for observation.\n\nThe medical intensive care team was notified 7 h after admission when the patient’s noninvasive mean arterial pressure (MAP) fell to the low 50s and was not responsive to fluid resuscitation and her mental status deteriorated to a GCS of 7. She was transferred to the medical intensive care unit where she required intubation for airway protection, had two central lines placed for medication compatibility concerns, and had an arterial line placed. In the ICU, lactic acid was found to be 6.4 mmol/L, and arterial blood gas showed a pH of 6.95, partial pressure of carbon dioxide (pCO2) of 43 mmHg, a partial pressure of oxygen (pO2) of 79 mmHg, and calculated bicarbonate of 9 mmol/L on 60% fraction of inspired oxygen (FiO2). Electrocardiogram at that time showed normal sinus rhythm, rate of 72 beats per minute, QTc of 408 ms, and low voltage in precordial leads.\n\nA dopamine drip (10 μg/min titrated to 20 μg/min at maximum) through peripheral line, glucagon drip (5 mg loading dose followed by 5 mg/h drip), and a bolus of 3 amps of 8.4% sodium bicarbonate (150 mEq NaCO3 in 1L) in 1L D5W were subsequently started. After central access was obtained, calcium carbonate (12 mg/hr), norepinephrine (starting at 75 μg/min titrated up to 100 μg/min at maximum), epinephrine (5 μg/min titrated up to 10 μg/min), dobutamine (10 μg/kg/min titrated up to 25 μg/kg/min), methylprednisolone (100 mg every 8 h), and phenylephrine (100 μg/min) were started in rapid succession. Despite these interventions, arterial line MAPs were ranging between 45 and 60. Poison control was consulted and recommended continuing calcium carbonate while monitoring ionized calcium every 2 h, along with the bicarbonte drip in D5W, and glucagon drip. They also recommended starting an insulin drip which was administered per hospital ICU protocol targeting blood glucose of 180 mmol/L. Hemodynamic state was monitored using an arterial line and target MAP was >65.\n\nCardiology was consulted and performed a stat two-dimensional transthoracic echocardiogram, which showed mildly reduced left ventricular contractility with the ejection fraction measured at 51%. Methylene blue (2 mg/kg administered over 1 h) and vasopressin (0.04 units/min at set rate) were started per cardiology’s recommendations.\n\nWithin 18 h of these therapies, the patient’s MAP stabilized above 65, and vasopressors were slowly weaned starting with dobutamine, as echocardiogram result made cardiogenic shock unlikely. Phenylephrine, dopamine, and vasopressin were also weaned off on the first day. Epinephrine, insulin, and steroids were discontinued in ICU day 2. On day 3, the patient required only norepinephrine and glucagon drips to maintain a MAP >65. By day 4, the patient was requiring no vasopressors, was following commands, and was extubated. She was transferred to the floor the next day for treatment of acute kidney injury and aspiration pneumonia. She was discharged without sequelae on hospital day 7.\n\nDiscussion\nCalcium channel blockers (CCBs) are a heterogeneous group of chemicals that inhibit L-type calcium channels. These channels control myocardial and vascular smooth muscle contractility as well as the cardiac conduction system and pacemaker cells. CCBs are used extensively to treat angina pectoris, hypertension, Raynaud’s syndrome, supraventricular tachycardias, and migraine headaches. CCBs are divided based on their primary physiologic effects. Dihydropyridine CCBs (DHP’s), such as amlodipine and nifedipine, preferentially block calcium channels in the vasculature, acting as vasodilators with little to no effect on cardiac contractility or conduction. All other CCBs are grouped together as nondihydropyridine (non-DHP) CCBs. The most common are verapamil and diltiazem. These act on cardiomyocytes to reduce vascular permeability and affect cardiac contractility and conduction, though they also have some mild vasodilatory action 1.\n\nIn 2010, the American Association of Poison Control Centers reported 3298 CCBs overdoses in adults, causing the second highest number of overdose deaths of any cardiovascular medication 2. CCBs are highly protein bound, have a large volume of distribution, and are metabolized by the liver. As the dose increases, there is a change in pharmacokinetics from first-order elimination to zero-order clearance by the liver, which results in accumulation of the drug systemically. This change in metabolism is further confounded by CCBs action of splanchnic vasoconstriction, reducing drug delivery to the liver 3. The unpredictability of drug clearance at toxic levels makes caring for these patients in a standardized fashion difficult.\n\nInitial treatment for CCBs overdose patients includes airway maintenance, crystalloid fluid boluses, and atropine for symptomatic bradycardia. Activated charcoal can be administered to an intubated patient or a patient able to protect their airway within 1–2 h of overdose. Despite favorable gastrointestinal clearance of CCB at 2 h or less with charcoal, efficacy declines as time from ingestion increases and carries risk for aspiration obtunded patients 4–7. Whole bowel irrigation may be beneficial early after ingestion prior to hemodynamic compromise, but becomes dangerous after hypotension develops because CCBs slow gut motility and increase risk of obstruction or perforation 8.\n\nFollowing these initial therapies, there is no set treatment algorithm. Intravenous calcium, preferably calcium chloride through a central line, is recommended to increase calcium entry into cells via nonblocked channels, counteracting negative inotropy, and vasoplegia. Glucagon increases intracellular cyclic adenosine monophosphate (cAMP) and contraction of smooth muscle via a beta-receptor independent pathway. While this has become a mainstay in the treatment of beta-blocker overdose, glucagon is of questionable usefulness in CCBs overdose mechanistically, but there are case reports of improved hemodynamics with glucagon administration 9. Further, glucagon is associated with dose-dependent nausea and vomiting and increased risk of aspiration, diarrhea, hypokalemia, and theoretical tachyphylaxis 10.\n\nHyperinsulinemia euglycemia treatment (HIET) (1 unit/kg bolus of regular insulin with 0.5 g/kg dextrose push followed by 0.5–1 unit/kg/hr of regular insulin with concomitant dextrose drip) was originally shown to improve survival in dogs poisoned with verapamil in a controlled environment 11. First reported in humans in 1999, HIET therapy showed improvement in circulatory shock in five CCBs overdose patients who did not adequately respond to “standard” treatment which was variable amongst the reported patients 12. HIET has been described stabilizing cardiovascular parameters, decreasing vasopressor support, and improving patient outcomes when instituted early because of delayed onset-of-benefit 10,13. The proposed mechanism involves improved smooth muscle contractility by increased efficiency of carbohydrate uptake and utilization which counteracts CCBs blockade of indigenous insulin release and decreased myocardial free fatty acid extraction. This optimizes the glucose-dependent energy formation required to overcome CCBs overdose 14. Both glucose and potassium should be frequently monitored on this therapy and potassium should be replaced if the level falls below 3 mmol/L 10.\n\nA case series in non-DHP CCBs overdose found that the use of fluid challenge and alpha- and beta-adrenoreceptor agonists (classic vasopressors and dobutamine) without HIET in hypotensive overdose patients was not detrimental to outcomes. This study did not standardize the agents used, the order in which they were employed, or the maximum dose of each agent. However, it did show that an approach consisting solely of early administration of adrenoreceptor agonists alone may lead to successful outcomes 15. Further, the addition of vasopressin has been reported to improve MAP and improve cardiac function in patients’ refractory to a combination of other vasopressors, insulin, and glucagon 16.\n\nThere is no recommended gold standard for hemodynamic monitoring during the resuscitation of these patients. However, opinion suggests that differentiating between negative inotropy and vasoplegia may be useful for choosing between adrenoreceptor agonists 17. Observing signs of cardiogenic shock would suggest that inotropic agents such as dobutamine and dopamine would be beneficial and will prevent exposure to the side effects of arrythmia and cardiac ischemia in patients with preserved inotropic performance 17,18.\n\nA recent report of two cases using lipid emulsions in CCB overdose shows promise for yet another therapy directed at hemodynamic support. Lipid emulsions add free fatty acid substrate for HIET therapy and sequester free lipophilic CCBs molecules. In both cases, lipid emulsion (1.5 mL/kg bolus followed by 0.25 mL/kg/min for 60 min) was initiated after vasopressors and HIET had been started, and were followed by discontinuation of vasopressors at 1 and 10 h, respectively 19. Lipid emulsion therapy was not shown to enhance HIET without simultaneous vasopressor treatment.\n\nMethylene blue has been used as a novel approach to treat refractory CCB overdose based on reports of its use to counteract postcoronary artery bypass vasoplegia when added to vasopressors and HIET. Methylene blue resolves vasoplegia by decreasing intracellular cyclic guanosine monophosphate (cGMP), scavenging nitric oxide, and inhibiting nitric oxide synthesis, all in direct opposition to the action of CCBs 20,21.\n\nA single case report describes success with using continuous venovenous hemodiafiltration and concomitant charcoal hemoperfusion in the treatment of hypotension secondary to CCBs overdose that was refractory to multiple vasopressors and HIET therapy 22.\n\nIt is difficult to recommend one specific strategy to address the complicated issue of CCBs overdose. Urgent administration of fluids, calcium, atropine, vasopressors, and HIET therapy seem to be the most well validated initial approaches to treatment, with the addition of the novel adjunct therapy being added into treatment based on necessity. However, because of the unpredictable and often dire nature of CCBs overdose, it is beneficial to be aware of all reported therapies as potential treatment modalities.\n\nConsent\nThe patient was deemed decisional and not psychotic by psychiatry while in the hospital. Approximately 1 month after her discharge and hospital follow-up with her primary care physician she was contacted by telephone and the nature of this case report was described to her. She was agreeable to the use of her information in this report and returned a signed consent by mail, which can be made available to the editors of this journal upon request.\n\nConflict of Interest\nNeither Dr. Wendorf nor Dr. Burkes have any conflict of interest to report.\n==== Refs\nReferences\nTomaszewski CA Olson KR Benowitz NL Calcium channel antagonists Poisoning & drug overdose, 6e 2012 New York, NY McGraw-Hill in, eds., and. Chapter 40. http://accessmedicine.mhmedical.com.echo.louisville.edu/content.aspx?bookid=391&Sectionid=42069854 . Accessed July 15, 2014 \nBronstein AC Spyker DA Cantelina LR Green JL Rumack BH Dart RC Annual report of the American association of poison control centers’ national poison data system (NPDS): 28th annual report Clin. Toxicol 2010 49.10 910 941 \nMcAllister RG Jr Hamann SR Blouin RA Pharmacokinetics of calcium-entry blockers Am. J. Cardiol 1985 55 30B \nBond GR The role of activated charcoal and gastric emptying in gastrointestinal decontamination: a state-of-the-art review Ann. Emerg. Med 2002 39 273 286 11867980 \nChyka PA Seger D Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists J. Toxicol. Clin. Toxicol 1996 35 721 741 9482427 \nBailey B Glucagon in β -blocker and calcium channel blocker overdoses: a systematic review Clin. Toxicol 2003 41 595 602 \nLaine K Kivistö KT Laakso I Neuvonen PJ Prevention of amlodipine absorption by activated charcoal: effect of delay in charcoal administration Br. J. Clin. Pharmacol 1997 43 29 33 9056049 \nCumpston KL Aks SE Sigg T Pallasch E Whole bowel irrigation and the hemodynamically unstable calcium channel blocker overdose: primum non nocere J. Emerg. Med 2010 38 171 174 18614321 \nWalter FG Frye G Mullen JT Ekins BR Khasigian PA Amelioration of nifedipine poisoning associated with glucagon therapy Ann. Emerg. Med 1993 22 1234 1237 8517581 \nMarraffa JM Cohen V Howland MA Antidotes for toxalogical emergencies: a practical review Am. J. Health-Sys. Pharm 2012 69 199 212 \nKline JA Tomaszewski CA Schroeder D Raymond RM Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine J. Pharmacol. Exp. Ther 1993 267 744 750 8246150 \nYuan TH Kerns WP Tomaszewski CA Ford MD Kline JA Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning J. Toxicol. Clin. Toxicol 1999 37 463 474 10465243 \nMégarbane B Karyo S Baud FJ The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calcium channel antagonist and beta-blocker poisoning Toxicol. Rev 2004 23 215 222 15898827 \nLheureux PE Zahir S Gris M Derrey AS Penaloza A Bench-to-bedside review: hyperinsulinaemia/euglycaemia therapy in the management of overdose of calcium-channel blockers Crit. Care 2006 10 212 16732893 \nLevine M Curry SC Padilla-Jons A Ruha A Critical care management of verapamil and diltiazem overdose with a focus on vasopressors: a 25-year experience at a single center Ann. Emerg. Med 2013 62 252 258 23642908 \nKanagarajan K Marraffa JM Bauchard NC The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel blocker overdose Clin. Toxicol 2007 45 56 59 \nOlson KR What is the best treatment for acute calcium channel blocker overdose? Ann. Emerg. Med 2013 62 259 261 23567061 \nOvergaard CB Vladimír D Inotropes and vasopressors review of physiology and clinical use in cardiovascular disease Circulation 2008 118 1047 1056 18765387 \nDoepker B Healy W Cortez E Adkins E High dose insulin and lipid emulsion therapy for cardiogenic shock induced by intentional calcium-channel blocker and beta-blocker overdose: a case series J. Emerg. Med 2014 46 486 490 24530120 \nPagni S Austin EH Use of intravenous methylene blue for the treatment of refractory hypotension after cardiopulmonary bypass J. Thorac. Cardiovasc. Surg 2000 119 1297 1298 10838557 \nAggarwal N Kupfer Y Seneviratne C Tessler S Methylene blue reduces recalcitrant shock in beta-blocker and calcium channel blocker overdose BMJ Case Rep 2013 Published Online January 18, 2013. doi: 10.1136/bcr-2012-007402 \nNasa P Singh A Juneja D Singh O Javeri Y Continuous venovenous hemodiafiltration along with charcoal hemoperfusion for the management of life-threatening lercanidipine and amlodipine overdose Saudi J. Kidney Dis. Transpl 2014 25 1255 1258 25394445\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-0904",
"issue": "3(7)",
"journal": "Clinical case reports",
"keywords": "Calcium channel blocker; hyperinsulinemia-euglycemia therapy; lipid emulsion; methylene blue; overdose",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "566-9",
"pmc": null,
"pmid": "26273444",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports",
"references": "24530120;10838557;8517581;16732893;9482427;8246150;23642908;25394445;22165864;14514004;23567061;3881917;9056049;23334490;17357383;10465243;11867980;15898827;18614321;22261941;18765387",
"title": "A multifaceted approach to calcium channel blocker overdose: a case report and literature review.",
"title_normalized": "a multifaceted approach to calcium channel blocker overdose a case report and literature review"
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"companynumb": "US-APOTEX-2017AP007020",
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"activesubstancename": "OXYCODONE"
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{
"abstract": "Objective: We examined the short-term efficacy and safety of rufinamide (RFN) in patients with Lennox-Gastaut syndrome (LGS). Methods: We performed a retrospective review of clinical records of patients with LGS who started RFN treatment between July 2013 and June 2014 at the Hokkaido Medical Center for Child Health and Rehabilitation and Midorigaoka Ryo-iku-en. Efficacy and safety were evaluated when the patients had completed three months of treatment. Patients were classified into four categories according to percent seizure reduction : remission (seizure-free), response (seizure reduction≥50%), no change (seizure reduction<50% or increase) and aggravation (seizure increase≥50%). Responder rate (RR) was the percentage of patients with≥50% decrease in seizure frequency. Results: Thirteen LGS patients (8 males, 5 females) were studied. The efficacy for tonic seizures (13 patients) was remission 1 patient, response 3 patients, no change 8 patients and aggravation 1 patient, with RR of 30.8%. Two patients discontinued LGS due to seizure aggravation. Four patients experienced transient remission. For generalized tonic clonic seizures (2 patients), 1 patient achieved remission and 1 patient showed no change. Two patients of atonic seizures showed no change. Of 2 patients of atypical absence, 1 patient showed response and 1 patient no change. Eight patients had adverse effects such as somnolence (6 patients), sleep disturbance (1 patient), and appetite loss (4 patients) including weight loss in 2 patients. There were no severe adverse effects and no discontinuation due to adverse effects. Conclusions: Short-term effectiveness for tonic seizures was observed when patients with LGS were treated with RFN, with transient remission in some patients. We consider that RFN is worth trying in patients with LGS due to its efficacy for tonic seizures and absence of severe adverse effects.",
"affiliations": null,
"authors": "Takayama|Rumiko|R|;Fukumura|Shinobu||;Minagawa|Kimio|K|;Watanabe|Toshihide|T|",
"chemical_list": "D000927:Anticonvulsants; D014230:Triazoles; C079703:rufinamide",
"country": "Japan",
"delete": false,
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"issn_linking": "0029-0831",
"issue": "48(5)",
"journal": "No to hattatsu = Brain and development",
"keywords": null,
"medline_ta": "No To Hattatsu",
"mesh_terms": "D000927:Anticonvulsants; D002648:Child; D005260:Female; D006801:Humans; D065768:Lennox Gastaut Syndrome; D008297:Male; D010375:Pedigree; D014230:Triazoles",
"nlm_unique_id": "0215224",
"other_id": null,
"pages": "322-6",
"pmc": null,
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"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Short-term efficacy and safety of rufinamide for Lennox-Gastaut syndrome.",
"title_normalized": "short term efficacy and safety of rufinamide for lennox gastaut syndrome"
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"companynumb": "JP-LUNDBECK-DKLU2021363",
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... |
{
"abstract": "Autoimmune haemolytic anaemia (AIHA) is a disease characterised by the production of pathological antibodies that attach to the surface of a patient's own red blood cells, resulting in haemolysis. It can present in either an acute or a chronic manner. In addition to the obvious consequence of anaemia, there are other potentially deadly complications that can arise from AIHA, such as venous thromboembolism (VTE) and pulmonary hypertension. We report a case of a 52-year-old woman who developed a pulmonary embolism (PE) soon after being diagnosed with AIHA. Despite having a very small pulmonary venous clot burden, she developed profound haemodynamic compromise with severe right ventricular dysfunction, which quickly reversed with inhaled nitric oxide treatment. This case makes an interesting observation of cell-free haemoglobin-associated nitric oxide scavenging as a mechanism of pulmonary hypertension and highlights the possible benefit of nitric oxide in treatment.",
"affiliations": "Department of Internal Medicine, Bridgeport Hospital-Yale New Haven Health, Bridgeport, Connecticut, USA.;Department of Internal Medicine, Yale New Haven Hospital, New Haven, Connecticut, USA.;Department of Internal Medicine, Bridgeport Hospital-Yale New Haven Health, Bridgeport, Connecticut, USA.;Department of Hematology, Yale School of Medicine, New Haven, Connecticut, USA.",
"authors": "Woodson|Kevin Andrew|KA|;Lee|Yungah|Y|;Gopalratnam|Kavitha|K|;Halene|Stephanie|S|",
"chemical_list": "D045462:Endothelium-Dependent Relaxing Factors; D009569:Nitric Oxide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D004452:Echocardiography; D045462:Endothelium-Dependent Relaxing Factors; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008875:Middle Aged; D009569:Nitric Oxide; D011655:Pulmonary Embolism; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26768839",
"pubdate": "2016-01-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "24938564;23062526;12199802;4739592;21924850;15811985;19880774;22520988;18024612;24716681;20948876;6034957",
"title": "Adding insult to injury: autoimmune haemolytic anaemia complicated by pulmonary embolism.",
"title_normalized": "adding insult to injury autoimmune haemolytic anaemia complicated by pulmonary embolism"
} | [
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"companynumb": "US-MALLINCKRODT-T201601153",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstancename": "HEPARIN SODIUM"
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"abstract": "Aim. To report our preliminary single-center experience with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for management of peritoneal sarcomatosis (PS). Methods. Eleven patients were retrospectively analyzed for perioperative details. Results. Cytoreduction completeness (CC-0/1) was achieved in all patients with median peritoneal cancer index (PCI) of 14 ± 8.9 (range: 3-29). Combination cisplatin + doxorubicin HIPEC chemotherapy was used in 6 patients. Five patients received intraoperative radiation therapy (IORT). The median operative time, estimated blood loss, and hospital stay were 8 ± 1.4 hours (range: 6-10), 1000 ± 250 mL (range: 700-3850), and 11 ± 2.4 days (range: 7-15), respectively. Major postoperative Clavien-Dindo grade III/IV complications occurred in 1 patient and none developed HIPEC chemotherapy-related toxicities. The median overall survival (OS) and disease-free survival (DFS) after CRS + HIPEC were 28.3 ± 3.2 and 18.0 ± 4.0 months, respectively. The median follow-up time was 12 months (range: 6-33). Univariate analysis of several prognostic factors (age, gender, PS presentation/pathology, CC, PCI, HIPEC chemotherapy, and IORT) did not demonstrate statistically significant differences of OS and DFS. Conclusion. CRS + HIPEC appear to be feasible, safe, and offer survival oncological benefits. However, definitive conclusions cannot be deduced.",
"affiliations": "College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.;Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt; King Faisal Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.;Department of Obstetrics and Gynecology, King Fahad Medical City, Riyadh 11525, Saudi Arabia.;King Faisal Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.;College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.;College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.;Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.;King Faisal Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.;King Faisal Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.;College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia.",
"authors": "Abu-Zaid|Ahmed|A|;Azzam|Ayman|A|;Abuzaid|Mohammed|M|;Elhassan|Tusneem|T|;Albadawi|Naryman|N|;Alkhatib|Lynn|L|;AlOmar|Osama|O|;Alsuhaibani|Abdullah|A|;Amin|Tarek|T|;Al-Badawi|Ismail A|IA|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2016/6567473",
"fulltext": "\n==== Front\nGastroenterol Res PractGastroenterol Res PractGRPGastroenterology Research and Practice1687-61211687-630XHindawi Publishing Corporation 10.1155/2016/6567473Clinical StudyCytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy for Management of Peritoneal Sarcomatosis: A Preliminary Single-Center Experience from Saudi Arabia Abu-Zaid Ahmed \n1\nAzzam Ayman \n2\n\n3\nAbuzaid Mohammed \n4\nElhassan Tusneem \n3\nAlbadawi Naryman \n1\nAlkhatib Lynn \n1\nAlOmar Osama \n5\nAlsuhaibani Abdullah \n3\nAmin Tarek \n3\nAl-Badawi Ismail A. \n1\n\n5\n\n*\n1College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia2Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt3King Faisal Oncology Centre, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia4Department of Obstetrics and Gynecology, King Fahad Medical City, Riyadh 11525, Saudi Arabia5Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia*Ismail A. Al-Badawi: i_albadawi@yahoo.comAcademic Editor: Giuseppe Nigri\n\n2016 24 4 2016 2016 656747323 1 2016 8 3 2016 7 4 2016 Copyright © 2016 Ahmed Abu-Zaid et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAim. To report our preliminary single-center experience with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) for management of peritoneal sarcomatosis (PS). Methods. Eleven patients were retrospectively analyzed for perioperative details. Results. Cytoreduction completeness (CC-0/1) was achieved in all patients with median peritoneal cancer index (PCI) of 14 ± 8.9 (range: 3–29). Combination cisplatin + doxorubicin HIPEC chemotherapy was used in 6 patients. Five patients received intraoperative radiation therapy (IORT). The median operative time, estimated blood loss, and hospital stay were 8 ± 1.4 hours (range: 6–10), 1000 ± 250 mL (range: 700–3850), and 11 ± 2.4 days (range: 7–15), respectively. Major postoperative Clavien-Dindo grade III/IV complications occurred in 1 patient and none developed HIPEC chemotherapy-related toxicities. The median overall survival (OS) and disease-free survival (DFS) after CRS + HIPEC were 28.3 ± 3.2 and 18.0 ± 4.0 months, respectively. The median follow-up time was 12 months (range: 6–33). Univariate analysis of several prognostic factors (age, gender, PS presentation/pathology, CC, PCI, HIPEC chemotherapy, and IORT) did not demonstrate statistically significant differences of OS and DFS. Conclusion. CRS + HIPEC appear to be feasible, safe, and offer survival oncological benefits. However, definitive conclusions cannot be deduced.\n==== Body\n1. Introduction\nSoft tissue sarcomas (STSs) are quite rare neoplasms accounting for roughly 1% of all adult solid malignancies [1]. Approximately 30% [2] to 36% [3] of all STSs originate in the retroperitoneum or abdominopelvic cavity. The natural biological behavior of STSs is characterized by an increased tendency for disease dissemination [4] and recurrence [5, 6]. Modes of disease dissemination include local invasion, peritoneal infiltration, blood-borne, and rarely lymph-borne spread [4]. Around 35% to 82% of all STSs will experience disease recurrence after the initial surgical management [5, 6]. The vast majority of these recurred STSs (80–90%) will progress and present as peritoneal sarcomatosis (PS)—multinodular intraperitoneal dissemination of STS [7]. This PS is especially true for abdominal/retroperitoneal STSs; however, trunk and limb STSs only exceptionally result in PS. Also, it should be recognized that PS may be the primary presentation in a proportion of patients [8].\n\nPrognosis of patients with primary or secondary (recurrent) PS is generally poor with an estimated median overall survival ranging from 6 to 15 months [5, 9–11]. Current therapeutic modalities such as surgery, radiotherapy, and chemotherapy are largely ineffective against PS [8]. Therefore, an aggressive locoregional approach for management of patients with PS and no extraperitoneal disease has been suggested [8, 12]. There is a universally agreed upon consensus that aggressive locoregional management of PS requires a well-studied comparison between cytoreductive surgery (CRS) alone and combined modalities of CRS plus hyperthermic intraperitoneal chemotherapy (HIPEC) [13].\n\nThe combination of CRS plus HIPEC has been employed successfully in locoregional management of peritoneal mesothelioma [14] as well as peritoneal carcinomatosis arising from epithelial ovarian [15], nonepithelial ovarian [16], endometrial [17], appendiceal (pseudomyxomaperitonei) [18], colorectal [19], and gastric [20] cancer origins. The use of CRS plus HIPEC for management of primary or recurrent PS remains a subject of controversy [6, 8, 21–26].\n\nThe aim of this study is to report our single-center experience (feasibility, morbidity/mortality, and oncological outcomes) regarding the use of CRS plus HIPEC for management of patients with primary and recurrent PS.\n\n2. Materials and Methods\nThe study took place at King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh, Saudi Arabia—a tertiary healthcare center. The study protocol was approved by the Research Advisory Council (RAC) and Institutional Review Board (IRB) at KFSH&RC, Riyadh, Saudi Arabia (RAC Project #22161039).\n\nFrom November 2008 to October 2014, all patients with primary (first disease presentation) and secondary (recurrent disease presentation) PS managed by CRS plus HIPEC were retrospectively analyzed for perioperative (preoperative, operative, and postoperative) details.\n\nPreoperative details included age, gender, presenting symptoms, PS presentation, Eastern Cooperative Oncology Group (ECOG) performance status, PS primary site of origin, PS pathology, and previous treatment (surgery, radiotherapy, and chemotherapy). Operative details included visceral surgical resections, cytoreduction completeness (CC), peritoneal cancer index (PCI), HIPEC chemotherapeutics, use of intraoperative radiation therapy (IORT), use of prophylactic (not routine) ureteral stents, operative time (OT), estimated blood loss (EBL), and hospital stay. Postoperative details included follow-up duration, 60-day morbidity (Clavien-Dindo surgical complications), 60-day mortality, 60-day readmission, adjuvant therapy (radiotherapy and/or chemotherapy), disease progression, site of recurrence (local, locoregional, distant, or combination), and current status (alive with disease, alive without disease, or dead).\n\nIn our tertiary healthcare center, intraoperative administration of HIPEC is optional. Patients were informed in detail about the current literature, benefits and risks of undergoing the standard treatment (CRS ± adjuvant therapy), or the optional recommended treatment (CRS + HIPEC ± IORT ± adjuvant therapy). Afterwards, patients were requested to sign a written consent regarding the desired treatment option.\n\nInclusion criteria for considering CRS plus HIPEC included (1) age below 75 years, (2) ECOG performance status ≤2, (3) satisfactory hematological, hepatic, coagulation, renal, and electrolyte profiles, (4) proven diagnosis of primary or secondary PS confirmed by imaging modality and/or intraoperative biopsy, (5) no evidence of PS distant extra-abdominopelvic metastatic foci to brain, lungs, liver, or bones, and (6) signed written informed consent by patients.\n\nAll operations were carried out by the same surgeons from Department of Surgical Oncology and Department of Obstetrics and Gynecology. IORT was performed by the same team from Department of Radiation Oncology.\n\nUnder general anesthesia, justified prophylactic (not routine) ureteral stents were inserted by the urology team at the beginning of the operation before carrying out CRS plus HIPEC procedure. Afterwards, a midline incision extending from xiphoid process to pubic tubercle was performed to completely explore the abdominopelvic cavity for PS. The extent of PS was evaluated intraoperatively using PCI [27]. CRS was performed as previously documented by Sugarbaker [12] and included multiple visceral resections directed towards optimal eradication of neoplastic foci from abdominopelvic cavity. After completion of CRS, assessment of residual tumors was determined intraoperatively using the standard CC scores, as documented by Sugarbaker [27]. CC-0 (no gross residual disease) score was regarded as complete cytoreduction, whereas CC-1 (up to 2.5 mm gross residual disease) score was regarded as near-complete cytoreduction. Only patients with CC-0 or CC-1 scores were considered for intraoperative HIPEC intervention.\n\nOpen-abdomen HIPEC technique was performed at the end of CRS. Abdominopelvic cavity was lavaged 15 times with 1 liter of normal saline prior to HIPEC. Two inflow drains were positioned below hemidiaphragms whereas two outflow drains were positioned in pouch of Douglas. All drains were connected to an extracorporeal closed sterile circuit in which a 2-liter perfusate was circulated by means of two peristaltic rollup pumps (one inflow and one outflow) at a flow rate of 2 L/min. HIPEC drugs were supplemented to the perfusate and allowed to circulate in abdominopelvic cavity for 90 min at 41.0–42.2°C. The heated perfusate plus chemotherapy (41.0–42.2°C) was achieved by a mean of heat exchanger connected to the sterile circuit. Intraperitoneal temperature was continuously checked by thermometers situated in abdominopelvic cavity to ensure maintenance of 41.0–42.2°C. Options of HIPEC drugs included combination of cisplatin (50 mg/m2) plus doxorubicin (15 mg/m2), single-agent melphalan (20 mg/m2), or single-agent mitomycin-c (15 mg/m2) as per the treating surgical oncology and medical oncology multidisciplinary team.\n\nDuring HIPEC procedure, hemodynamic and cardiopulmonary parameters were continuously and carefully monitored. At the end of HIPEC procedure, abdominopelvic cavity was again lavaged 10–15 times with 1 liter of normal saline. A number of selected patients received IORT following HIPEC as deemed necessary by the treating surgical oncology and medical oncology multidisciplinary team.\n\nAt the end of CRS plus HIPEC plus/minus IORT procedure, ureteral stents were removed by the urology team and all patients were extubated, transferred to intensive care unit (ICU) for 1–3 days (median: 1 day), and afterwards transferred to the surgical ward for recovery.\n\nPostoperative morbidity and mortality following CRS plus HIPEC were evaluated according to the Clavien-Dindo classification system for postoperative complications [28].\n\nFollowing CRS plus HIPEC, some patients received postoperative adjuvant therapy (radiotherapy, chemotherapy, or both) as deemed necessary by the treating surgical oncology and medical oncology multidisciplinary team.\n\nAll patients were followed up regularly. No patient was lost during follow-up visits. During the first year following HIPEC, patients were followed up every 3 months. During the second year and afterwards, patients were followed up every 6 months. The follow-up work-up included routine physical examination, hematological profiles (complete blood count), biochemical profiles (electrolyte, renal, bone, hepatic, and coagulation), serum tumor markers, chest X-ray, whole-body computed tomography (CT) scan, or position emission tomography/CT scan (whenever deemed necessary).\n\nThe study endpoints were disease-free survival (DFS) and overall survival (OS). DFS was calculated from the day of CRS plus HIPEC to the time of local/distant disease progression or last date of follow-up, whichever comes first. OS was calculated from the day of CRS plus HIPEC to the time of death or last follow-up, whichever comes first. DFS and OS rates were calculated according to the Kaplan-Meier method and compared by using the two-tailed log-rank test. Univariate analysis was performed using the Cox proportional hazards model to predict prognostic variables (age, gender, PS presentation, PS pathology, CC, PCI, IORT, and HIPEC chemotherapeutics) of DFS and OS. All statistical analyses were performed using SPSS software version 19 for Windows (SPSS Inc., Chicago, IL, USA). For all purposes, p values <0.05 were regarded as statistically significant.\n\n3. Results\nEleven patients met the study inclusion criteria. Patients' preoperative details are summarized in Table 1. There were 9 males and 2 females. Four and seven patients had PS at primary (first disease) and secondary (recurrent disease) presentations, respectively. Ten and two patients had abdominopelvis and extra-abdominopelvis PS sites of origin, respectively. PS histologies included 7 retroperitoneal liposarcomas and 4 retroperitoneal nonliposarcomas.\n\nPatients' operative details are summarized in Table 2. CC-0 and CC-1 were achieved in 7 and 4 patients, respectively. The median PCI was 14 ± 8.9 (range: 3–29). IORT was performed in 5 patients. Reasons for using IORT during the same procedure included one or more of the following: anatomically locally advanced deep-seated invasion of retroperitoneum, psoas major muscle, renal capsule, trigone of urinary bladder and seminal vesicles, hemidiaphragm, external iliac, abdominal aorta, and inferior vena cava vicinities by the PS tumor residues, and hence making surgical dissection/resection of such tumor residues—to a greater degree—technically unfeasible with potential critical intraoperative morbidity/mortality.\n\nRegarding patients' postoperative complications, 1 patient developed grade I lung atelectasis that was managed conservatively with chest physiotherapy. Three patients developed grade II postoperative complications (pneumonia, wound infection, and upper limb thrombosis) that were managed with conservative pharmacological treatments (antibiotics, antibiotics and wound dressing, and anticoagulation, resp.). Lastly, 1 patient developed grade IVa unilateral obstructive uropathy leading to acute renal failure and was managed with intensive care unit (ICU) admission, intravenous fluids, and temporary nephrostomy tube insertion.\n\nOverall, there was no renal or hematological systemic toxicity.\n\nRegarding patients' postoperative details, the median hospital stay was 11 ± 2.4 days (range: 7–15). The median follow-up time was 12 months (range: 6–33). Two and four patients received adjuvant radiotherapy and chemotherapy, respectively. The rates of 60-day readmission and 60-day mortality were zero. Six patients developed disease progression. Two patients died at 6 and 10 months after CRS plus HIPEC due to combined local and distant recurrences. Four patients were alive with disease at 12, 19, 27, and 30 months. Five patients were alive and disease-free without proof of recurrence at 34, 21, 13, 7, and 7 months.\n\nKaplan-Meier survival curves for OS and DFS are portrayed in Figures 1 and 2, respectively. For all patients, the median OS and DFS were 28.3 ± 3.2 (95% CI: 21.9–34.6) and 18.0 ± 4.0 (95% CI: 10.2–25.8) months, respectively.\n\nUnivariate analysis of the examined prognostic factors did not demonstrate statistically significant differences of OS and DFS.\n\n4. Discussion\nAlthough controversial, combination of CRS plus HIPEC has been advocated as an aggressive locoregional treatment for PS with fairly promising results [13]. This novel combined approach has been adopted by many oncological centers [6, 8, 21–26]. Table 3 summarizes a selected literature review on the role of CRS plus HIPEC for management of PS till the end of 2014.\n\nHerein, from a developing country in Saudi Arabia, we presented our tertiary-care single-center experience of CRS plus HIPEC for management of primary and recurrent PS. Complete and near-complete cytoreduction with residual tumor nodules ≤2.5 mm was achieved in all 11 patients (100%). This percentage was fairly similar to the 68–100% reported in other studies [6, 8, 21–26]. Moreover, HIPEC was associated with tolerable grade III/IV morbidity (9.1%). This percentage was less than the 16–56% postoperative morbidity reported elsewhere [6, 8, 21–26]. Also, HIPEC was associated with neither intraoperative nor 60-day postoperative mortality. A recent systematic review of CRS plus HIPEC for management of PS showed that the perioperative mortality rate that ranged from as low as 0% to as high as 11% [6, 8, 21–26].\n\nComplete/optimal cytoreduction (no microscopic residual disease)—irrespective of the number of multiple recurrences—remains the standard of care in management of PS and has been shown to be technically feasible and greatly influence the OS and DFS rates [6–10, 22, 29, 30]. Salti et al. [8] reported higher statistically significant mean DFS and OS in patients with optimal (CC-0) versus suboptimal (≥CC-1) cytoreduction (DFS: 27.3 versus 4.3 months, resp.; OS: 35.3 versus 5.3 months, resp.). In our study, the median OS and DFS rates did not differ between both groups and yet did not yield statistically significant differences on OS (p = 0.6) and DFS (p = 0.9).\n\nThe influence of PCI (disease volume) has been previously explored. Berthet et al. [29] reported higher 5-year OS rate in patients with PCI <13 than patients with PCI >13 (75% versus 12.8%, resp.). Conversely, our study (concerning DFS) as well as other several studies [6, 22, 24] failed to demonstrate any correlation between PCI and OS/DFS. This could be rationalized by the fact that the reported mean and/or median of PCI scores were most often low (<15), possibly implying the wise selection of patients with lower disease volumes.\n\nThe logic for employing HIPEC is centrally based on the direct hyperthermia-enhanced penetrative, synergistic, and cytotoxic effects of anticancer therapy on the neoplastic PS cells [4, 31]. In addition, as opposed to systemic chemotherapy, administration of intraperitoneal chemotherapy [8, 31] (1) effectively delivers higher locoregional drug concentrations without related undesirable systemic toxicities and (2) optimally sterilizes the surgical field against microscopic cancerous residues before development of postoperative adhesions and subsequent entrapment of cancerous cells in scar tissues—the most substantial factor prompting PS recurrence [6–10, 22, 29, 30]. The aforementioned advantages of HIPEC enable the combination of CRS plus HIPEC to mount as potentially noteworthy treatment for PS.\n\nThe choice of intraperitoneal chemotherapy drugs should be justified by confirmed scientific evidence of hyperthermia-improved effects of the chosen intraperitoneal chemotherapies. Examples of such chemotherapies include cisplatin [32], mitomycin-c [33], doxorubicin [34], mitoxantrone [35], and melphalan [36, 37]. In our study, mitomycin-c was used only in 1 patient which was the first early case of HIPEC. Reasons for its use included (1) proven profile of hyperthermia-enhanced cytotoxic effects [33], (2) good pharmacokinetic profile for locoregional administration, despite poor effectiveness in sarcoma, and (3) limited availability of HIPEC drugs at the time of procedure at our institute.\n\nIn our study, age, gender, PS presentation, and PS pathology did not influence OS or DFS on univariate analysis. Similar results were obtained elsewhere [6, 8, 22, 23].\n\nAdjuvant therapies such as systemic chemotherapy and external beam radiation therapy (EBRT) do not appear to provide any clinical benefits [6], as STSs are largely chemoresistant and radio-resistant tumors [38, 39]. Moreover, additional novel therapeutic modalities such as preoperative EBRT combined with postoperative brachytherapy [40], IORT [41, 42], and photodynamic therapy [43, 44] have been suggested to enhance the life expectancy of these patients, but there are no solid clinical results to offer solid conclusions.\n\nPrevious studies showed that application of IORT (dose: 8.75–30 Gy) is associated with improved 5-year OS (45–64.8%), 5-year local disease control (40–62%), and 5-year DFS (28–55%) in patients with primary advanced or recurrent STSs [41, 42, 45, 46]. To the best of our knowledge, none of the previous CRS plus HIPEC studies used IORT in the same procedure; hence, this is the first ever study of such combination (CRS plus HIPEC plus IORT) in the literature. At present, there is limited effectiveness of the available therapies for PS [22]. Moreover, there are no universally agreed upon guidelines for management of PS [6], and consequently there is lack of adequate studies to conclude solid recommendations. That being said, the process of identifying novel treatment modalities for PS is continuingly evolving. In our study, the novel combination modality (CRS plus HIPEC plus IORT) was carried out in an optimistic attempt to provide synergistic anticancer treatment, achieve better aggressive locoregional disease control especially in the setting of neighboring technically unresectable tumor residues, and ultimately yield improved survival benefits in such patients. However, IORT did not influence OS or DFS on univariate analysis. More studies regarding this novel combination are needed and this is an interesting area for future research.\n\nLimitations to this study include the following: retrospective study design, relatively small sample size, relatively short period of follow-up, and lack of consistent therapy and control group; all of which limitations were previously documented in earlier studies [6, 8, 21–26].\n\n5. Conclusion\nCRS plus HIPEC appear to be feasible and safe and offer survival oncological benefits. Despite the current results being encouraging, definitive conclusions regarding the role of HIPEC in providing locoregional disease control cannot be deduced. The novel firstly introduced addition of IORT to CRS plus HIPEC during the same procedure did not significantly influence OS or DFS on univariate analysis. The impact of HIPEC following CRS remains questionable and still has to be further investigated in randomized controlled large-sized multi-institutional studies. Until then, cytoreduction to no macroscopic disease remains the standard of care in management of PS, and the administration of HIPEC remains a topic of debate with no conclusive recommendations.\n\nEthical Approval\nThe publication of this paper has been approved by the Research Advisory Council (RAC) at the King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia (RAC Project #22161039).\n\nCompeting Interests\nThe authors declare no competing interests regarding the production of this paper. The authors have no personal financial or institutional interests in any of the drugs, materials, or devices described in this paper.\n\nAuthors' Contributions\nAhmed Abu-Zaid, Ayman Azzam, and Mohammed Abuzaid drafted the paper; Ahmed Abu-Zaid, Ayman Azzam, Osama Alomar, Tarek Amin, and Ismail A. Al-Badawi contributed to study design and conception; Ahmed Abu-Zaid, Mohammed Abuzaid, Osama AlOmar, Abdullah Alsuhaibani, Naryman Albadawi, and Lynn Alkhatib reviewed the literature, collected data, and prepared tables; Tusneem Elhassan performed all statistical analysis; Ayman Azzam, Osama Alomar, Abdullah Alsuhaibani, Tarek Amin, and Ismail A. Al-Badawi contributed to medical and surgical management of patients; Ahmed Abu-Zaid, Ayman Azzam, Mohammed Abuzaid, Tusneem Elhassan, Tarek Amin, and Ismail A. Al-Badawi critically reviewed the paper for intellectual contents; all authors approved the final version of the paper.\n\nFigure 1 Kaplan-Meier figure for overall survival (OS) of all patients.\n\nFigure 2 Kaplan-Meier curve for disease-free survival (DFS) of all patients.\n\nTable 1 Preoperative details of patients.\n\nVariable\t\nn (%)\t\nMedian age ± SD (range) \t46 ± 10.9 (19–57)\t\nMedian ECOG performance status score ± SD (range)\t1 ± 0.6 (0–2)\t\nGender\t \t\n Male\t9 (81.8%)\t\n Female\t2 (18.2%)\t\nPS presentation\t \t\n Primary (first disease)\t4 (36.4)\t\n Secondary (recurrent disease)\t7 (63.6)\t\nSite of origin \t \t\n Abdominal/pelvic\t9 (81.8)\t\n Extra-abdominal/pelvic\t2 (18.2)\t\n \nBoth cases were liposarcomas from lower limb, specifically thigh and calf muscles\n\t \t\nHistology (pathology)\t \t\n Retroperitoneal liposarcomas\t7 (63.6)\t\n Retroperitoneal non-liposarcomas\t4 (36.4)\t\n Leiomyosarcoma\t1 (9.1)\t\n Ewing's Sarcoma\t1 (9.1)\t\n GIST (fundus and body origins)\t2 (18.2)\t\nPrevious treatment\t \t\n Surgery\t7 (63.6)\t\n Radiotherapy\t2 (18.2)\t\n Chemotherapy\t4 (36.4)\t\nSymptoms\t \t\n Asymptomatic\t1 (9.1)\t\n Flank pain\t2 (18.2)\t\n Abdominal pain\t8 (72.7)\t\n Increased abdominal circumference\t2 (18.2)\t\n Early satiety, nausea, and vomiting\t2 (18.2)\t\n Weight loss\t3 (27.3)\t\nSD: standard deviation; PS: peritoneal sarcomatosis; ECOG: Eastern Cooperative Oncology Group; GIST: gastrointestinal stromal tumor.\n\nTable 2 Operative details of CRS plus HIPEC.\n\n \t\nn (%)\t\nViscera resected\t \t\n Appendectomy\t4 (36.4)\t\n Cholecystectomy\t7 (63.6)\t\n Splenectomy\t2 (18.2)\t\n Distal pancreatectomy\t1 (9.1)\t\n Omentectomy\t4 (36.4)\t\n Peritonectomy\t5 (45.5)\t\n Anterior parietal peritonectomy\t3 (27.3)\t\n Pelvic peritonectomy\t2 (18.2)\t\n Urinary bladder dissection\t1 (9.1)\t\n Diaphragm resection\t1 (9.1)\t\n Small bowel resection\t4 (36.4)\t\n Large bowel resection\t8 (72.7)\t\n Low anterior resection\t1 (9.1)\t\n TAH + BSO\t2 (18.2)\t\n Median enteric anastomosis (range)\t1 (1–3)\t\nCC\t \t\n CC-0\t7 (63.6)\t\n CC-1\t4 (36.4)\t\nMedian PCI ± SD (range)\t14 ± 8.9 (3–29)\t\nHIPEC chemotherapeutic\t \t\n Cisplatin plus doxorubicin\t6 (54.5)\t\n Melphalan\t4 (36.4)\t\n Mitomycin-c\t1 (9.1)\t\nIntraoperative radiation therapy (IORT)\t5 (45.5)\t\nMedian operative time ± SD (range)\t8 ± 1.4 hr (6–10)\t\nMedian EBL ± SD (range)\t1000 mL ± 250 (700–3850)\t\nIntraoperative morbidity \t0\t\nIntraoperative mortality\t0\t\nSD: standard deviation; CC: cytoreduction completeness; PCI: peritoneal cancer index; HIPEC: hyperthermic intraperitoneal chemotherapy; TAH + BSO: total abdominal hysterectomy and bilateral salpingo-oophorectomy; EBL: estimated blood loss.\n\nTable 3 Selected literature review on CRS + HIPEC for management of PS (till end of 2014).\n\nRef\tAuthor\tYear\t\nn\n\tHIPEC Chemo\tCC-0/1\tPCI\tMedian FU\tMedian DFS\tMedian OS\tMedian 5-year OS\tMortality\tMorbidity\tHS\tPathology\t\n[6]\tRossi et al.\t2004\t60\tCis + dox\t68\t7.7\t28\t22\t34\t38\t0\t33\t12\tGIST = 14, RPS = 34, and LMS = 12\t\n\n\n\t\n[21]\tLim et al.\t2007\t19\tCis\t95\tNR\tNR\t4.4\t16.9\tNR\t0\t16\t15\tGIST = 15, DSRCT = 3, and LS = 1\t\n\n\n\t\n[21]\tLim et al.\t2007\t9\tCis + mitox\t100\tNR\tNR\t2.3\t5.5\tNR\t11\t44\t16\tGIST = 2, DSRCT = 2, LS = 1, sarcomatoid = 1, and unclassified = 3\t\n\n\n\t\n[22]\tBaratti et al.\t2010\t37\tCis + dox or MMC\t84\t14.7\t104\t12.1\t26.2\t24.3\t2.7\t21.6\tNR\tRPS = 13, uterine = 11, GIST = 8, DSRCT = 3, myxofibrosarcoma = 1, and LMS = 1\t\n\n\n\t\n[8]\tSalti et al.\t2012\t13\tCis + dox\t70\t12.1\t12\t11\t12\tNR\t0\t15.4\tNR\tLS = 8, pleomorphic sarcomas = 2, angiosarcoma = 1, and carcinosarcoma = 2\t\n\n\n\t\n[23]\tBaumgartner et al.\t2013\t17\tCis, dox or MMC\t100\t6#\n\t17.4\t17.2\t22.6\t35\t0\t23.5\t8\tSCS = 4, LS = 5, LMS = 3, GIST = 2, and others = 3\t\n\n\n\t\n[24]\tSommariva et al.\t2013\t15\tCis + dox or cis + MMC\t100\t5.5\t28\t15\t27\t29\t0\t46.6\tNR\tLS = 4, GIST = 2, LMS = 4, histiocytoma fibrous malignant = 1, DSRCT = 1, SCS = 1, schwannoma = 1, and stromal sarcoma = 1\t\n\n\n\t\n[25]\tRandle et al.\t2013\t10\tCis or mitox\t60\tNR\t84.8\tNR\t21.6\t50\t0\tNR\t10$\n\tDSRCT = 1, fibrosarcoma = 1, LMS = 2, SS = 4, and hemangiopericytoma = 2\t\n\n\n\t\n[26]\tBryan et al.\t2014\t18\tMMC ± mitox\t72.2\tNR\tNR\tNR\t40\t56∗\n\t5.6\t33.3\t8\tGIST before era of TKI\t\n\n\n\t\n \tCurrent study\t2015\t11\tCis + dox or MMC or mel\t100\t14\t12\t18\t28.3\tNR\t0\t18.2\t11\tLS = 7, GIST = 2, uterine LMS = 2, and ES = 1\t\nRef: reference; HIPEC: hyperthermic intraperitoneal chemotherapy; Chemo: chemotherapy; CC: cytoreduction completeness; PCI: peritoneal cancer index; FU: follow-up; DFS: disease-free survival; OS: overall survival; HS: hospital stay; cis: cisplatin; dox: doxorubicin; mitox: mitoxantrone; MMC: mitomycin-c; Mel: melphalan; GIST: gastrointestinal stromal tumor; RPS: retroperitoneal sarcoma; LMS: leiomyosarcoma, LS: liposarcoma; DSRCT: desmoplastic small round cell tumor; SS: spindle-cell sarcoma; SCS: synovial cell sarcoma; TKI: tyrosine kinase inhibitor; NR: not reported.\n\n\n∗3-year survival.\n\n\n$mean.\n\n\n#SPCI (simplified peritoneal cancer index).\n==== Refs\n1 Torre L. A. Bray F. Siegel R. L. Ferlay J. Lortet-Tieulent J. Jemal A. Global cancer statistics, 2012 CA: A Cancer Journal for Clinicians 2015 65 2 87 108 10.3322/caac.21262 2-s2.0-84924271853 25651787 \n2 Jaques D. P. Coit D. G. Hajdu S. I. Brennan M. F. Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum Annals of Surgery 1990 212 1 51 59 10.1097/00000658-199007000-00008 2-s2.0-0025350429 2363604 \n3 Singer S. Maki R. G. O'Sullivan B. DeVita V. T. Jr. Lawrence T. S. Rosenberg S. A. Part II: molecular biology of individual cancers: sarcomas Cancer: Principles & Practice of Oncology: Primer of the Molecular Biology of Cancer 2011 Philadelphia, Pa, USA Wolters Kluwer Health/Lippincott Williams & Wilkins 1533 1577 \n4 Sugarbaker T. A. Chang D. Koslowe P. Sugarbaker P. H. Patterns of spread of recurrent intraabdominal sarcoma Cancer Treatment and Research 1996 82 65 77 10.1007/978-1-4613-1247-5_5 2-s2.0-0029680036 8849944 \n5 Mudan S. S. Conlon K. C. Woodruff J. M. 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Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal sarcomatosis Annals of Surgical Oncology 2012 19 5 1410 1415 10.1245/s10434-012-2240-7 2-s2.0-84862565067 22302269 \n9 Bilimoria M. M. Holtz D. J. Mirza N. Q. Tumor volume as a prognostic factor for sarcomatosis Cancer 2002 94 9 2441 2446 10.1002/cncr.10504 2-s2.0-0036570111 12015769 \n10 Karakousis C. P. Blumenson L. E. Canavese G. Rao U. Surgery for disseminated abdominal sarcoma The American Journal of Surgery 1992 163 6 560 564 10.1016/0002-9610(92)90556-7 2-s2.0-0026695733 1375814 \n11 Munene G. MacK L. A. Temple W. J. Systematic review on the efficacy of multimodal treatment of sarcomatosis with cytoreduction and intraperitoneal chemotherapy Annals of Surgical Oncology 2011 18 1 207 213 10.1245/s10434-010-1229-3 2-s2.0-78651372008 20697824 \n12 Sugarbaker P. H. Peritonectomy procedures Annals of Surgery 1995 221 1 29 42 10.1097/00000658-199501000-00004 2-s2.0-0028797043 7826158 \n13 Rossi C. R. Casali P. Kusamura S. Baratti D. Deraco M. The consensus statement on the locoregional treatment of abdominal sarcomatosis Journal of Surgical Oncology 2008 98 4 291 294 10.1002/jso.21067 2-s2.0-50849099545 18726899 \n14 Yan T. D. Deraco M. Baratti D. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience Journal of Clinical Oncology 2009 27 36 6237 6242 10.1200/jco.2009.23.9640 2-s2.0-74949123203 19917862 \n15 Bijelic L. Jonson A. Sugarbaker P. H. Systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer Annals of Oncology 2007 18 12 1943 1950 10.1093/annonc/mdm137 2-s2.0-34547976092 17496308 \n16 Al-Badawi I. A. Abu-Zaid A. Azzam A. Alomar O. Alhusaini H. Amin T. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for management of recurrent/relapsed ovarian granulosa cell tumor: a single-center experience Journal of Obstetrics and Gynaecology Research 2014 40 9 2066 2075 10.1111/jog.12460 2-s2.0-84906858387 25181627 \n17 Abu-Zaid A. Azzam A. Z. AlOmar O. Salem H. Amin T. Al-Badawi I. A. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for managing peritoneal carcinomatosis from endometrial carcinoma: a single-center experience of 6 cases Annals of Saudi Medicine 2014 34 2 159 166 10.5144/0256-4947.2014.159 2-s2.0-84907532917 24894786 \n18 Sugarbaker P. H. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? The Lancet Oncology 2006 7 1 69 76 10.1016/s1470-2045(05)70539-8 2-s2.0-29744469602 16389186 \n19 Elias D. Gilly F. Boutitie F. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study Journal of Clinical Oncology 2010 28 1 63 68 10.1200/jco.2009.23.9285 19917863 \n20 Canbay E. Yonemura Y. Brucher B. Baik S. H. Sugarbaker P. H. Intraperitoneal chemotherapy and its evolving role in management of gastric cancer with peritoneal metastases Chinese Journal of Cancer Research 2014 26 1 1 3 10.3978/j.issn.1000-9604.2014.02.06 2-s2.0-84901449034 24653620 \n21 Lim S. J. Cormier J. N. Feig B. W. Toxicity and outcomes associated with surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with sarcomatosis Annals of Surgical Oncology 2007 14 8 2309 2318 10.1245/s10434-007-9463-z 2-s2.0-34547466644 17541691 \n22 Baratti D. Pennacchioli E. Kusamura S. Peritoneal sarcomatosis: is there a subset of patients who may benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy? Annals of Surgical Oncology 2010 17 12 3220 3228 10.1245/s10434-010-1178-x 2-s2.0-78650973415 20585874 \n23 Baumgartner J. M. Ahrendt S. A. Pingpank J. F. Aggressive locoregional management of recurrent peritoneal sarcomatosis Journal of Surgical Oncology 2013 107 4 329 334 10.1002/jso.23232 2-s2.0-84874260881 23386388 \n24 Sommariva A. Pasquali S. Del Fiore P. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal sarcomatosis: long-term outcome from a single institution experience Anticancer Research 2013 33 9 3989 3994 2-s2.0-84884996167 24023339 \n25 Randle R. W. Swett K. R. Shen P. Stewart J. H. Levine E. A. Votanopoulos K. I. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in peritoneal sarcomatosis The American Surgeon 2013 79 6 620 624 2-s2.0-84878252064 23711273 \n26 Bryan M. L. Fitzgerald N. C. Levine E. A. Shen P. Stewart J. H. Votanopoulos K. I. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in sarcomatosis from gastrointestinal stromal tumor American Surgeon 2014 80 9 890 895 2-s2.0-84908353839 25197876 \n27 Jacquet P. Sugarbaker P. H. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis Cancer Treatment and Research 1996 82 359 374 10.1007/978-1-4613-1247-5_23 2-s2.0-0029680270 8849962 \n28 Dindo D. Demartines N. Clavien P.-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey Annals of Surgery 2004 240 2 205 213 10.1097/01.sla.0000133083.54934.ae 2-s2.0-3242713145 15273542 \n29 Berthet B. Sugarbaker T. A. Chang D. Sugarbaker P. H. Quantitative methodologies for selection of patients with recurrent abdominopelvic sarcoma for treatment European Journal of Cancer 1999 35 3 413 419 10.1016/s0959-8049(98)00375-x 2-s2.0-0033105659 10448292 \n30 Bonvalot S. Cavalcanti A. Le Péchoux C. Randomized trial of cytoreduction followed by intraperitoneal chemotherapy versus cytoreduction alone in patients with peritoneal sarcomatosis European Journal of Surgical Oncology 2005 31 8 917 923 10.1016/j.ejso.2005.04.010 2-s2.0-26444537915 15975759 \n31 Ceelen W. P. Flessner M. F. Intraperitoneal therapy for peritoneal tumors: biophysics and clinical evidence Nature Reviews Clinical Oncology 2010 7 2 108 115 10.1038/nrclinonc.2009.217 2-s2.0-76449101754 \n32 Rietbroek R. C. Van De Vaart P. J. M. Haveman J. 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Stuart O. A. Hyperthermic intraperitoneal chemotherapy with melphalan: a summary of clinical and pharmacological data in 34 patients Gastroenterology Research and Practice 2012 2012 5 827534 10.1155/2012/827534 2-s2.0-84864955017 \n37 Jimenez W. A. Sardi A. Nieroda C. Gushchin V. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the management of recurrent high-grade uterine sarcoma with peritoneal dissemination American Journal of Obstetrics and Gynecology 2014 210 3 259.e1 259.e8 10.1016/j.ajog.2013.11.002 2-s2.0-84894570251 24211479 \n38 Weichselbaum R. R. Beckett M. A. Hallahan D. E. Kufe D. W. Vokes E. E. Molecular targets to overcome radioresistance Seminars in Oncology 1992 19 4, supplement 11 14 20 2-s2.0-0026776117 1509276 \n39 Plaat B. E. C. Hollema H. Molenaar W. M. 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Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas International Journal of Radiation Oncology Biology Physics 2002 52 2 469 475 10.1016/S0360-3016(01)02595-0 2-s2.0-0036471013 \n43 Bauer T. W. Hahn S. M. Spitz F. R. Kachur A. Glatstein E. Fraker D. L. Preliminary report of photodynamic therapy for intraperitoneal sarcomatosis Annals of Surgical Oncology 2001 8 3 254 259 10.1245/aso.2001.8.3.254 2-s2.0-0035071523 11314943 \n44 Hendren S. K. Hahn S. M. Spitz F. R. Phase II trial of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors Annals of Surgical Oncology 2001 8 1 65 71 10.1245/aso.2001.8.1.65 2-s2.0-0035155063 11206227 \n45 Krempien R. Roeder F. Oertel S. Intraoperative electron-beam therapy for primary and recurrent retroperitoneal soft-tissue sarcoma International Journal of Radiation Oncology Biology Physics 2006 65 3 773 779 10.1016/j.ijrobp.2006.01.028 2-s2.0-33646950450 \n46 Gieschen H. L. Spiro I. J. Suit H. D. Long-term results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma International Journal of Radiation Oncology, Biology, Physics 2001 50 1 127 131 10.1016/s0360-3016(00)01589-3\n\n",
"fulltext_license": "CC BY",
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"issue": "2016()",
"journal": "Gastroenterology research and practice",
"keywords": null,
"medline_ta": "Gastroenterol Res Pract",
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"nlm_unique_id": "101475557",
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"pmid": "27212941",
"pubdate": "2016",
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"title": "Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy for Management of Peritoneal Sarcomatosis: A Preliminary Single-Center Experience from Saudi Arabia.",
"title_normalized": "cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for management of peritoneal sarcomatosis a preliminary single center experience from saudi arabia"
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"abstract": "Cryptococcus albidus, synonymous with Naganishia albida, rarely causes opportunistic infection in immunocompromised individuals. Its clinical features, particularly in children, are not well defined. Here, we report a case of C albidus fungemia in an immunosuppressed child; we also present results of a systematic review, for which we searched PubMed, Embase, and Web of Science using the keywords \"cryptococcus\" and \"albidus.\" Our goal was to describe the spectrum of disease, diagnostic approaches, therapies, and outcomes. We identified 20 cases of invasive infection, only 2 of which involved children, and 7 cases of noninvasive infection. The reports originated in the Americas, Europe, and Asia. Of those with invasive infection, 16 (80%) patients had an underlying chronic disorder or had received immunosuppressive therapy, 8 (40%) had fungemia, and 6 (30%) had a central nervous system infection. The attributable case fatality rate was 40%. C albidus is an opportunistic yeast that can rarely cause life-threatening fungemia and central nervous system infection in individuals of any age, especially those who are immunocompromised.",
"affiliations": "Division of Infectious Diseases, Departments of Pediatrics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence.;Division of Infectious Diseases, Departments of Pediatrics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence.;Division of Rheumatology, Department of Pediatrics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence.;Division of Infectious Diseases, Departments of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence.;Division of Infectious Diseases, Departments of Pathology and Laboratory Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence.;Division of Infectious Diseases, Departments of Pediatrics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence.",
"authors": "Choe|Young June|YJ|;Blatt|Daniel B|DB|;Yalcindag|Ali|A|;Geffert|Sara F|SF|;Bobenchik|April M|AM|;Michelow|Ian C|IC|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B; D015725:Fluconazole",
"country": "England",
"delete": false,
"doi": "10.1093/jpids/piz039",
"fulltext": null,
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"issn_linking": "2048-7193",
"issue": "9(1)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": "\n Cryptococcus albidus\n ; \n Naganishia albida\n ; fungemia; immunosuppression; systematic review",
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000666:Amphotericin B; D000935:Antifungal Agents; D002675:Child, Preschool; D003453:Cryptococcosis; D003454:Cryptococcus; D005260:Female; D015725:Fluconazole; D006801:Humans; D016867:Immunocompromised Host; D007231:Infant, Newborn; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009894:Opportunistic Infections; D013625:Takayasu Arteritis; D014182:Transplantation, Autologous",
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "100-105",
"pmc": null,
"pmid": "31183496",
"pubdate": "2020-02-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Cryptococcus albidus Fungemia in an Immunosuppressed Child: Case Report and Systematic Literature Review.",
"title_normalized": "cryptococcus albidus fungemia in an immunosuppressed child case report and systematic literature review"
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"companynumb": "US-TEVA-2020-US-1227993",
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"activesubstancename": "FLUCYTOSINE"
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... |
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"abstract": "BACKGROUND\nMetastatic germ cell cancers are highly chemosensitive and have 80% cure rate with cisplatin-based chemotherapy. Postchemotherapy teratoma can usually be surgically resected. However, teratoma, which is pluripotent tissue, can undergo malignant transformation along mesodermal elements to primitive neuroectodermal tumor (PNET). Unlike teratoma, PNET can metastasize and render a patient unresectable and incurable. We report the results of treatment of patients with malignant transformation to PNET with cyclophosphamide+doxorubicin+vincristine (CAV) alternating with ifosfamide+etoposide (IE).\n\n\nMETHODS\nWe reviewed 86 patients with histologically confirmed PNET transformed from testicular teratoma at Indiana University from 1998 to 2012. We identified 18 patients who were treated with chemotherapy comprising cyclophosphamide (1000 to 1200 mg/m), doxorubicin (50 to 75 mg/m), and vincristine (2 mg) alternating with ifosfamide (1.8 g/m) plus etoposide (100 mg/m) for 5 consecutive days. Treatment was given every 3 weeks with a maximum of 6 cycles or until progression or undue toxicity. Hematopoietic growth factors were usually incorporated. The remaining 68 patients underwent surgical resection.\n\n\nRESULTS\nTwelve patients had unresectable disease and 6 were treated in an adjuvant setting. Median age was 29 years (range, 20 to 53 y). Nine of the 12 metastatic patients achieved objective response by RECIST criteria. Six of those were rendered with no evidence of disease (NED) with further surgery. Although 4 of the 6 patients subsequently relapsed, 1 patient remains alive and NED at 78 months. The 6 patients who received adjuvant treatment are alive with NED at 9 to 90 months with a median duration of 32.7 months.\n\n\nCONCLUSIONS\nCAV and IE alternating chemotherapy has high objective response rate for PNET transformed from teratoma and results in occasional long-term disease-free survival when combined with subsequent resection. We recommend adjuvant CAV alternating with IE chemotherapy for patients with PNET after RPLND due to the high probability of recurrent disease and their high chemosensitivity to this regimen.",
"affiliations": "*Division of Hematology/Oncology, Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN †Talahassee Memorial Healthcare, Tallahassee, FL.",
"authors": "Al-Hader|Ahmad A|AA|;Jain|Amit|A|;Al-Nasrallah|Nawar|N|;Einhorn|Lawrence H|LH|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1097/COC.0b013e31829d1ed7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3732",
"issue": "38(4)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001859:Bone Neoplasms; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D006801:Humans; D007069:Ifosfamide; D008175:Lung Neoplasms; D008198:Lymph Nodes; D008297:Male; D008479:Mediastinal Neoplasms; D008875:Middle Aged; D018241:Neuroectodermal Tumors, Primitive, Peripheral; D010997:Pleural Neoplasms; D012186:Retroperitoneal Neoplasms; D012189:Retrospective Studies; D013724:Teratoma; D013736:Testicular Neoplasms; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "364-6",
"pmc": null,
"pmid": "23799289",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Metastatic malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): results with PNET-based chemotherapy.",
"title_normalized": "metastatic malignant transformation of teratoma to primitive neuroectodermal tumor pnet results with pnet based chemotherapy"
} | [
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{
"abstract": "•There is a critical need for therapeutic options in uterine serous carcinoma (USC).•A substantial proportion of USC cases express estrogen receptors (ER).•This report describes use of letrozole therapy in recurrent, ER-positive USC.•Zoledronic acid may enhance letrozole efficacy against hormone-sensitive tumors.•Aromatase inhibitors could be a potential treatment option in ER-positive USC.",
"affiliations": "The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.;Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.;Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.;Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.;The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States.",
"authors": "Najjar|Omar|O|;Varghese|Aaron|A|;Shahi|Maryam|M|;Vang|Russell|R|;Gaillard|Stephanie|S|;Smith|Thomas|T|;Fader|Amanda N|AN|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gore.2020.100555",
"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789 2352-5789 Elsevier \n\nS2352-5789(20)30021-7\n10.1016/j.gore.2020.100555\n100555\nCase Report\nAromatase inhibitor therapy in recurrent, estrogen-receptor positive uterine serous carcinoma: A case report\nNajjar Omar a Varghese Aaron a Shahi Maryam b Vang Russell b Gaillard Stephanie ac Smith Thomas c Fader Amanda N. afader1@jhmi.edua⁎ a The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States\nb Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States\nc Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21205, United States\n⁎ Corresponding author at: 600 N. Wolfe St., Phipps Bldg., Rm 281, Baltimore, MD 21287, United States. afader1@jhmi.edu\n02 3 2020 \n5 2020 \n02 3 2020 \n32 10055519 12 2019 7 2 2020 24 2 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/).Highlights\n• There is a critical need for therapeutic options in uterine serous carcinoma (USC).\n\n• A substantial proportion of USC cases express estrogen receptors (ER).\n\n• This report describes use of letrozole therapy in recurrent, ER-positive USC.\n\n• Zoledronic acid may enhance letrozole efficacy against hormone-sensitive tumors.\n\n• Aromatase inhibitors could be a potential treatment option in ER-positive USC.\n==== Body\n1 Introduction\nUterine serous carcinoma (USC) is a subtype of endometrial cancer associated with poorer survival outcomes compared to the more common subtype, endometrioid endometrial carcinoma (EEC). The biologically aggressive nature of this malignancy has prompted investigation of novel treatments, particularly targeted therapies tailored to the specific gene and receptor expression profiles in individual patients. For instance, targeting tumors that overexpress HER2 with trastuzumab reduces recurrence rates and increases progression free survival in women with advanced or recurrent USC (Fader et al., 2018). Hormone receptors, namely estrogen receptors (ER) and progesterone receptors (PR), are other potential therapeutic targets in USC.\n\nWhile endocrine therapy has not been evaluated in USC, it is commonly used in EEC, where over 90% of tumors express ER or PR (Shen et al., 2017). Progestin-based treatments have been adopted in advanced or recurrent endometrial carcinoma (Koh et al., 2018). Recent trials have demonstrated the efficacy of other regimens in recurrent endometrial carcinoma, including alternating megestrol acetate and tamoxifen or the combination of everolimus and letrozole (Fiorica et al., 2004, Slomovitz et al., 2015).\n\nA substantial proportion of USC tumors also express ER and PR. An analysis of 628 USC tumor samples demonstrated ERα and PR expression in 60% and 32% of tumors respectively (Jones et al., 2015). However, studies of the genomic profiles of USC and EEC suggest that different molecular pathways are involved in the pathogenesis of these tumors (Levine and Network, 2013). These data support the hypothesis that EEC and USC are separate entities, raising the question of whether endocrine therapy can be utilized to effectively treat USC as in EEC. This case report describes the treatment of a woman with ER-positive, recurrent, metastatic USC with letrozole, an aromatase inhibitor.\n\n2 Case report\nA 61-year-old black, gravida 1 para 1 female with a BMI of 33.6 kg/m2 underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic and para-aortic lymphadenectomy, demonstrating stage IIIC1 USC on pathology. Her past medical history was significant for atrial fibrillation, hypertension, and depression, all well-controlled pharmacologically. Her family history was notable for pancreatic cancer in her mother. She had a 20 pack-year smoking history with cessation 2 decades prior to diagnosis. After surgery, she received 6 cycles of adjuvant carboplatin-paclitaxel chemotherapy.\n\nThe patient experienced disease-free survival for over 9 years until routine surveillance imaging revealed innumerable punctate osseous blastic lesions in the vertebral column, as well as two sub-centimeter lung nodules. These lesions were new developments, strongly suggesting metastatic disease (Fig. 1a, 1b). PET/CT showed no fluorodexyglucose (FDG)-avidity, and bone scintigraphy demonstrated no increased uptake of the radiotracer, Tc99m-methyl-diphosphonate. At this time, the patient reported a new complaint of right buttock pain that radiated down her leg and worsened with exertion. X-ray imaging of the hip showed additional blastic lesions in the right pelvis and femoral head. A biopsy of the right iliac crest confirmed the diagnosis of metastatic poorly-differentiated carcinoma, consistent with the patient’s known USC. On immunohistochemical analysis, the sample stained diffusely positive for ER and negatively for HER2 (Fig. 2).Fig. 1 (a) Sagittal CT image 12 months prior to recurrence obtained from outside medical institution, where no sclerotic lesions are visible. (b) Sagittal CT image at the time of diagnosis of recurrence, showing innumerable punctate sclerotic lesions throughout the spine. Examples of sclerotic foci are indicated with white arrows. (c) Sagittal CT image demonstrating stable disease 2 years following the initiation of letrozole therapy. Examples of sclerotic foci are indicated with white arrows.\n\nFig. 2 (a) Hematoxylin and eosin (H&E) stain of biopsy sample obtained from the right iliac crest, demonstrating the recurrence of uterine serous carcinoma, metastatic to bone. (b) Immunohistochemical staining of the biopsy sample for ER at 200× magnification. Strong, diffuse nuclear expression of ER is exhibited in tumor cells and is indicated by white arrows.\n\n\n\nThe patient began a chemotherapy regimen of intravenous carboplatin-paclitaxel every 21 days, with concurrent intravenous zoledronic acid 4 mg every 4 weeks to promote bone health. Her CA-125 level prior to chemotherapy was 14U/mL. The chemotherapy regimen was marked by significant neurological adverse effects. After two cycles, she experienced unilateral facial nerve palsy, reporting difficulty closing her left eye and smiling. MRI imaging of the brain revealed a 4x7mm focal enhancement in the left internal auditory canal, raising suspicion for a metastasis or a vestibular schwannoma. The lesion was monitored through routine imaging, and chemotherapy was continued as planned. By the time the patient completed her fourth cycle, she had developed grade 3 peripheral motor neuropathy, reporting lower extremity weakness and frequent falls. These symptoms prompted a 4-day admission, where the patient experienced an acute kidney injury in the setting of dehydration, with creatinine rising to 2.0 mg/dL from 0.8 mg/dL at baseline. She now required a walker to ambulate, and her ECOG performance status worsened to 3 from a baseline of 0. At the completion of the sixth cycle of chemotherapy, the patient’s poor functional status prompted discussions of hospice care. Cytotoxic chemotherapy was discontinued, and her CA-125 level was 17U/mL. CT imaging at the completion of chemotherapy showed no significant changes.\n\nAt a follow-up appointment 12 weeks after the completion of chemotherapy, the patient’s performance status had improved to an ECOG score of 1. She felt stronger, and her facial paresis had resolved completely. She began letrozole 2.5 mg daily therapy for her ER-positive disease, while continuing intravenous zoledronic acid therapy. Regarding the internal auditory canal lesion, repeat brain MRI showed no changes at 3, 9, and 15 months, and yearly thereafter. The lesion was deemed to be a likely vestibular schwannoma rather than metastatic USC.\n\nSince the initiation of combined letrozole-zoledronic acid therapy 30 months ago, the patient has had no evidence of disease progression on CT imaging every 6 months, with the most recent scan depicted in Fig. 1c. Her neurological symptoms have improved significantly, and she continues to have stable grade 2 neuropathy, with decreased sensation at her fingertips and the soles of her feet. She often wears thin gloves to minimize the symptoms, and she has declined therapeutics or interventions to improve these symptoms. Now 73-years-old, the patient is fully ambulatory with an ECOG score of 0, and she leads an active lifestyle mostly unimpeded by her illness.\n\n3 Discussion\nGiven the tumor biology of USC and the limited repertoire of available treatments, there is a critical unmet need for therapeutic options in women with advanced stage or recurrent disease. Investigators should weigh the overall clinical benefit of potential treatments, including criteria for both survival and quality of life. In this case report, carboplatin-paclitaxel chemotherapy led to significant neurological side effects with no improvement in tumor status. The patient’s functional debilitation affected perceptions of disease prognosis and prompted discussions of hospice care. In contrast, the patient found letrozole therapy tolerable with minimal adverse effects. Letrozole therapy in USC has not been investigated thus far, yet it demonstrated substantial clinical benefit in this particular case. The patient has maintained an excellent quality of life while remaining progression-free for 30 months to date.\n\nWeighing the clinical benefit of letrozole requires an understanding of its adverse effect profile. Letrozole is well-tolerated, particularly compared to chemotherapy, but patients may experience symptoms similar to those of menopause: hot flashes, night sweats, and weight gain. Arthralgias and myalgias are also occasionally reported. Letrozole may increase cholesterol levels but has no significant adverse impact on cardiovascular outcomes. In terms of bone health, estrogen suppression by letrozole may lead to the loss of bone mineral density.\n\nIn patients receiving aromatase inhibitor therapy, concurrent treatment with zoledronic acid reduces the risk of progression to osteopenia and may exhibit synergistic antitumor effects. A recent trial followed 1065 women with early-stage breast cancer, randomized to receive letrozole with or without zoledronic acid. Not only did zoledronic acid increase lumbar spine bone mineral density, but it also reduced the risk of local and distant recurrence (Coleman et al., 2013). USC shares clinical and pathological features with basal-like breast carcinomas (Levine and Network, 2013). Therefore, the observed efficacy of combined letrozole-zoledronic acid treatment in hormone-sensitive breast cancer may be applicable to USC as well. Furthermore, preclinical studies have demonstrated independent antitumor properties of bisphosphonates, including induction of apoptosis, inhibition of invasion, and modulation of tumor-associated macrophages (Neville-Webbe et al., 2010). Zoledronic acid appears to serve two functions: preventing osteopenia and potentially enhancing the efficacy of letrozole against hormone-sensitive tumors.\n\nThis report also describes the metastasis of USC to bone. In cases of osseous metastases, treatment with osteoclast inhibitors such as zoledronic acid is particularly important to promote bone stabilization. It remains unclear whether the antitumor effects of zoledronic acid are enhanced against bone metastases.\n\nTreatment strategies for USC are predominantly based on studies that include other endometrial cancer subtypes. USC patients are often poorly represented in such studies in comparison to the more common subtype, EEC. ER/PR-positive EEC is responsive to progestin- and aromatase inhibitor-based treatments (Fiorica et al., 2004, Koh et al., 2018, Slomovitz et al., 2015). However, the clinical significance of ER/PR expression in USC is poorly understood. In a study of 71 women with USC, ER or PR expression was associated with lower recurrence rates and longer recurrence-free and overall survival (Togami et al., 2012).\n\nGuidelines for evaluating ER expression have not been described in USC specifically. The limited existing data suggest that a substantial portion of USC appears to express ER and may have a more indolent course than the ER-negative variant. Consistent with such observations, this report describes the relatively indolent course of metastatic, ER-positive USC in one patient. Furthermore, this report suggests that letrozole may exhibit clinical and survival benefits in patients with ER-positive USC, particularly in combination with zoledronic acid. In contrast, a recent phase II trial of everolimus and letrozole in recurrent endometrial carcinoma found that the 7 patients with serous histology did not respond to letrozole (Slomovitz et al., 2015). The ER status of the tumors was not assessed. One question arising from these divergent findings is whether the degree of ER expression impacts the efficacy of aromatase inhibitor therapy.\n\nIn summary, this report describes a case of ER-positive USC, widely metastasized to the bone, with a remarkable response to letrozole therapy. Zoledronic acid was started concurrently with chemotherapy and did not demonstrate clear clinical benefit at the time. When letrozole maintenance therapy was added to the regimen, the patient experienced symptomatic improvement and no further disease progression. These observations suggest that letrozole may have been the major driver of stable disease. This case report encourages further exploration of aromatase inhibitor therapy in ER-positive USC, as well as regular pathological testing of USC tumor samples to identify targets for therapy. The potential synergistic effects of letrozole and zoledronic acid also warrant further study. This would provide a novel option to patients in critical need of therapeutic alternatives.\n\n4 Consent statement\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nCRediT authorship contribution statement\nOmar Najjar: Writing - original draft, Project administration. Aaron Varghese: Writing - review & editing. Maryam Shahi: Visualization, Writing - review & editing. Russell Vang: Writing - review & editing. Stephanie Gaillard: Writing - review & editing. Thomas Smith: . Amanda N. Fader: Conceptualization, Supervision, Writing - review & editing.\n\nDeclaration of Competing Interest\nDr. Stephanie Gaillard reports the following disclosures outside of the submitted work: grants and personal fees from Merck, Tesaro, Pfizer, Genentech/Roche, PharmaMar; grants to institution from Abbvie, Bristol-Myers Squibb, Gradalis, Iovance Biotherapeutics, Tetralogic Pharmaceuticals; personal fees from AstraZeneca and Immunogen. Otherwise, the authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript.\n==== Refs\nReferences\nColeman R. De Boer R. Eidtmann H. Llombart A. Davidson N. Neven P. Von Minckwitz G. Sleeboom H.P. Forbes J. Barrios C. Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results Ann. Oncol. 24 2013 398 405 23047045 \nFader, A.N., Roque, D.M., Siegel, E., Buza, N., Hui, P., Abdelghany, O., Chambers, S.K., Secord, A.A., Havrilesky, L., O’Malley, D.M., 2018. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu.\nFiorica J.V. Brunetto V.L. Hanjani P. Lentz S.S. Mannel R. Andersen W. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study Gynecol. Oncol. 92 2004 10 14 14751131 \nJones N.L. Xiu J. Reddy S.K. Burke W.M. Tergas A.I. Wright J.D. Hou J.Y. Identification of potential therapeutic targets by molecular profiling of 628 cases of uterine serous carcinoma Gynecol. Oncol. 138 2015 620 626 26123645 \nKoh W.-J. Abu-Rustum N.R. Bean S. Bradley K. Campos S.M. Cho K.R. Chon H.S. Chu C. Cohn D. Crispens M.A. Uterine neoplasms, version 1.2018, NCCN clinical practice guidelines in oncology J. Natl. Compr. Cancer Netw. 16 2018 170 199 \nLevine D.A. Network C.G.A.R. Integrated genomic characterization of endometrial carcinoma Nature 497 2013 67 23636398 \nNeville-Webbe H.L. Gnant M. Coleman R.E. Potential anticancer properties of bisphosphonates Semin. Oncol. Elsevier 2010 S53 S65 \nShen F. Gao Y. Ding J. Chen Q. Is the positivity of estrogen receptor or progesterone receptor different between type 1 and type 2 endometrial cancer? Oncotarget 8 2017 506 27888807 \nSlomovitz B.M. Jiang Y. Yates M.S. Soliman P.T. Johnston T. Nowakowski M. Levenback C. Zhang Q. Ring K. Munsell M.F. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma J. Clin. Oncol. 33 2015 930 25624430 \nTogami S. Sasajima Y. Oi T. Ishikawa M. Onda T. Ikeda S. Kato T. Tsuda H. Kasamatsu T. Clinicopathological and prognostic impact of human epidermal growth factor receptor type 2 (HER 2) and hormone receptor expression in uterine papillary serous carcinoma Cancer Sci. 103 2012 926 932 22329832\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "32()",
"journal": "Gynecologic oncology reports",
"keywords": null,
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "100555",
"pmc": null,
"pmid": "32215315",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": "26123645;29584549;27888807;20682373;23047045;22329832;23636398;29439178;14751131;25624430",
"title": "Aromatase inhibitor therapy in recurrent, estrogen-receptor positive uterine serous carcinoma: A case report.",
"title_normalized": "aromatase inhibitor therapy in recurrent estrogen receptor positive uterine serous carcinoma a case report"
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"companynumb": "US-FRESENIUS KABI-FK202003991",
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"abstract": "We had previously reported on S-1-induced hypertriglyceridemia. Here, we report fluorouracil-induced hypertriglyceridemia in a patient with capecitabine-induced hypertriglyceridemia and the corresponding therapeutic process. A woman in her forties who had experienced grade 3 hypertriglyceridemia due to oxaliplatin + capecitabine was administered fluorouracil ± oxaliplatin + levofolinate calcium + panitumumab; however, grade 4 hypertriglyceridemia occurred after the thirteenth administration. Bezafibrate normalized the elevation. Chemotherapy cessation resulted in its decrease to normal, and bezafibrate was stopped. Nine months after cessation, treatment with fluorouracil + irinotecan + levofolinate calcium + ramucirumab was initiated. After four cycles of treatment, her serum triglyceride levels increased again to grade 3, and then, fenofibrate was administered, resulting in a significant decrease to grade 1-2. Serum triglyceride levels significantly reduced after cessation of the prior fluorouracil-containing regimen, although its elevation was observed again following the latter treatment. Therefore, fluorouracil-induced hypertriglyceridemia was strongly speculated in this case. We have speculated that the most probable cause of tegafur and capecitabine-induced hypertriglyceridemia is fluorouracil or its metabolic enzymes since their end product is fluorouracil in the previous report. Results from this patient suggest that our supposition was correct. Fibrates administration, cessation of the treatment, and monitoring of serum triglyceride level was effective in this case as well as previous reports. Fluorouracil-induced hypertriglyceridemia is associated with the one caused by tegafur and capecitabine and presents the possibility of severe complications. Elucidation of its exact mechanism and epidemiological features is needed for better understanding.",
"affiliations": "Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.;Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.;Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.;Cancer Center, Hokkaido University Hospital, Sapporo, Japan.;Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.",
"authors": "Saito|Yoshitaka|Y|;Takekuma|Yoh|Y|;Yuki|Satoshi|S|;Komatsu|Yoshito|Y|;Sugawara|Mitsuru|M|",
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"doi": "10.1159/000512820",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. 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.com\n\n10.1159/000512820\ncro-0014-0207\nCase Report\nHypertriglyceridemia Induced by Fluorouracil: A Novel Case Report\nSaito Yoshitaka a\nTakekuma Yoh a\nYuki Satoshi b\nKomatsu Yoshito c\nSugawara Mitsuru ad*\naDepartment of Pharmacy, Hokkaido University Hospital, Sapporo, Japan\nbDepartment of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan\ncCancer Center, Hokkaido University Hospital, Sapporo, Japan\ndLaboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan\n*Mitsuru Sugawara, Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo 060-8648 (Japan), msuga@med.hokudai.ac.jp\nJan-Apr 2021\n1 3 2021\n1 3 2021\n14 1 207211\n26 10 2020\n27 10 2020\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nThis article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nWe had previously reported on S-1-induced hypertriglyceridemia. Here, we report fluorouracil-induced hypertriglyceridemia in a patient with capecitabine-induced hypertriglyceridemia and the corresponding therapeutic process. A woman in her forties who had experienced grade 3 hypertriglyceridemia due to oxaliplatin + capecitabine was administered fluorouracil ± oxaliplatin + levofolinate calcium + panitumumab; however, grade 4 hypertriglyceridemia occurred after the thirteenth administration. Bezafibrate normalized the elevation. Chemotherapy cessation resulted in its decrease to normal, and bezafibrate was stopped. Nine months after cessation, treatment with fluorouracil + irinotecan + levofolinate calcium + ramucirumab was initiated. After four cycles of treatment, her serum triglyceride levels increased again to grade 3, and then, fenofibrate was administered, resulting in a significant decrease to grade 1–2. Serum triglyceride levels significantly reduced after cessation of the prior fluorouracil-containing regimen, although its elevation was observed again following the latter treatment. Therefore, fluorouracil-induced hypertriglyceridemia was strongly speculated in this case. We have speculated that the most probable cause of tegafur and capecitabine-induced hypertriglyceridemia is fluorouracil or its metabolic enzymes since their end product is fluorouracil in the previous report. Results from this patient suggest that our supposition was correct. Fibrates administration, cessation of the treatment, and monitoring of serum triglyceride level was effective in this case as well as previous reports. Fluorouracil-induced hypertriglyceridemia is associated with the one caused by tegafur and capecitabine and presents the possibility of severe complications. Elucidation of its exact mechanism and epidemiological features is needed for better understanding.\n\nKeywords\n\nHypertriglyceridemia\nFluorouracil\nTriglyceride\nFluoropyrimidine\nCapecitabine\n==== Body\nIntroduction\n\nWe had previously reported on S-1-induced hypertriglyceridemia [1]. Here, we report fluorouracil-induced hypertriglyceridemia in a colorectal cancer (CRC) patient with capecitabine-induced hypertriglyceridemia, and the measures taken to treat it.\n\nCase Presentation\n\nA woman in her forties without hyperlipidemia had been administered CapeOX (oxaliplatin 130 mg/m2 on day 1 along with capecitabine 2,000 mg/m2/day on days 1–14, every 3 weeks) for stage IV rectal cancer, which resulted in grade 3 hypertriglyceridemia (serum triglyceride level, 518 mg/dL) after the fifth administration (Fig. 1). Consequently, the treatment was discontinued, and her triglyceride level decreased without further treatment to grade 1 (around 200 mg/dL). About 6 months later, treatment with mFOLFOX6 (fluorouracil 400 mg/m2 on day 1 and 2,400 mg/m2 for 46 h from day 1, oxaliplatin 85 mg/m2 on day 1, and levofolinate calcium 200 mg/m2 on day 1, every 2 weeks) and panitumumab (6 mg/kg, every 2 weeks) was initiated. Oxaliplatin was discontinued after the third administration due to hypersensitivity, whereas fluorouracil + levofolinate calcium (sLV+5FU2) + panitumumab were continued. Grade 3 hypertriglyceridemia (serum triglyceride level, 533 mg/dL) manifested after the seventh administration, which further developed to grade 4 hypertriglyceridemia (1,254 mg/dL) after the thirteenth administration. Sustained-release bezafibrate 200 mg twice a day was administered from the fourteenth administration, attenuating the elevation to normal level. Chemotherapy was discontinued after the twenty-sixth cycle, and we followed a wait-and-see approach without any chemotherapy. This resulted in a decrease in serum triglyceride levels to normal, and bezafibrate administration was stopped. Intrapelvic and lymph node recurrence was observed 9 months after cessation, and treatment with FOLFIRI (fluorouracil 400 mg/m2 on day 1 and 2,400 mg/m2 for 46 h from day 1, irinotecan 150 mg/m2 on day 1, and levofolinate calcium 200 mg/m2 on day 1, every 2 weeks) + ramucirumab (8 mg/kg, every 2 weeks) was initiated. After four cycles of treatment, her serum triglyceride levels increased again to grade 3 (676 mg/dL), and then, fenofibrate 160 mg once a day was administered, resulting in a significant decrease to grade 1–2. The patient experienced grade 2 nausea, anorexia, and fatigue during fluorouracil-containing regimens, and grade 2–3 skin toxicity during the former regimen. This patient had normal liver and renal function during the treatment, and supportive care was similar in both fluorouracil-containing regimens; palonosetron 0.75 mg on day 1, aprepitant (125 mg on day 1 and 80 mg on days 2 and 3), dexamethasone 9.9 mg infusion on day 1, 8 mg orally on days 2 and 3, and domperidone 10 mg three times a day from day 1 to nausea disappearance. The regular medication was mirabegron 25 mg twice a day, urapidil 15 mg twice a day, sustained-release tramadol 200–300 mg once a day, and vonoprazan 10 mg once a day during both fluorouracil-containing treatments. However, there were differences in the regular medication between the two regimens. Minocycline 100 mg once a day was administered for the entire duration of the former regimen, while in the latter regimen, edoxaban 30 mg, started 7 months prior to the initiation of chemotherapy, was administered once a day, and azilsartan 20 mg was administered once a day from the second cycle due to ramucirumab-induced hypertension. In summary, differences between the treatments were: (1) chemotherapy regimen and (2) regular administration of minocycline, edoxaban, and azilsartan.\n\nDiscussion\n\nChemotherapy is the first-line treatment for metastatic CRC, and pyrimidine fluoride agents belong to the most effective chemotherapeutic drugs in metastatic CRC treatment [2, 3]. We encountered a patient who had developed severe capecitabine-induced hypertriglyceridemia with both sLV+5FU2 + panitumumab and FOLFIRI + ramucirumab therapies. There are no reports regarding hypertriglyceridemia caused by oxaliplatin, irinotecan, levofolinate calcium, panitumumab, antiemetics, minocycline, and azilsartan. Edoxaban has been reported to induce hypertriglyceridemia (1.0%) [4]; however, as it was administered 7 months before FOLFIRI + ramucirumab treatment, the possibility for that is low. Ramucirumab has also been suggested to cause this adverse reaction, as shown in the RAISE study (0.9%) [5]; however, as it was co-administered with FOLFIRI, its involvement is unclear. Furthermore, as the patient experienced grade 2 nausea and anorexia in both treatments, it is speculated that her dietary triglyceride intake was poor. Thus, fluorouracil-induced hypertriglyceridemia was strongly indicated in this case and was evaluated using the Naranjo adverse drug reaction probability scale [6]. A score of 7, which is classified as “probable,” was obtained (online suppl. Table 1, available at www.karger.com/doi/10.1159/000512820).\n\nIt is important to manage the risk of chemotherapy-induced hypertriglyceridemia since it may lead to vascular disease and acute pancreatitis [1]. We have reported S-1-induced, while others have reported capecitabine-induced hypertriglyceridemia [7, 8, 9]. In addition, there has been a report about a patient who had developed capecitabine-induced hypertriglyceridemia and also experienced tegafur/uracil-induced hypertriglyceridemia [10]. Even though the detailed mechanisms behind this are still unknown, we have proposed the hypothesis that tegafur, capecitabine, fluorouracil itself, or their metabolizing enzymes might have affected lipid metabolism [1]. Specifically, we have speculated that the most probable cause is fluorouracil or its metabolic enzymes since the end product of both tegafur and capecitabine is fluorouracil [1]. Results from this patient suggest that our supposition was correct. Therefore, it is necessary to elucidate the mechanism of fluorouracil-induced hypertriglyceridemia. Javot et al. [9] guessed that thymidine phosphorylase could play a role in inducing hypertriglyceridemia. It has been reported that thymidine phosphorylase and thymidine kinase compete for thymidine, resulting in catalysis of synthetic and catabolic reactions involving proliferation and angiogenesis [11]. It is also known that modification of the expression and activity of thymidine kinase as well as a strong increase in secretory phospholipase-A2 occur in resistant colon cancer cells [12]. These may explain a relationship between thymidine metabolic pathways and phospholipid metabolism, which might be a partial cause of fluorouracil-induced hypertriglyceridemia [1]. In addition, genetic factors influencing metabolic enzymes such as dihydropyrimidine dehydrogenase, thymidine phosphorylase, and pyrimidine nucleotide phospholylase might have contributed to the occurrence of this symptom.\n\nMoreover, Michie et al. [7] have reported that capecitabine-induced hypertriglyceridemia occurs in 3.7% of patients receiving capecitabine-containing regimens, although the exact epidemiology is unknown. In addition to the mechanism, it is also important to understand the epidemiological features of this adverse effect in order to implement early detection and appropriate preventative treatment.\n\nFibrates significantly reduced the serum triglyceride level, which, in this case, was normalized after cessation of the treatment. These results are similar to those of previous reports on other fluoropyrimidines [1, 7, 8, 9, 10] and support the recommendation regarding its management [1, 7, 8]. Results obtained in this and previous reports also suggest that observation at baseline and periodic assessment of lipid profiles are necessary in patients administering fluoropyrimidines [1, 7, 8, 9, 10]. Notably, we strongly recommend monitoring patients with cardiovascular disease or at risk, such as those with hypertension, coronary heart disease, dyslipidemia, obesity, and diabetes [1, 9]. Interestingly, the serum triglyceride level did not return to normal after 6 months from the last CapeOX administration in this case, suggesting that monitoring is necessary after the cessation of the suspected drug for a certain period. As hypertriglyceridemia is non-symptomatic in most cases, we should be aware of its possible occurrence.\n\nConclusion\n\nHypertriglyceridemia caused by fluorouracil is associated with the one caused by tegafur and capecitabine and presents the possibility of severe complications. However, its exact mechanism and epidemiological features such as time and frequency of appearance and risk factor(s) are still unclear. Thus, further studies are needed for better understanding.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflict of Interest Statement\n\nY.S., Y.T., S.Y., and M.S. have no conflicts of interest. Y.K. reports honoraria from Pfizer, Novartis, and Bayer; research funding from Eli Lilly, MSD, Ono Pharmaceutical, Novartis, Bayer, Chugai Pharma, Yakult, and Taiho; and provided speaker services for Eli Lilly, Chugai Pharma, Merck Serono, Novartis, Pfizer, Bayer, and Taiho.\n\nFunding Sources\n\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAuthor Contributions\n\nY.S. contributed the design of the report and collected the data, and drafted the manuscript. Y.T., S.Y., Y.K., and M.S. revised the manuscript. All authors have read and approved the final version of the manuscript.\n\nSupplementary Material\n\nSupplementary data\n\nClick here for additional data file.\n\nFig. 1 Variations in the serum triglyceride level of the patient. (1) Baseline before CapeOX administration. (2) After fourth CapeOX administration. (3) After fifth CapeOX administration. (4) Baseline before mFOLFOX6 + panitumumab administration. (5) After fourth sLV+5FU2 + panitumumab administration. (6) After seventh sLV+5FU2 + panitumumab administration. (7) After thirteenth sLV+5FU2 + panitumumab administration. (8) After fourteenth sLV+5FU2 + panitumumab administration. (9) Two months after cessation of sLV+5FU2 + panitumumab administration. (10) Baseline before FOLFIRI + ramucirumab administration. (11) After fourth FOLFIRI + ramucirumab administration. (12) After eighth FOLFIRI + ramucirumab administration. (13) After twelfth FOLFIRI + ramucirumab administration. CapeOX: oxaliplatin + capecitabine; mFOLFOX6: fluorouracil + levofolinate calcium + oxaliplatin; sLV+5FU2: fluorouracil + levofolinate calcium; FOLFIRI: fluorouracil + levofolinate calcium + irinotecan.\n==== Refs\nReferences\n\n1 Saito Y Takekuma Y Komatsu Y Sugawara M Hypertriglyceridemia induced by S-1: a novel case report and review of the literature J Oncol Pharm Pract 2020 Sep 16 1078155220956691 Online ahead of print 32936722\n2 Chiorean EG Nandakumar G Fadelu T Temin S Alarcon-Rozas AE Bejarano S Treatment of patients with late-stage colorectal cancer: ASCO resource-stratified guideline JCO Global Oncology 2020 Mar 6 (6) 414 38 32150483\n3 Tabernero J Yoshino T Cohn AL Obermannova R Bodoky G Garcia-Carbonero R Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study Lancet Oncol 2015 May 16 (5) 499 508 25877855\n4 LIXIANA® TABLETS [interview form on the internet] DAIICHI SANKYO COMPANY 2020 https://www.medicallibrary-dsc.info/di/lixiana_tablets_30mg/pdf/if_lix_2003_12.pdf. Accessed July 7, 2020\n5 CYRAMZA® injection [interview form on the internet] Eli Lilly Japan 2019 https://www.lillymedical.jp/assets/ja-jp/documents/RAM_IF.pdf. Accessed July 7, 2020\n6 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 Aug 30 (2) 239 45 7249508\n7 Michie CO Sakala M Rivans I Strachan MW Clive S The frequency and severity of capecitabine-induced hypertriglyceridaemia in routine clinical practice: a prospective study Br J Cancer 2010 Aug 24 103 (5) 617 21 20664584\n8 Uche A Vankina R Gong J Cho M Yeh JJ Kim P Capecitabine-induced hypertriglyceridemia: a rare but clinically relevant treatment-related adverse event J. Gastrointest. Oncol 2018 Dec 9 (6) 1213 9 30603144\n9 Javot L Spaëth D Scala-Bertola J Gambier N Petitpain N Gillet P Severe hypertriglyceridaemia during treatment with capecitabine Br J Cancer 2011 Mar 29 104 (7) 1238 9 21386842\n10 Yildiz B Kavgaci H Fidan E Gungor E Ersoz HO Ozdemir F Oral fluoropyrimidine-induced severe hyperlipidemia Asian Biomed 2010 4 (4) 627 30\n11 Brockenbrough JS Morihara JK Hawes SE Stern JE Rasey JS Wiens LW Thymidine kinase 1 and thymidine phosphorylase expression in non-small-cell lung carcinoma in relation to angiogenesis and proliferation J Histochem Cytochem 2009 Nov 57 (11) 1087 97 19654105\n12 Temmink OH Bijnsdorp IV Prins HJ Losekoot N Adema AD Smid K Trifluorothymidine resistance is associated with decreased thymidine kinase and equilibrative nucleoside transporter expression or increased secretory phospholipase A2 Mol Cancer Ther 2010 Apr 9 (4) 1047 57 20371715\n\n",
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"keywords": "Capecitabine; Fluoropyrimidine; Fluorouracil; Hypertriglyceridemia; Triglyceride",
"medline_ta": "Case Rep Oncol",
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"pages": "207-211",
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"title": "Hypertriglyceridemia Induced by Fluorouracil: A Novel Case Report.",
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"abstract": "Immunoglobulin light-chain amyloidosis (AL) affects multiple organs, most prominently the kidney and the heart. Renal and cardiac impairment are both associated with poor prognosis and most patients die as a consequence of renal or cardiac failure. Monoclonal antibodies such as daratumumab (human IgG1 anti-CD38) and elotuzumab (anti-SLAMF7) have shown promising efficacy for the treatment of relapsed and refractory multiple myeloma. In this case report we show 2 patients with severe AL, one with severe heart failure and one with heart and renal failure, undergoing treatment with daratumumab. Both patients showed a rapid decrease in FLC in response to daratumumab infusions, with few associated adverse events. Using therapeutic CD38 antibodies as a front-line treatment for AL could induce rapid responses while maintaining a tolerable safety profile in these ultra-fragile patients.",
"affiliations": "Department of Medicine, Karolinska Institutet Department of Medicine Huddinge, Huddinge, Sweden.;Department of Medicine, Karolinska Institutet Department of Medicine Huddinge, Huddinge, Sweden.;Department of Medicine, Karolinska Institutet Department of Medicine Huddinge, Huddinge, Sweden.;Department of Medicine, Karolinska Institutet Department of Medicine Huddinge, Huddinge, Sweden.",
"authors": "Gran|Charlotte|C|http://orcid.org/0000-0002-6069-6615;Gahrton|Gösta|G|;Alici|Evren|E|;Nahi|Hareth|H|",
"chemical_list": "D000911:Antibodies, Monoclonal; D015415:Biomarkers; D007074:Immunoglobulin G; D007147:Immunoglobulin Light Chains; C556306:daratumumab",
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"issue": "100(4)",
"journal": "European journal of haematology",
"keywords": "multiple myeloma",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000686:Amyloidosis; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D003131:Combined Modality Therapy; D005260:Female; D006333:Heart Failure; D006334:Heart Function Tests; D006801:Humans; D007074:Immunoglobulin G; D007147:Immunoglobulin Light Chains; D007677:Kidney Function Tests; D008875:Middle Aged; D051437:Renal Insufficiency; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
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"publication_types": "D002363:Case Reports",
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"title": "Case Report: Treatment of light-chain amyloidosis with daratumumab monotherapy in two patients.",
"title_normalized": "case report treatment of light chain amyloidosis with daratumumab monotherapy in two patients"
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"abstract": "Post-hypoxic myoclonus (PHM) is characterized by generalized myoclonus after hypoxic brain injury. Myoclonus is often functionally impairing and refractory to medical therapies. Deep brain stimulation (DBS) has been used to treat myoclonus-dystonia, but few cases of PHM have been described.\n\n\n\nA 33-year-old woman developed severe, refractory generalized myoclonus after cardiopulmonary arrest from drowning. We performed MRI-guided asleep bilateral pallidal DBS placement, resulting in improvement in action myoclonus at one year.\n\n\n\nOur case contributes to growing evidence for DBS for PHM. Interventional MRI guided DBS technique can be used for safe and accurate lead placement.\n\n\n\nWe report a case of a patient who developed post-hypoxic myoclonus after cardiopulmonary arrest from drowning, who later underwent deep brain stimulation to treat refractory myoclonus. This is the first case to describe asleep, interventional MRI-guided technique for implanting DBS leads in post-hypoxic myoclonus.",
"affiliations": "Department of Neurology, Movement Disorders and Neuromodulation Center, Weill Institute of Neurosciences, University of California, San Francisco, San Francisco, CA, US.;Department of Neurology, Movement Disorders and Neuromodulation Center, Weill Institute of Neurosciences, University of California, San Francisco, San Francisco, CA, US.;Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, US.",
"authors": "Gao|Fay|F|;Ostrem|Jill L|JL|;Wang|Doris D|DD|",
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"doi": "10.5334/tohm.544",
"fulltext": "\n==== Front\nTremor Other Hyperkinet Mov (N Y)\nTremor Other Hyperkinet Mov (N Y)\n2160-8288\nTremor and Other Hyperkinetic Movements\n2160-8288 Ubiquity Press \n\n10.5334/tohm.544\nCase Report\nTreatment of Post-Hypoxic Myoclonus using Pallidal Deep Brain Stimulation Placed Using Interventional MRI Methods\nGao Fay MDfaygao1@gmail.com1 Ostrem Jill L. MD1 Wang Doris D. MD, PhD2 1 Department of Neurology, Movement Disorders and Neuromodulation Center, Weill Institute of Neurosciences, University of California, San Francisco, San Francisco, CA, US\n2 Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, US\nCorresponding author: Fay Gao, MD (faygao1@gmail.com)\n13 10 2020 \n2020 \n10 4218 6 2020 15 8 2020 Copyright: © 2020 The Author(s)2020This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.Background:\nPost-hypoxic myoclonus (PHM) is characterized by generalized myoclonus after hypoxic brain injury. Myoclonus is often functionally impairing and refractory to medical therapies. Deep brain stimulation (DBS) has been used to treat myoclonus-dystonia, but few cases of PHM have been described.\n\nCase report:\nA 33-year-old woman developed severe, refractory generalized myoclonus after cardiopulmonary arrest from drowning. We performed MRI-guided asleep bilateral pallidal DBS placement, resulting in improvement in action myoclonus at one year.\n\nDiscussion:\nOur case contributes to growing evidence for DBS for PHM. Interventional MRI guided DBS technique can be used for safe and accurate lead placement.\n\nHighlights:\nWe report a case of a patient who developed post-hypoxic myoclonus after cardiopulmonary arrest from drowning, who later underwent deep brain stimulation to treat refractory myoclonus. This is the first case to describe asleep, interventional MRI-guided technique for implanting DBS leads in post-hypoxic myoclonus.\n\nmyoclonusGPiiMRIDBSLance-Adams syndromeDoris Wang has consulting agreements with Medtronic Inc. and Boston Scientific Inc. Jill Ostrem has grant support from Boston Scientific Inc. and consulting agreements with Medtronic Inc. and Abbott Inc.\n==== Body\nIntroduction\nPost-hypoxic myoclonus (PHM) is characterized by generalized myoclonus with rest, action, and stimulus-provoked components, occurring after global hypoxic brain injury, in most cases due to cardiopulmonary arrest [1]. For patients who survive the initial hypoxic event, some develop chronic PHM, also known as Lance-Adams syndrome (LAS), days or weeks after regaining consciousness. In conjunction with other neurological symptoms from widespread cortical injury, including dysarthria, ataxia, postural lapses, and seizures, PHM can lead to debilitating functional impairments, with pharmacologic options limited to benzodiazepines and anti-epileptic medications [123]. However, up to 50% of patients may not respond to pharmacologic therapy [3]. While dysarthria and ataxia may improve with time, action myoclonus often persists for years despite optimal medical therapy [4].\n\nDeep brain stimulation (DBS) is a well-established treatment for many movement disorders including essential tremor, Parkinson’s disease, and dystonia. In recent years, investigations into the utility of DBS to treat myoclonus-dystonia, a genetic disorder due to DYT11 mutation, have yielded promising results [56]. We identified four other reports that described use of DBS to improve chronic PHM, with three targeting the globus pallidus internus and one targeting the ventral intermediate nucleus of the thalamus [78910], all using awake stereotactic technique with microelectrode recording.\n\nWe present the first reported case of a patient with PHM who underwent interventional MRI-guided (iMRI) implantation of bilateral pallidal DBS. Our patient had significant improvement in her action myoclonus after DBS, similar to the two other reported cases of patients with PHM treated with bilateral pallidal DBS [78]. We illustrate that asleep MR-guided DBS placement is safe and accurate and eliminates concerns associated with awake surgery. This report provides further evidence to the small but growing cases of DBS treating rare hyperkinetic movement disorders.\n\nCase Description\nA 33-year-old woman was found in cardiopulmonary arrest after being submerged in a pool for 15 minutes. She was resuscitated and treated with hypothermia protocol. Complications included persistent respiratory failure requiring tracheostomy and gastrostomy tubes, as well as electrographic and clinical seizures characterized by generalized tonic-clonic movements and, later, behavioral arrests. She was treated with an antiepileptic drug (AED) regimen that included levetiracetam, clonazepam, phenobarbital, phenytoin, and lacosamide. After a month in a comatose state, she gradually recovered consciousness and regained language and sensorimotor functions. She was extubated and tracheostomy reversed. A brain MRI 1 month after initial injury showed subtle cortical and subcortical FLAIR signal hyperintensities in the corona radiata (Figure 1A) and the head of the caudate nuclei bilaterally (Figure 1B).\n\nFigure 1 Preoperative MRI. A. Axial FLAIR-weighted preoperative MRI image showing diffuse cortical FLAIR signal hyperintensities as well as areas of FLAIR signal changes in the corona radiata (arrows). B. Axial FLAIR-weighted MRI image showing subtle FLAIR hyperintensities in the head of the bilateral caudate nuclei (arrows).\n\nOver this time, she developed involuntary, large amplitude jerking of her limbs and trunk, without electrographic correlates, which were diagnosed as myoclonus. Laboratory workup revealed no clear metabolic disturbances, and EEG showed no electrographic correlates. Myoclonus remained during all waking hours that interfered with all activities. She could not sit or stand, and was dependent for feeding, cleaning, grooming, and toileting. Clonazepam and levetiracetam mitigated symptoms, but even with maximum titration, her myoclonus rendered her bedbound. She was discharged to an acute rehabilitation center but was frequently readmitted due to breakthrough seizures, urinary tract infections, and other complications from immobility. After five months of persistent myoclonus despite AED titration, she was referred to our center for consideration of DBS.\n\nOn examination, she was alert, oriented to time and location, spoke slowly and sparsely, and followed simple commands, but had impaired executive function, abstraction, and insight. Motor examination revealed mild symmetric weakness in the upper extremity extensor muscles and lower extremity flexor muscles, diffuse hyperreflexia, and normal tone. Coordination examination revealed dysmetria in proportion to weakness. She had minimal spontaneous jerks in the resting, supine position. On action, she had multifocal proximal and distal muscle jerks in her face, neck, trunk, and limbs, consistent with negative and positive myoclonus. Generalized jerks were also elicited by visual threat, clapping, and tactile stimulation in all extremities. She could not hold her limbs outstretched, use utensils, hold a cup, or sit upright (Video 1). There were no dystonic postures or movements. Given significant functional impairment and complications from myoclonus, our multidisciplinary movement disorder team offered DBS implantation as a palliative treatment for medication-refractory myoclonus. We chose the globus pallidus internus (GPi) as the target based on literature review [78911].\n\nVideo 1 Pre-DBS. Demonstration of the patient’s resting and action myoclonus which impair her ability to perform functional tasks.\n\nSeven months after the hypoxic event, she underwent asleep, iMRI-guided implantation of bilateral DBS electrodes in GPi (Medtronic 3389, Medtronic Inc., St. Paul, MN) (Figure 2). Targeting of the GPi based on iMRI-guided technique was performed as previously described [1213]. This yielded radial errors of 0.3 mm in the anteromedial direction for the left side and 0 mm for the right side at the targeting plane (1 mm superior to the mid-commissural plane). One pass was performed for each side. Total operative time for lead implantation was 216 minutes. Bilateral chest Activa SC pulse generators (Medtronic Inc., St. Paul. MN) were later implanted. Her postoperative course was complicated by severe incisional pain and headache, which was treated aggressively with intravenous and oral medications.\n\nFigure 2 Pallidal DBS lead placement. A. Axial T2-weighted postoperative MRI image showing DBS lead artifacts (white arrows) at the AC-PC plane. B. Coronal T1-weighted posteropative MRI image showing DBS lead artifacts (white arrows) in the region of the posterior pallidum. C and D. Axial (C) and coronal (D) inversion recovery images showing borders of the globus pallidus externa and interna. DBS lead trajectories are indicated by orange lines. Intended left DBS target: 21 mm lateral, 2 mm anterior, 1 mm superior to MC with final DBS tip location extended 3.5 mm beyond the targeting plane to reach the base of the pallidum (above the optic tract). Intended right DBS target: 21.3 mm lateral, 2.3 mm anterior, 1 mm superior to MC with final DBS tip location extended 3.5 mm beyond the targeting plane. Left DBS lead location at targeting plane: 21.2 mm lateral, 1.9 mm anterior, 1 mm superior to MC (radial error of 0.3 mm). Right DBS lead location at targeting plane: 21.3 mm lateral, 2.3 mm anterior, 1 mm superior to MC (radial error of 0). MC=mid-commissural point (half point between anterior commissure to posterior commissure).\n\nInitial programming was performed three days postoperatively. Monopolar review suggested motor benefit from contacts 1 or 2 for each DBS lead. Initial settings were C+,1-, pulse width 60 microseconds, frequency 180 Hz, and amplitude 1.0 V, bilaterally. On higher amplitudes, she reported severe headache which, while not clearly related to stimulation side effect, led us to take a cautious approach to programming. The patient was transferred back to her community hospital and eventually discharged to a rehabilitation center. She returned to our clinic for further programming two months postoperatively. There was no indication of significant benefit, so stimulation was increased bilaterally to 2.0 V, then slowly increased further to 3.2 V over a course of a month. At the nine-month visit, only slight improvement in symptoms was noted. To provide more benefit, a new double monopolar configuration with C+,1-2-, pulse width 60 microseconds, frequency 180 Hz, and amplitude 3.2 V was created bilaterally. After this change, her family reported that her myoclonic movements were notably improved, and later recalled this time as a major positive change in her quality of life. One year after surgery, she could grasp utensils to feed herself and drink water from a cup with some spillage. She could hold a toothbrush and use a comb. She sat upright in a chair without assistance and could stand for a few minutes with significant bracing and support, but could not ambulate (Video 2). AEDs were continued after surgery.\n\nVideo 2 12 Months Post-DBS. The patient’s myoclonic movements are reduced, and ability to perform functional tasks are improved.\n\nObjective assessment using the Unified Myoclonus Rating Scale (UMRS) [14] showed 35% improvement in action myoclonus (from 62 to 40), and 16% improvement in the functional testing component (from 19 to 16). Resting myoclonus was minimal pre-DBS but abolished post-surgery (2 to 0). To directly assess the effect of stimulation on her myoclonus, we compared her clinical examination on and off DBS in clinic. However, no clear change was observed up to one hour after DBS was turned off. This may have been due to an inadequate “washout” period following deactivation, as well as confounding effect from AEDs taken a few hours before her visit. Plans for future visits include cautiously raising stimulation and exploring other parameters.\n\nDiscussion\nOur case is the third report of a patient with PHM treated with bilateral GPi DBS resulting in improvement of resting and action myoclonus. One report demonstrated an 80% improvement in action myoclonus [7] and another showed a 38% improvement [8] (Table 1). All three reports demonstrated complete resolution of resting myoclonus. Additionally, there is another report of a patient who received unilateral GPi DBS following a putamen hemorrhage and cardiac arrest due to pulmonary embolism, whose unilateral action myoclonus improved by 71% and resting myoclonus improved by 75% after DBS [9]. In a subset of these cases, including ours, there are ataxic movements that traditional DBS targets do not treat and may unmask or worsen [7], limiting the degree of functional score improvement in the UMRS which does not take into account changes to ataxia. In all cases, pre- and post-operative UMRS was used to assess DBS efficacy. It is possible improvement may be confounded by natural recovery. This limitation must be better characterized by future studies using more rigorous assessment of DBS stimulation effect, comparing UMRS in the DBS on and off states with longer (1–2 day) washout periods. Despite these limitations, we felt that the time course and degree of motor improvement occurring after DBS surgery suggested that DBS stimulation improved our patient’s myoclonus. Although she remained functionally limited even with stimulation, she and her family reported that stimulation improved her quality of life. Altogether, we feel that consideration of DBS for treatment of medically-refractory PHM is reasonable in the right surgical candidate.\n\nTable 1 Summary of published cases of post-hypoxic myoclonus treated with bilateral pallidal deep brain stimulation.\n\nCase\tAge\tSex\tMechanism of hypoxic injury\tTime from injury to DBS\tTarget site and method\tStimulation parameters\tDBS Efficacy\t\n\t\nPreop UMRS\tPostop UMRS\n(Length of follow up)\t% improve-ment\t\n\t\nCurrent case\t33\tF\tAsphyxia due to drowning leading to CPA\t5 months\tBilateral GPi\nAsleep, iMRI guided\tL and R: Double monopolar C(+),1(–),2(–)\nAmp: 3.2 V\nFreq: 180 Hz\nPW: 60 µs\tAction: 61\nResting: 2\tAction: 40\nResting: 0\n(1 yr)\tAction: 35%\nResting: 100%\t\nRamdhani et al\t23\tM\tAsthma attack leading to CPA\t3 years\tBilateral GPi\nAwake, stereotactic\tR: Monopolar C(+),3(–)\nAmp: 2.8 V\nFreq: 130 Hz\nPW: 90 µs\nL: Triple monopolar C(+),1(–),2(–),3(–)\nAmp: 2.5 V\nFreq: 130 Hz\nPW: 60 µs\tAction: 52\nResting: 75\tAction: 32\nResting: 0\n(6 mo)\tAction: 38%\nResting: 100%\t\nAsahi et al\t54\tM\tRespiratory distress leading to CPA\t1 year\tBilateral GPi\nAwake, stereotactic\tL and R: Bipolar 1(–),2(+)\nAmp: 2.0 V\nFreq: 125 Hz\nPW: 60 µs\tAction: 25\nResting: 8\tAction: 5\nResting: 0\n(6 mo)\tAction: 80%\nResting: 100%\t\nUMRS: Unified Myoclonus Rating Scale; CPA: cardiopulmonary arrest; Amp: amplitude, Freq: frequency; PW: pulse width; L: left; R: right.\n\nPreviously published case reports of DBS for PHM used the awake stereotactic technique involving microelectrode recording and intraoperative testing for placement [78910]. Here, we report the first use of asleep iMR-guided method for lead placement in PHM. This technique offers several advantages compared to awake surgery. First, patients with PHM may have cognitive and functional impairments that limit participation during awake procedures. Second, global cerebral hypoxia may cause tissue injury that renders microelectrode mapping challenging and inaccurate. Finally, because of cortical tissue loss or subcortical structural damage from the initial injury, gliosis may deflect lead trajectories; therefore, the ability to directly visualize lead pathway with serial MRIs can lead to highly accurate placement. The iMRI technique for DBS lead implantation can expand the application of DBS to treating patients who otherwise cannot tolerate awake surgery.\n\nWe conclude that pallidal stimulation is a safe and well-tolerated treatment for PHM and that asleep iMRI guidance is an effective, accurate method for lead placement. Additional clinical trials with more structured protocol for patient selection, systematic programming guidelines, and objective, blinded, assessment of improvement are needed. As DBS improves with more technological and surgical advances, we anticipate that its application to treatment of rare movement disorders will continue to grow.\n\nAcknowledgements\nThe authors would like to acknowledge Oana Spataru, MD, Maxwell Merkow, MD, Philip Starr, MD PhD, and Steven Schadendorf, MD, for their participation in the care of the patient, and Darel Ogbonna for his assistance with video editing.\n\nEthics and Consent\nSubject has given her written informed consent to publish her case (including publication of images and videos).\n\nFunding Information\nDoris Wang has consulting agreements with Medtronic Inc. and Boston Scientific Inc.\n\nJill Ostrem has grant support from Boston Scientific Inc. and consulting agreements with Medtronic Inc. and Abbott Inc.\n\nCompeting Interests\nThe authors have no competing interests to declare.\n\nAuthor Contributions\nFG was responsible for clinical assessment and writing the manuscript. JLO was responsible for supervising clinical assessment and reviewing the manuscript. DDW was responsible for patient surgery and writing the manuscript.\n==== Refs\n1 Hallett \nM . Physiology of human posthypoxic myoclonus\n. Mov Disord . 2000 ; 15 (Suppl 1 ): 8 –13\n. DOI: 10.1002/mds.870150703 10755266 \n2 Lance \nJW , Adams \nRD . The syndrome of intention or action myoclonus as a sequel to hypoxic encephalopathy\n. Brain . 1963 ; 86 : 111 –36\n. DOI: 10.1093/brain/86.1.111 13928398 \n3 Frucht \nS , Fahn \nS . The clinical spectrum of posthypoxic myoclonus\n. Mov Disord . 2000 ; 15 (Suppl 1 ): 2 –7\n. DOI: 10.1002/mds.870150702 10755265 \n4 Gupta \nHV , Caviness \nJN . Post-hypoxic Myoclonus: Current Concepts, Neurophysiology, and Treatment\n. Tremor Other Hyperkinet Mov (N Y) . 2016 ; 6 : 409 DOI: 10.5334/tohm.323 27708982 \n5 Starr \nPA . Deep brain stimulation for other tremors, myoclonus, and chorea\n. Handb Clin Neurol . 2013 ; 116 : 209 –15\n. DOI: 10.1016/B978-0-444-53497-2.00016-4 24112895 \n6 Smith \nKM , Spindler \nMA . Uncommon applications of deep brain stimulation in hyperkinetic movement disorders\n. Tremor Other Hyperkinet Mov (N Y) . 2015 ; 5 : 278 DOI: 10.5334/tohm.265 25713746 \n7 Asahi \nT , Kashiwazaki \nD , Dougu \nN , Oyama \nG , Takashima \nS , Tanaka \nK , et al. Alleviation of myoclonus after bilateral pallidal deep brain stimulation for Lance-Adams syndrome\n. J Neurol . 2015 ; 262 (6 ): 1581 –3\n. DOI: 10.1007/s00415-015-7748-x 25929661 \n8 Ramdhani \nRA , Frucht \nSJ , Kopell \nBH . Improvement of Post-hypoxic Myoclonus with Bilateral Pallidal Deep Brain Stimulation: A Case Report and Review of the Literature\n. Tremor Other Hyperkinet Mov (N Y) . 2017 ; 7 : 461 DOI: 10.5334/tohm.342 28616357 \n9 Yamada \nK , Sakurama \nT , Soyama \nN , Kuratsu \nJ . Gpi pallidal stimulation for Lance-Adams syndrome\n. Neurology . 2011 ; 76 (14 ): 1270 –2\n. DOI: 10.1212/WNL.0b013e31821482f4 21464432 \n10 Kobayashi \nK , Katayama \nY , Otaka \nT , Obuchi \nT , Kano \nT , Nagaoka \nT , et al. Thalamic deep brain stimulation for the treatment of action myoclonus caused by perinatal anoxia\n. Stereotact Funct Neurosurg . 2010 ; 88 (4 ): 259 –63\n. DOI: 10.1159/000315464 20530980 \n11 Magarinos-Ascone \nCM , Regidor \nI , Martinez-Castrillo \nJC , Gomez-Galan \nM , Figueiras-Mendez \nR . Pallidal stimulation relieves myoclonus-dystonia syndrome\n. J Neurol Neurosurg Psychiatry . 2005 ; 76 (7 ): 989 –91\n. DOI: 10.1136/jnnp.2004.039248 15965208 \n12 Starr \nPA , Markun \nLC , Larson \nPS , Volz \nMM , Martin \nAJ , Ostrem \nJL . Interventional MRI-guided deep brain stimulation in pediatric dystonia: first experience with the ClearPoint system\n. J Neurosurg Pediatr . 2014 ; 14 (4 ): 400 –8\n. DOI: 10.3171/2014.6.PEDS13605 25084088 \n13 Starr \nPA . Placement of deep brain stimulators into the subthalamic nucleus or Globus pallidus internus: technical approach\n. Stereotact Funct Neurosurg . 2002 ; 79 (3–4 ): 118 –45\n. DOI: 10.1159/000070828 12890973 \n14 Frucht \nSJ , Leurgans \nSE , Hallett \nM , Fahn \nS . The Unified Myoclonus Rating Scale\n. Adv Neurol . 2002 ; 89 : 361 –76\n.11968461\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2160-8288",
"issue": "10()",
"journal": "Tremor and other hyperkinetic movements (New York, N.Y.)",
"keywords": "DBS; GPi; Lance-Adams syndrome; iMRI; myoclonus",
"medline_ta": "Tremor Other Hyperkinet Mov (N Y)",
"mesh_terms": "D000328:Adult; D046690:Deep Brain Stimulation; D004332:Drowning; D005260:Female; D005917:Globus Pallidus; D006323:Heart Arrest; D006801:Humans; D002534:Hypoxia, Brain; D058542:Implantable Neurostimulators; D008279:Magnetic Resonance Imaging; D009207:Myoclonus; D015642:Radiology, Interventional",
"nlm_unique_id": "101569493",
"other_id": null,
"pages": "42",
"pmc": null,
"pmid": "33117600",
"pubdate": "2020-10-13",
"publication_types": "D002363:Case Reports; D059040:Video-Audio Media",
"references": "13928398;11968461;10755265;28616357;10755266;12890973;21464432;25713746;24112895;25929661;27708982;20530980;15965208;25084088",
"title": "Treatment of Post-Hypoxic Myoclonus using Pallidal Deep Brain Stimulation Placed Using Interventional MRI Methods.",
"title_normalized": "treatment of post hypoxic myoclonus using pallidal deep brain stimulation placed using interventional mri methods"
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"abstract": "The purpose of this study was to evaluate safety and efficacy of the pipeline embolization device (PED) in different patient age groups with unruptured intracranial aneurysms (UIA). All patients with UIA treated with the PED between 2011 and 2017 were included. Based on their age, patients were trichotomized to: young (≤45 years), middle-aged (46 to <65 years) and older (≥65 years) groups. Patient's vascular risk factors, presenting symptoms and mRS on admission were collected. Follow-up imaging was evaluated for presence/absence of aneurysm occlusion. Clinical outcome at discharge, 3-9 months and 12-18 months was also documented when available. A total of 260 patients harboring 307 aneurysms (young = 57, middle-age = 144 and older age group = 64). Most aneurysms were located in the anterior circulation (94.8%). Overall morbidity and mortality was 2.3% each (6/260). At 3-9 months near complete to complete aneurysm occlusion was 82.5% (47/57) in the young age group, 82.6% (100/121) in the middle age, and 70.2% (40/57) in the older age group. At 12-18-month, near complete to complete occlusion was 100% in the young age group (32/32), 91.4% (64/70) in the middle age, and 78.4% (29/37) in the older age group. After adjustment for potential confounders, older age patients less frequently achieved near complete to complete occlusion by 3 years than younger subjects (p = 0.009, HR 1.34 95%, CI 1.08-1.66). Our results indicate feasibility and safety of PED across different age groups. Further study is required to determine age-related factors relating to aneurysm occlusion after PED to improve outcome and patient counseling.",
"affiliations": "Division of Neuroimaging and Intervention, Department of Radiology and New England Center for Stroke Research, University of Massachusetts, Worcester, MA, USA.;Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.;Department of Neurology, University of Massachusetts, Worcester, MA, USA.;Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.;Division of Neuroimaging and Intervention, Department of Radiology and New England Center for Stroke Research, University of Massachusetts, Worcester, MA, USA.;Lahey Clinic and Medical Center, Department of Neurointerventional Radiology, Burlington, MA, USA.;Division of Neuroimaging and Intervention, Department of Radiology and New England Center for Stroke Research, University of Massachusetts, Worcester, MA, USA.;Division of Neuroimaging and Intervention, Department of Radiology and New England Center for Stroke Research, University of Massachusetts, Worcester, MA, USA. Electronic address: ajit.puri@umassmemorial.org.",
"authors": "Kühn|Anna Luisa|AL|;Kan|Peter|P|;Henninger|Nils|N|;Srinivasan|Visish|V|;de Macedo Rodrigues|Katyucia|K|;Wakhloo|Ajay K|AK|;Gounis|Matthew J|MJ|;Puri|Ajit S|AS|",
"chemical_list": null,
"country": "Scotland",
"delete": false,
"doi": "10.1016/j.jocn.2019.04.024",
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"issn_linking": "0967-5868",
"issue": "65()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Age; Flow diverter; Intracranial aneurysm; Occlusion; Pipeline embolization device; Stent; Unruptured",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D000328:Adult; D000367:Age Factors; D000368:Aged; D001807:Blood Vessel Prosthesis; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "23-27",
"pmc": null,
"pmid": "31072739",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article",
"references": "26363511;12538420;28912285;16139655;27489165;22054213;26723288;22998483;25051964;22282890;25395659;27382125;26405085;12775880;21206898;28541503;22547440;26544776;24072620;23418004;26700827;28692909;28565979;23321438;27153163;23624409;28638672;12414200;25635478",
"title": "Impact of age on cerebral aneurysm occlusion after flow diversion.",
"title_normalized": "impact of age on cerebral aneurysm occlusion after flow diversion"
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"abstract": "Mycobacterium abscessus is an environmental organism that has been implicated in pulmonary and extrapulmonary infections. Cases of furunculosis have been described in patients who underwent footbaths in nail salons; however, no cases of severe soft tissue infections or osteomyelitis have been reported following manicures. Here, we present the case of a 50-year-old woman who developed a felon in right index finger one week after having a manicure. She underwent incision and drainage of affected area. Cultures from purulence grew Mycobacterium abscessus. Imaging revealed osteomyelitis of distal phalanx. She was successfully treated with a prolonged course of antibiotics that included imipenem, linezolid, tigecycline, and clarithromycin. We highlight the importance of recognizing this uncommon complication and advocate the use of combined antibiotic regimens for an adequate treatment of this infection.",
"affiliations": "Division of Infectious Diseases, Department of Medicine, University of Miami, Miller School of Medicine , Miami, FL, USA.;Department of Radiology, Clinica Ortega , Huancayo, Peru.",
"authors": "Gonzales Zamora|Jose Armando|JA|https://orcid.org/0000-0002-2768-9712;Villar Astete|Abelardo|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D015378:Imipenem; D017291:Clarithromycin; D000069349:Linezolid",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2019.1637390",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "75(6)",
"journal": "Acta clinica Belgica",
"keywords": "Mycobacterium abscessus; felon; manicure; osteomyelitis",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000038:Abscess; D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D003646:Debridement; D005260:Female; D050278:Finger Phalanges; D006801:Humans; D015378:Imipenem; D000069349:Linezolid; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009165:Mycobacterium Infections, Nontuberculous; D000073358:Mycobacterium abscessus; D010019:Osteomyelitis; D000078304:Tigecycline",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "429-433",
"pmc": null,
"pmid": "31253072",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mycobacterium abscessus felon complicated with osteomyelitis: not an ordinary nail salon visit.",
"title_normalized": "mycobacterium abscessus felon complicated with osteomyelitis not an ordinary nail salon visit"
} | [
{
"companynumb": "US-009507513-1907USA010879",
"fulfillexpeditecriteria": "2",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CILASTATIN SODIUM\\IMIPENEM"
},
"drugadditio... |
{
"abstract": "Leiomyomas can develop in any organ containing smooth muscles. They most commonly occur in the gastrointestinal and the female genital tracts. Leiomyoma of the prostate is a rare, benign tumor. We report 3 cases of rare prostatic leiomyomas. The paucity of literature describing prostatic leiomyoma increases the chance for misdiagnosis. Fewer than 30 cases in the English literature, with none including magnetic resonance imaging, computed tomography (CT), ultrasound, positron emission tomography-CT, and pathological findings together were found. Over the past decade, there has been a shift in the management of prostatic leiomyomas. Prostatectomy was once considered a standard approach for treatment, but now nonsurgical treatment options such as embolization are preferred. Conservative management including surveillance is an option for asymptomatic patients.",
"affiliations": "Department of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address: mkvirarkar@mdanderson.org.;Department of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.;Department of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.;Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.;Department of Diagnostic Radiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.",
"authors": "Virarkar|Mayur|M|;de Castro Faria|Silvana|S|;Patnana|Madhavi|M|;Zhang|Miao|M|;Sagebiel|Tara|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clgc.2018.01.012",
"fulltext": null,
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"issn_linking": "1558-7673",
"issue": "16(4)",
"journal": "Clinical genitourinary cancer",
"keywords": "Embolization; MRI; Smooth muscle cell tumors; Spindle; Surveillance",
"medline_ta": "Clin Genitourin Cancer",
"mesh_terms": "D055011:Ablation Techniques; D000072700:Conservative Treatment; D006801:Humans; D007889:Leiomyoma; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011468:Prostatectomy; D011471:Prostatic Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101260955",
"other_id": null,
"pages": "e771-e776",
"pmc": null,
"pmid": "29483044",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Leiomyoma of the Prostate: Case Report and Review of the Literature.",
"title_normalized": "leiomyoma of the prostate case report and review of the literature"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-040502",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMSULOSIN HYDROCHLORIDE"
... |
{
"abstract": "BACKGROUND\nData specific to late-life bipolar disorder (BD) are limited. Current research is sparse and present guidelines are not adapted to this group of patients.\n\n\nOBJECTIVE\nWe present a literature review on clinical characteristics, comorbidities, and cognitive impairment in patients with late-life BD. This review discusses common comorbidities that affect BD elders and how aging might affect cognition and treatment.\n\n\nMETHODS\nEligible studies were identified in MedLine by the Medical Subject Headings terms \"bipolar disorder\" and \"aged\". We only included original research reports published in English between 2012 and 2015.\n\n\nRESULTS\nFrom 414 articles extracted, 16 studies were included in the review. Cardiovascular and respiratory conditions, type II diabetes, and endocrinological abnormalities were observed as highly prevalent. BD is associated with a high suicide risk. Bipolar elderly had an increased risk of dementia and performed worse on cognitive screening tests compared to age-matched controls across different levels of cognition. Despite high rates of medical comorbidity among bipolar elderly, a systematic under-recognition and undertreatment of cardiovascular disease have been suggested.\n\n\nCONCLUSIONS\nThere was a high burden of physical comorbidities and cognitive impairment in late-life BD. Bipolar elderly might be under-recorded and undertreated in primary medical care, indicating that this group needs an adapted clinical assessment and specific clinical guidelines need to be established.",
"affiliations": "Department of Psychiatry, Sorlandet Hospital, Arendal, Norway.;Research Unit, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain; Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain; CIBERSAM (Centro de Investigación Biomédica En Red de Salud Mental), Madrid, Spain.;Department of Psychiatry, North-Trondelag Hospital Trust, Levanger, Norway; Department of Medicine, Institute of Neuromedicine, Norwegian University of Science and Technology, Trondheim, Norway.",
"authors": "Rise|Ida Vikan|IV|;Haro|Josep Maria|JM|;Gjervan|Bjørn|B|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/NDT.S100843",
"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S100843ndt-12-1203ReviewClinical features, comorbidity, and cognitive impairment in elderly bipolar patients Rise Ida Vikan 1Haro Josep Maria 234Gjervan Bjørn 561 Department of Psychiatry, Sorlandet Hospital, Arendal, Norway2 Research Unit, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Spain3 Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain4 CIBERSAM (Centro de Investigación Biomédica En Red de Salud Mental), Madrid, Spain5 Department of Psychiatry, North-Trondelag Hospital Trust, Levanger, Norway6 Department of Medicine, Institute of Neuromedicine, Norwegian University of Science and Technology, Trondheim, NorwayCorrespondence: Ida Vikan Rise, Sørlandet Hospital, Psykiatrisk, Sykehusavdeling (Arendal), Postboks 416, 4604 Kristiansand, Norway, Tel +47 37 01 44 00, Email theida@gmail.com2016 17 5 2016 12 1203 1213 © 2016 Rise et al. This work is published and licensed by Dove Medical Press Limited2016The 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.Introduction\nData specific to late-life bipolar disorder (BD) are limited. Current research is sparse and present guidelines are not adapted to this group of patients.\n\nObjectives\nWe present a literature review on clinical characteristics, comorbidities, and cognitive impairment in patients with late-life BD. This review discusses common comorbidities that affect BD elders and how aging might affect cognition and treatment.\n\nMethods\nEligible studies were identified in MedLine by the Medical Subject Headings terms “bipolar disorder” and “aged”. We only included original research reports published in English between 2012 and 2015.\n\nResults\nFrom 414 articles extracted, 16 studies were included in the review. Cardiovascular and respiratory conditions, type II diabetes, and endocrinological abnormalities were observed as highly prevalent. BD is associated with a high suicide risk. Bipolar elderly had an increased risk of dementia and performed worse on cognitive screening tests compared to age-matched controls across different levels of cognition. Despite high rates of medical comorbidity among bipolar elderly, a systematic under-recognition and undertreatment of cardiovascular disease have been suggested.\n\nConclusion\nThere was a high burden of physical comorbidities and cognitive impairment in late-life BD. Bipolar elderly might be under-recorded and undertreated in primary medical care, indicating that this group needs an adapted clinical assessment and specific clinical guidelines need to be established.\n\nKeywords\nbipolar disorderagedcomorbiditycognitionimpairmenttreatment\n==== Body\nIntroduction\nBipolar disorder (BD) is a major affective disorder marked by recurrent/cyclical episodes of mania/hypomania and depression as described in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.1 The subtypes of BD include bipolar disorder I (BD-I) and bipolar disorder II (BD-II). Patients with BD-I experience manic episodes and nearly always experience major depressive and hypomanic episodes whereas BD-II is marked by at least one hypomanic episode, at least one major depressive episode, and the absence of manic episodes. To satisfy a clinical diagnosis of BD, the abnormal mood episodes should have a detrimental effect on the social and occupational functioning of the individual. Late-life BD or geriatric BD usually refers to patients older than 60 years with BD. However, some authorities use an age cut-off of 50, 55, or 65 years. Late-life BD includes both patients diagnosed in their younger years (early-onset BD) and in late-life, often called late-onset BD. Due to no validated age-at-onset threshold, this definition remains arbitrary.2 One out of four bipolar patients is reported to be older than 60 years.3 A systematic review of the prevalence of BD in population-based studies revealed heterogeneous findings concerning the prevalence of BD, ranging from 0.1% to 7.5%.4 Community surveys in 14 countries found that the lifetime prevalence of BD was 2.8%,5 while another set of community surveys in eleven countries found a considerably lower lifetime prevalence of BD, with rates of BD-I and BD-II reported to be 0.6% and 0.4%, respectively.6 In both sexes, the pattern of bipolar diagnoses has been reported to increase similarly over the years until middle age where it was observed to reach a plateau.7 The considerable variety of prevalence rates in BD may be related to the consideration of subthreshold criteria upon diagnosis, differences in study design, and psychiatric assessment. The annual incident rate has been reported to be 30 per 100,000 capita.7 The mean standardized mortality ratio for BD has been reported to be 2.00 with a reduced life expectancy of 9 years among bipolar patients.7 The relative risk of all-cause mortality was reported to be 2.9 in the age group 65–75 years and highest among adults under 45 years (8.95), suggesting that the younger population with BD have a specially reduced life expectancy compared to the general population.7 An elevated leukocyte count often seen in acute affective episode has previously been suggested to increase the risk of early natural death from all causes in bipolar patients, independent of smoking and other cardiovascular risk factors.8\n\nDue to physiological age-related changes, different pharmacodynamics and kinetics, cognitive impairment, medical comorbidity and concomitant medication, long-term treatment with mood stabilizers and their potential negative effect, older patients may have different clinical characteristics and treatment response than the younger bipolar population.9,10 Late-life BD has been associated with multiple medical comorbidities, and the dominating conditions observed are type II diabetes, respiratory and cardiovascular conditions, and other endocrine abnormalities.10 It has been suggested that medical comorbidity accounts for 40%–70% of personal and societal costs of BD.11 Yet, it is not clear whether medical disorders among individuals with BD are truly comorbid disorders, or a consequence of treatment, or a combination of both.12 Lifestyle characteristics such as smoking, diet, substance abuse, and metabolic abnormalities related to psychotropic drug use contribute to medical complication and poor prognosis.13 Psychiatric comorbidities have previously been reported to be less prevalent than physical comorbidities, and the prevalence has appeared to be lower in elderly bipolar patients compared to the younger BD population, with anxiety and substance abuse disorders being the most common concurrent psychiatric illnesses.10 There are however some limitations to be considered regarding this literature, as no prospective studies have evaluated this topic and most studies have been small, retrospective, and conducted only on hospitalized patients.10\n\nThere seems to be an increase in the amount of published research on this topic over the past decade.9 Emerging research suggests that BD is not solely an illness of mood but that it affects multiple domains impacting overall functioning, considering it to be a multisystem condition in which medical comorbidity, cognitive impairment, and early mortality may have underlying common mechanistic elements. To our knowledge, all of the reviews regarding this topic consider there is a lack of adapted assessment for this group of patients, as their treatment is based on guidelines drawn up for younger patients with BD. The aim of the study was to identify specific clinical characteristics in individuals older than 60 years with BD and to gain more knowledge of how aging in these individuals might affect cognitive function and treatment.\n\nMethods\nPubMed/MedLine was searched for studies about elderly (>60 years) patients with BD and their characteristics. Selected articles were those with Medical Subject Headings term “Bipolar Disorder”, restricted to Medical Subject Headings Major Topic, and “aged”. The search was limited to studies published in the period January 2012 till January 2015 in order to obtain the most recent scientific articles. The database was searched for original research reports published in English from the period November 2014 to January 2015. Titles and abstracts from the obtained articles were reviewed and all retrieved papers were screened to meet the following inclusion criteria:\nStudies including patients aged 60 or older or studies with participants of any age, only if separate data were reported for the patients aged 60 years and older.\n\nMinimum sample size of N=30, as small samples may reduce the likelihood that findings reflect a true effect.14\n\nA clear definition of BD with diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders-IV and -V, and ICD-9 and -10.\n\n\n\nSearch results\nThe data search by keywords yielded 414 potentially eligible articles. A total of 398 articles were excluded, resulting in 16 studies meeting the inclusion criteria. Reasons for exclusion were no data specific to patients above 60 years. The characteristics of the included studies are listed in Table 1. We identified six articles that reported medical comorbidity,2,7,15–18 two on suicide,19,20 six on cognitive impairment/dementia,21–26 and two on aspects related to pharmacological therapy in BD.27,28\n\nThe additional burden in the elderly with BD\nComorbidity and impairment in the older BD population\nElderly bipolar patients were more likely to be diagnosed with diabetes mellitus,2 cancer,7 thyroid disorders,2,15 and hypertension,2,7 compared to age-matched controls. One of the studies comparing comorbidities in bipolar versus non-bipolar subjects found a high prevalence of viral hepatitis and Parkinson’s disease among older bipolar patients.15 A recent study reported that most of the elderly bipolar patients did not present psychiatric comorbidities, and those who did were mainly patients with early-onset BD. However, the majority of the patients (81.2%) had various physical comorbidities.2 A recent cross-sectional analysis found that elderly individuals with BD were significantly less likely to have no recorded physical conditions and significantly more likely to have one (odds ratio [OR] 1.27), two (OR 1.45), and three or more (OR 1.44) physical conditions compared to age-matched controls.15 The same study also reported that individuals with BD and coronary heart disease or hypertension were less likely to have a primary-care record and experienced much less intensive prescribing for these conditions and were treated less intensively compared to non-bipolar subjects. Another physical health problem observed to be highly prevalent was obesity.16 Findings from a longitudinal study examining the impact of obesity on comorbidity in BD showed that obese subjects were observed to be significantly more likely to report any new-onset medical condition (OR 2.32), new-onset hypertension, arthritis, diabetes, and hyperlipidemia.17 There are indications that obesity independently predicts the accumulation of medical conditions among adults with BD. Results from a recent cross-sectional study showed that BD was independently associated with an increased risk of having a diagnosis of chronic pain conditions.17 This study investigated the rates of seven chronic, noncancer pain conditions in veterans with BD, finding elevated rates of pain in these patients compared to controls. Patients with BD had significantly higher odds of having any pain condition (OR 1.83), as well as specific pain condition (adjusted odds ratios [aOR] ranging from 1.50 to 6.24). Elevated rates of chronic pain conditions were also reported by another recent cross-sectional study.15\n\nBD is associated with an elevated risk of suicide and suicide mortality in BD has been estimated to be approximately nine times that of the general population.10 Elevated levels of suicide incidents in elderly persons with BD have also been documented by other studies, especially in those presenting a current mood episode.19 Mixed and depressive episodes of BD as well as major depression were found to be the most frequent diagnoses in elderly individuals committing suicide. The same study suggested that bipolar subjects with depressive episodes might have a greater risk of committing suicide than subjects with unipolar depression. Another study observed a considerable lower rate of suicides in the oldest group of patients compared to the middle age groups (25–64-year age groups) in which the highest rates of suicides were reported. The majority of suicides in the sample of bipolar patients took place at least 5 years after diagnosis.20 A possible high-risk group of bipolar patients with alcohol dependence, concomitant personality disorder, depression, and current or recent in-patient admission was also identified.20\n\nDementia and cognitive impairment in later life are common features of BD. Elderly people with BD have been reported to have an increased risk of stroke, dementia, and other cognitive impairments.9 Compared to non-BD subjects, euthymic older adults with BD have been found to perform worse on cognitive tests such as the Clock Drawing Test and the verbal fluency test, but not on the Mini Mental State Examination.21 Findings from a recent population-based study of older patients with BD suggested a positive association between the presence of a lifetime history of BD and an increased risk of developing dementia (aOR 4.07), even after controlling for pertinent risk factors.22 These subjects tended to develop dementia already in middle age (aOR 3.77). A recent longitudinal study investigated the neurocognitive performance in the elderly with BD.23 At baseline and follow-up, the bipolar patients performed worse on all neurocognitive measures compared to the healthy elderly group, although the cognitive decline during this period was similar in both groups. The association between subjective complaints of cognition and objective neuropsychological performance has also been investigated. The results provided evidence for a clear association between few subjective complaints and poorer attentional and executive functioning in euthymic elderly bipolar patients.24 It is not clear whether BD and major depressive disorder (MDD) have similar or different cognitive profiles and levels of impairment in older age. Cognition in aged euthymic bipolar patients was compared with older adults with MDD by using multiple tests measuring different cognitive domains.25 The results showed that subjects with BD and MDD were impaired across all cognitive domains compared with controls, and this was remarkably so concerning information processing speed and executive function. Bipolar patients did worse than patients with MDD across all cognitive domains, despite protective effects of having a higher education and lower vascular burden. Cognitive abilities of older bipolar patients (BD-I) in euthymic state have also been compared with patients with schizophrenia in the same age range.26 Strikingly limited differences in cognitive performance between the community-living patients with schizophrenia and the bipolar patients were found. However, both groups were impaired compared to controls in terms of executive functions. In a descriptive study comparing a group of geriatric bipolar patients with a sample of younger bipolar patients, a remarkably significant cognitive impairment was found across age groups. The older patients were distinguished from the younger by having a lower overall cognitive and executive functioning.27\n\nPharmacological therapy\nAlterations in pharmacokinetics and dynamics, increasing comorbidity, drug interactions, and the subsequent polypharmacy combined with functional and cognitive limitations related to aging condition the response to mood stabilizers, which is necessary to consider when prescribing medication. Previous evidence suggests that pharmacological treatment of BD may reduce not only suicide risk but also premature mortality from natural causes, such as respiratory and circulatory diseases.8 A recent study observed that most of the sample of elderly outpatients received surprisingly only pharmacological therapy rather than additional psychosocial interventions for BD,2 even though there is evidence that these interventions are effective, especially in early stages of the disease.29 An average of three different psychotropic medications were prescribed to the elderly patients.2 A similar need of polytherapy has previously been reported in late-life BD.30 As expected, antidepressants were more frequently prescribed to patients with BD-II than to patients with BD-I and twice as much to patients with an early-onset BD than to patients with late-onset BD.\n\nLithium still remains a pharmacological cornerstone for the prevention of manic and depressive recurrences in BD.27 It has been previously suggested that lithium may also have neuroprotective abilities and may reduce the risk of developing dementia.31 In a recent longitudinal study, lithium treatment was not associated with cognitive decline.23 Considering the narrow therapeutic window of lithium and the well-known harmful adverse effects of chronic lithium intoxication, lithium concentration monitoring is considered to be essential. Pharmacological variability, comorbidities, and polypharmacy related to the aged could also result in instability of serum lithium concentrations. For instance, a variety of antihypertensives (thiazide diuretics, angiotensin-converting-enzyme inhibitors) and nonsteroidal anti-inflammatory agents, which are common medications in elderly patients, can increase lithium concentrations.32 However, a retrospective study which compared serum lithium concentrations of bipolar patients in different age groups concluded that age does not seem to be a determinant of serum lithium concentration instability as they found no significant difference between the age groups.28 In the majority of patients on long-term lithium therapy, a decrease in urinary concentration ability is observed and chronic interstitial nephropathy may develop. A study assessing the long-term effect of lithium on kidney function compared older patients on long-term lithium therapy (with a mean of 16 years of treatment) with age-matched patients never exposed to lithium.27 They found that lithium treatment caused an impairment of kidney function reflected also by abnormal levels of novel markers of kidney injury such as plasma neutrophil gelatinase-associated lipocalin and urinary beta-2 microglobulin, the latter probably being a better predictor because it showed multiple clinical and biochemical correlations.\n\nDiscussion\nThe present review examined mainly specific clinical characteristics, common comorbid physical conditions, and cognitive dysfunction in elderly with BD. The reviewed studies suggest that the burden of BD is not limited to higher disability and comorbidity, but is also reflected in earlier mortality. Comorbid cardiovascular diseases, suicide, and cancer have earlier been suggested as the leading causes of excess mortality among bipolar patients33 based on findings similar to those of the studies included in this review. The reviewed studies investigating medical comorbidities found many similarities to previous research, providing further evidence of high comorbidity in elderly patients with BD. Cardiovascular and respiratory conditions, type II diabetes, and endocrinological abnormalities have previously been reported as the most frequent comorbidities in bipolar elderly.10 In addition, Parkinson’s disease and viral hepatitis were found to be highly prevalent.15 Although cardiovascular diseases were not particularly prevalent in the reviewed studies, several comorbidities well known as risk factors to cardiovascular disease, such as hypertension, diabetes, obesity, and alcohol abuse, were reported as highly prevalent among bipolar elderly compared to the elderly in general. These results underscore the importance of contemplating these risk factors when assessing and treating BD in elderly patients. Evidence for a systematic under-recognition and undertreatment of cardiovascular illnesses in primary medical care was also found,15 which has been mentioned previously.34 There are several possible reasons for this association. Mood episodes and/or low awareness of cardiovascular risk factors and associated symptoms could have resulted in lower attendance rate to the general practitioner. Additionally, individuals with BD frequently experience social isolation and lower levels of education, which are also associated with higher unmet need for treatment. We cannot rule out that the cardiovascular risk factors in these subjects may be overlooked by the general practitioners while engaging their attention toward their mental illness. An average of three to four medical comorbid conditions have previously been reported in elderly bipolar patients;10 similar findings are reported in the reviewed studies. A strong association between obesity and a high medical burden in BD was also observed16 suggesting that overweight is an additional burden in many elderly with BD. It is noteworthy to consider that treatment of obesity could potentially mitigate the psychiatric and medical burden of BD. Also, pain conditions were reported to be highly prevalent in bipolar elderly.15,17 This association has previously received little attention, despite being related to reduced quality of life among those with mental illness. Even though such an association may be caused by depressive symptoms, it demonstrates another clinical area of need for this population that is being overlooked. Chronic pain conditions have also been related to an increased suicide risk, an aspect that needs to be considered also in the approach of the elderly bipolar population.35 The extent to which chronic pain might impact mental health recovery remains to be investigated.\n\nThe association between cognitive dysfunction and BD was corroborated by findings in this review. The pathophysiology behind the relationship between BD and the subsequent development of dementia largely remains unclear. Many possible mechanisms may underlie cognitive deficits in older adults with BD, such as residual mood symptoms, structural brain abnormalities, long-term side effects of medications, adverse psychosocial conditions, and medical comorbidities. Bipolar elderly performed significantly worse on some screening tests of cognitive function,21 and a positive association between the presence of BD and an increased risk of developing dementia was found.22 The elderly, in particular, represented a heterogeneous group, suggesting that various causes of cognitive impairment may have played a role in its development, emphasizing the need for further investigation of the underlying neuropathophysiological and pathological mechanisms that connect BD and dementia. One of the studies reviewed compared older bipolar subjects with a group of non-BD patients matched for distinct degrees of cognitive impairment, providing greater evidence to the results.21 However, it is important to consider confounding factors that can bias the link between cognitive dysfunction and BD, such as educational level, a family history of dementia, and socioeconomic status. Even though data were statistically significant, the clinical meaning of these differences is uncertain. Results showed that older adults with BD exhibited worse cognitive functioning compared to healthy controls, regardless of comparable vascular risk factors.23 This implies that there may be inherent factors related to the disease process that results in cognitive impairment, and not simply a manifestation of vascular risk factors. Even though disease exacerbations are associated with increasing cognitive dysfunction, there is increasing evidence of a higher risk of permanent cognitive impairment in bipolar patients. It is important to underline that all of the reviewed studies regarding this topic compared only bipolar patients in euthymic state with controls. Another important finding was the relation between having few subjective complaints about cognition and poor attentional and executive functioning suggesting that impaired awareness of cognition might be a reflection of cognitive deterioration. If so, this may influence assessment and treatment of these individuals as poor perception of such function may compromise communication of symptoms and functional deficits. Subjects with BD were observed to have cognitive dysfunction comparable to patients with schizophrenia and they were also reported to be more impaired across all cognitive domains compared with patients with MDD.25,26 Recommendations to preserve cognitive function target known risk factors associated indirectly with cognitive decline, such as hypertension, hypercholesterolemia, and diabetes mellitus. The relative neglect of the management of severe medical comorbidity associated with BD is still a significant challenge.\n\nThe consensus regarding high suicide risk among elderly bipolar patients compared to elderly in general was also suggested by the studies included in our review.19 Although, the risk was found to be lower among older patients compared to middle-aged,20 which is consistent to previous findings.36 Nevertheless, the committed suicide rates are higher among the elderly in comparison with young people,37 an aspect not mentioned in the included studies in this review.\n\nLong-term treatment with lithium is often indicated in BD, which means extensive monitoring is essential to minimize adverse effects. Due to age-related factors, age has been suggested as a determinant of serum lithium concentration instability, which may be one of several reasons why lower daily dosages of lithium have been used in older patients with BD.30 Findings in one recent study differed from this idea suggesting that age is not an indication to not initiate or discontinue lithium therapy.28 As lithium can be associated with nephropathy, kidney function should be assessed frequently. Novel markers of kidney injury were compared in one study, suggesting urinary beta-2 microglobulin, a marker of tubular function, to be a better predictor than plasma neutrophil gelatinase-associated lipocalin.27 It remains to be seen if beta-2 microglobulin can make a better marker of kidney function than estimated glomerular filtration rate.\n\nThere are limitations to consider in this review. As most of the included studies were cross-sectional analyses, causal relationship cannot be established. This highlights the importance of future longitudinal studies allowing inferences to be drawn about important characteristics of this population. Due to limited age criteria in our search, sample sizes of the included studies varied. Further, some cross-sectional studies used data from nationwide datasets with reasonably large samples while other study designs were longitudinal having smaller samples. However, given the relatively sparse number of longitudinal studies in the field the results from these studies contribute significantly to the current knowledge. We found that studies of psychiatric comorbidity in the reviewed age group were scarce. Few articles were identified within our searched timeframe; thus, this topic was not emphasized in the review. A global tendency in the reviewed articles was a lack of bipolar subtype specificity, which means that some of the findings may be more suitable for either BD-I or BD-II. This is a major problem in general as the prevalence of the two bipolar types is different, with BD-I being rather rare compared to BD-II. The majority of the studies are either European or North American and hence the findings reflect mainly the population in these areas. It would be interesting that future investigation on this topic would highlight the possible differences among bipolar subtype, sex, and ethnicity. There was a lack of recent studies published regarding pharmacotherapy and considering its essential role in BD treatment, it would be convenient for more empirical data concerning psychotropic medications in late-life BD.\n\nConclusion and future perspective\nOur review supports what recent studies have suggested: there is a high burden of comorbidities in late-life BD and cognitive impairment is common. Individuals with the disorder have an elevated risk of being affected by several comorbid psychiatric and especially somatic disorders, and hence clinicians should be especially attentive to physical comorbidity and early signs of cognitive decline, which may decrease mortality and herald polytherapy and the dementia outcome. Bipolar elderly may be under-recorded and undertreated in primary medical care, particularly for cardiovascular comorbidity, which is one of the leading causes of excess mortality in BD; thus, improved recognition of BD and provision of primary medical care may effectively reduce mortality and cognitive decline among these patients. Integrated treatment focusing simultaneously on psychiatric and medical outcomes may offer substantial advantages over usual care, which is often fragmented. The review of the literature indicates that clinical characteristics between the elderly and the younger population differ, suggesting that the clinical assessment of each group should be different and adapted. The heterogeneity of function and comorbid symptoms in this group of elderly bipolar patients clearly shows that it is important to highlight the need of an individual approach to each patient.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nTable 1 An overview of the characteristics of the included studies\n\nAuthors\tDesign\tSample\tMeasurements of outcome\tObjectives\tResults\t\nAprahamian et al21\tCross-sectional\tN=86 patients with BD (mean age: 69.2)\tMMSE, VFT, and CDT\tTo investigate the performance on cognitive screening tests in a sample of older adults with BD, as compared to non-BD subjects\tNondemented patients with BD had a slightly worse global cognitive performance as compared with healthy controls and patients with cognitive impairment but no dementia.\nPatients with BD performed worse on the VFT, both in the normal cognition range and in the dementia range.\t\nBirgenheir et al17\tCross-sectional\tN=12,857 patients with BD ≥65 years\tPrimary dependent variables were seven specific pain conditions: arthritis, back pain, chronic noncancer pain, migraine headache, tension, and other headache, psychogenic and neuropathic\tTo assess the rates of chronic, noncancer pain conditions in patients with BD within the Veterans Health Administration System\tNoncancer pain conditions occur in elevated rates among patients with BD.\nAfter adjusting for other demographic and patient factors, patients with BD had significantly higher odds of having any pain condition (OR 1.83) as well as every specific pain condition (aORs ranging from 1.50 to 6.24).\t\nCiulla et al19\tCross-sectional\tN=32 patients with BD ≥60 years\tPrevalence of ideation, attempts, and suicide risk measured by MINIplus\tTo examine prevalence and level of suicide risk and its associations with sociodemographic factors and mood disorders\tBD was associated with a high suicide risk. The increased suicide risk was reported for those with and without a current mood episode.\t\nClements et al20\tCross-sectional\tN=156 patients with BD ≥65 years\tSuicide database NCI\tTo describe the frequency, trends over time, and characteristics of those with BD who died by suicide in England\tFactors such as alcohol dependence/misuse, personality disorder, depressive illness, and current/recent in-patient admission seemed to characterize a high-risk group.\t\nGildengers et al25\tCross-sectional study\tN=43 patients with BD ≥65 years (mean age: 74.0)\t21 well-established and validated individual tests measuring multiple cognitive domains\tTo examine the overall patterns of cognitive function in patients with BD and MDD\tBoth subjects with BD and MDD were impaired across all cognitive domains compared to controls, most prominently in information processing speed and executive function. Despite the protective effects of having higher education and lower vascular burden, BD subjects were more impaired across all cognitive domains compared with MDD subjects.\t\nGoldstein et al16\tCohort study\tN=64 patients with BD ≥65 years\tObesity was defined as having a BMI of ≥30 kg/m2. Respondents were asked about the presence of eleven medical conditions. Short Form 12 version 2, a measure of health-related quality of life in large populations, was used\tTo examine if obesity is associated with an increased medical and psychiatric burden in BD\tObesity independently predicts the accumulation of medical conditions among adults with BD. Obese subjects with BD remained significantly more likely to report any new-onset medical condition (OR 2.32), new-onset hypertension (OR 1.81), arthritis (OR 1.64), physician-diagnosed diabetes (OR 6.98), and hyperlipidemia (OR 2.32).\t\nKodesh et al7\tHistorical cohort study\tN=1,521 patients with BD ≥65 years\tDatabase containing demographic information, medical diagnoses, laboratory results, medications, treatment documentation, and information regarding medical encounters. The database forms the basis for merging separate registers of patients with different chronic diseases (CVD, DM, hypertension, and cancer)\tTo investigate the epidemiology of schizophrenia and bipolar affective disorder among adults, and to assess their comorbidity and mortality compared to the general population\tThe crude prevalence rate of BD was 3 per 1,000 capita. The annual incidence rate of BD was 30 per 100,000 capita. Compared to the general population, BD patients had a 9-year shorter life expectancy. They were also more likely to be diagnosed with DM (OR 1.6). Results showed that both bipolar individuals had a slightly higher age-adjusted risk of having cancer, diabetes, and hypertension compared to the general population.\t\nMeesters et al26\tCross-sectional\tN=74, patients with BD type I (mean age: 70)\tSeveral tests spanning four cognitive domains; attention/working memory, verbal memory, executive function, and verbal fluency\tTo investigate differences in cognitive impairment between schizophrenia and BD\tPatients with schizophrenia and BD-I were impaired compared to healthy controls, with mostly large effect sizes for verbal memory and verbal fluency, but with smaller effect sizes for the domain of attention/working memory.\t\nvan Melick et al28\tRetrospective study\tN=288 patients with BD and ≥60 years\tVGR, TiTR, TbTR, TaTR, and annual number of measurements were considered a proxy for instability\tTo investigate age as a determinant of serum lithium concentration instability during both the titration and maintenance phase of lithium treatment\tAge was not a determinant of serum lithium concentration instability. VGR and TiTR, TaTR, and TbTR did not differ significantly between the reference group and the two oldest age groups (60–69) and (≥70). The annual number of lithium serum concentration measurements was higher in the oldest age groups, and this difference was significant (P<0.05).\t\nMontes et al2\tCross-sectional\tN=69, patients with BD ≥65 years\tSociodemographic and treatment (pharmacological and nonpharmacological) characteristics. Measures of severity and disability\tTo examine demographic, clinical, and treatment correlates of BD-I vs BD-II and patients with early onset versus late onset of the illness\tGeriatric BD has similar clinical characteristics with those of younger ages, and these do not seem to greatly differ with BD subtype or age of onset. The patients were receiving a mean of three different psychotropic medications. The prevalence of lifetime psychiatric comorbidity (18.8%) was significantly lower than the prevalence of physical comorbidity (81.2%). The most prevalent physical comorbidities were arterial hypertension (37.7%), DM (24.6%), and hypothyroidism (13%).\t\nRybakowski et al27\tCross-sectional\tN=120 patients with BD, 90 of them who were exposed to lithium (mean age: 60±10)\tMeasures of kidney functions; urine examination with specific gravity evaluation, serum creatine concentration, eGFR evaluation, and two markers of kidney injury: serum concentration of neutrophil NGAL and urinary concentration of β2-MG\tTo compare the novel markers of kidney injury between a group of long-term lithium-treated bipolar patients and age-matched bipolar patients not exposed to lithium\tLithium treatment causes an impairment of kidney function reflected also by abnormal levels of novel markers of kidney injury. Urinary β2-MG seemed to be a better predictor than serum NGAL in lithium-treated patients because it showed multiple clinical and biochemical correlations, especially in men.\t\nSchouws et al23\tCohort study\tN=65 patients with BD >60 (mean age: 68.4)\tMMSE was used to provide an overall assessment of cognitive function. Several neuropsychological tests grouped into four cognitive domains were used: attention, learning and memory, executive functioning, and verbal fluency\tTo investigate neurocognitive performance in BD over a period of 2 years\tAt baseline and at follow-up, patients with BD performed worse on all neurocognitive measures compared to the healthy elderly group. However, they did not have greater cognitive decline compared to the healthy controls.\t\nSchouws et al24\tCross-sectional\tN=101 patients with BD >60 years (mean age: 67.8)\tMMSE was used to provide an overall assessment of cognitive function. Self-reported cognitive problems were assessed through “The Cognitive Failures Questionnaire”. All subjects completed several neuropsychological tests grouped into five cognitive domains: attention, learning and memory, visuoconstructional ability, executive functioning and verbal fluency\tTo determine whether subjective cognitive complaints were associated with objective neuropsychologic performance and to consider the role of frontal lobe dysfunction in the awareness of cognitive impairment\tElderly bipolar patients had no more subjective cognitive complaints than comparison subjects, whereas they showed less cognitive functioning in several domains. Having few subjective cognitive complaints was associated with poorer attentional and executive functioning. More than 40% of elderly bipolar patients who were euthymic had considerable subjective cognitive complaints.\t\nSheeran et al18\tCross-sectional\tN=50 patients with BD ≥60 years\tCognitive status was assessed via the MMSE and executive functioning was assessed via the Initiation–Perseveration subscale of the DRS\tTo conduct a descriptive analysis of geriatric and younger adult residents with BD or mania in nonclinical adult congregate facilities in the greater New York City region\tComparing the two age groups, the elderly sample had lower overall cognitive status and executive functioning, and were using a larger number of medication classes than the younger group.\t\nSmith et al15\tCross-sectional\tN=702 patients with BD ≥65 years\tData on the presence of 32 of the most common chronic physical health conditions\tTo assess physical comorbidities in BD within primary care and prescription of cardiovascular medications\tPrevalence was higher for bipolar versus non-bipolar for viral hepatitis (OR 5.69), constipation (OR 3.37), and Parkinson’s disease (OR 3.05). Bipolar patients with coronary heart disease and bipolar patients with hypertension were more likely to be current smokers than controls (OR 1.55, OR 1.87), less likely to be on a statin (OR 0.69, OR 0.82), more likely not to be on a antihypertensive (OR 2.08 OR 1.70) and less likely to be on two or more antihypertensive medications (OR 0.46, OR 0.53). Compared to controls, individuals with BD were significantly less likely to have no recorded physical conditions, and significantly more likely to have one or more physical conditions. All P-values were <0.002.\t\nWu et al22\tCross-sectional\tN=263 patients with BD (mean age: 74.1±8.6)\tA conditional logistic regression model was performed using data from a nationwide dataset\tTo investigate whether patients with BD were at an increased risk for developing dementia\tBD was significantly associated with an increased risk of subsequent dementia (aOR 4.32). A significantly increased risk was observed in subjects diagnosed with dementia before the age of 65 years (aOR 3.77).\t\nAbbreviations: aOR, adjusted odds ratio; BD, bipolar disorder; BMI, body mass index; CDT, Clock Drawing Test; CVD, cardiovascular disease; DM, diabetes mellitus; DRS, Dementia Rating Scale; eGFR, estimated glomerular filtration rate; MDD, major depressive disorder; MINIplus, Mini International Neuropsychiatric Interview plus; MMSE, Mini Mental State Examination; NCI, National Confidential Inquiry into Suicide and Homicide by People with Mental Illness; NGAL, plasma neutrophil gelatinase-associated lipocalin; OR, odds ratio; TaTR, percentage of treatment time that serum lithium concentrations were above the therapeutic range; TbTR, percentage of treatment time that serum lithium concentrations were below the therapeutic range; TiTR, percentage of treatment time that serum lithium concentrations were in the therapeutic range; VFT, verbal fluency test; VGR, Variance Growth Rate; β2-MG, beta-2 microglobulin.\n==== Refs\nReferences\n1 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders 5th. ed Washington, DC American Psychiatric Association 2013 \n2 Montes JM Alegria A Garcia-Lopez A Understanding bipolar disorder in late life J Nerv Ment Dis 2013 201 8 674 679 23896848 \n3 Sajatovic M Blow FC Ignacio RV Kales HC Age-related modifiers of clinical presentation and health service use among veterans with bipolar disorder Psychiatr Serv 2004 55 9 1014 1021 15345761 \n4 Dell’Aglio Jr JC Basso LA Argimon I Arteche A Systematic review of the prevalence of bipolar disorder and bipolar spectrum disorders in population-based studies Trends Psychiatry Psychother 2013 35 2 99 105 25923299 \n5 Kessler RC Ormel J Petukhova M Development of lifetime comorbidity in the World Health Organization world mental health surveys Arch Gen Psychiatry 2011 68 1 90 100 21199968 \n6 Merikangas KR Jin R He J-P Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative Arch Gen Psychiatry 2011 68 3 241 251 21383262 \n7 Kodesh A Goldshtein I Gelkopf M Goren I Chodick G Shalev V Epidemiology and comorbidity of severe mental illnesses in the community: findings from a computerized mental health registry in a large Israeli health organization Soc Psychiatry Psychiatr Epidemiol 2012 47 11 1775 1782 22310700 \n8 Tsai SY Lee CH Kuo CJ Chen CC A retrospective analysis of risk and protective factors for natural death in bipolar disorder J Clin Psychiatry 2005 66 12 1586 1591 16401162 \n9 Sajatovic M Forester BP Gildengers A Mulsant BH Aging changes and medical complexity in late-life bipolar disorder: emerging research findings that may help advance care Neuropsychiatry (London) 2013 3 6 621 633 24999372 \n10 Lala SV Sajatovic M Medical and psychiatric comorbidities among elderly individuals with bipolar disorder: a literature review J Geriatr Psychiatry Neurol 2012 25 1 20 25 22467842 \n11 Kilbourne AM Post EP Nossek A Service delivery in older patients with bipolar disorder: a review and development of a medical care model Bipolar Disord 2008 10 6 672 683 18837861 \n12 Krishnan KR Psychiatric and medical comorbidities of bipolar disorder Psychosom Med 2005 67 1 1 8 15673617 \n13 Kemp DE Gao K Chan PK Ganocy SJ Findling RL Calabrese JR Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome Bipolar Disord 2010 12 4 404 413 20636638 \n14 Button KS Ioannidis JPA Mokrysz C Power failure: why small sample size undermines the reliability of neuroscience Nat Rev Neurosci 2013 14 5 365 376 23571845 \n15 Smith DJ Martin D McLean G Langan J Guthrie B Mercer SW Multimorbidity in bipolar disorder and undertreatment of cardiovascular disease: a cross sectional study BMC Med 2013 11 263 24359325 \n16 Goldstein BI Liu SM Schaffer A Sala R Blanco C Obesity and the three-year longitudinal course of bipolar disorder Bipolar Disord 2013 15 3 284 293 23286532 \n17 Birgenheir DG Ilgen MA Bohnert ASB Pain conditions among veterans with schizophrenia or bipolar disorder Gen Hosp Psychiatry 2013 35 5 480 484 23639185 \n18 Sheeran T Greenberg RL Davan LA Dealy JA Young RC Bruce ML A descriptive study of older bipolar disorder residents living in New York City’s adult congregate facilities Bipolar Disord 2012 14 7 756 763 23107221 \n19 Ciulla L Lopes Nogueira E da Silva Filho IG Suicide risk in the elderly: Data from Brazilian public health care program J Affect Disord 2013 152–154 513 516 \n20 Clements C Morriss R Jones S Peters S Roberts C Kapur N Suicide in bipolar disorder in a national English sample, 1996–2009: frequency, trends and characteristics Psychol Med 2013 43 12 2593 2602 23510515 \n21 Aprahamian I Ladeira RB Diniz BS Forlenza OV Nunes PV Cognitive impairment in euthymic older adults with bipolar disorder: a controlled study using cognitive screening tests Am J Geriatr Psychiatry 2014 22 4 389 397 23567429 \n22 Wu KY Chang CM Liang HY Increased risk of developing dementia in patients with bipolar disorder: a nested matched case-control study Bipolar Disord 2013 15 7 787 794 23992521 \n23 Schouws SN Stek ML Comijs HC Dols A Beekman AT Cognitive decline in elderly bipolar disorder patients: a follow-up study Bipolar Disord 2012 14 7 749 755 22998105 \n24 Schouws SNTM Comijs HC Stek ML Beekman ATF Self-reported cognitive complaints in elderly bipolar patients Am J Geriatr Psychiatry 2012 20 8 700 706 21857220 \n25 Gildengers AG Butters MA Chisholm D Cognition in older adults with bipolar disorder versus major depressive disorder Bipolar Disord 2012 14 2 198 205 22420595 \n26 Meesters PD Schouws S Stek M Cognitive impairment in late life schizophrenia and bipolar I disorder Int J Geriatr Psychiatry 2013 28 1 82 90 22407730 \n27 Rybakowski JK Abramowicz M Chłopocka-Wozniak M Czekalski S Novel markers of kidney injury in bipolar patients on long-term lithium treatment Hum Psychopharmacol 2013 28 6 615 618 24519695 \n28 van Melick EJ Souverein PC den Breeijen JH Tusveld CE Egberts TCG Wilting I Age as a determinant of instability of serum lithium concentrations 2013 35 5 643 648 \n29 Vieta E Pacchiarotti I Valentí M Berk L Scott J Colom F A critical update on psychological interventions for bipolar disorders Curr Psychiatry Rep 2009 11 6 494 502 19909673 \n30 Al Jurdi RK Marangell LB Petersen NJ Martinez M Gyulai L Sajatovic M Prescription patterns of psychotropic medications in elderly compared with younger participants who achieved a “recovered” status in the systematic treatment enhancement program for bipolar disorder Am J Geriatr Psychiatry 2008 16 11 922 933 18978253 \n31 Kessing LV Forman JL Andersen PK Does lithium protect against dementia? Bipolar Disord 2010 12 87 94 20148870 \n32 Dunner DL Drug interactions of lithium and other antimanic/mood-stabilizing medications J Clin Psychiatry 2003 64 Suppl 5 38 43 12720483 \n33 Leboyer MDJK Bipolar disorder: new perspectives in health care and prevention J Clin Psychiatry 2010 71 12 1689 1695 21190640 \n34 Carney CP Jones LE Medical comorbidity in women and men with bipolar disorders: a population-based controlled study Psychosom Med 2006 68 5 684 691 17012521 \n35 Hassett AL Aquino JK Ilgen MA The risk of suicide mortality in chronic pain patients Curr Pain Headache Rep 2014 18 8 436 24952608 \n36 Vasudev A Thomas A “Bipolar disorder” in the elderly: What’s in a name? Maturitas 2010 66 3 231 235 20307944 \n37 Pritchard C Amanullah S An analysis of suicide and undetermined deaths in 17 predominantly Islamic countries contrasted with the UK Psychol Med 2006 37 03 421 17176500\n\n",
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"keywords": "aged; bipolar disorder; cognition; comorbidity; impairment; treatment",
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"title": "Clinical features, comorbidity, and cognitive impairment in elderly bipolar patients.",
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"abstract": "We describe the cautionary case of a patient with advanced-stage large B-cell lymphoma (DLBCL). After combination chemotherapy, CT-PET revealed a persistent focus of likely DLBCL for which he received radiotherapy. Follow-up CT-PET showed diffuse hypermetabolic adenopathy and recurrent DLBCL was presumed. As part of clinical trial assessment, multiple biopsies showed non-caseating lymphadenitis consistent with sarcoidosis. No treatment for asymptomatic sarcoidosis was required and 18 months later he remains cancer-free. The presentation of sarcoidosis masquerading as recurrent DLBCL highlights the importance of tissue sampling prior to engaging in toxic and potentially life-threatening chemotherapy and the interesting link between DLBCL and sarcoidosis.",
"affiliations": "Division of General Internal Medicine, Virginia Mason Medical Center, Seattle, WA, United States.;Section of Pathology, Virginia Mason Medical Center, Seattle, WA, United States.;Floyd & Delores Jones Cancer Institute at Virginia Mason Medical Center, Seattle, WA, United States.",
"authors": "Whooley|Peter D|PD|;Dorer|Russell K|RK|;Aboulafia|David M|DM|",
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"doi": "10.1016/j.lrr.2018.04.003",
"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(18)30006-210.1016/j.lrr.2018.04.003ArticleThe fear of lymphadenopathy: A cautionary case of sarcoidosis masquerading as recurrent diffuse large b-cell lymphoma (DLBCL) Whooley Peter D. aDorer Russell K. bAboulafia David M. david.aboulafia@virginiamason.orgcd⁎a Division of General Internal Medicine, Virginia Mason Medical Center, Seattle, WA, United Statesb Section of Pathology, Virginia Mason Medical Center, Seattle, WA, United Statesc Floyd & Delores Jones Cancer Institute at Virginia Mason Medical Center, Seattle, WA, United Statesd Division of Hematology, University of Washington, United States⁎ Correspondence to: Section of Hematology and Oncology, Virginia Mason Medical Center, 1100 Ninth Avenue (C2-HEM), Seattle, WA 98101, United States. david.aboulafia@virginiamason.org09 4 2018 2018 09 4 2018 9 48 53 23 1 2018 7 4 2018 © 2018 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/).We describe the cautionary case of a patient with advanced-stage large B-cell lymphoma (DLBCL). After combination chemotherapy, CT-PET revealed a persistent focus of likely DLBCL for which he received radiotherapy. Follow-up CT-PET showed diffuse hypermetabolic adenopathy and recurrent DLBCL was presumed. As part of clinical trial assessment, multiple biopsies showed non-caseating lymphadenitis consistent with sarcoidosis. No treatment for asymptomatic sarcoidosis was required and 18 months later he remains cancer-free. The presentation of sarcoidosis masquerading as recurrent DLBCL highlights the importance of tissue sampling prior to engaging in toxic and potentially life-threatening chemotherapy and the interesting link between DLBCL and sarcoidosis.\n\nKeywords\nDiffuse large B-cell lymphomaSarcoidosisLymphadenopathy\n==== Body\n1 Introduction\nNon-Hodgkin Lymphomas (NHL) are a heterogeneous group of malignancies arising from lymphoid tissue with varied clinical and biological features. In 2012, roughly 6500 cases of diffuse large B-cell lymphoma (DLBCL) were diagnosed in the United States [1], [2], [3]. Diagnosis and staging is designed to identify all sites of known disease and to determine prognosis relative to known clinical risk factors. The revised International Prognostic Index (R-IPI) identifies specific groups of patients who are more or less likely to be cured with standard therapy [4]. DLBCL, while aggressive, is curable, and with treatment, approximately 50% of patients with advanced-stage DLBCL will attain cure [5], [6].\n\nEfforts to evaluate for complete remission (CR) are often clouded by interim assessments through surveillance imaging with computerized tomography (CT) or CT - positron emission tomography (PET). For treated lymphoma, surveillance and restaging imaging with CT-PET scans can yield false-positive results and should not be used to guide changes in therapy without overt evidence of progressive disease (PD) through tissue analysis [4]. The National Comprehensive Cancer Network (NCCN) guidelines do not recommend the use of CT or CT-PET for routine surveillance for patients with stage I-II disease who have achieved a CR following initial therapy. For patients with stage III-IV disease who achieve a CR, the NCCN recommends CT scans no more than once every six months for up to two years after completion of treatment [4]. Evaluating for PD or recurrence should, however, include regular history and physical exams and serial laboratory assessments, typically every three-to-six months for the first five years after induction therapy.\n\nWe describe the case of a previously healthy man with stage IVA DLBCL. He received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. A CT-PET scan after six cycles of treatment revealed a persistent focus of likely DLBCL involving the splenic hilum for which he received involved field external beam radiation therapy. Three months later, a CT-PET scan showed increased mediastinal, perihilar and retroperitoneal fluorodeoxyglucose (FDG) -avid lymphadenopathy. At the time of our consultation, the patient was exploring further treatment options and had received recommendations elsewhere to consider salvage chemotherapy followed by consolidation high-dose chemotherapy and autologous stem cell transplantation (ASCT) and was also considering chimeric antigen receptor (CAR) T-cell therapy through a clinical trial. He was anxious, had difficulty sleeping at night and had begun plans to liquidate his estate.\n\nLymphadenopathy (localized or widespread) found during routine physical exam or with imaging is a nonspecific finding, but can elicit intense fear and anxiety from both the patient and clinician, particularly in the post-lymphoma induction or reassessment period [7]. The overlap of clinical symptoms and radiographic findings between lymphoma and other causes of lymphadenopathy underscores the challenge of disease surveillance while highlighting an opportunity for potential new diagnostic technologies [8]. When confronted with evidence of hypermetabolic lymphadenopathy, clinicians must remain aware of sarcoidosis (among other infectious, inflammatory, or granulomatous etiologies) as an alternative diagnosis even in the backdrop of recently treated DLBCL [9].\n\n2 Case report\nA 70-year-old Caucasian man with a past medical history which included gastroesophageal reflux disease, episodic gout, and benign prostatic hypertrophy presented to medical attention with asymptomatic and painless left groin adenopathy of several weeks duration. After a concerted effort to lose thirty pounds through diet and exercise, he no longer required medications to control hypertension or hyperlipidemia. His family history was unremarkable. He had never been a smoker, but did report exposure to Agent Orange in Vietnam 50 years earlier.\n\nHis physical exam was within normal limits, except for bilateral shotty groin adenopathy, and a 2.5 cm palpable right axillary node. An ultrasound of the left groin showed a 2.5 cm cystic-appearing mass. A core needle biopsy of the mass revealed lymphoma. Flow cytometry findings included a monoclonal B-cell population expressing CD20, CD5, CD10 (partial), CD19, CD38, CD22, CD25 (partial), CD11c (partial), and CD8 (partial). B cells were negative for CD23, CD3, CD103, and FMC-7. He subsequently underwent an excisional biopsy of a left inguinal lymph node, which revealed DLBCL not otherwise specified (Fig. 1A). By immunohistochemistry analysis, the cells expressed CD5, CD10 (weak), CD79a, BCL-2, BCL-6, MUM-1, and Pax-5. Cells were negative for CD3, CD30, and Cyclin D1. The Ki-67 index was greater than 95% (Fig. 1B). Given the high Ki-67 index and unusual co-expression of CD5 and CD10 antigens, the tissue was sent to the lymphoma branch at the National Institutes of Health for further review where the diagnosis of non-germinal CD5+ DLBCL was confirmed. There was further agreement that the expression of CD10 was unusual, but given the strong MUM1 expression, activated B-cell phenotype (ABC type) was favored. Additional laboratory studies included the following: a normal complete blood count and hepatic panel; lactate dehydrogenase (LDH) of 530 U/L (normal <243); and beta-2 microglobulin of 3.0 mcg/mL (normal <2.70). Hepatitis A, B and C viral assays were pan negative as was an HIV enzyme-linked immunosorbent assay (ELISA) test.Fig. 1 Representative photos of the patient's excisional biopsy of a left inguinal lymph node. A) Hematoxylin and eosin stain showing diffuse large B-cell lymphoma. B) Immunohistochemistry showing Ki-67 index greater than 95%.\n\nFig. 1\n\nA CT-PET scan showed hypermetabolic axillary, splenic, and retroperitoneal adenopathy with standardized uptake values (SUV) ranging between 25 and 30 (Fig. 2A). A bone marrow aspirate and biopsy showed no morphologic or immunophenotypic evidence of DLBCL. A multi-gated acquisition (MUGA) scan revealed a normal left ventricular ejection fracture of 64%, and a lumbar spinal puncture to assess for leptomeningeal lymphoma proved unremarkable. The patient was diagnosed with stage IVA DLBCL with an R-IPI score of four (i.e., age greater than 60, advanced stage, more than one extra-nodal site, and elevated LDH).Fig. 2 Computerized tomography and positron emission tomography (CT-PET) scan from skull base to mid-thigh, coronal view. A) Staging CT-PET scan noted right axillary, splenic, and retroperitoneal adenopathy (white arrows) with intense fluorodeoxyglucose uptake. The maximum standardized uptake value was 26. B) CT-PET scan after completion of six cycles of R-CHOP revealed marked reduction in lymphadenopathy and associated hypermetabolic disease, though with a persistent small focus of hypermetabolic activity at the splenic hilum (white arrow) with a standardized uptake value of 11.5. C) Surveillance CT-PET scan three months after completion of consolidative radiotherapy displayed significant interval lymphadenopathy, with multiple, new, fluorodeoxyglucose-avid mediastinal, peri-hilar, peri-portal, and retroperitoneal lymph nodes (white arrows) with standardized uptake values ranging from 12.6 to 25.\n\nFig. 2\n\nAfter three cycles of R-CHOP, an interim CT scan of the chest, abdomen, and pelvis revealed marked interval improvement in the diffuse adenopathy with shrinkage of his axillary and para-aortic lymph nodes as well as his liver and splenic nodules. His first four cycles proved otherwise uneventful but with his fifth cycle, he was hospitalized for treatment of a neutropenic fever. He received empiric parenteral antibiotics for culture-negative pneumonia. There was a two-week delay in treatment before he received a sixth and final cycle of chemotherapy.\n\nA post-treatment CT-PET scan showed an excellent response to chemotherapy with marked reduction in hypermetabolic lymphadenopathy and resolution of splenic and hepatic nodules. There was, however, continued hypermetabolic activity involving the splenic hilum corresponding with an SUV of 11.5 (Fig. 2B). He received 40 Gy of consolidative radiotherapy over four weeks to that area.\n\nThree months later, a repeat CT-PET scan showed multiple enlarged FDG-avid lymph nodes above and below the diaphragm with an SUV range from 12.6 to 25 (Fig. 2C). Brain magnetic resonance imaging and a lumbar puncture proved unremarkable and further laboratory assessment included a white blood cell count of 3 × 109/L with an unremarkable differential, hematocrit of 43%, and platelet count of 100 × 109/L. Electrolytes and renal function were all in the normal range, and aspartate transaminase (AST) and alanine transaminase (ALT) were 47 U/L (normal < 40) and 51 U/L (normal < 44), respectively. Serum LDH was 192 U/L and β2 microglobulin was 2.94 mcg/mL. Quantitative immunoglobulins were within normal limits and a serum protein electrophoresis did not reveal a monoclonal gammopathy.\n\nGiven the CT-PET scan findings suggestive of relapsed DLBCL and the known aggressive nature of lymphoma recurring within 12 months of R-CHOP, the patient sought opinions at various medical centers. Options that he received for presumed relapsed DLBCL included standard salvage therapy with R-ICE (ifosfamide, carboplatin, etoposide), R-DHAP (dexamethasone, cytarabine, cisplatin), and R-GDP (gemcitabine, dexamethasone, cisplatin) for 2–3 cycles, followed by high-dose therapy and autologous stem cell transplantation (ASCT) if his DLBCL proved chemo-sensitive. The patient was further offered participation in a randomized trial of R-ICE alone versus R-ICE with an anti-CD19 antibody-drug conjugate. Another potential choice included high-dose anti-CD45 radiolabeled antibody and BEAM (carmustine, etoposide, cytarabine, melphalan) as a prelude to ASCT. And lastly, he was presented with the option of participating in a clinical trial of chimeric antigen receptor (CAR) T-cell therapy with a novel anti-CD19 construct plus durvalumab (a PD-L1 antibody). This was the choice he ultimately settled on after much deliberation and angst.\n\nTo confirm pathologic recurrence as a necessary requisite prior to clinical trial participation, the patient underwent an endo-bronchial ultrasound with trans-bronchial biopsies of several enlarged mediastinal and para-tracheal nodes. Fine needle biopsy revealed multiple non-necrotizing granulomas, without evidence of recurrent lymphoma. He additionally underwent a core needle biopsy of a right supraclavicular lymph node which also revealed granulomatous lymphadenitis with nearly complete replacement of normal lymph node architecture with non-caseating granuloma and no evidence of recurrent lymphoma, and with findings clearly favoring sarcoidosis (Fig. 3, A-C).Fig. 3 Representative images of the patient's supraclavicular lymph node biopsy. A) Hematoxylin and eosin showing non-necrotizing granulomas. Immunohistochemical staining for CD3 (B) highlights small T cells (brown) and for CD19 (C) which was negative, without any B cells present.\n\nFig. 3\n\nPulmonary function tests (PFTs) showed a normal forced vital capacity (FVC) with an FVC ≥ 80% of predicted, with normal forced expiratory volume in one second (FEV1) with a FEV1 ≥ 80% predicted, normal FEV1/FVC ≥ 0.7, and only a mildly reduced diffusing capacity (DLCO) of 64%. Serum angiotensin converting enzyme (ACE) was mildly elevated at 79 U/L (normal 8–53). No ocular manifestations of sarcoidosis were identified by exam or magnetic resonance imaging of the brain.\n\nAlthough intensely anxious due to persistent concerns that he might have recurrent DLBCL, he experienced no pulmonary symptoms (i.e., cough, dyspnea), nor did he have fevers, night sweats, or weight loss. He was diagnosed with stage I sarcoidosis and no systemic therapy was recommended. Twelve months later the patient remains well and without recurrent DLBCL.\n\n3 Discussion\nOur patient experienced significant hardship in the evaluation for relapsed lymphoma. While approximately 50–60% of patients with DLBCL achieve and maintain a CR after first-line therapy, 30–40% of patients relapse, and 10% of patients are destined to have refractory disease [10]. s-line chemotherapy followed by ASCT, as well as new therapeutic agents including those currently available through clinical trials do, however, offer the possibility of cure for patients with relapsed or refractory disease [11], [12], [13].\n\nThe rationale for surveillance imaging is detection of preclinical relapse with the expectation of improvement in survival when tumor burden is low and remains sensitive to second-line chemotherapy. For DLBCL, however, the large majority of relapses are detected clinically and there is no compelling data to support routine imaging as a strategy that leads to improved patient outcomes [14], [15], [16]. In a prospective study of 552 patients with DLBCL who achieved a CR after induction chemotherapy, 104 (19%) relapsed [14]. The majority of those relapses (67; 64%) were identified before scheduled follow-up due to symptomatic disease. The remaining 37 relapses (36%) were detected at a scheduled follow-up visit, of which 24 had symptoms or abnormal physical exam findings. Of the 13 (12.5%) asymptomatic patients with imaging suggestive of recurrent disease, 4 were of other NHL subtypes. Surveillance imaging detected asymptomatic DLBCL relapse in only 9 of the 552 patients (1.6%) and there was no difference in survival among these individuals when compared to patients whose relapse was discovered clinically [14].\n\nThe utility of CT-PET scans is further diminished in the DLBCL surveillance period due to false positive findings that often lead to unnecessary, extensive and invasive evaluations. Among 151 patients with mediastinal lymphoma (57 with Hodgkin Lymphoma; 94 with NHL) who were followed with CT-PET scans after completion of front-line therapy, radiographic imaging suggested relapsed lymphoma in 30 of the 151 patients (20%) [17]. Histologic analysis confirmed relapse in only 17 of the 30 patients (57%), whereas the remaining 13 patients (43%) demonstrated either benign disease (nine patients with fibrosis; three patients with sarcoid-like granulomatosis) or an unrelated neoplastic condition (one patient). The importance of obtaining tissue for analysis if a CT-PET scan suggests relapse was further underscored in a study involving 103 patients with NHL, 49 of whom had scans which revealed findings suggestive of recurrent lymphoma [18]. Of those with suspected relapse, seven (14%) were found to have alternative diagnoses (aspergillosis in one, sarcoidosis in one, and secondary malignancy in five).\n\nCurrent recommendations take these and other studies into account [19], [20], [21], [22], [23]. Surveillance CT and CT-PET scans are generally discouraged as their use does not offer survival benefit, are associated with significant false-positive rates, and expose patients to unnecessary radiation, biopsies, expense and anxiety, the latter of which was particularly salient to our patient's experience.\n\nWhile our patient was clinically stable after completing chemotherapy and radiation therapy, there remained concerns for relapse due to his high R-IPI score at diagnosis and a tumor biopsy which showed a high nuclear protein Ki-67 index. Ki-67 is synthesized at the beginning of cell division and is expressed during all active phases of the cell cycle (G1, S, G2, and mitosis) [24]. Ki-67 expression has been widely used in clinical practice as an index for the proliferative activity of numerous cancers, including NHL, and offers prognosis for survival; the higher the Ki-67 index, the poorer prognosis of survival [25].\n\nWith the introduction of immunotherapy (rituximab) to CHOP therapy, the survival rate for patients with DLBCL has considerably improved [26]. The R-IPI scoring system was developed to create a model for predicting outcomes in patients with aggressive NHL on the basis of clinical characteristics before treatment [27]. The scoring system utilizes a patient's clinical and disease characteristics at diagnosis (age > 60, Ann Arbor stage III-IV, Eastern Cooperative Oncology Group [ECOG] performance status ≥ 2, serum LDH, and extra-nodal disease sites) to provide a score that correlates with a particular prognosis for progression-free survival (PFS) and overall survival (OS). The R-IPI identifies three distinct prognostic groups, ascribing patients a very good (R-IPI score of 0; four-year PFS of 94%, four-year OS of 94%), good (R-IPI score of 1–2; four-year PFS 80%, four-year OS 79%), or a poor (R-IPI score of 3–5; four-year PFS 53%, four-year OS 55%) outcome, respectively [26]. Our patient's elevated R-IPI score, as consistent with a poor prognosis, raised concerns for potential relapse and likely contributed towards the overreliance on imaging studies in surveillance.\n\nWhile this case highlights the challenges of monitoring patients for relapsed lymphoma and reinforces the recommendations against regularly scheduled imaging studies, it also serves to remind us that other causes of lymphadenopathy may be present even in the context of advanced stage NHL. Etiologies for lymphadenopathy are numerous and can be recalled by the pneumonic “MAGIC” which broadly includes malignancy, allergic and autoimmune disorders, granulomatous disease, infection and iatrogenic causes, and chronic disease states (Table 1) [28], [29], [30], [31], [32].Table 1 MAGIC mnemonic – etiologies of lymphadenopathy.\n\nTable 1M\tMalignancy\tLeukemia, lymphoma, solid organ cancer ± metastases [i.e., breast, lung, renal, colon, prostate], Waldenstrom macroglobulinemia; systemic mastocytosis]\t\nA\tAllergic / Autoimmune\tHypersensitivity pneumonitis, autoimmune diseases (i.e., dermatomyositis, rheumatoid arthritis, Sjögren syndrome, Still disease, systemic lupus erythematosus)\t\nG\tGranulomatous disease\tSarcoidosis, granulomatosis with polyangitiis, berylliosis, silicosis\t\nI\tInfection / Iatrogenic\tBacterial (i.e., tuberculosis, melioidosis, cat-scratch disease); viral (i.e., adenovirus, cytomegalovirus, hepatitis,human immunodeficiency virus, infectious mononucleosis (Epstein-Barr virus), herpes zoster, rubella); fungal (i.e., coccidiomycosis, histoplasmosis); parasitic; iatrogenic (i.e., medications, serum sickness)\t\nC\tChronic conditions (with reactive lymphadenopathy)\tChronic obstructive pulmonary disease, congestive heart failure, bronchiectasis\t\n\n\nAs was evident in this case, sarcoidosis, a multisystem inflammatory disorder of undetermined etiology, can manifest as diffuse hypermetabolic adenopathy on imaging. The disorder is characterized by T-lymphocyte infiltration, granuloma formation, and distortion of normal microarchitecture. The prevailing theory holds that sarcoidosis develops in genetically susceptible individuals from a cell-mediated immune response to one or more unidentified antigens [33]. The cell-mediated response to antigenic stimuli results in well-formed, non-caseating epithelioid granulomas [34].\n\nSarcoidosis is commonly associated with systemic symptoms such as fatigue, night sweats, and weight loss, which can mimic symptoms associated with malignancy. Pulmonary symptoms, however, are the most common and thoracic involvement (i.e., hilar adenopathy on radiograph) is seen in more than 90% of patients with sarcoidosis. PFTs often yield decreased DLCO and a restrictive physiology [33]. Sarcoidosis, usually an insidious and chronic disease, can present through involvement in the skin, eyes, and with lesser frequency, as cardiac and CNS manifestations [33], [34], [35]. Sarcoidosis may also present acutely as Lofgren syndrome. Lofgren syndrome is typically manifest by erythema nodosum, bilateral hilar adenopathy, and poly-arthralgia, whereby a presumptive diagnosis can be made without biopsy [29], [33].\n\nWhole-body PET scans may also suggest occult sarcoidosis through display of hypermetabolic activity. According to one study, among 139 patients with sarcoidosis, SUV activity ranged between 2.0 and 15.8 [36]. Imaging can suggest sarcoidosis; however, the diagnosis relies on the pairing of clinical and radiographic findings with histologic evidence of non-caseating granulomas. To obtain tissue, bronchoscopy with trans-bronchial biopsy is heavily utilized and has a diagnostic yield of 85% [33].\n\nWhile sarcoidosis more often occurs in patients without a history of lymphoma, the overlap between sarcoidosis and lymphoma is an important one. Utilizing a Danish health-registry to review a series of cases of coexistent sarcoidosis and malignant lymphoproliferative disease, Brincker and colleagues found that there were 5.5 times more cases of lymphoma observed in patients with a history of sarcoidosis than in the general population [37]. The syndrome linking sarcoidosis and lymphoma possessed several characteristics: the lymphoma occurred after a patient was found to have sarcoidosis; the diagnosis of sarcoidosis occurred at a later age than was typical in the general sarcoid population; and Hodgkin lymphoma occurred more frequently in sarcoidosis patients than would otherwise have been expected in the general population [9], [29], [37].\n\nWhile Brincker's work suggests a mechanism whereby persistent immune system activation by sarcoidosis yields a lymphoproliferative state, there are also instances of sarcoidosis occurring after the diagnosis of lymphoma. London and colleagues reported on 14 such cases and through a literature review identified an additional 25 patients presenting with sarcoidosis following lymphoma [9]. Much like our patient, most of the patients developed sarcoidosis shortly after achieving a PR or a CR with chemotherapy for their lymphoma, arguing that the development of sarcoidosis may be related to an excessive immune response to the lymphoma cells, or reactive to chemotherapy (i.e., R-CHOP) [9]. In these patients, sarcoidosis was most commonly asymptomatic and was manifest by hypermetabolic lymphadenopathy.\n\n4 Conclusion\nIn summary, this case illustrates the unusual presentation of sarcoidosis in an asymptomatic man presumed to have recurrent DLBCL. We highlight the lack of evidence to support routine imaging in surveillance for relapsed DLBCL as well as the importance of tissue sampling before altering the treatment plan. Despite our patient's incredible psychological strain, financial stress, and exposure to a battery of potentially hazardous tests, he remains asymptomatic, without need for systemic therapy for sarcoidosis, and without any suspicion for recurrent lymphoma.\n==== Refs\nReferences\n1 Bray F. Ren J.S. Masuyer E. Ferlay J. Estimates of global cancer prevalence for 27 sites in the adult population in 2008 Int. J. Cancer 132 2013 1133 1145 22752881 \n2 Surveillance, Epidemiology and End Results (SEER) Program. SEER*Stat Database: North American Association of Central Cancer Registries (NAACCR) Incidence-CiNA Analytic File, 1995–2010, Custom File With County, ACS Facts and Figures Projection Project. Bethesda, MD: National Cancer Institute, Division of Cancer Control and Population Sciences, Surveillance Research Program, Surveillance Systems Branch; 2013.\n3 Al-Hamadani M. Habermann T.M. Cerhan J.R. Macon W.R. Maurer M.J. Go R.S. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: a longitudinal analysis of the National Cancer Data Base from 1998 to 2011 Am. J. Hematol. 90 2015 790 795 26096944 \n4 Zelenetz A.D. Gordon L.I. Wierda W.G. Abramson J.S. Advani R.H. Andreadis C.B. Bartlett N. Byrd J.C. Fayad L.E. Fisher R.I. Glenn M.J. Habermann T.M. Lee Harris N. Hernandez-Ilizaliturri F. Hoppe R.T. Horwitz S.M. Kaminski M.S. Kelsey C.R. Kim Y.H. Krivacic S. LaCasce A.S. Lunning M. Nademanee A. Porcu P. Press O. Rabinovitch R. Reddy N. Reid E. Roberts K. Saad A.A. Sokol L. Swinnen L.J. Vose J.M. Yahalom J. Zafar N. Dwyer M. Sundar H. Diffuse large B-cell lymphoma version 1.2016 J. Natl. Compr. Cancer Netw. 14 2016 196 231 \n5 Miller T.P. Dahlberg S. Cassady J.R. Adelstein D.J. Spier C.M. Grogan T.M. LeBlanc M. Carlin S. Chase E. Fisher R.I. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma N. Engl. J. Med. 339 1998 21 26 9647875 \n6 Coiffier B. State-of-the-art therapeutics: diffuse large B-cell lymphoma J. Clin. Oncol. 23 2005 6387 6393 16155024 \n7 Yoneda K.Y. Louie S. Shelton D.K. Mediastinal tumors Curr. Opin. Pulm. Med. 7 2001 226 233 11470979 \n8 Kwok M. Wu S.P. Mo C. Summers T. Roschewski M. Circulating tumor DNA to monitor therapy for aggressive B-cell lymphomas Curr. Treat. Options Oncol. 17 2016 47 27461036 \n9 London J. Grados A. Fermé C. Charmillon A. Maurier F. Deau B. Crickx E. Brice P. Chapelon-Abric C. Haioun C. Burroni B. Alifano M. Le Jeunne C. Guillevin L. Costedoat-Chalumeau N. Schleinitz N. Mouthon L. Terrier B. Sarcoidosis occurring after lymphoma: report of 14 patients and review of the literature Medicine 93 2014 e121 25380084 \n10 Raut L.S. Chakrabarti P.P. Management of relapsed-refractory diffuse large B cell lymphoma South Asian J. Cancer 3 2014 66 70 24665451 \n11 Philip T. Guglielmi C. Hagenbeek A. Somers R. Van der Lelie H. Bron D. Sonneveld P. Gisselbrecht C. Cahn J.Y. Harousseau J.L. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma N. Engl. J. Med. 333 1995 1540 1545 7477169 \n12 A. Goodman, January 25). CAR T-cell therapy KTE-C19 appears successful in aggressive B-Cell lymphoma. Retrieved September 8, 2017, from 〈http://www.ascopost.com/issues/january-25-2017/car-t-cell-therapy-kte-c19-appears-successful-in-aggressive-b-cell-lymphoma/〉.\n13 Davies A. Tailoring front-line therapy in diffuse large B-cell lymphoma: who should we treat differently? Hematol. Am. Soc. Hematol. Educ. Program 2017 2017 284 294 \n14 Thompson C.A. Ghesquieres H. Maurer M.J. Cerhan J.R. Biron P. Ansell S.M. Chassagne-Clément C. Inwards D.J. Gargi T. Johnston P.B. Nicolas-Virelizier E. Macon W.R. Peix M. Micallef I.N. Sebban C. Nowakowski G.S. Porrata L.F. Weiner G.J. Witzig T.E. Habermann T.M. Link B.K. Utility of routine post-therapy surveillance imaging in diffuse large B-cell lymphoma J. Clin. Oncol. 32 2014 3506 3512 25267745 \n15 Goldschmidt N. Or O. Klein M. Savitsky B. Paltiel O. The role of routine imaging procedures in the detection of relapse of patients with Hodgkin lymphoma and aggressive non-Hodgkin lymphoma Ann. Hematol. 90 2011 165 171 20706721 \n16 El-Galaly T.C. Jakobsen L.H. Hutchings M. de Nully Brown P. Nilsson-Ehle H. Székely E. Mylam K.J. Hjalmar V. Johnsen H.E. Bøgsted M. Jerkeman M. Routine imaging for diffuse large B-cell lymphoma in first complete remission does not improve post-treatment survival: a Danish-Swedish population-based study J. Clin. Oncol. 33 2015 3993 3998 26438115 \n17 Zinzani P.L. Tani M. Trisolini R. Fanti S. Stefoni V. Alifano M. Castellucci P. Musuraca G. Dalpiaz G. Alinari L. Marchi E. Fina M. Pellegrini C. Farsad M. Cancellieri A. Busca A. Canini R. Pileri S. Baccarani M. Boaron M. Histological verification of positive positron emission tomography findings in the follow-up of patients with mediastinal lymphoma Haematologica 92 2007 771 777 17550849 \n18 Sonet A. Graux C. Nollevaux M.C. Krug B. Bosly A. Vander Borght T. Unsuspected FDG-PET findings in the follow-up of patients with lymphoma Ann. Hematol. 86 2007 9 15 17021839 \n19 Cheson B.D. Fisher R.I. Barrington S.F. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and Non-Hodgkin lymphoma: the Lugano Classification J. Clin. Oncol. 32 2014 3059 3067 25113753 \n20 Abel G.A. Does surveillance imaging after treatment for diffuse large B-cell lymphoma really work? J. Clin. Oncol. 33 2015 1427 1429 25823731 \n21 Deimling G.T. Bowman K.F. Sterns S. Wagner L.J. Kahana B. Cancer-related health worries and psychological distress among older adult, long-term cancer survivors Psychooncology 15 2006 306 320 16041841 \n22 Avivi I. Zilberlicht A. Dann E.J. Leiba R. Faibish T. Rowe J.M. Bar-Shalom R. Strikingly high false positivity of surveillance FDG-PET/CT scanning among patients with diffuse large cell lymphoma in the rituximab era Am. J. Hematol. 88 2013 400 405 23423884 \n23 Brenner D.J. Hall E.J. Computed tomography--an increasing source of radiation exposure N. Engl. J. Med. 357 2007 2277 2284 18046031 \n24 Scholzen T. Gerdes J. The Ki-67 protein: from the known and the unknown J. Cell Physiol. 182 2000 311 322 10653597 \n25 He X. Chen Z. Fu T. Jin X. Yu T. Liang Y. Zhao X. Huang L. Ki-67 is a valuable prognostic predictor of lymphoma but its utility varies in lymphoma subtypes: evidence from a systematic meta-analysis BMC Cancer 14 2014 153 24597851 \n26 Sehn L.H. Berry B. Chhanabhai M. Fitzgerald C. Gill K. Hoskins P. Klasa R. Savage K.J. Shenkier T. Sutherland J. Gascoyne R.D. Connors J.M. The revised International Prognostic index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP Blood 109 2007 1857 1861 17105812 \n27 International Non-Hodgkin's Lymphoma Prognostic Factors Project A predictive model for aggressive non-Hodgkin's lymphoma N. Engl. J. Med. 329 1993 987 994 8141877 \n28 Gaddey H.L. Riegel A.M. Unexplained lymphadenopathy: evaluation and differential diagnosis Am. Fam. Phys. 94 2016 896 903 \n29 Solbes E. Harper R.W. Louie S. The fear of lymphoadenopathy: does it portend sarcoidosis or lymphoma? Consultant 360 56 2016 1016 2020 〈http://www.consultant360. com/articles/fear-lymphadenopathy-does-it-portend-sarcoidosis-or-lymphoma〉 (Retrieved from September 02, 2017) \n30 Kirchner J. Kirchner E.M. Goltz J.P. Obermann A. Kickuth R. Enlarged hilar and mediastinal lymph nodes in chronic obstructive pulmonary disease J. Med. Imaging Radiat. Oncol. 54 2010 333 338 20718913 \n31 Thomas R.D. Blaquiere R.M. Reactive mediastinal lymphadenopathy in bronchiectasis assessed by CT Acta Radiol. 34 1993 489 491 8369187 \n32 Ngom A. Dumont P. Diot P. Lemarié E. Benign mediastinal lymphadenopathy in congestive heart failure Chest 119 2001 653 656 11171755 \n33 Iannuzzi M.C. Fontana J.R. Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics JAMA 305 2011 391 399 21266686 \n34 Iannuzzi M.C. Rybicki B.A. Teirstein A.S. Sarcoidosis N. Engl. J. Med. 357 2007 2153 2165 18032765 \n35 Kellinghaus C. Schilling M. Lüdemann P. Neurosarcoidosis: clinical experience and diagnostic pitfalls Eur. Neurol. 51 2004 84 88 14752214 \n36 Teirstein A.S. Machac J. Almeida O. Lu P. Padilla M.L. Iannuzzi M.C. Results of 188 whole-body fluorodeoxyglucose positron emission tomography scans in 137 patients with sarcoidosis Chest 132 2007 1949 1953 17925421 \n37 Brincker H. The sarcoidosis-lymphoma syndrome Br. J. Cancer 54 1986 467 473 3756082\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0489",
"issue": "9()",
"journal": "Leukemia research reports",
"keywords": "Diffuse large B-cell lymphoma; Lymphadenopathy; Sarcoidosis",
"medline_ta": "Leuk Res Rep",
"mesh_terms": null,
"nlm_unique_id": "101608906",
"other_id": null,
"pages": "48-53",
"pmc": null,
"pmid": "29892550",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "8369187;8141877;26850490;26096944;24665451;25113753;18046031;18032765;24597851;16155024;17925421;7477169;20718913;14752214;26438115;25380084;25823731;20706721;10653597;29222268;11171755;11470979;16041841;9647875;17550849;17021839;27929264;3756082;22752881;27461036;17105812;21266686;23423884;25267745",
"title": "The fear of lymphadenopathy: A cautionary case of sarcoidosis masquerading as recurrent diffuse large b-cell lymphoma (DLBCL).",
"title_normalized": "the fear of lymphadenopathy a cautionary case of sarcoidosis masquerading as recurrent diffuse large b cell lymphoma dlbcl"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/18/0099338",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": n... |
{
"abstract": "In patients with ischemic stroke of unknown cause cerebral vasculitis is a rare but relevant differential diagnosis, especially when signs of intracranial artery stenosis are found and laboratory findings show systemic inflammation. In such cases, high-resolution T1w vessel wall magnetic resonance imaging (MRI; 'black blood' technique) at 3 T is preferentially performed, but may not be available in every hospital. We report a case of an 84-year-old man with right hemispheric transient ischemic attack and signs of distal occlusion in the right internal carotid artery (ICA) in duplex sonography. Standard MRI with contrast agent pointed the way to the correct diagnosis since it showed an intramural contrast uptake in the right ICA and both vertebral arteries. Temporal artery biopsy confirmed the suspected diagnosis of a giant cell arteritis and dedicated vessel wall MRI performed later supported the suspected intracranial large artery inflammation. Our case also shows that early diagnosis and immunosuppressive therapy may not always prevent disease progression, as our patient suffered several infarcts in the left middle cerebral artery (MCA) territory with consecutive high-grade hemiparesis of the right side within the following four months.",
"affiliations": "Department of Neurology, Neurocenter, University of Freiburg, Germany.;Department of Radiology, Kreiskliniken Lörrach, Germany.;Department of Neurology, Kreiskliniken Lörrach, Germany.;Department of Neuroradiology, Neurocenter, University of Freiburg, Germany.;Institute of Pathology, University Hospital Basel, Switzerland.;Department of Neurology, Kreiskliniken Lörrach, Germany.;Department of Neurology, Neurocenter, University of Freiburg, Germany matthias.reinhard@uniklinik-freiburg.de.",
"authors": "Oeinck|Maximilian|M|;Rozeik|Christoph|C|;Wattchow|Jens|J|;Meckel|Stephan|S|;Schlageter|Manuel|M|;Beeskow|Christel|C|;Reinhard|Matthias|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1971400916638354",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1971-4009",
"issue": "29(3)",
"journal": "The neuroradiology journal",
"keywords": "Intracranial internal carotid artery stenosis; cerebral vasculitis; cranial magnetic resonance imaging; giant cell arteritis; ischemic stroke",
"medline_ta": "Neuroradiol J",
"mesh_terms": "D000369:Aged, 80 and over; D002343:Carotid Artery, Internal; D016893:Carotid Stenosis; D006801:Humans; D002546:Ischemic Attack, Transient; D008279:Magnetic Resonance Imaging; D008297:Male; D018616:Ultrasonography, Doppler, Duplex",
"nlm_unique_id": "101295103",
"other_id": null,
"pages": "208-12",
"pmc": null,
"pmid": "26988083",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7839388;24722305;24854377;18668559;25102371;5078894;17139651;25526454;3347337;22928809;23795218;25169925;24947295;22859280;22156692;19221296;12928927;9704651;20479365",
"title": "Why a standard contrast-enhanced MRI might be useful in intracranial internal carotid artery stenosis.",
"title_normalized": "why a standard contrast enhanced mri might be useful in intracranial internal carotid artery stenosis"
} | [
{
"companynumb": "DE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-37807BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
... |
{
"abstract": "BACKGROUND\nWe hypothesized that engineering a combined lymph node/melanoma organoid from the same patient would allow tumor, stroma, and immune system to remain viable for personalized immunotherapy screening.\n\n\nMETHODS\nSurgically obtained matched melanoma and lymph node biospecimens from the same patient were transferred to the laboratory and washed with saline, antibiotic, and red blood cell lysis buffer. Biospecimens were dissociated, incorporated into an extracellular matrix (ECM)-based hydrogel system, and biofabricated into three dimensional (3D) mixed melanoma/node organoids. Cells were not sorted, so as to preserve tumor heterogeneity, including stroma and immune cell components, resulting in immune-enhanced patient tumor organoids (iPTOs). Organoid sets were screened in parallel with nivolumab, pembrolizumab, ipilimumab, and dabrafenib/trametinib for 72 h. LIVE/DEAD staining and quantitative metabolism assays recorded relative drug efficacy. Histology and immunohistochemistry were used to compare tumor melanoma cells with organoid melanoma cells. Lastly, node-enhanced iPTOs were employed to activate patient-matched peripheral blood T cells for killing of tumor cells in naïve PTOs.\n\n\nRESULTS\nTen biospecimen sets obtained from eight stage III and IV melanoma patients were reconstructed as symbiotic immune/tumor organoids between September 2017 and June 2018. Successful establishment of viable organoid sets was 90% (9/10), although organoid yield varied with biospecimen size. Average time from organoid development to initiation of immunotherapy testing was 7 days. In three patients for whom a node was not available, it was substituted with peripheral blood mononuclear cells. iPTO response to immunotherapy was similar to specimen clinical response in 85% (6/7) patients. In an additional pilot study, peripheral T cells were circulated through iPTOs, and subsequently transferred to naïve PTOs from the same patient, resulting in tumor killing, suggesting a possible role of iPTOs in generating adaptive immunity.\n\n\nCONCLUSIONS\nDevelopment of 3D mixed immune-enhanced tumor/node organoids is a feasible platform, allowing individual patient immune system and tumor cells to remain viable for studying of personalized immunotherapy response.",
"affiliations": "Department of Surgery - Oncology, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, USA. kvotanop@wakehealth.edu.;Wake Forest Organoid Research Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.;Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Wake Forest Organoid Research Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.;Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.;Comprehensive Cancer Center at Wake Forest Baptist Medical, Medical Center Boulevard, Winston-Salem, NC, USA.;Department of Surgery - Oncology, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, USA.;Department of Surgery - Oncology, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, USA.;Comprehensive Cancer Center at Wake Forest Baptist Medical, Medical Center Boulevard, Winston-Salem, NC, USA. skardal.1@osu.edu.",
"authors": "Votanopoulos|Konstantinos I|KI|;Forsythe|Steven|S|;Sivakumar|Hemamylammal|H|;Mazzocchi|Andrea|A|;Aleman|Julio|J|;Miller|Lance|L|;Levine|Edward|E|;Triozzi|Pierre|P|;Skardal|Aleksander|A|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological",
"country": "United States",
"delete": false,
"doi": "10.1245/s10434-019-08143-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1068-9265",
"issue": "27(6)",
"journal": "Annals of surgical oncology",
"keywords": null,
"medline_ta": "Ann Surg Oncol",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D004354:Drug Screening Assays, Antitumor; D005240:Feasibility Studies; D006801:Humans; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear; D008198:Lymph Nodes; D008545:Melanoma; D008954:Models, Biological; D009940:Organoids; D010865:Pilot Projects; D057285:Precision Medicine",
"nlm_unique_id": "9420840",
"other_id": null,
"pages": "1956-1967",
"pmc": null,
"pmid": "31858299",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Model of Patient-Specific Immune-Enhanced Organoids for Immunotherapy Screening: Feasibility Study.",
"title_normalized": "model of patient specific immune enhanced organoids for immunotherapy screening feasibility study"
} | [
{
"companynumb": "NVSC2019US081380",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRAMETINIB"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Epilepsy with the main symptom of amnesia is known as transient epileptic amnesia (TEA). Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia. The concept that Lewy body disease includes Parkinson's disease with dementia and dementia with Lewy bodies was proposed in the 2005 revision of the Clinical Diagnostic Criteria. Here, we describe a woman with cognitive impairment, olfactory dysfunction, and reduced 123 I-meta-iodobenzylguanidine uptake on myocardial scintigraphy. The patient and her family and friends were unaware of parkinsonism, visual hallucinations, or epilepsy for a long period. After syncope occurred twice within a short interval, electroencephalography revealed sharp waves from the bilateral frontal to parietal lobes, indicating a diagnosis of TEA. The present case prompted us to compare the symptoms of TEA with the clinical diagnostic criteria for dementia with Lewy bodies, revealing their similarities. We also discuss whether Lewy body disease may cause TEA rather than having an incidental association with it.",
"affiliations": "Department of Psychogeriatrics, Kamiiida Daiichi General Hospital, Nagoya, Japan.;Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Shinjuku Shinkei Clinic, Tokyo, Japan.;Clinic Ian Center Minami, Yokohama, Japan.;Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.",
"authors": "Ukai|Katsuyuki|K|;Fujishiro|Hiroshige|H|;Watanabe|Masako|M|;Kosaka|Kenji|K|;Ozaki|Norio|N|",
"chemical_list": "D000927:Anticonvulsants; D019797:3-Iodobenzylguanidine; D000077287:Levetiracetam; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": "10.1111/psyg.12199",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-3500",
"issue": "17(2)",
"journal": "Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society",
"keywords": "\nLewy body disease; complex partial seizures; dementia with Lewy bodies; levetiracetam; temporal lobe epilepsy; transient epileptic amnesia",
"medline_ta": "Psychogeriatrics",
"mesh_terms": "D019797:3-Iodobenzylguanidine; D000368:Aged; D000647:Amnesia; D000927:Anticonvulsants; D003072:Cognition Disorders; D004569:Electroencephalography; D005260:Female; D006212:Hallucinations; D006801:Humans; D000077287:Levetiracetam; D020961:Lewy Body Disease; D055414:Myocardial Perfusion Imaging; D020734:Parkinsonian Disorders; D010889:Piracetam; D012640:Seizures; D015899:Tomography, Emission-Computed, Single-Photon",
"nlm_unique_id": "101230058",
"other_id": null,
"pages": "120-125",
"pmc": null,
"pmid": "27356810",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Similarity of symptoms between transient epileptic amnesia and Lewy body disease.",
"title_normalized": "similarity of symptoms between transient epileptic amnesia and lewy body disease"
} | [
{
"companynumb": "JP-CIPLA LTD.-2016JP19023",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAVASTATIN"
},
"drugadditional": "3",
... |
{
"abstract": "AF might be a life threatening disease. Patients have been under oral antithrombotic treatment in order to avoid thrombotic events. Although this treatment proved to be effective in the last decades there was always the inconvenience of a regular blood control. In the last months NOACs have been flooding the market promising to be as effective as their older concurrents in certain circumstances and highlighting the fact that the control of INR has become obsolete. However, as there is no specific antidote up to date, NOACs might present a life threatening event in case of an intracerebral haemorrhage. The brain surgeons might find themselves in a difficult situation when they have to decide whether to operate on a patient with a compromised haemostasis or not. We present four patients who were treated with NOACs for AF. Three of them were admitted with intracerebral haemorrhage in our neurosurgical unit from January to October 2013. The fourth patient bled one week after stopping his treatment with NOAC. Furthermore we take a closer look to the existing literature and try to portray the issue from a neurosurgical point of view.",
"affiliations": null,
"authors": "Hana|A|A|;Berthold|C|C|;Gunness|V R N|VR|;Hana|A|A|;Dooms|G|G|;Standhardt|H|H|;Koy|J|J|;Matgé|G|G|;Boecher-Schwarz|H|H|;Hertel|F|F|",
"chemical_list": "D000925:Anticoagulants; D001562:Benzimidazoles; D009025:Morpholines; D013876:Thiophenes; D015091:beta-Alanine; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "Luxembourg",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0037-9247",
"issue": null,
"journal": "Bulletin de la Societe des sciences medicales du Grand-Duche de Luxembourg",
"keywords": null,
"medline_ta": "Bull Soc Sci Med Grand Duche Luxemb",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D001562:Benzimidazoles; D002543:Cerebral Hemorrhage; D000069604:Dabigatran; D005260:Female; D006801:Humans; D006973:Hypertension; D008297:Male; D009025:Morpholines; D000069552:Rivaroxaban; D013876:Thiophenes; D015091:beta-Alanine",
"nlm_unique_id": "7503402",
"other_id": null,
"pages": "57-66",
"pmc": null,
"pmid": "25011204",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "NOAC and intracerebral bleeding--presentation of four cases and review of the literature.",
"title_normalized": "noac and intracerebral bleeding presentation of four cases and review of the literature"
} | [
{
"companynumb": "LU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2014-BI-38577GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "LU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "BACKGROUND\nTakotsubo cardiomyopathy has been associated with the use of catecholamines; however, its development after the use of nebulised adrenaline for the management of acute airway obstruction has not previously been described.\n\n\nMETHODS\nA 66-year-old man with squamous cell carcinoma of the larynx, with tumour-node-metastasis staging of T3N2cM0, confirmed by biopsy and computed tomography, presented to the emergency department with acute airway obstruction. He was treated twice with nebulised adrenaline and intravenous dexamethasone. After a period of 24 hours, cardiac rhythm changes were noted on telemetry. A 12-lead electrocardiogram showed widespread T-wave inversion and QT prolongation suggestive of an acute coronary syndrome. Coronary angiography demonstrated no coronary artery disease, but left ventricular angiography showed marked apical ballooning and apical wall akinesia consistent with a diagnosis of takotsubo cardiomyopathy.\n\n\nCONCLUSIONS\nTakotsubo cardiomyopathy can mimic true ischaemic heart disease and the diagnosis requires a high index of suspicion in patients managed with nebulised adrenaline.",
"affiliations": "Department of Otolaryngology,Gloucestershire Royal Hospital,Gloucester,UK.;Department of Otolaryngology,Gloucestershire Royal Hospital,Gloucester,UK.;Department of Otolaryngology,Gloucestershire Royal Hospital,Gloucester,UK.;Department of Otolaryngology,Gloucestershire Royal Hospital,Gloucester,UK.",
"authors": "Keshtkar|F|F|;Dale|O T|OT|;Bennett|W O|WO|;Hall|C E|CE|",
"chemical_list": "D004837:Epinephrine",
"country": "England",
"delete": false,
"doi": "10.1017/S0022215116008288",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-2151",
"issue": "130(9)",
"journal": "The Journal of laryngology and otology",
"keywords": "Adrenaline; Epinephrine; Airway Obstruction; Apical Ballooning Syndrome; Broken Heart Syndrome; Catecholamines; Laryngeal Neoplasm; Stress Cardiomyopathy; Takotsubo Cardiomyopathy; Takotsubo Syndrome; Transient Apical Ballooning Syndrome",
"medline_ta": "J Laryngol Otol",
"mesh_terms": "D000368:Aged; D000402:Airway Obstruction; D002294:Carcinoma, Squamous Cell; D004837:Epinephrine; D006801:Humans; D007822:Laryngeal Neoplasms; D008297:Male; D009330:Nebulizers and Vaporizers; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "8706896",
"other_id": null,
"pages": "883-6",
"pmc": null,
"pmid": "27377118",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of airway obstruction with nebulised adrenaline resulting in takotsubo cardiomyopathy: case report.",
"title_normalized": "management of airway obstruction with nebulised adrenaline resulting in takotsubo cardiomyopathy case report"
} | [
{
"companynumb": "GB-MYLANLABS-2016M1048608",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": null,
... |
{
"abstract": "Gabapentin is an antiepileptic medication that also has been used for restless legs syndrome. The mechanism of action is unknown. The most commonly reported adverse effects of this medication include somnolence, dizziness, ataxia, fatigue, nystagmus, and tremor. Myalgia has been reported in 2% of gabapentin users compared with 1.9% of patients in placebo-controlled add-on trials. Two patients on short daily hemodialysis therapy developed neuromuscular symptoms and an elevation in creatine kinase levels after starting gabapentin therapy. To our knowledge, this is the first case report of an increase in creatine kinase level after the administration of gabapentin.",
"affiliations": "Ottawa Hospital, Department of Medicine, Kidney Research Centre, University of Ottawa, Ontario, Canada.",
"authors": "Lipson|Jennifer|J|;Lavoie|Susan|S|;Zimmerman|Deborah|D|",
"chemical_list": "D000588:Amines; D000927:Anticonvulsants; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000069059:Atorvastatin",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2005.02.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "45(6)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": null,
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000328:Adult; D000588:Amines; D000927:Anticonvulsants; D000069059:Atorvastatin; D015220:Calcium Channels; D015897:Comorbidity; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D005921:Glomerulonephritis; D015432:Glomerulonephritis, Membranoproliferative; D006538:Heptanoic Acids; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009468:Neuromuscular Diseases; D010530:Peritoneal Dialysis; D005082:Physical Exertion; D011183:Postoperative Complications; D011758:Pyrroles; D012008:Recurrence; D006435:Renal Dialysis; D012148:Restless Legs Syndrome; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "e100-4",
"pmc": null,
"pmid": "15957120",
"pubdate": "2005-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gabapentin-induced myopathy in 2 patients on short daily hemodialysis.",
"title_normalized": "gabapentin induced myopathy in 2 patients on short daily hemodialysis"
} | [
{
"companynumb": "CA-PFIZER INC-2005092127",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": "1",
... |
{
"abstract": "The most common adverse event after cervical mediastinoscopy is recurrent laryngeal nerve (RLN) injury, which has an incidence of 0.6% [1]. We report the case of a 68-year-old man with non-small cell lung cancer (NSCLC) who experienced transient bilateral vocal cord paralysis after mediastinoscopy, which manifested in complete aphonia. This patient's ability to maintain his airway was carefully followed up, but neither endotracheal intubation nor tracheostomy was required. The vocal cord paralysis resolved without intervention after 5 hours. To our knowledge, this is the first reported case in which bupivicaine used at the end of a cervical mediastinoscopy diffused through the freshly dissected planes to paralyze both RLNs along the tracheoesophageal grooves.",
"affiliations": "Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida.;University of South Florida Morsani College of Medicine, Tampa, Florida.;University of South Florida Morsani College of Medicine, Tampa, Florida.;Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida; Department of Thoracic Surgery, Bay Pines Veterans Affairs Healthcare System, Bay Pines, Florida; Department of Thoracic Surgery, Kaiser Permanente, Santa Clara, California.;Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida; Department of Thoracic Surgery, Bay Pines Veterans Affairs Healthcare System, Bay Pines, Florida; Department of Surgery, University of Central Florida, Orlando, Florida. Electronic address: edward.hong@va.gov.",
"authors": "Velez-Cubian|Frank O|FO|;Toosi|Kavian|K|;Glover|Jessica|J|;Pancholy|Bharat|B|;Hong|Edward|E|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2017.01.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "103(6)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000368:Aged; D001044:Aphonia; D002289:Carcinoma, Non-Small-Cell Lung; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008481:Mediastinoscopy; D014826:Vocal Cord Paralysis",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e549-e550",
"pmc": null,
"pmid": "28528064",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient Aphonia After Mediastinoscopy.",
"title_normalized": "transient aphonia after mediastinoscopy"
} | [
{
"companynumb": "US-PFIZER INC-2017247848",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPIVACAINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Microsporidiosis is a rare, but emerging opportunistic infection in solid organ transplant and stem cell transplant recipients. Renal involvement in microsporidiosis is very rarely seen in these recipients. We describe two cases of pediatric renal microsporidiosis, diagnosed on renal biopsies, following bone marrow transplantation presenting as severe acute kidney injury. The first patient died, whereas the second survived due to early diagnosis based on high index of suspicion and prompt treatment with Albendazole. We believe these are the first such reported cases of renal microsporidiosis in pediatric bone marrow transplant recipients.",
"affiliations": "Department of Histopathology, Apollo Hospitals, CHENNAI, TAMIL NADU, INDIA.",
"authors": "Shah|Saloni|S|;Jacob|Sheba Sweetline|SS|;Mani|Rama|R|;Parameswaran|Ashok|A|;Kumar|Sunil|S|;Annigeri|Rajeev A|RA|;Mahesh|Raja|R|;Uppuluri|Ramya|R|",
"chemical_list": "D000977:Antiparasitic Agents; D007166:Immunosuppressive Agents; D015766:Albendazole",
"country": "Turkey",
"delete": false,
"doi": "10.5146/tjpath.2017.01416",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-5615",
"issue": "36(1)",
"journal": "Turk patoloji dergisi",
"keywords": null,
"medline_ta": "Turk Patoloji Derg",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D015766:Albendazole; D000977:Antiparasitic Agents; D016026:Bone Marrow Transplantation; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007223:Infant; D008297:Male; D016814:Microsporidia; D016881:Microsporidiosis; D009894:Opportunistic Infections; D016896:Treatment Outcome",
"nlm_unique_id": "9440471",
"other_id": null,
"pages": "68-72",
"pmc": null,
"pmid": "29630083",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Renal Microsporidiosis in Pediatric Bone Marrow Transplant Recipients: A Case Series.",
"title_normalized": "renal microsporidiosis in pediatric bone marrow transplant recipients a case series"
} | [
{
"companynumb": "IN-PFIZER INC-2020130100",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Monoclonal immunoglobulin heavy chain (HC) diseases are rare proliferative disorders of B lymphocytes or plasma cells characterized by the presence of monoclonal α-, µ-, or γ-HC without associated light chains in the blood, urine, or both. We report a 59-year-old woman with a history of Hodgkin disease who developed hypercalcemia, proteinuria, and impaired kidney function. Protein electrophoresis and immunofixation displayed γ-HC without associated light chains in the serum and urine. Pathologic examination demonstrated severe tubulointerstitial nephritis associated with diffuse and strong linear staining of the glomerular and tubular basement membranes as well as Bowman capsules for γ-HC, but not for κ- or λ-light chains. Immunohistochemical examination of the kidney and bone marrow demonstrated numerous CD138+ plasma cells immunoreactive for γ-HC, but not for κ- or λ-light chains. This is the first report of tubulointerstitial nephritis associated with γ-HC deposition and γ-HC restricted plasma cells in the kidney. This report heightens awareness about tubulointerstitial nephritis as a possible manifestation of γ-HC deposition in the kidney.",
"affiliations": "Division of Nephrology and Hypertension, University of Miami, Miami, FL, USA. anayer@med.miami.edu.",
"authors": "Nayer|Ali|A|;Green|Dollie F|DF|;Gonzalez-Suarez|Maria L|ML|;Sujoy|Victoria|V|;Ikpatt|Offiong F|OF|;Thomas|David B|DB|",
"chemical_list": "D015415:Biomarkers; D007142:Immunoglobulin gamma-Chains; D053668:Syndecan-1",
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1735-8582",
"issue": "8(5)",
"journal": "Iranian journal of kidney diseases",
"keywords": null,
"medline_ta": "Iran J Kidney Dis",
"mesh_terms": "D015415:Biomarkers; D001797:Blood Protein Electrophoresis; D005260:Female; D006362:Heavy Chain Disease; D006801:Humans; D006934:Hypercalcemia; D007142:Immunoglobulin gamma-Chains; D007668:Kidney; D008875:Middle Aged; D009395:Nephritis, Interstitial; D010950:Plasma Cells; D011507:Proteinuria; D053668:Syndecan-1",
"nlm_unique_id": "101316967",
"other_id": null,
"pages": "417-23",
"pmc": null,
"pmid": "25194410",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tubulointerstitial nephritis accompanying gamma-heavy chain deposition and gamma-heavy chain restricted plasma cells in the kidney.",
"title_normalized": "tubulointerstitial nephritis accompanying gamma heavy chain deposition and gamma heavy chain restricted plasma cells in the kidney"
} | [
{
"companynumb": "US-BAYER-2014-144030",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINBLASTINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFLT3-internal tandem duplication (ITD) mutations are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 inhibitors have shown clinical activity in AML with FLT3-ITD, but responses are usually short-lived.\n\n\nMETHODS\nThis study examined 69 FLT3-mutated patients with AML, who were treated with different FLT3 inhibitors to analyze emergence of new mutations.\n\n\nRESULTS\nAt baseline, 87% of patients had an ITD mutation, 7% had a D835/I836 mutation, and 6% had combined ITD and D835/I836 mutations. Responses occurred in 32% of patients, all with FLT3-ITD; none of the patients with D835/I836 or ITD+D835/I836 responded. Mutational assessment at the time of FLT3 inhibitor discontinuation showed that 68% of patients were unchanged, 10% had become undetectable, and 22% of patients progressed from a single ITD to have combined ITD+D835/I836 mutations. In those patients with unchanged FLT3 mutation at progression, the median survival was 5 months, whereas in those with undetectable and with combined ITD+D835/I836 mutations, the median survival was 7 months, respectively.\n\n\nCONCLUSIONS\nThese data confirm in vitro observations that a secondary tyrosine kinase domain mutation may arise after the use of FLT3 inhibitors in patients with single FLT3-ITD mutated AML, a phenomenon that is associated with resistance and a poor prognosis.",
"affiliations": "Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.",
"authors": "Alvarado|Yesid|Y|;Kantarjian|Hagop M|HM|;Luthra|Rajyalakshmi|R|;Ravandi|Farhad|F|;Borthakur|Gautam|G|;Garcia-Manero|Guillermo|G|;Konopleva|Marina|M|;Estrov|Zeev|Z|;Andreeff|Michael|M|;Cortes|Jorge E|JE|",
"chemical_list": "D000970:Antineoplastic Agents; D052160:Benzothiazoles; D002227:Carbazoles; D005663:Furans; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C544967:quizartinib; D000077157:Sorafenib; C119379:lestaurtinib; C497970:FLT3 protein, human; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3",
"country": "United States",
"delete": false,
"doi": "10.1002/cncr.28705",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-543X",
"issue": "120(14)",
"journal": "Cancer",
"keywords": "FLT3 inhibitors; FLT3-ITD; FLT3-TKD; acute myeloid leukemia; secondary FLT3 mutations",
"medline_ta": "Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D002227:Carbazoles; D004252:DNA Mutational Analysis; D005260:Female; D005663:Furans; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D012189:Retrospective Studies; D000077157:Sorafenib; D016019:Survival Analysis; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "0374236",
"other_id": null,
"pages": "2142-9",
"pmc": null,
"pmid": "24737502",
"pubdate": "2014-07-15",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "19389879;21263155;15959528;7506935;21319142;19776405;12951584;20515557;16616042;20952518;16857985;11535508;17940205;8677746;11290608;12692519;11520776;19318574;8946930;12707374;24002496;16150941;17047150;8056344;22504184;16857987;19654408;22291086;15120929;17965322;16435386;14673054;5910392;20733134;12393388;14604974;18450602;19808698;20610543;21586749;18230792;18483393;12176867;2185339;19144991;20705759;15256420;20119833;16868253;12070009;12036858;19144992",
"title": "Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations.",
"title_normalized": "treatment with flt3 inhibitor in patients with flt3 mutated acute myeloid leukemia is associated with development of secondary flt3 tyrosine kinase domain mutations"
} | [
{
"companynumb": "US-BAYER-2014-117263",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PLERIXAFOR"
},
"drugadditional": null,
... |
{
"abstract": "In patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1-20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.",
"affiliations": "University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, UKRUB, University of Bochum, Hans-Nolte-Straße 1, D-32429, Minden, Germany. Karlo.Huenerbein@ruhr-uni-bochum.de.;University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, UKRUB, University of Bochum, Hans-Nolte-Straße 1, D-32429, Minden, Germany.;University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, UKRUB, University of Bochum, Hans-Nolte-Straße 1, D-32429, Minden, Germany.;University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, UKRUB, University of Bochum, Hans-Nolte-Straße 1, D-32429, Minden, Germany.;University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, UKRUB, University of Bochum, Hans-Nolte-Straße 1, D-32429, Minden, Germany.;Statistical Consulting and Data analysis, Hameln, Germany.;University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, UKRUB, University of Bochum, Hans-Nolte-Straße 1, D-32429, Minden, Germany.;University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, UKRUB, University of Bochum, Hans-Nolte-Straße 1, D-32429, Minden, Germany.",
"authors": "Huenerbein|Karlo|K|https://orcid.org/0000-0003-1464-4061;Sadjadian|Parvis|P|;Becker|Tatjana|T|;Kolatzki|Vera|V|;Deventer|Eva|E|;Engelhardt|Carina|C|;Griesshammer|Martin|M|;Wille|Kai|K|",
"chemical_list": "D065427:Factor Xa Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-04350-6",
"fulltext": "\n==== Front\nAnn Hematol\nAnn Hematol\nAnnals of Hematology\n0939-5555\n1432-0584\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n33216197\n4350\n10.1007/s00277-020-04350-6\nOriginal Article\nDirect oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms\nhttps://orcid.org/0000-0003-1464-4061\nHuenerbein Karlo Karlo.Huenerbein@ruhr-uni-bochum.de\n\n1\nSadjadian Parvis parvis.sadjadian@muehlenkreiskliniken.de\n\n1\nBecker Tatjana tatjana.becker@muehlenkreiskliniken.de\n\n1\nKolatzki Vera vera.kolatzki@muehlenkreiskliniken.de\n\n1\nDeventer Eva eva.deventer@googlemail.com\n\n1\nEngelhardt Carina engelhardt@statistik-angewandt.de\n\n2\nGriesshammer Martin martin.griesshammer@muehlenkreiskliniken.de\n\n1\nWille Kai kai.wille@muehlenkreiskliniken.de\n\n1\n1 grid.5570.7 0000 0004 0490 981X University Clinic for Hematology, Oncology, Hemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, UKRUB, University of Bochum, Hans-Nolte-Straße 1, D-32429 Minden, Germany\n2 Statistical Consulting and Data analysis, Hameln, Germany\n20 11 2020\n20 11 2020\n2021\n100 8 20152022\n3 11 2020\n11 11 2020\n© The Author(s) 2020\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nIn patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial or venous thromboembolic events (ATE/VTE) are a major burden. In order to control these complications, vitamin K antagonists (VKA) are widely used. There is no robust evidence supporting the use of direct oral anticoagulants (DOAC) in MPN patients. We therefore compared the efficacy and safety of both anticoagulants in 71 cases from a cohort of 782 MPN patients. Seventy-one of 782 MPN patients (9.1%) had ATE/VTE with nine ATE (12.7%) and 62 VTE (87.3%). Forty-five of 71 ATE/VTE (63.4%) were treated with VKA and 26 (36.6%) with DOAC. The duration of anticoagulation therapy (p = 0.984), the number of patients receiving additional aspirin (p = 1.0), and the proportion of patients receiving cytoreductive therapy (p = 0.807) did not differ significantly between the VKA and DOAC groups. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1–20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. For all bleeding events (p = 0.516) or major bleeding (p = 1.0), no significant differences were observed between VKA and DOAC. In our experience, the use of DOAC was as effective and safe as VKA, possibly even potentially beneficial with a lower number of recurrences and no increased risk for bleedings. However, further and larger studies are required before DOAC can be routinely used in MPN patients.\n\nKeywords\n\nMyeloproliferative neoplasms\nDirect oral anticoagulants\nThrombosis\nAnticoagulation therapy\nBleeding\nRuhr-Universität Bochum (1007)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2021\n==== Body\nIntroduction\n\nIn patients with BCR-ABL-negative myeloproliferative neoplasms (MPN), arterial and venous thromboembolic events (ATE/VTE) occur frequently and have a significant impact on morbidity and mortality [1–3]. Several studies reported up to 10 times higher incidence of such complications compared to the healthy population [4–12].\n\nVitamin K antagonists (VKA) are widely used for both primary therapy and secondary prevention of MPN-associated ATE/VTE [13–15]. The introduction of direct oral anticoagulants (DOAC) provides a new treatment option [14, 16–20] with data comparable to the VKA [16–21]. However, the DOAC have no drug approval for patients with cancer or hematological malignancies, and published experience with its use in MPN-associated vascular events is currently very limited.\n\nCurto-Garcia et al. [22] retrospectively reported on the results of 32 MPN patients with 38 venous thromboembolism and DOAC treatment. During a median follow-up period of 2.1 years, neither VTE recurrences nor major bleedings were observed.\n\nIanotto et al. [21] reported on the retrospective course of 25 MPN patients under DOAC treatment. During a median follow-up time of 2.1 years, two arterial thromboembolic and three bleeding events were observed. A case-control comparison of 25 MPN patients treated with low-dose aspirin (ASS) showed no difference in efficacy and safety [21].\n\nPreliminary and retrospective data from Fedorov et al. [23] reported 22 DOAC- and 31 VKA-treated MPN patients with comparable incidences of recurrence and bleeding events.\n\nHowever, there is no robust evidence supporting the use of DOAC in MPN, including a direct comparison with VKA treatment. Therefore, at our center, we retrospectively evaluated 71 MPN patients with 71 ATE/VTE treated with VKA (n = 45) or DOAC (n = 26) to compare the efficacy and safety of both anticoagulants.\n\nPatients and methods\n\nClinical data of all MPN patients, who regularly present in our university department, were collected from June 2007 to April 2020 (time of last data cut-off April 1, 2020). All MPN were diagnosed according to the WHO 2008 criteria [24–26]. A total of 782 MPN patients (478 female, 61.1%, and 304 males, 38.9%) are currently registered in our outpatient clinic specializing in MPN. The median age is 50.5 years (range: 11.0–88.9), and the median follow-up time is 1.8 years (range: 0.1–28.4). The different MPN subtypes within the whole group are essential thrombocythemia (ET), n = 254 (32.5%); polycythemia vera (PV), n = 264 (33.8%); myelofibrosis (MF) including primary and secondary myelofibrosis, n = 238 (30.4%); and MPN unclassifiable, n = 26 (3.3%). The driver mutations are distributed within the 782 MPN patients as follows: JAK2 mutation, 534 (68.3%); CALR mutation, 110 (14.1%); MPL mutation, 19 (2.4%); triple negative, 42 (5.4%); and unknown 70 (9.0%).\n\nThe main objective of this retrospective, non-interventional, single-center study was to compare VKA with DOAC therapy in MPN patients. Of particular interest was the efficacy in ATE/VTE treatment, the prevention of ATE/VTE relapses, and the subsequent risk of bleeding complications under both anticoagulants. The data were collected in an electronic system. The Ethics Committee of our center approved the study. We focused on each patient with at least one MPN-associated arterial (ATE) or venous (VTE) thromboembolic event treated with VKA or DOAC. In line with previous studies, we defined an ATE or VTE associated with MPN if it occurred within 2 years prior to MPN diagnosis or after [27, 28].\n\nThe follow-up time was defined as the time between the first occurrence of an ATE/VTE and last visit to our center. Treatment time was defined as the time between the start of anticoagulation (= after the first ATE/VTE) and the end of anticoagulation or the last visit to our center (if anticoagulation was not stopped) or first relapse (whichever came first).\n\nFor each MPN patient with an ATE/VTE and anticoagulation with VKA or DOAC, we collected demographic data, mutational profile, method of objective diagnosis of ATE/VTE, and presence of cardiovascular (CV) risk factors. In addition, further details on ATE/VTE such as localization, total number, PT (prothrombin time)-INR (international normalized ratio), time of diagnosis and other cytoreductive or antiplatelet therapy were collected. Cytoreductive treatment was defined as the use of hydroxyurea, busulfan, anagrelide, interferon-alpha, ruxolitinib, and/or other JAK inhibitors at the time of ATE/VTE or within 6 months thereafter. Finally, time intervals regarding anticoagulation treatment, duration of treatment, occurrence of bleeding complications, and the number of relapses that occurred during or after completion of anticoagulation were recorded. The diagnosis of an ATE/VTE event required objective diagnostic procedures such as ultrasound, computed tomography, angiography, or scintigraphy.\n\nThe severity of bleeding complications was defined according to the criteria of the International Society on Thrombosis and Hemostasis [29]. According to these criteria, we considered a bleeding greater than II° (e.g., transfusion-related anemia, central nervous system involvement, or other life-threatening bleeding) to be clinically relevant.\n\nStatistical methods\n\nFor continuous variables, the median and range are provided. The annual incidence of ATE/VTE recurrences was calculated by dividing the number of events by the sum of patient-years. Differences in the proportions were estimated using Fisher’s exact test, Chi-square test, Mann-Whitney U test (statistical significance threshold set at p < 0.05), or log-rank test (Mantel-Haenszel test).\n\nResults\n\nOf the total 71 MPN-associated ATE/VTE, nine (12.7%) were ATE and 62 (87.3%) VTE. Table 1 provides an overview of demographic data and clinical characteristics of all 71 patients diagnosed with 71 initial ATE/VTE. Most ATE/VTE patients were female (n = 49, 69.0%) and were diagnosed as PV (n = 30, 42.3%), followed by MF (n = 20, 28.2%) or ET (n = 19, 26.8%). Two MPN patients with ATE/VTE were found to have a MPN at bone marrow biopsy, but both could not be further classified and were referred to as MPN unclassifiable. The JAK2 V617F mutation was the most frequent driver mutation (n = 63, 88.7%). The median age at ATE/VTE diagnosis was 54.0 years (22.0–82.0).Table 1 Overview of demographic data and clinical features of 71 MPN patients with 71 arterial and venous thromboembolic events (ATE/VTE) treated with either VKA or DOAC\n\nMale/female; n (%)\t22/49 (31.0/69.0)\t\nMedian age at first ATE/VTE; years (range)\t54.0 (22.0–82.0)\t\nMedian follow-up time from first ATE/VTE; years (range)\t3.2 (0.1–20.4)\t\nMPN diagnosis\t\n Polycythemia vera (PV); n (%)\t30 (42.3)\t\n Myelofibrosis (MF); n (%)\t20 (28.2)\t\n Essential thrombocythemia (ET); n (%)\t19 (26.8)\t\n MPN unclassifiable; n (%)\t2 (2.8)\t\nDriver mutations\t\n JAK2; n (%)\t63 (88.7)\t\n CALR; n (%)\t3 (4.2)\t\n MPL; n (%)\t1 (1.4)\t\n Triple negative; n (%)\t2 (2.8)\t\n Unknown; n (%)\t2 (2.8)\t\nATE/VTE\t\n VTE; n (%)\t62 (87.3)\t\n ATE; n (%)\t9 (12.7)\t\n\nThe localizations of all 71 ATE/VTE events together with corresponding localizations of ATE/VTE in VKA- or DOAC-treated MPN patients are shown in Table 2. Most ATE (6/9 = 67%) consisted of transient ischemic attacks (n = 2) or a stroke (n = 4). The remaining three had two embolisms each on a lower limb (n = 2, 2.8%) and an arterial splenic infarction (n = 1, 1.4%). About half VTE (28/62 = 45%) were atypical with 22 splanchnic and six sinus vein thromboses. Deep vein thrombosis simultaneously with pulmonary embolism was observed in nine MPN patients (n = 9, 12.7%). Isolated deep vein thrombosis or pulmonary embolism occurred in 14 (19.7%) and nine (n = 9, 12.7%) MPN cases with VTE, respectively. The two remaining VTE were each thrombophlebitis (n = 1, 1.4%) and arm vein thromboses (n = 1, 1.4%).Table 2 Localization of all first arterial and venous thromboembolic events (ATE/VTE, n = 71) with corresponding localizations of ATE/VTE in DOAC (n = 26) or VKA (n = 45) treated MPN patients together with localization of first ATE/VTE recurrences (n = 26)\n\n\tFirst ATE/VTE event (n = 71)\tFirst ATE/VTE treated with DOAC (n = 26)\tFirst ATE/VTE treated with VKA (n = 45)\tATE/VTE recurrences (n = 26)\tATE/VTE recurrences after DOAC therapy (n = 4)\tATE/VTE recurrence during or after VKA therapy (n = 22)\t\nLocalization\t\nArterial thromboembolic events (ATE); n (%)\t9 (12.7)\t3 (11.5)\t6 (13.3)\t12 (46.2)\t1 (25.0)\t11 (50.0)\t\nTransient ischemic attack (TIA); n (%)\t2 (2.8)\t-\t2 (4.4)\t1 (3.8)\t-\t1 (4.5)\t\nAngina pectoris; n (%)\t-\t-\t-\t1 (3.8)\t-\t1 (4.5)\t\nStroke; n (%)\t4 (5.6)\t1 (3.8)\t3 (6.7)\t2 (7.7)\t-\t2 (9.1)\t\nArterial embolism of lower limb; n (%)\t2 (2.8)\t1 (3.8)\t1 (2.2)\t3 (11.5)\t-\t3 (13.6)\t\nRenal infarction; n (%)\t-\t-\t-\t1 (3.8)\t1 (25.0)\t-\t\nSplenic infarction; n (%)\t1 (1.4)\t1 (3.8)\t-\t4 (15.4)\t-\t4 (18.2)\t\nVenous thromboembolic events (VTE)\t62 (87.3)\t23 (88.5%)\t39 (86.7)\t14 (53.8)\t3 (75.0)\t11 (50.0)\t\nDeep vein thrombosis; n (%)\t14 (19.7)\t5 (19.2)\t9 (20.0)\t6 (23.1)\t1 (25.0)\t5 (22.7)\t\nPulmonary embolism; n (%)\t9 (12.7)\t6 (23.1)\t3 (6.7)\t1 (3.8)\t1 (25.0)\t-\t\nDeep vein thrombosis simultaneous to pulmonary embolism; n (%)\t9 (12.7)\t4 (15.4)\t5 (11.1)\t-\t-\t-\t\nSplanchnic vein thrombosis; n (%)\t22 (31.0)\t5 (19.2)\t17 (37.8)\t4 (15.4)\t-\t4 (18.2)\t\nThrombophlebitis; n (%)\t1 (1.4)\t1 (3.8)\t-\t1 (3.8)\t1 (25.0)\t-\t\nSinus vein thrombosis; n (%)\t6 (8.5)\t2 (7.7)\t4 (8.9)\t2 (7.7)\t-\t2 (9.1)\t\nArm vein thrombosis; n (%)\t1 (1.4)\t-\t-\t-\t-\t-\t\nNo recurrences were observed during DOAC therapy, but there were four recurrences after stopping DOAC. 22 recurrences occurred during or after VKA therapy\n\nAll 71 patients had a median total follow-up time of 3.2 years (range: 0.1–20.4) with an incidence rate for all 71 ATE/VTE of 3.4% per patient/year. The corresponding rates for ATE and for VTE were 0.4% and 3.0% per patient/year, respectively.\n\nOut of 71 MPN with a first ATE/VTE, 45 (63.4%) were treated with VKA and 26 (36.6%) with DOAC. Most patients with DOAC received rivaroxaban (n = 21), and the remaining were treated with apixaban (n = 5). The median duration on anticoagulation was 1.0 years (range 0.1–20.4) with a median time on VKA of 1.0 years (range 0.1–20.4) and a median time on DOAC of 1.3 years (range 0.2–7.3). During the entire anticoagulation period, low-dose acetylsalicylic acid was additionally used in the 71 ATE/VTE in seven patients with VKA therapy (7/45, 9.9%) and in four patients with DOAC treatment (4/26, 5.5%). Cytoreductive treatment was initiated in 39 MPN patients (39/71, 63.9%) simultaneously or within 6 months after ATE/VTE. In the VKA group 22 of 45 patients (48.9%) and in the DOAC group 17 of 26 patients (65.4%) additionally received cytoreductive drugs.\n\nWithin a median time of 1.5 years (range: 0.1–8.5), 26 first ATE/VTE recurrences were observed in 26 patients. This corresponds to an ATE /VTE recurrence rate of 8.0% per patient/year. No recurrence was observed in 45 patients (63.4%). The localizations of the first 26 recurrences together with the corresponding localizations of recurrent ATE/VTE in VKA- or DOAC-treated MPN patients are shown in Table 2. Of 26 first recurrences, 12 (12/26 = 46.2%) were ATE and 14 (14/26 = 53.8%) were VTE. After a median time of 0.9 years (range: 0.1–8.5), 16 ATE/VTE recurrences occurred during anticoagulation with VKA therapy (16/26 = 61.5%). No recurrences were observed during DOAC therapy. This difference is statistically significant (p = 0.0003) (Fig. 1).Fig. 1 First ATE/VTE recurrences (n = 26) during follow-up time: significantly more recurrences (p = 0.0003) occurred during VKA (n = 16) compared to no recurrences during DOAC (n = 0) treatment (red). After termination of anticoagulation, four of 26 DOAC and six of 45 VKA-treated patients had ATE/VTE recurrences (green). Overall, significantly more recurrences were recorded in patients with VKA treatment (n = 22) compared to DOAC (n = 4) (p = 0.0053)\n\nIn 17 out of 45 patients (38%) treated with VKA, sufficient PT (prothrombin time) and/or INR (international normalized ratio) values were documented during anticoagulation, and 53% of these were in the therapeutic range. At the time of relapse, seven out of 22 patients treated with VKA had documented PT and/or INR values, and four (57%) were in the therapeutic range.\n\nDuring the entire follow-up time, 22 recurrences occurred in VKA-treated (n = 22, 84.6%) and four in DOAC-treated (n = 4, 15.4%) patients. In the latter group, all four recurrences were recorded within a median time of 0.7 years (range: 0.3–1.3) after termination of DOAC treatment. Sixteen of all 22 VKA-associated ATE/VTE recurrences (16/22 = 72.7%) were observed during VKA anticoagulation therapy. The remaining six recurrences (6/22 = 27.3%) were observed within a median time of 0.9 years (range: 0.4–4.0) after termination of the VKA. Comparing the total number of recurrences in VKA-treated patients (n = 22) with the recurrences registered in patients treated with DOAC (n = 4) shows a statistically significant difference during the follow-up time (p = 0.0053) (Fig. 1).\n\nAfter comparing the absolute number of ATE/VTE recurrences, an analysis was performed that considered the probability of “recurrence-free” survival during the follow-up time. In this analysis, the difference between VKA- and DOAC-treated patients was not statistically different (Fig. 2, p = 0.2). The incidence rate of ATE/VTE recurrences in VKA-treated patients was 8.1% per patient/year and 7.2% per patient/year in DOAC-treated patients. This difference was also not statistically different (alpha = 5%).Fig. 2 Probability of recurrence-free survival: the cumulative probability of the ATE/VTE recurrence-free survival in 71 MPN patients treated with DOAC (n = 26, red curve) or VKA (n = 45, blue curve) was statistically not significantly different (p = 0.2)\n\nBleedings\n\nDuring anticoagulation with either VKA or DOAC, 10 of 71 patients (14.1%) experienced 11 bleeding complications over a median period of 1.6 years (range: 0.1–6.8). Six out of 11 bleedings (54.5%) were classified as severe bleedings.\n\nIn the VKA group, seven bleeding complications (63.6%), including four major bleeding complications, were recorded after a median time of 1.6 years (range: 0.1–6.8). Three out of four major bleedings (one esophageal varicose vein bleeding and two severe epistaxis episodes) occurred during VKA use alone (without low-dose acetylsalicylic acid). One patient underwent a combination therapy of VKA and low-dose acetylsalicylic acid and experienced major postoperative bleeding 1 day after total hip replacement implantation. During VKA treatment, three minor bleedings occurred (a menorrhagia, an episode with bloody semen, and an unspecified bleeding tendency).\n\nDuring DOAC therapy, two minor and two major bleeding complications (n = 4, 36.4%) occurred after a median time of 0.5 years (range: 0.3–1.6). Both major bleeding episodes under DOAC anticoagulation (without low-dose acetylsalicylic acid) were gastrointestinal bleedings of unknown localization. The remaining two minor bleedings were epistaxis and petechial bleeding during DOAC therapy.\n\nOverall, no significant differences were observed between DOAC and VKA anticoagulation therapy for both overall (p = 0.516) or major bleeding (p = 1.0). A comparison regarding different clinical and laboratory parameters between VKA- and DOAC-treated patients is shown in Table 3. In the VKA group, only the total follow-up time (p = 0.0005) and number of ATE/VTE recurrences (p = 0.0053) were statistically different.Table 3 Comparison of different clinical and laboratory parameters between DOAC- (n = 26) and VKA-treated MPN patients (n = 45)\n\nParameters\tDOAC\tVKA\tp\t\nNumber of pts.*\t26\t45\t\t\nMedian age at MPN diagnosis; years (range)\t55.5 (24.0–81.0)\t50.0 (22.0–82.0)\t0.131\t\nMedian age at first ATE/VTE event; years (range)\t57.5 (27.0–88.0)\t53.0 (22.0–81.0)\t0.070\t\nGender (male/female)\t8/18\t14/31\t0.976\t\nEssential thrombocythemia\t8\t11\t0.816\t\nPolycythemia vera\t10\t20\t\nMyelofibrosis\t7\t13\t\nJAK2 Mutation\t24\t39\t0.701\t\nCardiovascular risk factors (yes/no)\t15/11\t30/15\t0.450\t\nATE\t3\t6\t1.0\t\nVTE\t23\t39\t\nMedian treatment time; years (range)\t1.3 (0.2–7.3)\t1.0 (0.1–20.4)\t0.984\t\nMedian total follow up time; years (range)\t1.7 (0.2–7.3)\t4.8 (0.6–20.4)\t0.0005**\t\nATE/VTE recurrences\t4\t22\t0.0053**\t\nCombined ASS use***\t4\t7\t1.0\t\nCytoreductive therapy for first ATE/VTE****\t17\t22\t0.22\t\nBleeding events total\t4\t7\t1.0\t\nMajor bleeding events\t2\t4\t1.0\t\nDeaths\t1\t3\t1.0\t\n*Pts. = patients\n\n**Significantly different\n\n***During time on anticoagulation after first ATE/VTE\n\n****Begin at time of ATE/VTE or within 6 months thereafter\n\nDiscussion\n\nMyeloproliferative neoplasm (MPN) patients have an increased risk of arterial and venous thromboembolic events (ATE/VTE). In larger MPN cohorts, the proportion of patients suffering from ATE/VTE is reported to be 10 to 30% [22]. Accordingly, vascular events occurred in 9.1% (71/782) of our 782 MPN patients. The incidence rate for the first 71 ATE/VTE was 3.4% per patient/year with a VTE rate of 3.0% per patient/year. Prospective studies in MPN observed comparable VTE rates of 0.5–3.7% [6, 7]. The ATE incidence rate of 0.4% per patient/year in our MPN patients was also similar to the reported ATE rates of 0.2 to 1.5% [5, 11].\n\nIn recent decades, anticoagulation with vitamin K antagonists (VKA) has been the treatment of choice to prevent ATE/VTE recurrences in MPN patients. Hernández-Boluda et al. [14] reported a 2.8-fold risk reduction for recurrence in 150 ET and PV patients with ATE/VTE and VKA treatment. In 206 MPN patients, De Stefano et al. [15] also found a reduction in the recurrence rate of VTE with VKA. The incidence rate of recurrent VTE was 5.3% per patient/year among patients with long-term VKA and 12.8% per patient/year after VKA discontinuation (p = 0.008). The VTE recurrence rate in our cohort was comparable at 8.0% per patient/year.\n\nAs far as anticoagulation with direct oral anticoagulants (DOAC) is concerned, there are few studies in MPN that indicate good efficacy with sufficient safety. In a retrospective study by Curto-Garcia et al. [22] in 32 MPN patients receiving DOAC for MPN-associated venous thromboembolism treated with DOAC, no VTE relapse but one ATE occurred. No major and three minor bleedings were reported. Ianotto et al. [21] retrospectively reported two ATE and no VTE recurrences in a cohort of 25 DOAC-treated MPN patients. Three major and two minor bleedings were observed. Curto-Garcia et al. [22] reported a median age of 49.9 years and a median follow-up of 2.1 years in their publication. The median follow-up time in the study of Ianotto et al. [21] was quite similar with 2.1 years. However, both studies did not compare DOAC treatment with VKA in their cohort [21, 22]. Fedorov et al. [23] reported preliminary data on recurrence rates and bleeding complications in 22 DOAC- and 31 VKA-treated MPN patients. During a short follow-up of 8 months, the number of ATE/VTE recurrences (DOAC, n = 5 versus VKA, n = 6) and of all bleeding complications (DOAC, n = 5 versus VKA, n = 11) were not significantly different.\n\nThe median age of our 71 MPN patients at the time of ATE/VTE was 54 years and was comparable to the studies of Curto-Garcia et al. and Ianotto et al. [21, 22]. The median duration of anticoagulation was lower at 1.0 years for VKA and 1.3 for DOAC. During anticoagulation therapy, significantly more relapses occurred under VKA (n = 16) compared to DOAC treatment (n = 0, p = 0.0003). However, during the entire observation period of median 3.2 years (0.1–20.4), ATE/VTE relapse-free survival (p = 0.2) did not differ significantly between the two anticoagulants. This is mainly due to the significantly longer follow-up time for VKA patients (p = 0.0005). The corresponding recurrence rates for VKA and DOAC treatment (during and after discontinuation of anticoagulation) did not differ significantly either.\n\nDuring anticoagulation with VKA, 53% and at the time of relapse, 57% of patients treated with VKA were in the therapeutic range with PT-INR. A major disadvantage of the VKA is the narrow therapeutic range and the time patients spend in the therapeutic range (TTR, “time in therapeutic range”). Even in well-conducted comparative studies of VKA and DOAK, the TTR was on average only between 55 and 65% [17, 20, 30, 31].\n\nAs in the studies mentioned above, we have not observed any increased bleeding propensity under DOAC. In particular, the rate of major bleeding was not higher under DOAC compared to VKA. Regarding bleeding complications with anticoagulation, the German MPN Registry of the Leukemia Study Alliance [32] reported bleeding in 437 MPN patients, including eight with DOAC (rivaroxaban) treatment. In a multivariate analysis, the risk of bleeding during DOAC treatment was slightly reduced compared to VKA.\n\nIn summary, our results complement the currently limited literature [21–23, 32] on the efficacy and safety of DOAC-treated MPN patients. Despite the limitations—small number of patients, retrospective analysis, and short treatment time—our data suggest that the use of DOAC was as effective and safe as VKA. However, further and larger studies are required before DOAC can be routinely used in MPN patients.\n\nAuthors’ contributions\n\nAll authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Karlo Huenerbein. The first draft of the manuscript was written by Karlo Huenerbein and Dr. Kai Wille, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nData availability\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nCompliance with ethical standards\n\nConflict of interest\n\nThe authors declare that they have no conflict of interest.\n\nEthics approval\n\nEthical approval was waived by the local Ethics Committee of the Ruhr University Bochum in view of the retrospective nature of the study, and all the procedures being performed were part of the routine care.\n\nConsent to participate/for publication\n\nInformed consent was obtained from all individual participants included in the study. Patients signed informed consent regarding publishing their data and photographs.\n\nCode availability\n\nNot applicable.\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Tefferi A Rumi E Finazzi G Gisslinger H Vannucchi AM Rodeghiero F Randi ML Vaidya R Cazzola M Rambaldi A Gisslinger B Pieri L Ruggeri M Bertozzi I Sulai NH Casetti I Carobbio A Jeryczynski G Larson DR Müllauer L Pardanani A Thiele J Passamonti F Barbui T Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study Leukemia 2013 27 1874 1881 10.1038/leu.2013.163 23739289\n2. 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Barbui T Finazzi G Carobbio A Thiele J Passamonti F Rumi E Ruggeri M Rodeghiero F Randi ML Bertozzi I Gisslinger H Buxhofer-Ausch V de Stefano V Betti S Rambaldi A Vannucchi AM Tefferi A Development and validation of an International Prognostic Score of thrombosis in World Health Organization–essential thrombocythemia (IPSET-thrombosis) Blood 2012 120 5128 5133 10.1182/blood-2012-07-444067 23033268\n6. Landolfi R Marchioli R Kutti J Gisslinger H Tognoni G Patrono C Barbui T Efficacy and safety of low-dose aspirin in polycythemia vera NEJM 2004 350 114 124 10.1056/NEJMoa035572 14711910\n7. Harrison CN Campbell PJ Buck G Wheatley K East CL Bareford D Wilkins BS van der Walt J Reilly JT Grigg AP Revell P Woodcock BE Green AR United Kingdom Medical Research Council Primary Thrombocythemia 1 Study Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia NEJM 2005 353 33 45 10.1056/NEJMoa043800 16000354\n8. Goldhaber SZ Venous thromboembolism: epidemiology and magnitude of the problem Best Pract Res Clin Haematol 2012 25 235 242 10.1016/j.beha.2012.06.007 22959540\n9. Rothwell PM Coull AJ Silver LE Fairhead JF Giles MF Lovelock CE Redgrave JNE Bull LM Welch SJV Cuthbertson FC Binney LE Gutnikov SA Anslow P Banning AP Mant D Mehta Z Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study) The Lancet 2005 366 1773 1783 10.1016/S0140-6736(05)67702-1\n10. Carobbio A Thiele J Passamonti F Rumi E Ruggeri M Rodeghiero F Randi ML Bertozzi I Vannucchi AM Antonioli E Gisslinger H Buxhofer-Ausch V Finazzi G Gangat N Tefferi A Barbui T Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients Blood 2011 117 5857 5859 10.1182/blood-2011-02-339002 21490340\n11. Barbui T Carobbio A Rumi E Finazzi G Gisslinger H Rodeghiero F Randi ML Rambaldi A Gisslinger B Pieri L Bertozzi I Casetti I Pardanani A Passamonti F Vannucchi AM Tefferi A In contemporary patients with polycythemia vera, rates of thrombosis and risk factors delineate a new clinical epidemiology Blood 2014 124 3021 3023 10.1182/blood-2014-07-591610 25377561\n12. Antithrombotic Trialists' (ATT) Collaboration Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials The Lancet 2009 373 1849 1860 10.1016/S0140-6736(09)60503-1\n13. Bertozzi I Bogoni G Biagetti G Duner E Lombardi AM Fabris F Randi ML Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden Ann Hematol 2017 96 1297 1302 10.1007/s00277-017-3040-8 28585070\n14. Hernández-Boluda J-C Arellano-Rodrigo E Cervantes F Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia Ann Hematol 2015 94 911 918 10.1007/s00277-015-2330-2 25680896\n15. de Stefano V Ruggeri M Cervantes F Alvarez-Larrán A Iurlo A Randi ML Elli E Finazzi MC Finazzi G Zetterberg E Vianelli N Gaidano G Rossi E Betti S Nichele I Cattaneo D Palova M Ellis MH Cacciola R Tieghi A Hernandez-Boluda JC Pungolino E Specchia G Rapezzi D Forcina A Musolino C Carobbio A Griesshammer M Sant’Antonio E Vannucchi AM Barbui T High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists Leukemia 2016 30 2032 2038 10.1038/leu.2016.85 27113812\n16. Sherwood MW Douketis JD Patel MR Piccini JP Hellkamp AS Lokhnygina Y Spyropoulos AC Hankey GJ Singer DE Nessel CC Mahaffey KW Fox KA Califf RM Becker RC ROCKET AF Investigators Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation Circulation 2014 129 1850 1859 10.1161/CIRCULATIONAHA.113.005754 24552831\n17. Giugliano RP Ruff CT Braunwald E Murphy SA Wiviott SD Halperin JL Waldo AL Ezekowitz MD Weitz JI Špinar J Ruzyllo W Ruda M Koretsune Y Betcher J Shi M Grip LT Patel SP Patel I Hanyok JJ Mercuri M Antman EM ENGAGE AF-TIMI 48 Investigators Edoxaban versus warfarin in patients with atrial fibrillation NEJM 2013 369 2093 2104 10.1056/NEJMoa1310907 24251359\n18. Agnelli G Buller HR Cohen A Curto M Gallus AS Johnson M Porcari A Raskob GE Weitz JI AMPLIFY-EXT Investigators Apixaban for extended treatment of venous thromboembolism NEJM 2012 368 699 708 10.1056/NEJMoa1207541 23216615\n19. Agnelli G Buller HR Cohen A Curto M Gallus AS Johnson M Masiukiewicz U Pak R Thompson J Raskob GE Weitz JI AMPLIFY Investigators Oral apixaban for the treatment of acute venous thromboembolism NEJM 2013 369 799 808 10.1056/NEJMoa1302507 23808982\n20. Connolly SJ Ezekowitz MD Yusuf S Eikelboom J Oldgren J Parekh A Pogue J Reilly PA Themeles E Varrone J Wang S Alings M Xavier D Zhu J Diaz R Lewis BS Darius H Diener HC Joyner CD Wallentin L Dabigatran versus warfarin in patients with atrial fibrillation NEJM 2009 361 1139 1151 10.1056/NEJMoa0905561 19717844\n21. Ianotto J-C Couturier M-A Galinat H Mottier D Berthou C Guillerm G Lippert E Delluc A Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms Int J Hematol 2017 106 517 521 10.1007/s12185-017-2282-5 28623609\n22. Curto-Garcia N Doyle AJ Breen KA McLornan DP Radia DH Hunt BJ Ling G Harrison CN Outcomes of patients receiving direct oral anticoagulants for myeloproliferative neoplasm-associated venous thromboembolism in a large tertiary centre in the UK Br J Haematol 2020 189 e79 e81 10.1111/bjh.16485 32011726\n23. Fedorov K Goel S Kushnir M Billett HH Direct oral anticoagulants for prevention of recurrent thrombosis in myeloproliferative neoplasms Blood 2019 134 4193 10.1182/blood-2019-127600\n24. Barbui T Barosi G Birgegard G Cervantes F Finazzi G Griesshammer M Harrison C Hasselbalch HC Hehlmann R Hoffman R Kiladjian JJ Kröger N Mesa R McMullin M Pardanani A Passamonti F Vannucchi AM Reiter A Silver RT Verstovsek S Tefferi A European LeukemiaNet Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European leukemia Net J Clin Oncol 2011 29 761 770 10.1200/JCO.2010.31.8436 21205761\n25. Campo E Swerdlow SH Harris NL Pileri S Stein H Jaffe ES The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications Blood 2011 117 5019 5032 10.1182/blood-2011-01-293050 21300984\n26. Tefferi A Vardiman JW Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms Leukemia 2008 22 14 22 10.1038/sj.leu.2404955 17882280\n27. Wille K Sadjadian P Becker T Kolatzki V Horstmann A Fuchs C Griesshammer M High risk of recurrent venous thromboembolism in BCR-ABL-negative myeloproliferative neoplasms after termination of anticoagulation Ann Hematol 2019 98 93 100 10.1007/s00277-018-3483-6 30155552\n28. de Stefano V Za T Rossi E Vannucchi AM Ruggeri M Elli E Mico C Tieghi A Cacciola RR Santoro C Gerli G Vianelli N Guglielmelli P Pieri L Scognamiglio F Rodeghiero F Pogliani EM Finazzi G Gugliotta L Marchioli R Leone G Barbui T for the GIMEMA CMD-Working Party Recurrent thrombosis in patients with polycythemia vera and essential thrombocythemia: incidence, risk factors, and effect of treatments Haematologica 2008 93 372 380 10.3324/haematol.12053 18268279\n29. Hurlen M Abdelnoor M Smith P Erikssen J Arnesen H Warfarin, aspirin, or both after myocardial infarction NEJM 2002 347 969 974 10.1056/NEJMoa020496 12324552\n30. Granger CB Alexander JH McMurray JJV Lopes RD Hylek EM Hanna M al-Khalidi HR Ansell J Atar D Avezum A Bahit MC Diaz R Easton JD Ezekowitz JA Flaker G Garcia D Geraldes M Gersh BJ Golitsyn S Goto S Hermosillo AG Hohnloser SH Horowitz J Mohan P Jansky P Lewis BS Lopez-Sendon JL Pais P Parkhomenko A Verheugt FW Zhu J Wallentin L ARISTOTLE Committees and Investigators Apixaban versus warfarin in patients with atrial fibrillation NEJM 2011 365 981 992 10.1056/NEJMoa1107039 21870978\n31. Patel MR Mahaffey KW Garg J Pan G Singer DE Hacke W Breithardt G Halperin JL Hankey GJ Piccini JP Becker RC Nessel CC Paolini JF Berkowitz SD Fox KAA Califf RM the ROCKET AF Steering Committee Rivaroxaban versus warfarin in nonvalvular atrial fibrillation NEJM 2011 365 883 891 10.1056/NEJMoa1009638 21830957\n32. Kaifie A Kirschner M Wolf D Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN): analysis from the German SAL-MPN-registry J Hematol Oncol 2016 9 18 10.1186/s13045-016-0242-9 26944254\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0939-5555",
"issue": "100(8)",
"journal": "Annals of hematology",
"keywords": "Anticoagulation therapy; Bleeding; Direct oral anticoagulants; Myeloproliferative neoplasms; Thrombosis",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders; D055502:Secondary Prevention; D013923:Thromboembolism; D054556:Venous Thromboembolism; D055815:Young Adult",
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"title": "Direct oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms.",
"title_normalized": "direct oral anticoagulants doac for prevention of recurrent arterial or venous thromboembolic events ate vte in myeloproliferative neoplasms"
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"abstract": "Anomalous left coronary artery from the pulmonary artery is a rare congenital abnormality that requires surgical correction.\nWe describe the case of a 33-year-old female with a history of anomalous left coronary artery of the pulmonary artery who presents with exertional angina. She underwent a Takeuchi repair that was complicated by a baffle leak. She was successfully treated with left internal mammary artery-left anterior descending (LAD) bypass grafting and percutaneous baffle leak closure.\nThe Takeuchi procedure involves the creation of an aortopulmonary window and an intrapulmonary tunnel that 'baffles' the aorta to the ostium of the anomalous left coronary artery. The most common late complication of the Takeuchi procedure is the presence of a baffle leak. Percutaneous baffle leak occlusion via vascular plug and coronary bypass of the LAD can successfully treat a baffle leak with excellent short-term follow-up.",
"affiliations": "Division of Interventional Cardiology, Department of Cardiology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA.;Division of Adult Congenital Cardiology, University of Rochester Medical Center, Rochester, NY, USA.;Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, NY, USA.;Division of Interventional Cardiology, Department of Cardiology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA.",
"authors": "Naqvi|Syed Yaseen|SY|https://orcid.org/0000-0001-9516-8954;Joynt|Michael|M|https://orcid.org/0000-0001-8613-6395;Prasad|Sunil|S|;Ling|Frederick|F|",
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"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n34113764\n10.1093/ehjcr/ytab074\nytab074\nCase Report\nAcademicSubjects/MED00200\nSevere baffle leak after Takeuchi repair successfully treated with coronary bypass and percutaneous baffle closure: a case report\nhttps://orcid.org/0000-0001-9516-8954\nNaqvi Syed Yaseen 1\nhttps://orcid.org/0000-0001-8613-6395\nJoynt Michael 2\nPrasad Sunil 3\nLing Frederick 1\n1 Division of Interventional Cardiology, Department of Cardiology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA\n2 Division of Adult Congenital Cardiology, University of Rochester Medical Center, Rochester, NY, USA\n3 Division of Cardiac Surgery, University of Rochester Medical Center, Rochester, NY, USA\nSinning Christoph Handling Editor\nMichel-Behnke Ina Editor\nVoges Inga Editor\nKurdi Hibba Editor\nChakir Mariame Material Editor\nCorresponding author. Email: syedalinaqvi1@gmail.com\n21 3 2021\n3 2021\n21 3 2021\n5 3 ytab07405 7 2020\n02 9 2020\n10 2 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 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.com\n\nAbstract\n\nBackground\n\nAnomalous left coronary artery from the pulmonary artery is a rare congenital abnormality that requires surgical correction.\n\nCase summary\n\nWe describe the case of a 33-year-old female with a history of anomalous left coronary artery of the pulmonary artery who presents with exertional angina. She underwent a Takeuchi repair that was complicated by a baffle leak. She was successfully treated with left internal mammary artery-left anterior descending (LAD) bypass grafting and percutaneous baffle leak closure.\n\nDiscussion\n\nThe Takeuchi procedure involves the creation of an aortopulmonary window and an intrapulmonary tunnel that ‘baffles’ the aorta to the ostium of the anomalous left coronary artery. The most common late complication of the Takeuchi procedure is the presence of a baffle leak. Percutaneous baffle leak occlusion via vascular plug and coronary bypass of the LAD can successfully treat a baffle leak with excellent short-term follow-up.\n\nCase report\nTakeuchi procedure\nBaffle leak\nCoronary bypass\nVascular plug\n==== Body\nLearning points\n\nAnomalous left coronary artery from the pulmonary artery is a rare congenital abnormality that results in high mortality and requires surgical correction.\n\nThe Takeuchi procedure involves the creation of an aortopulmonary window and an intrapulmonary tunnel that ‘baffles’ the aorta to the ostium of the anomalous left coronary artery.\n\nThe most common late complication of the Takeuchi procedure is the presence of a baffle leak and supravalvular pulmonary stenosis.\n\nThese complications may be repaired surgically although this often involves risk from repeat thoracotomy or using a percutaneous approach.\n\nIntroduction\n\nAnomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital abnormality that requires surgical correction. There are two types of ALCAPA syndrome, the infant type and the adult type.1 Both of these subtypes of ALCAPA have presenting features and outcomes. The infant type manifests as myocardial infarction and congestive heart failure, and approximately 90% die within the 1st year of life. The adult type is rare but can cause angina, congestive heart failure, or sudden cardiac death. In this case, we describe the case of an adult who presents with symptomatic ALCAPA syndrome.\n\nTimeline\n\nCase description\n\nA 33-year-old white Caucasian woman with a past medical history of peripartum cardiomyopathy, ALCAPA corrected with a Takeuchi procedure, who presented to her cardiologist’s office with progressive dyspnoea, fatigue, and exertional angina. The Takeuchi repair is a surgical procedure that involves the creation of an aortopulmonary (AP) window and an intrapulmonary tunnel that ‘baffles’ the aorta to the ostium of the anomalous left coronary artery. Our patient’s clinical history was unremarkable for any cardiac issues in infancy, early childhood, and adolescence. She initially became symptomatic after the delivery of her first child. She was diagnosed with post-partum cardiomyopathy after her transthoracic echocardiogram revealed a moderately reduced left ventricular ejection fraction (LVEF). She was treated medically with metoprolol succinate 25 mg daily and Lisinopril 10 mg daily. The diagnosis of ALCAPA was made after her cardiac magnetic resonance imaging (MRI) demonstrated a dilated left ventricle, mild mitral valve regurgitation, regional hypokinesis of the mid-to-apical anterior wall, and mid-to-apical anterior septum. The patient underwent a Takeuchi repair 7 months prior at an outside institution due to exertional angina for 4 months. It was unclear why Takeuchi repair was chosen over other surgical techniques such as left coronary button transfer to the aorta or bypass grafting with proximal ligation of the anomalous artery. Her echocardiogram showed a moderately reduced LVEF of 40%. Her symptoms of angina and LVEF normalized after her surgery until 1 month prior to presentation.\n\nShe presented to our institution with complaints of exertional angina, shortness of breath, and leg oedema worsening over the last 2 months. Her vital signs were within normal limits. Her cardiac exam was positive for a biphasic continuous murmur, with a two out of six decrescendo systolic murmur at the left upper sternal border followed by a soft one out of four diastolic murmur. She did not have physical findings of volume overload. Her complete blood count, basic chemistry panel, liver function tests, cardiac troponins, and N-terminal prohormone of brain natriuretic peptide were within normal limits. A repeat cardiac MRI showed findings consistent with chronic left anterior descending (LAD) territory myocardial scar (Supplementary material online, Figure S1). Nuclear stress test revealed a large perfusion defect in the anterior wall with moderate superimposed ischaemia (Supplementary material online, Figure S2). Cardiac computed tomography (CT) coronary angiogram revealed a 6.5 mm × 2.4 mm leak present from the distal inferior Takeuchi baffle to the main pulmonary artery (Figure 1A and B) as well as a smaller leak near the baffle origin (not shown). Right heart catheterization confirmed a Qp:Qs of 1.5 with mild pulmonary hypertension. Coronary angiogram revealed right coronary artery (RCA) ectasia. Angiography of the baffle revealed marked left-to-right shunting from the baffle to the main pulmonary artery. The proximal LAD and left circumflex (LCx) arteries were patent but dilated because of the ALCAPA prior to Takeuchi repair. There was also minor fistulous connections present from the LAD to the left ventricle. After multidisciplinary consultation with cardiac surgery, adult congenital heart disease, and interventional cardiology services, the decision was made to proceed with a hybrid treatment approach of bypass of left internal mammary artery (LIMA) grafting to the LAD followed by percutaneous baffle embolization using the Amplatzer Vascular Plug II (Abbott, USA). Redo-cardiac surgery to repair the baffle was considered but felt to be high-risk. Percutaneous baffle leak closure was considered, but the presence of two leaks suggested weakness of the baffle suture line, which could be exacerbated by placement of closure devices.\n\nFigure 1 (A/B). A computed tomography coronary angiogram revealed a 6.5 mm × 2.4 mm leak present from the distal inferior Takeuchi baffle to the main pulmonary artery.\n\nA LIMA-to-LAD bypass was performed followed by coronary angiography that showed graft patency with the back filling into the baffle (Figure 2A and B). An ascending aortogram was performed to identify the AP window origin of the baffle and confirmed the baffle leak with contrast leakage into the pulmonary artery (Figure 3A). Using a transfemoral artery approach, the baffle was engaged with an 8-Fr left coronary bypass coronary guide catheter, and the baffle crossed with a 0.014-inch Runthrough NS wire (Terumo, Japan) into the LAD. The Runthrough NS wire was exchanged over a Transit micro-catheter for a 0.014-inch Grand Slam wire (ASAHI, Japan) for better support (Figure 3B). A 14 mm Amplatzer Vascular Plug II was deployed from the left main coronary artery at the bifurcation back to the aorta through the full extent of the baffle. Repeat LIMA angiography (Figure 4A) and root aortography (Figure 4B) showed effective closure of both ends of the baffle without any leak into the pulmonary artery. The LIMA graft supplied the entire left coronary circulation. The patient recovered well post-operatively with resolution of her symptoms and normalization of her LVEF. Given the potential for thrombus formation presumably due to stagnant blood flow in ectatic coronary arteries with myocardial infarction which has been seen immediately after percutaneous coronary arteriovenous fistula embolization, oral anticoagulation with warfarin in addition to aspirin was started to prevent thrombosis in the ectatic left coronary artery which was now solely supplied by the LIMA graft. She took warfarin with a goal international normalized ratio (INR) of 2–3 for 4 months to allow some time for regression of vessel size at which point warfarin was discontinued.\n\nFigure 2 (A/B). Coronary angiography reveals left internal mammary artery-to-left anterior descending artery bypass graft patency and evidence of back filling into the baffle. LAD, left anterior descending artery; LIMA, left internal mammary artery.\n\nFigure 3 (A/B) Aortography shows the baffle with leakage of contrast into the pulmonary artery (left). The baffle was crossed with a Runthrough wire via an 8-Fr left coronary bypass guide catheter via the femoral artery (right).\n\nFigure 4 (A/B) A 14 mm Amplatzer Vascular Plug II was deployed from the left main coronary artery proximal to the bifurcation back to the aorta through the full extent of the baffle (left). Aortogram reveals no contrast flow into the pulmonary artery (right).\n\nTwo-years following her surgery, she re-presented to her cardiologist’s office with complaints of angina on moderate exertion with radiation to her left arm. Her angina was associated with shortness of breath, diaphoresis, and nausea and was relieved with rest. A repeat coronary CT angiogram revealed a patent RCA and LAD, but absent flow in the left circumflex artery (Figure 5A). There was no change in the configuration of the Vascular Plug II position or configuration compared to immediately following the procedure. Repeat cardiac catheterization revealed a patent RCA, persistent occlusion of the Takeuchi baffle by the vascular plug without any leaks, a patent LIMA graft to LAD, however, there was now a chronic total occlusion (CTO) of the proximal LCx artery with right to left collaterals filling her obtuse marginal branches (Figure 5B). In retrospect, it was thought that she likely had late thrombosis of her persistently ectatic left circumflex artery due to stagnant flow, now off of oral anticoagulation which was prescribed for only a short course following the procedure. She was started on medical therapy for her symptoms consisting of metoprolol succinate 50 mg once daily and isosorbide mononitrate 30 mg once daily with good effect. We opted to manage her angina medically and if she fails medical treatment, then to consider complex retrograde CTO percutaneous coronary intervention in the future. The patient remains asymptomatic from a cardiac standpoint after 8 months of medical therapy.\n\nFigure 5 (A/B) A repeat coronary computed tomography angiogram revealed a patent right coronary artery and left anterior descending artery, but absent flow in the left circumflex artery (left). A repeat cardiac catheterization revealed persistent occlusion of the Takeuchi baffle by the vascular plugs without any leaks, patent left internal mammary artery to left anterior descending artery, patent right coronary artery and chronic total occlusion of the proximal left circumflex artery with right to left collaterals filling her obtuse marginal branches (right). CTO, chronic total occlusion; LAD, left anterior descending; LCx, left circumflex artery; LIMA, left internal mammary artery; RCA, right coronary artery.\n\nDiscussion\n\nAnomalous left coronary artery from the pulmonary artery is a rare congenital abnormality that results in high mortality if left untreated. The mechanisms underlying morbidity and mortality involve left ventricular dysfunction as well as progressive ischaemic valvular disease. Anomalous left coronary artery from the pulmonary artery requires surgical closure soon after it is diagnosed. In certain situations, the Takeuchi procedure is a viable alternative. The most common late complication of the Takeuchi procedure is the presence of a baffle leak. Other common complications are the presence of supravalvular pulmonary stenosis.2 These complications may be repaired surgically although this often involves risk from repeat thoracotomy or using a percutaneous approach.3 To our knowledge, this is the first case of Takeuchi baffle leak successfully treated with LIMA-LAD bypass grafting and percutaneous baffle leak closure.\n\nLead author biography\n\nSyed Y. Naqvi is an Interventional Cardiology Fellow at the University of Rochester.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab074_Supplementary_Data Click here for additional data file.\n\n \n\nFor the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast\n==== Refs\nReferences\n\n1 Peña E , NguyenET, MerchantN, DennieC. ALCAPA syndrome: not just a pediatric disease. Radiographics 2009;29 :553–565.19325065\n2 Ginde S , EaringMG, BartzPJ, CavaJR, TweddellJS. Late complications after Takeuchi repair of anomalous left coronary artery from the pulmonary artery: case series and review of literature. Pediatr Cardiol 2012;33 :1115–1123.22438016\n3 Hai-Bo H , KaiY, Xiang-BinP. Transcatheter closure for baffle leak after Takeuchi repair of anomalous left coronary artery from the pulmonary artery: a case report. Eur Heart J Case Rep 2018;2 : doi: 10.1093/ehjcr/yty028.\n\n",
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"issn_linking": "2514-2119",
"issue": "5(3)",
"journal": "European heart journal. Case reports",
"keywords": "Baffle leak; Case report; Coronary bypass; Takeuchi procedure; Vascular plug",
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"title": "Severe baffle leak after Takeuchi repair successfully treated with coronary bypass and percutaneous baffle closure: a case report.",
"title_normalized": "severe baffle leak after takeuchi repair successfully treated with coronary bypass and percutaneous baffle closure a case report"
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"abstract": "Tuberculous epididymo-orchitis is an uncommon complication after intravesical bacilli Calmette-Guerin therapy for nonmuscle invasive bladder cancer. Spread of granulomatous disease through the genitourinary tract specifically to the testes occurs in 0.4% of treated patients. The following case presents a 77-year-old man who underwent intravesical therapy after transurethral resection of bladder tumor and developed testicular discomfort and a palpable mass 2 years after initiation of therapy. After wide range of serum and urine analyses, repeated testicular ultrasonography, and an unsuccessful course of antibiotics, the patient elected to undergo orchiectomy and was confirmed to have tuberculous epididymo-orchitis. Diagnosis based on imaging and laboratory serum and urine analysis may be elusive and therefore review of this entity and associated sonographic findings is discussed.",
"affiliations": "Morristown Medical Center, 100 Madison Avenue, Morristown, NJ 07960, USA.;Morristown Medical Center, 100 Madison Avenue, Morristown, NJ 07960, USA.;Morristown Medical Center, 100 Madison Avenue, Morristown, NJ 07960, USA.",
"authors": "Sadeghi|Akram|A|;Chaikin|David|D|;Calhoun|Sean|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2020.07.030",
"fulltext": "\n==== Front\nRadiol Case Rep\nRadiol Case Rep\nRadiology Case Reports\n1930-0433 Elsevier \n\nS1930-0433(20)30339-3\n10.1016/j.radcr.2020.07.030\nCase Report\nTesticular tuberculosis: An uncommon complication after treatment of urothelial carcinoma\nSadeghi Akram MDAkram.sadeghi@atlantichealth.org⁎ Chaikin David MD Calhoun Sean DO Morristown Medical Center, 100 Madison Avenue, Morristown, NJ 07960, USA\n⁎ Corresponding author. Akram.sadeghi@atlantichealth.org\n11 9 2020 \n11 2020 \n11 9 2020 \n15 11 2285 2293\n23 3 2020 11 7 2020 12 7 2020 © 2020 Published by Elsevier Inc. on behalf of University of Washington.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Tuberculous epididymo-orchitis is an uncommon complication after intravesical bacilli Calmette-Guerin therapy for nonmuscle invasive bladder cancer. Spread of granulomatous disease through the genitourinary tract specifically to the testes occurs in 0.4% of treated patients. The following case presents a 77-year-old man who underwent intravesical therapy after transurethral resection of bladder tumor and developed testicular discomfort and a palpable mass 2 years after initiation of therapy. After wide range of serum and urine analyses, repeated testicular ultrasonography, and an unsuccessful course of antibiotics, the patient elected to undergo orchiectomy and was confirmed to have tuberculous epididymo-orchitis. Diagnosis based on imaging and laboratory serum and urine analysis may be elusive and therefore review of this entity and associated sonographic findings is discussed.\n\nKey Words\nTesticular tuberculosisUrothelial carcinomaIntravesical BCG\n==== Body\nIntroduction\nThe earliest microbiological confirmation of tuberculosis (TB) dates back to the Neolithic Period approximately 9000 years ago [1]. TB is known as the great mimicker and can evade diagnosis due to clinical and radiologic overlap with several disease processes. TB reached epidemic proportions in the 18th and 19th centuries. In 1882, Robert Koch isolated the tubercular bacillus. Nearly a century later, a Canadian urologist used bacille Calmette-Guerin (BCG) to treat recurrent noninvasive bladder cancer via weekly intravesical instillation for 6 weeks [2]. Intravesical BCG was approved by the Food and Drug Administration in 1990 for the treatment of carcinoma in situ of the bladder and is currently also approved for stage TaT1 tumors at high risk for recurrence [3]. Adjuvant treatment with BCG is currently the most effective strategy in nonmuscle invasive bladder cancer after transurethral resection [4]. Intravesical BCG is effective in prophylaxis against both recurrence and progression of intermediate or high-risk non–muscle invasive bladder cancer.\n\nA standard dose of BCG is administered by diluting a powdered vial of BCG vaccine. After a urethral catheter is placed, the urinary bladder is drained and the BCG solution is infused into the bladder where it remains for 1-2 hours. The solution is drained through the catheter prior to catheter removal. Infusion is performed once weekly for 4-6 weeks and may commence 2-4 weeks after resection. Subsequent maintenance therapy may be given once per week for 3 weeks 3, 6, and 12 months after initial treatment and can be extended for up to 3 years. Clinical surveillance takes place by cystoscopy and urine cytology every 3-6 months for four years then once yearly. Imaging surveillance with computed tomography (CT) is often performed on a yearly basis.\n\nCase report\nA 77-year-old male with history of benign prostatic hyperplasia and urothelial carcinoma of the bladder presented with testicular discomfort and a palpable mass two years after intravesical BCG therapy. The patient initially presented with hematuria in 2017 and underwent CT (Fig. 1a) and post-CT abdominal radiograph in excretory phase (Fig. 1b) which demonstrated a soft tissue mass in the bladder suspicious for urothelial carcinoma. This was confirmed visually during cystoscopy at which time the patient underwent excision of the mass and transurethral resection of the bladder tumor. Pathology revealed noninvasive high grade papillary urothelial carcinoma, stage Ta. Therefore, the patient was determined to be a candidate for BCG therapy and was successfully treated with subsequent intravesical BCG instillation for 6 weeks followed by maintenance BCG instillation for 1 year.Fig. 1a Urogram phase CT performed on initial presentation for hematuria outlines an eccentric tissue mass at the base of the bladder suspicious for neoplasm. There is no lymphadenopathy in the pelvis.\n\nFig. 1aFig. 1b Frontal abdominal radiograph obtained on initial presentation after intravenous contrast administration demonstrates filling defect at the base of the bladder. Trabeculation in the bladder wall is identified due to longstanding history of benign prostatic hyperplasia and bladder outlet obstruction.\n\nFig. 1b\n\nTwo years after initiation of intravesical BCG therapy, the patient complained of mild left testicular pain and a palpable mass. Testicular ultrasound demonstrated multiple vague hypoechoic lesions in the left epididymis (Fig. 2a) and testicle (Figs. 2b-d) and fluid within the scrotal sac containing septations consistent in appearance with a complex hydrocele (Figs. 2a-d). The left testicle was mildly hyperemic compared to the right (Figs. 2e-f) suggestive of underlying infectious process. Urinalysis revealed small leukocyte esterase and urine culture was negative. The patient was treated with routine antibiotic therapy for epididymyo-orchitis without significant improvement.Figures 2 Two years after TURBT and subsequent initiation intravesical BCG therapy, the patient presented with testicular pain and palpable abnormality. Sonographic image of the left testicle shows hypoechoic areas within the testicular parenchyma and a complex hydrocele (a-d). There is asymmetric hyperemia of the left testicle (e-f).\n\nFigures 2\n\nFollow-up sonographic imaging after antibiotic therapy demonstrated interval resolution of complex hydrocele but increase in size and number of hypoechoic testicular lesions (Figs. 3b-c). Patient's urinalysis was again noted to be positive for leukocyte esterase and urine culture was again negative. Discussion between urology and radiology regarding the patient's history and imaging findings led to a differential diagnosis including sequalae of chronic infection such as testicular TB in light of prior intravesical BCG treatment. Serology was within normal limits including alpha feto-protein at 2.0 ng/mL, b-HCG at 1.0 mIU/mL, and lactate dehydrogenase at 162 U/L.Figures 3 (a-c) Follow-up sonography 4 weeks later after antibiotic therapy shows resolution of complex hydrocele but increasing size and number of hypoechoic lesions in the left testicle. Possibility of testicular tuberculosis was raised after initial failed antibiotic therapy.\n\nFigures 3\n\nDiscussion with the patient regarding treatment options led to the decision to undergo orchiectomy. Pathology from radical orchiectomy revealed necrotizing and non-necrotizing granulomatous inflammation involving the testis, epididymis, and rete testis, with rare acid-fast bacilli forming a 4.5-cm dominant mass consistent with tuberculous epididymo-orchitis. Staining for acid fast bacilli revealed rare acid-fast bacilli (Fig. 4a, Fig. 4b, Fig. 4c).Fig. 4a Low power photomicrograph of orchiectomy specimen demonstrates areas of granulomatous and nongranulomatous inflammatory change and displacement of testicular parenchyma.\n\nFig. 4aFig. 4b High power photomicrograph of orchiectomy specimen demonstrating giant cells suggestive of tuberculosis.\n\nFig. 4bFig. 4c Acid fast stain showing sparse acid-fast bacilli.\n\nFig. 4c\n\nSubsequent surveillance cystoscopy and biopsy of the bladder tumor scar showed predominantly denuded urothelial mucosa with mild chronic inflammation and reactive changes consistent with successful treatment of the tumor. Follow-up urinalysis was negative for leukocyte esterase suggesting successful treatment of testicular TB.\n\nDiscussion\nTB involving the genitourinary tract is most commonly seen after primary pulmonary TB. The kidneys, ureters, and bladder are commonly affected up to 15% of the time in the setting of extrapulmonary TB. Urinary tract TB may also occur in isolation and comprises 25% of cases of genitourinary TB. Spread of TB to the testicle and epididymis is thought to occur via retrograde spread of tubercular bacilli from the affected urinary tract into the prostate via reflux, followed by canalicular spread to the seminal vesicle, ductus deferens, and epididymis [5]. Disseminated spread may occur due to poor healing after transurethral resection of bladder tumor.\n\nIntravesical BCG therapy is not without risk as it uses an active but weakened strain of bovine TB bacillus, Mycobacterium bovis. Most common side effects are related to inflammatory response within the bladder leading to chemical cystitis including dysuria, frequency, and hematuria. Direct contact of the BCG solution may lead to anterograde or retrograde spread of M. bovis and associated granulomatous inflammation to involve to the remainder of the genitourinary tract including the penis, epididymis, testis, prostate, and kidney [6]. In this case, spread of live attenuated M. bovis from the prostatic urethra through the vas deferens and ductus deferens into the epididymis and testes and caused epididymal and testicular TB. Prostatitis and associated elevation of prostate-specific antigen levels is common after intravesical BCG therapy and may occur with an incidence of up to 10%. Tuberculous epididymo-orchitis is relatively uncommon and occurs in approximately 0.4% of patients [6]. Pyelonephritis and renal abscess are also less common at 0.3%. Systemic complications also occur infrequently at a rate of approximately 3% and include military TB, mycotic aneurysms, granulomatous hepatitis, tuberculous spondylitis, and BCG-related sepsis [6,7].\n\nSonographic findings of testicular TB include diffuse enlargement of the testicle, heterogeneous or homogeneous hypoechoic echotexture, and hypoechoic nodules [8], [9], [10]. Tuberculous epididymitis is similar in appearance with diffuse enlargement and hypoechoic areas of heterogeneity. Tuberculous orchitis usually is the result of contiguous extension from tuberculous epididymitis [8], [9], [10]. Extension of TB to the scrotum includes scrotal skin thickening, blurred separation between the testis and the epididymis, hydrocele, and calcification of the epididymis and tunica vaginalis [8], [9], [10].\n\nTesticular TB may be confirmed with fine needle aspiration and cytology or testicular biopsy [11]. Fine needle aspiration may show epithelioid granulomas and acid-fast bacilli staining may be positive for occasional acid-fast bacilli.\n\nTreatment options for testicular TB include anti-TB antibiotic therapy and orchiectomy. While the patient elected to undergo orchiectomy for his suspected testicular TB, an anti-TB antibiotic regimen could include rifampicin, isoniazid, pyrazinamide, and ethambutol with follow-up imaging to document resolution [12]. Ultimately, orchiectomy is the best current treatment option particularly in resistant cases [12].\n\nDrug Names and Instrument Names\nBCG vaccine, rifampicin, isoniazid, pyrazinamide, ethambutol.\n\n“I give consent to be included as the subject of a case report”. - R.K.\n==== Refs\nReferences\n1 Hershkovitz I Donoghue HD Minnikin DE Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean PLoS One 3 2008 e3426 18923677 \n2 Morales A Eidinger D Bruce AW. Intracavitary bacillus calmette-guérin in the treatment of superficial bladder tumors J Urol 116 2 1976 180 183 10.1016/S0022-5347(17)58737-6 820877 \n3 Aldousari S Kassouf W. Update on the management of non-muscle invasive bladder cancer Can Urol Assoc J 4 1 2010 56 64 10.5489/cuaj.777 20165581 \n4 Kamel A.I. El Baz A.G. Abdel Salam W.T. Ryad M.E. Mahena A.A. Low dose BCG regimen in T1 transitional cell carcinoma of the bladder: long term results J Egypt Natl Canc Inst 21 2009 151 155 21057566 \n5 Das A Batabyal S Bhattacharjee S Sengupta A A rare case of isolated testicular tuberculosis and review of literature J Family Med Prim Care 5 2016 468 470 10.4103/2249-4863.192334 27843865 \n6 Liu Yuqing Lu Jian Huang Yi Ma Lulin Clinical spectrum of complications induced by intravesical immunotherapy of Bacillus Calmette-Guérin for bladder cancer Journal of Oncology 2019 Article ID 6230409, 11 pages, 2019 \n7 Liaw F. Tan Y.Y. Hendry D. Systemic BCG-osis following intravesical BCG instillation for bladder carcinoma Clin Case Rep 5 10 2017 1569 1572 29026546 \n8 Muttarak M Peh WC Lojanapiwat B Chaiwun B Tuberculous epididymitis and epididymo-orchitis: sonographic appearances Am J Roentgenol 176 2001 1459 1466 11373214 \n9 Turkvatan A Kelahmet E Yazgan C Olcer T Sonographic findings in tuberculous epididymo-orchitis J Clin Ultrasound 32 2004 302 305 15211677 \n10 Jung YY Kim JK Cho KS Genitourinary tuberculosis: comprehensive cross-sectional imaging Am J Roentgenol 184 2005 143 150 15615965 \n11 Garbyal RS Sunil K. Diagnosis of isolated tuberculous orchitis by fine-needle aspiration cytology Diagn Cytopathol 34 2006 698 700 16955477 \n12 Shah H Shah K Dixit R Shah KV Isolated tuberculous epididymo-orchitis Indian J Tuberc 51 2004 159 162\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "15(11)",
"journal": "Radiology case reports",
"keywords": "Intravesical BCG; Testicular tuberculosis; Urothelial carcinoma",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101467888",
"other_id": null,
"pages": "2285-2293",
"pmc": null,
"pmid": "32983302",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": "29026546;15615965;27843865;30984262;18923677;16955477;11373214;21057566;15211677;820877;20165581",
"title": "Testicular tuberculosis: An uncommon complication after treatment of urothelial carcinoma.",
"title_normalized": "testicular tuberculosis an uncommon complication after treatment of urothelial carcinoma"
} | [
{
"companynumb": "US-009507513-2010USA001353",
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"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN"
... |
{
"abstract": "Dabigatran, a direct thrombin inhibitor, is increasingly used for stroke prevention in patients with non-valvular atrial fibrillation. Dabigatran has a stable pharmacokinetic profile with minimum drug interactions, and requires no routine laboratory evaluation to measure level of anticoagulation. This provides a huge advantage over warfarin, and has the potential to improve patient compliance. The disadvantages of dabigatran are the lack of a reversal agent to counter dabigatran-related bleeding and the absence of a widely available laboratory test that can quantify the extent of coagulopathy in dabigatran overdose. Hemodialysis can rapidly lower dabigatran levels and assist in controlling bleeding secondary to dabigatran overdose. However, in cases in which hemodynamic instability precludes the use of hemodialysis, alternative methods have to be utilized to control dabigatran-associated bleeding. Here we document a case of massive gastrointestinal bleeding secondary to dabigatran use that was successfully managed by continuous venovenous hemodialysis (CVVHD), along with supportive care with blood product transfusions. CVVHD reduces thrombin time and activated partial thrombin time, and causes a parallel decrease in amount of active bleeding. Finally, we show that compared to the rapid lowering of elevated thrombin time observed in hemodialysis, CVVHD requires several days to reduce thrombin time to normal range.",
"affiliations": "Department of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Ave, MS 1150, Toledo, OH, 43614, USA, suman.paul@utoledo.edu.",
"authors": "Paul|Suman|S|;Hamouda|Danae|D|;Prashar|Rohini|R|;Mbaso|Chiamaka|C|;Khan|Abdur|A|;Ali|Abdulmonam|A|;Shah|Sarthi|S|;Assaly|Ragheb|R|",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-015-1739-7",
"fulltext": null,
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"issn_linking": "0925-5710",
"issue": "101(6)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000368:Aged; D000991:Antithrombins; D001780:Blood Coagulation Tests; D001803:Blood Transfusion; D000069604:Dabigatran; D062787:Drug Overdose; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D006435:Renal Dialysis",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "594-7",
"pmc": null,
"pmid": "25633777",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20214409;16308283;20352166;22189016;23809871;22383791;19717844;21900088",
"title": "Management of dabigatran-induced bleeding with continuous venovenous hemodialysis.",
"title_normalized": "management of dabigatran induced bleeding with continuous venovenous hemodialysis"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2015-BI-07858GD",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "OBJECTIVE\nSubcutaneous entomophthoromycosis (EM) is an uncommon fungal infection of childhood. This article is intended to draw the attention of pediatric surgeons to the fact that EM can mimic soft-tissue tumor.\n\n\nMETHODS\nIt is a retrospective review of 16 children treated for subcutaneous EM between 2000 and 2013.\n\n\nRESULTS\nThe median age of patients was 3.5 years. The typical lesion was a discoid subcutaneous mass that can be easily lifted from deeper tissues (the doughnut lifting sign). Lesions were mostly distributed in the lower half of body. All the patients were immunocompetent. Correct clinical diagnosis was made only in 4 cases while others were mistaken for a tumor. All the 8 children who underwent wide excision of the pseudotumor had local recurrence. Supersaturated solution of potassium iodide was curative in 11 cases while addition of itraconazole was needed in one case. One child died of multi-drug resistant infection. The mean treatment duration was 4.7 months (range 2-8 months).\n\n\nCONCLUSIONS\nSubcutaneous EM can mimic soft-tissue tumor. High index of suspicion is essential to avoid misdiagnosis and inappropriate treatment. A newly described \"doughnut-lifting sign' may be helpful in clinical diagnosis. Emergence of multi-drug resistant infection is a source of concern.",
"affiliations": "Department of Pediatric Surgery, Sri Ramasamy Memorial (SRM) Medical College, Kattankulathur, Chennai, India; Hindu Mission Hospital, Tambaram, Chennai, India. Electronic address: vrthiran@yahoo.co.in.;Department of Microbiology, SRM Medical College, Kattankulathur, Chennai, India.;Department of Microbiology, SRM Medical College, Kattankulathur, Chennai, India.;Department of Pathology, Rajah Muthiah Medical College, Chidambaram, India.;Department of Pathology, Rajah Muthiah Medical College, Chidambaram, India.;Department of Microbiology, Rajah Muthiah Medical College, Chidambaram, India.",
"authors": "Raveenthiran|Venkatachalam|V|;Mangayarkarasi|Vincent|V|;Kousalya|Murugesan|M|;Viswanathan|Periyaswamy|P|;Dhanalakshmi|Manivachagam|M|;Anandi|Viswanathan|V|",
"chemical_list": "D011193:Potassium Iodide; D017964:Itraconazole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3468",
"issue": "50(7)",
"journal": "Journal of pediatric surgery",
"keywords": "Basidiobolus; Conidiobolus; Differential diagnosis; Fungal infection; Phycomycosis; Potassium iodide; Pseudo-tumor; Soft-tissue sarcoma; Zygomycosis",
"medline_ta": "J Pediatr Surg",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003881:Dermatomycoses; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D005260:Female; D006801:Humans; D017964:Itraconazole; D008297:Male; D010808:Physical Examination; D011193:Potassium Iodide; D012189:Retrospective Studies; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D020096:Zygomycosis",
"nlm_unique_id": "0052631",
"other_id": null,
"pages": "1150-5",
"pmc": null,
"pmid": "25783300",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Subcutaneous entomophthoromycosis mimicking soft-tissue sarcoma in children.",
"title_normalized": "subcutaneous entomophthoromycosis mimicking soft tissue sarcoma in children"
} | [
{
"companynumb": "IN-JNJFOC-20150613538",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTrabectedin plus pegylated liposomal doxorubicin (PLD) proved efficacious as second-line treatment for patients with recurrent ovarian cancer (ROC).\n\n\nMETHODS\nWe report a single-center retrospective analysis of the efficacy and tolerance of trabectedin 1.1 mg/m2 every 3 weeks in a cohort of real-life ROC patients.\n\n\nRESULTS\nFrom February 2012 to January 2014, 17 patients were treated with trabectedin alone or combined with PLD. Median age was 61 years (range: 48-78). Performance status was 0-1 in 16 patients (94%). Disease response rate was 53% and disease control rate was 76%. At the end of the follow-up, 8 patients (47%) were alive. Median overall survival was 17.6 months (95% CI 13.6 to not reached). Median progression-free survival was 6.7 months (95% CI 5.4-10.0). The most frequent grade 3-4 toxicities were neutropenia (n = 4, 24%) and nausea/vomiting (n = 4, 24%).\n\n\nCONCLUSIONS\nTrabectedin combined with PLD seems efficient in and well tolerated by real-life ROC patients.",
"affiliations": null,
"authors": "Moriceau|Guillaume|G|;Rivoirard|Romain|R|;Méry|Benoîte|B|;Vallard|Alexis|A|;Pacaut|Cécile|C|;Trone|Jane-Chloé|JC|;Espenel|Sophie|S|;Bosacki|Claire|C|;Jacquin|Jean-Philippe|JP|;Magné|Nicolas|N|",
"chemical_list": "D004149:Dioxoles; D044005:Tetrahydroisoquinolines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000077606:Trabectedin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000441378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "61(3)",
"journal": "Chemotherapy",
"keywords": null,
"medline_ta": "Chemotherapy",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004149:Dioxoles; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms; D011092:Polyethylene Glycols; D012189:Retrospective Studies; D015996:Survival Rate; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D016896:Treatment Outcome",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "122-6",
"pmc": null,
"pmid": "26752402",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-World Outcomes of Combination Chemotherapy with Trabectedin plus Pegylated Liposomal Doxorubicin in Patients with Recurrent Ovarian Cancer: A Single-Center Experience.",
"title_normalized": "real world outcomes of combination chemotherapy with trabectedin plus pegylated liposomal doxorubicin in patients with recurrent ovarian cancer a single center experience"
} | [
{
"companynumb": "FR-JNJFOC-20160117557",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRABECTEDIN"
},
"drugadditional": null,
... |
{
"abstract": "Tamoxifen is a synthetic, nonsteroidal antiestrogen widely used in the treatment of hormone-sensitive breast cancer that has also been shown to inhibit the enzyme protein kinase C (PKC). Upregulation of PKC is associated with disruption of prefrontal cortical regulation of thinking and behavior, which can lead to mania-like symptoms in animal models. Lithium and valproate, 2 mood stabilizers that are widely used in the treatment of bipolar disorder, have also been shown to inhibit PKC. We describe the case of a 48-year-old woman who entered a hypomanic state after discontinuation of tamoxifen while remaining on unopposed venlafaxine prescribed for depression. This case highlights the risk of misdiagnosing unipolar depression in breast cancer patients with undiagnosed bipolar disorder who are being treated with tamoxifen and subsequently started on antidepressants. The use of antidepressants in this population should be carefully monitored to avoid the development of manic, hypomanic, or mixed symptoms in patients with underlying bipolar disorder once tamoxifen is discontinued.",
"affiliations": null,
"authors": "Mora|Hector A|HA|;Kotbi|Nabil|N|;Avari|Jimmy N|JN|",
"chemical_list": "D000928:Antidepressive Agents; D013629:Tamoxifen; D000069470:Venlafaxine Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000504",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "27(1)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D000928:Antidepressive Agents; D001714:Bipolar Disorder; D001943:Breast Neoplasms; D003866:Depressive Disorder; D005260:Female; D006801:Humans; D000087122:Mania; D008875:Middle Aged; D013629:Tamoxifen; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "61-64",
"pmc": null,
"pmid": "33438870",
"pubdate": "2021-01-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Switch to Hypomania After Discontinuation of Tamoxifen: A Case Report.",
"title_normalized": "switch to hypomania after discontinuation of tamoxifen a case report"
} | [
{
"companynumb": "US-PFIZER INC-2021146477",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "In this retrospective study, we investigated the influence of chemotherapy and immunotherapy on thromboembolic risk among United States Veterans with lung cancer during their first 6 months (180 days) following initiation of systemic therapy. Included patients received treatment with common front-line agents that were divided into four groups: chemotherapy alone, immunotherapy alone, combination of chemo- and immunotherapies, and molecularly targeted therapies (control group). The cohort experienced a 7·4% overall incidence of thrombosis, but the analysis demonstrated significantly different rates among the different groups. We explored models incorporating multiple confounding variables as well as the competing risk of death, and these results indicated that both chemo- and immunotherapies were associated with an increased incidence of thrombosis, either alone or combined, compared with the control group (7·56%, P = 2.2 × 10-16 ; 10·2%, P = 2.2 × 10-16 ; and 7·87%, P = 2.4 × 10-14 respectively vs. 4·10%). The Khorana score was found to be associated with increased risk, as were vascular disease and metastases. We found an association between risk of thrombosis and the use of anticoagulation, accounting for several confounders, including history of thrombosis. Further study is warranted to better determine the drivers of thromboembolic risk and to identify ways to mitigate this risk for patients.",
"affiliations": "VA Portland Healthcare System, Portland, OR, USA.;VA Portland Healthcare System, Portland, OR, USA.;VA Portland Healthcare System, Portland, OR, USA.;VA Portland Healthcare System, Portland, OR, USA.;VA Portland Healthcare System, Portland, OR, USA.;VA Portland Healthcare System, Portland, OR, USA.",
"authors": "Madison|Cecelia J|CJ|0000-0002-0261-0414;Melson|Ryan A|RA|;Conlin|Michael J|MJ|;Gundle|Kenneth R|KR|0000-0003-0451-0561;Thompson|Reid F|RF|0000-0003-3661-5296;Calverley|David C|DC|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/bjh.17476",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "194(1)",
"journal": "British journal of haematology",
"keywords": "anticoagulation; chemotherapy; immunotherapy; lung cancer; thromboembolism",
"medline_ta": "Br J Haematol",
"mesh_terms": null,
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "179-190",
"pmc": null,
"pmid": "34137029",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "28951500;27913214;24227920;1988575;27273134;10737280;25891174;27906452;16224307;28806116;33067632;12756342;31697173;20062101;33436486;27882374;18216292;31881699;21911825;21810688;18766008;20842120;21515544;27664245;3558716;18313558;19398575;28404761;30207593;3340118;28424324;27992116;19711465;27364315",
"title": "Thromboembolic risk in patients with lung cancer receiving systemic therapy.",
"title_normalized": "thromboembolic risk in patients with lung cancer receiving systemic therapy"
} | [
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"companynumb": "US-ROCHE-2916235",
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"activesubstancename": "ERLOTINIB"
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"abstract": "Osimertinib has efficacy superior to that of standard epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance. MET missense mutations have been demonstrated to mediate resistance to MET-TKIs, such as crizotinib. But the role of MET missense mutations in mediating EGFR TKI resistance is undefined. With the increasing use of next-generation sequencing (NGS) at diagnosis, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Herein, we report the first case of MET D1228N mutation mediating acquired resistance to osimertinib in a MET TKI-naïve NSCLC. The patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion initially responded to osimertinib with progression-free survival (PFS) lasting 11 months and then developed resistance with an acquired mutation of MET D1228N. Subsequently, combination therapy of cabozantinib and osimertinib was administrated to the patient, and her clinical symptoms were rapidly relieved within one week with good tolerance. She remained on the combined treatment for 10 months. Finally, she achieved an overall survival (OS) of 25 months. Based on our findings, patient with MET D1228N mutant lung adenocarcinoma clinically benefited from combinatorial therapy of cabozantinib and osimertinib after osimertinib resistance.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.;Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.",
"authors": "Kuang|Yukun|Y|;Wang|Jiyu|J|;Xu|Peihang|P|;Zheng|Yifan|Y|;Bai|Lihong|L|;Sun|Xue|X|;Li|Zimu|Z|;Gan|Runjing|R|;Li|Huixia|H|;Ke|Zunfu|Z|;Tang|Kejing|K|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/atm-21-3861",
"fulltext": "\n==== Front\nAnn Transl Med\nAnn Transl Med\nATM\nAnnals of Translational Medicine\n2305-5839\n2305-5847\nAME Publishing Company\n\natm-09-16-1354\n10.21037/atm-21-3861\nCase Report\nA rapid and durable response to cabozantinib in an osimertinib-resistant lung cancer patient with MET D1228N mutation: a case report\nKuang Yukun 1 2 #\nWang Jiyu 1 2 #\nXu Peihang 1 2 #\nZheng Yifan 3 #\nBai Lihong 1 2\nSun Xue 1 2\nLi Zimu 1 2\nGan Runjing 1 2\nLi Huixia 1 2\nKe Zunfu 4\nTang Kejing 1 2 ^\n1 Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;\n2 Institute of Pulmonary Diseases, Sun Yat-sen University, Guangzhou, China;\n3 Department of Pharmacy, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;\n4 Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China\n# These authors contributed equally to this work.\n\nCorrespondence to: Zunfu Ke. Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Er Lu, Guangzhou 510080, China. Email: kezunfu@mail.sysu.edu.cn; Kejing Tang. Division of Pulmonary and Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University; Institute of Pulmonary Diseases, Sun Yat-sen University, No. 58, Zhongshan Er Lu, Guangzhou 510080, China. Email: tangkj@mail.sysu.edu.cn.\n^ ORCID: 0000-0002-5454-4666.\n\n8 2021\n8 2021\n9 16 135411 7 2021\n11 8 2021\n2021 Annals of Translational Medicine. All rights reserved.\n2021\nAnnals of Translational Medicine.\nOsimertinib has efficacy superior to that of standard epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance. MET missense mutations have been demonstrated to mediate resistance to MET-TKIs, such as crizotinib. But the role of MET missense mutations in mediating EGFR TKI resistance is undefined. With the increasing use of next-generation sequencing (NGS) at diagnosis, many mechanisms of acquired resistance have been discovered in patients with activated tyrosine kinase receptors. Herein, we report the first case of MET D1228N mutation mediating acquired resistance to osimertinib in a MET TKI-naïve NSCLC. The patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion initially responded to osimertinib with progression-free survival (PFS) lasting 11 months and then developed resistance with an acquired mutation of MET D1228N. Subsequently, combination therapy of cabozantinib and osimertinib was administrated to the patient, and her clinical symptoms were rapidly relieved within one week with good tolerance. She remained on the combined treatment for 10 months. Finally, she achieved an overall survival (OS) of 25 months. Based on our findings, patient with MET D1228N mutant lung adenocarcinoma clinically benefited from combinatorial therapy of cabozantinib and osimertinib after osimertinib resistance.\n\nKeywords:\n\nLung adenocarcinoma\nosimertinib resistance\nMET D1228N mutation\ncabozantinib\ncase report\n==== Body\npmcIntroduction\n\nThe irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), osimertinib, is a preferred first-line option for patients with EGFR-mutant metastatic non-small cell lung cancer (NSCLC) (1). With the wide application of osimertinib, its resistance mechanisms have been well elucidated, among which the activation of the MET pathway via MET gene activation and amplification is one of the most common bypass pathway mechanisms (2). Combining c-Met inhibitors, such as crizotinib, with osimertinib has been found to be effective in osimertinib-resistant EGFR-mutated NSCLC patients harbouring MET amplification (3). On the other hand, acquired mutations, including those at positions Y1230 and D1228, can occur over long-term exposure to MET inhibitors (4). However, bypass activation of MET by missense mutation has not been reported to mediate the resistance to EGFR TKIs thus far. In this study, we report the first case of MET D1228N mutation as the resistant mechanism to osimertinib in a MET TKI-naïve lung adenocarcinoma patient who subsequently benefited from the combinational therapy of EGFR and MET TKIs. We present the following case in accordance with the CARE reporting checklist (available at https://dx.doi.org/10.21037/atm-21-3861).\n\nCase presentation\n\nAn 81-year-old female patient presented to the hospital in May 2018 with symptoms of productive cough and shortness of breath for several months. A chest computed tomography (CT) scan showed a 58 mm × 62 mm nodule in the left lung with multiple small nodules, enlarged mediastinal lymph nodes, and pleural effusions (Figure 1A). She was diagnosed with stage IV lung adenocarcinoma and capture-based next-generation sequencing (NGS) with a panel of 168 cancer-related genes (Lung Plasma, Burning Rock, Guangzhou, China) was conducted with a lung biopsy specimen. EGFR c.2236_2250del (p.E746_A750del) mutation (abundance 11.52%) was identified, and she thus received osimertinib (80 mg, qd) as the first-line therapy. Her symptoms improved rapidly, and no significant adverse events were observed. A chest CT evaluation 12 weeks later showed a partial response (PR) and the lung lesion significantly decreased (38 mm × 22 mm; Figure 1B). After 11 months of disease control, a CT scan showed an enlarged left lung mass (66 mm × 50 mm; Figure 1C). Ultra-deep plasma-derived circulating tumor DNA (ctDNA) NGS revealed EGFR E746_A750del (abundance 0.54%) and TP53 H179R mutation (abundance 1.32%). The patient presented asymptomatic disease progression (PD) and refused chemotherapy, so she continued osimertinib treatment (80 mg, qd). She was readmitted to the hospital with progressive aggravating symptoms in July 2019. Chest CT showed that the mass in the upper lobe of the left lung was enlarged and densified significantly with increased left pleural effusion (97 mm × 67 mm; Figure 1D), indicating PD with serious clinical symptoms. Along with intensive respiratory support, the patient received ultrasound-guided pleural puncture and catheterization. Hydrothorax exudate NGS showed EGFR E746_A750 deletion (abundance 4.95%) and MET D1228N missense mutation (abundance 3.86%). Treatment was subsequently changed to cabozantinib (40 mg, qd) plus osimertinib (80 mg, qd), and she experienced an overall improvement in her clinical symptoms within 1 week. Re-examination of CT 10 days later revealed that the primary lesion of the left lung had dramatically shrunk (65 mm × 65 mm; Figure 1E), and the efficacy was evaluated as PR. After discharge, the patient continued the combined treatment of cabozantinib and osimertinib, and no other adverse events occurred except for grade 2–3 diarrhea. Due to personal reasons, the patient did not return regularly. She took cabozantinib and osimertinib until her symptoms worsened again in May 2020. Finally, she died 1 month later with an overall survival (OS) of 25 months. The overall process of diagnosis and treatment is shown in Figure 2. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.\n\nFigure 1 Chest CT images of an advanced NSCLC patient with EGFR exon 19 deletion. (A) At baseline. (B) Confirmed PR after 3 months of osimertinib. (C) Asymptomatic PD after 11 months of osimertinib. (D) Left lung lesion growth with left pleural effusion. (E) Immediate remission after the addition of cabozantinib. CT, computed tomography; NSCLC, non-small cell lung cancer; EGFR, epidermal growth factor receptor; PR, partial response; PD, progressive disease.\n\nFigure 2 Timeline and duration of each treatment.\n\nDiscussion\n\nThe acquired resistance mechanisms to first-line or second-line osimertinib therapy have been illustrated, including EGFR-dependent and bypass resistance mechanisms. One of the most frequent causes of bypass pathway activation is MET amplification. Furthermore, oncogenic alteration MET exon 14 skipping can induce resistance to osimertinib, which has been confirmed in EGFR-mutated cell models (5). However, mutations in the MET tyrosine kinase domain have rarely been found in NSCLC as a secondary event resulting from exposure to prior therapies, such as TKIs (6).\n\nIn a recent case reported by Kang et al., one patient benefited from the combination of osimertinib and cabozantinib after simultaneous development of secondary MET mutations upon crizotinib treatment (7). A combination of osimertinib and trastuzumab emtansine (T-DM1), a conjugate of the monoclonal antibody trastuzumab (Herceptin) and the cytotoxic agent DM1, was reported to delay and overcome osimertinib resistance in T790M-positive EGFR-mutated NSCLC cell lines that gained HER2 amplification (8).\n\nIn our case, MET D1228N mutation, a known resistance mutation to type I MET inhibitors, was acquired after first-line osimertinib failure without any prior exposure to MET inhibitors. Given that D1228N shows an increased level of tyrosine phosphorylation with respect to wild-type MET (9), we consider it could mediate the resistance to EGFR-TKI osmertinib.\n\nMET D1228N mutation shows resistance to type I MET inhibitors, such as crizotinib and capmatinib, but displays sensitivity to type II inhibitors, such as cabozantinib in vitro (10). However, in clinical settings, the sensitivity of MET D1228N to MET inhibitors is equivocal. MET D1228N bypass activation was identified as the potential mechanism to crizotinib resistance in a CD74-ROS1 fusion lung cancer patient. Second-line cabozantinib brought significant improvement and 3 months of progression-free survival for the patient (11). In another report, lung cancer patient who was resistant to osimertinib due to MET amplification received crizotinib and osimertinib therapy (7). Upon confirmation of PD, novel acquired MET mutations, D1228N/Y, Y1230H, and D1231Y were detected (7). The treatment was changed from crizotinib to cabozantinib, and, after the combinatorial treatment, repeat dynamic liquid biopsy revealed that all MET point mutations were undetectable, except for D1228N (7). The allelic fraction of this mutation increased compared to the baseline, suggesting the subclonal lesion bearing this variant was nonresponsive to cabozantinib (7). MET D1228N was also reported to be an acquired resistance mutation to crizotinib in an MET-amplified advanced triple-negative breast cancer patient. She was treated with cabozantinib for 7 weeks followed by rapid progression (12).\n\nAlthough the efficacy of cabozantinib to MET D1228N mutation remains inconclusive, we treated our patient with cabozantinib and osimertinib after consulting with the patient and her family. Her clinical symptoms were rapidly relieved with 1 week, and she obtained an OS of 25 months. The limitation of this case was loss to follow up during late course of treatment, and the PFS was not available. Collectively, the effectiveness of cabozantinib against MET D1228N mutation may differ among patients due to the type of cancer, performance status, and other unknown tumor-intrinsic characteristics. Further investigations are still needed to elucidate the resistance mechanism of acquired MET D1228N mutations to develop more efficacious MET inhibitors.\n\nConclusions\n\nOur study was the first to report that MET D1228N mutation can also mediate resistance to first-line osimertinib therapy. Patient with MET D1228N mutation clinically benefited from combinatorial therapy of cabozantinib and osimertinib after osimertinib resistance.\n\nAcknowledgments\n\nFunding: This work was supported by grants from the Guangzhou Science and Technology Planning Program [No. 202002030023]; and Natural Science Foundation of Guangdong Province [18zxxt17].\n\nEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.\n\nOpen Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.\n\nReporting Checklist: The authors have completed the CARE reporting checklist. Available at https://dx.doi.org/10.21037/atm-21-3861\n\nConflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-3861). The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Soria JC Ohe Y Vansteenkiste J Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378 :113-25. 10.1056/NEJMoa1713137 29151359\n2 Ramalingam SS Yang JC Lee CK Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2018;36 :841-9. 10.1200/JCO.2017.74.7576 28841389\n3 Leonetti A Sharma S Minari R Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer 2019;121 :725-37. 10.1038/s41416-019-0573-8 31564718\n4 Heist RS Sequist LV Borger D Acquired Resistance to Crizotinib in NSCLC with MET Exon 14 Skipping. J Thorac Oncol 2016;11 :1242-5. 10.1016/j.jtho.2016.06.013 27343442\n5 Suzawa K, Offin M, Schoenfeld AJ, et al. Acquired MET Exon 14 Alteration Drives Secondary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in EGFR-Mutated Lung Cancer. JCO Precis Oncol 2019;3:PO.19.00011.\n6 Engelman JA Jänne PA . Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer. Clinical Cancer Research 2008;14 :2895-9. 10.1158/1078-0432.CCR-07-2248 18483355\n7 Kang J Chen HJ Wang Z Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR-Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to Crizotinib. J Thorac Oncol 2018;13 :e49-e53. 10.1016/j.jtho.2017.10.028 29128427\n8 La Monica S Cretella D Bonelli M Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines. J Exp Clin Cancer Res 2017;36 :174. 10.1186/s13046-017-0653-7 29202823\n9 Bardelli A Longati P Gramaglia D Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth. Proc Natl Acad Sci U S A 1998;95 :14379-83. 10.1073/pnas.95.24.14379 9826708\n10 Engstrom LD Aranda R Lee M Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models. Clin Cancer Res 2017;23 :6661-72. 10.1158/1078-0432.CCR-17-1192 28765324\n11 Wang Y Chen Z Han X Acquired MET D1228N Mutations Mediate Crizotinib Resistance in Lung Adenocarcinoma with ROS1 Fusion: A Case Report. Oncologist 2021;26 :178-81. 10.1002/onco.13545 33000474\n12 Parsons BM Meier DR Richmond CS Acquisition of Cabozantinib-Sensitive MET D1228N Mutation During Progression on Crizotinib in MET-Amplified Triple-Negative Breast Cancer. Clin Breast Cancer 2020;20 :e433-8. 10.1016/j.clbc.2020.02.003 32234363\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2305-5839",
"issue": "9(16)",
"journal": "Annals of translational medicine",
"keywords": "Lung adenocarcinoma; MET D1228N mutation; cabozantinib; case report; osimertinib resistance",
"medline_ta": "Ann Transl Med",
"mesh_terms": null,
"nlm_unique_id": "101617978",
"other_id": null,
"pages": "1354",
"pmc": null,
"pmid": "34532491",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": "27343442;9826708;18483355;33000474;28765324;29128427;29151359;28841389;29202823;31157314;31564718;32234363",
"title": "A rapid and durable response to cabozantinib in an osimertinib-resistant lung cancer patient with MET D1228N mutation: a case report.",
"title_normalized": "a rapid and durable response to cabozantinib in an osimertinib resistant lung cancer patient with met d1228n mutation a case report"
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"abstract": "ACLF is characterized by acute deterioration of liver function in patients with chronic liver disease. HBV is one of the most important causes of both acute insult and underlying chronic liver disease in ACLF. Reactivation of HBV is one of the common causes of ACLF in our region. ACLF requires multiple organ support and is associated with high short and medium term mortality. This is the reason why early, rapid reduction of HBV DNA is essential in treating ACLF-B.\nConsecutive patients of ACLF-B due to spontaneous reactivation of HBV (ALT> 5xULN or >2 x baseline and HBV DNA >20,000 IU/ml) were randomized into tenofovir group (300mg/day) and telbivudine group (600mg/day) along with standard medical treatment. Clinical and laboratory parameters were evaluated at baseline, day-7, day-14, day-30 and day-90. HBV DNA was evaluated at baseline and after three months of therapy. Primary end point was survival or death at three months. Secondary end point was improvement of liver function assessed by Child-Turcotte Pugh score and MELD score at three months.\n30 patients were enrolled in the study and 15 of them received tenofovir and 15 patients received telbivudine. Most of the baseline parameters showed no difference except serum AST and serum creatinine level that showed statistically significant difference between two groups. After antiviral therapy both groups showed significant clinical improvement along with CTP and MELD scores. However statistically significant improvement between tenofovir and telbivudine groups was only seen with MELD score. Survival rate was 80% in tenofovir group and 60% in telbivudine group, but this was not statistically significant. Low serum albumin at baseline was predictor of mortality.\nIn patients of ACLF-B, antiviral therapy with both tenofovir and telbivudine improve liver function, but there is no statistically significant difference in survival between tenofovir and telbivudine.",
"affiliations": "Civil Surgeon Office, Munshiganj, Bangladesh.;Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.;Department of Hepatology, Dhaka Medical College Hospital, Dhaka, Bangladesh.;Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.;Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.;Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.;Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime, Japan.;Department of Primary Care and Microbiology, Brahminbaria Medical College, Brahminbaria, Bangladesh.;Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.;Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.",
"authors": "Malakar|Debraj|D|;Mahtab|Mamun A|MA|;Manik|Abul H|AH|;Alam|Sheikh M Noor E|SMNE|;Das|Dulal C|DC|;Mamun|Ayub A|AA|;Khan|Md Sakirul Islam|MSI|;Rahman|Zakiur|Z|;Rahman|Salimur|S|;Akbar|Sheikh Mohammad Fazle|SMF|",
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"fulltext": "\n==== Front\nJ Family Med Prim Care\nJ Family Med Prim Care\nJFMPC\nJournal of Family Medicine and Primary Care\n2249-4863\n2278-7135\nWolters Kluwer - Medknow India\n\nJFMPC-10-2381\n10.4103/jfmpc.jfmpc_2302_20\nOriginal Article\nRole of tenofovir and telbivudine in treatment of hepatitis B related acute on chronic liver failure\nMalakar Debraj 1\nMahtab Mamun A 2\nManik Abul H 3\nAlam Sheikh M Noor E 2\nDas Dulal C 2\nMamun Ayub A 2\nKhan Md. Sakirul Islam 4\nRahman Zakiur 5\nRahman Salimur 2\nAkbar Sheikh Mohammad Fazle 6\n1 Civil Surgeon Office, Munshiganj, Bangladesh\n2 Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh\n3 Department of Hepatology, Dhaka Medical College Hospital, Dhaka, Bangladesh\n4 Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Ehime, Japan\n5 Department of Primary Care and Microbiology, Brahminbaria Medical College, Brahminbaria, Bangladesh\n6 Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan\nAddress for correspondence: Dr. Mamun Al Mahtab, Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Bangladesh. Postal Address: House # 109, Road # 4, Block # B, Banani, Dhaka - 1213, Bangladesh. E-mail: shwapnil@agni.com\n6 2021\n02 7 2021\n10 6 23812385\n23 11 2020\n02 2 2021\n23 2 2021\nCopyright: © 2021 Journal of Family Medicine and Primary Care\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nIntroduction:\n\nACLF is characterized by acute deterioration of liver function in patients with chronic liver disease. HBV is one of the most important causes of both acute insult and underlying chronic liver disease in ACLF. Reactivation of HBV is one of the common causes of ACLF in our region. ACLF requires multiple organ support and is associated with high short and medium term mortality. This is the reason why early, rapid reduction of HBV DNA is essential in treating ACLF-B.\n\nMethods:\n\nConsecutive patients of ACLF-B due to spontaneous reactivation of HBV (ALT> 5xULN or >2 x baseline and HBV DNA >20,000 IU/ml) were randomized into tenofovir group (300mg/day) and telbivudine group (600mg/day) along with standard medical treatment. Clinical and laboratory parameters were evaluated at baseline, day-7, day-14, day-30 and day-90. HBV DNA was evaluated at baseline and after three months of therapy. Primary end point was survival or death at three months. Secondary end point was improvement of liver function assessed by Child-Turcotte Pugh score and MELD score at three months.\n\nResults:\n\n30 patients were enrolled in the study and 15 of them received tenofovir and 15 patients received telbivudine. Most of the baseline parameters showed no difference except serum AST and serum creatinine level that showed statistically significant difference between two groups. After antiviral therapy both groups showed significant clinical improvement along with CTP and MELD scores. However statistically significant improvement between tenofovir and telbivudine groups was only seen with MELD score. Survival rate was 80% in tenofovir group and 60% in telbivudine group, but this was not statistically significant. Low serum albumin at baseline was predictor of mortality.\n\nConclusion:\n\nIn patients of ACLF-B, antiviral therapy with both tenofovir and telbivudine improve liver function, but there is no statistically significant difference in survival between tenofovir and telbivudine.\n\nACLF-B\nHBV\ntelbivudine\ntenofovir\n==== Body\nIntroduction\n\nAcute on chronic liver failure (ACLF) is characterized by acute deterioration of liver function in patients with chronic liver disease.[1] Asian-Pacific Association for the Study of Liver Disease (APASL) defines ACLF as an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis and is associated with a high 28-day mortality.[2]\n\nChronic hepatitis B virus (HBV) infection is a serious health problem worldwide. It has been estimated that more than 2,00,000 and 3,00,000 chronic HBV-infected people die worldwide each year due to HBV-related liver cirrhosis and hepatocellular carcinoma (HCC).[3] Some CHB patients develop acute exacerbations of HBV leading to liver failure and even death. ACLF-B is associated with mortality ranging from 30% to 70%.[4] Liver transplantation remains only definitive therapy for patients with ACLF, but limited donor availability, high cost and lack of availability limit its usefulness in the management of patients of ACLF. Besides many patients cannot eventually be transplanted due to hemodynamic instability, raised intracranial pressure, reduced cerebral perfusion pressure and bacterial and/or fungal infections. Mortality due to ACLF-B may be prevented with antiviral therapy drugs during the golden window period. It is assumed that antiviral drugs reduce HBV load and reduce hepatocyte death with improved survival outcome.[5] It has been shown that nucleos (t) ide analogues significantly reduce HBV DNA[6] with significantly lower 3-month mortality (44.8% vs. 73.3%) and also reduced reactivation (1.80% vs. 18.4%).[4]\n\nMethodology\n\nIt was an observational study carried out on patients admitted at the in-patient department of Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka. Prior to the commencement of this study, the research protocol was approved by the Institutional Review Board (IRB) of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. Clinically suspected patients of ACLF-B were admitted through the out-patient department. Necessary investigations were done after admission. Patients of ACLF-B of age >18 years of both sexes were enrolled as study population. Patients of ACLF-B with undetectable HBV DNA, underlying cirrhosis due to any other etiology other than HBV, patients testing positive for anti-HAV IgM, anti-HEV IgM and anti-HCV IgM, coexistent HCC, patients on antiviral, cytotoxic, or immune-modulator drugs and with co-morbidity like heart failure, malignancy and uncontrolled diabetes were excluded. In all, 30 patients were recruited. After enrollment, the patients were randomized into two groups (A and B). Group A was selected for tenofovir and group B for telbivudine. Tenofovir 300 mg orally daily was given on an empty stomach at least 1 h before or 2 h after breakfast and telbivudine 600 mg orally daily in the morning along with standard medical therapy and was followed up for next 3 months. Data were collected on admission, at days 7, 14, 30, and 90. In case of death, cause of death was evaluated.\n\nEvery patient was received standard medical treatment including intravenous antibiotics, lactulose, supervised diet, and close monitoring. Patients were also treated with albumin and proton pump inhibitors when required. Enteral or parenteral nutrition was ensured to those patients where caloric requirement was not fulfilled orally.\n\nAll data were presented as mean ± SD and analyzed by SPSS. Qualitative data were analyzed by Chi-square test and quantitative data were be analyzed by Student's t-test. The Wilcoxon rank sum was used to compare laboratory parameters and measurement obtained in the first and last visits. A statistically significant result was considered when P value < 0.05.\n\nResult\n\nThe mean age was found 43.5 ± 13.5 years in tenofovir group and 44.0 ± 14.3 years in telbivudine group. The majority patients were males in both groups [Table 1]: 100.0% patients in both groups had jaundice and ascites. Altered level of consciousness was found 26.7% in tenofovir group and 20% in telbivudine group [Table 2].\n\nTable 1 Distribution of the study patients by demographic variables\n\nDemographic variables\tTenofovir group (n=15)\tTelbivudine group (n=15)\tP\t\n\t\t\nn\t%\tn\t%\t\nAge (in years)\t\t\t\t\t\t\n ≤50\t10\t66.7\t11\t73.3\t\t\n >50\t5\t33.3\t4\t26.7\t\t\n Mean±SD\t43.5\t±13.5\t44.0\t±14.3\ta0.922ns\t\n Range (min, max)\t23\t, 70\t25\t,78\t\t\nSex\t\t\t\t\tb0.542ns\t\n Male\t13\t86.7\t14\t93.3\t\t\n Female\t2\t13.3\t1\t6.7\t\t\nMarital status\t\t\t\t\t\t\n Married\t14\t93.3\t15\t100.0\tb0.500ns\t\n Unmarried\t1\t6.7\t0\t0.0\t\t\nOccupational status\t\t\t\t\t\t\n Service\t8\t53.3\t10\t66.7\t\t\n Farmer\t2\t13.3\t1\t6.7\tb0.926ns\t\n Teacher\t1\t6.7\t1\t6.7\t\t\n Business\t2\t13.3\t2\t13.3\t\t\n Housewife\t2\t13.3\t1\t6.7\t\t\nns=not significant, aP-value reached from unpaired t-test, bP-value reached from Chi-square test\n\nTable 2 Distribution of the study patients by symptom and sign\n\nPresenting complaints\tTenofovir group (n=15)\tTelbivudine group (n=15)\tP\t\n\t\t\nn\t%\tn\t%\t\nYellow coloration of eye and urine\t15\t100.0\t15\t100.0\t-\t\nIf yes (days)\t\t\t-\t\t\t\n Mean±SD\t27.7\t±11.6\t33.7\t±13.4\t0.200ns\t\n Range (min, max)\t15\t, 45\t15\t, 60\t\t\nAbdominal swelling and/or legs swelling\t15\t100.0\t15\t100.0\t\t\nIf yes (days)\t\t\t\t\t\t\n Mean±SD\t17.3\t±9.1\t22.0\t±10.5\t0.200ns\t\n Range (min, max)\t7\t, 30\t7\t, 45\t\t\n Altered level of consciousness\t4\t26.7\t3\t20.0\t\t\nIf yes (days)\t\t\t\t\t\t\n Mean±SD\t4.2\t±1.2\t5.1\t±1.9\t0.132ns\t\n Range (min, max)\t3\t, 7\t5\t,7\t\t\nns=not significant\n\nMean Child–Turcotte Pugh (CTP)score was 12.2 ± 0.8 in tenofovir group and 12.1 ± 0.8 in telbivudine group, while mean Model of end stage liver disease (MELD) score was 25.3 ± 2.7 in tenofovir group and 25.6 ± 5.4 in telbivudine group [Table 3]. Virological status of the study patients is shown in Tables 4(i) and 4(ii).\n\nTable 3 Baseline investigations of the study patients\n\nInvestigation\tTenofovir group (n=15)\tTelbivudine group (n=15)\tP\t\n\t\t\nMean\t±SD\tMean\t±SD\t\nHb (gm/dl)\t11.2\t±1.8\t10.9\t±1.5\t0.623ns\t\nRange (min-max)\t7.5\t, 14\t8.5\t, 14\t\t\nTotal count (/mm3)\t8726.7\t±2229.5\t9140.0\t±3765.2\t0.717ns\t\nRange (min-max)\t4000\t, 12000\t2100\t, 16000\t\t\nPlatelet count (/mm3)\t188666.7\t±102111.1\t196333.3\t±134874.4\t0.861ns\t\nRange (min-max)\t50000\t, 480000\t40000\t, 500000\t\t\nAlpha feto protein (ng/ml)\t95.7\t±227.9\t66.2\t±76.6\t0.638ns\t\nRange (min-max)\t1.3\t, 904\t0.69\t, 242\t\t\nALT (U/L)\t376.7\t±211.1\t249.6\t±137.9\t0.061ns\t\nRange (min-max)\t75\t, 828\t69\t, 493\t\t\nAST (U/L)\t328.5\t±167.3\t197.8\t±110.6\t0.017s\t\nRange (min-max)\t113\t821\t21\t, 396\t\t\nSerum sodium (mmol/l)\t132.0\t±6.3\t130.5\t±8.3\t0.581ns\t\nRange (min-max)\t119\t, 142\t113\t, 144\t\t\nSerum potassium (mmol/l)\t4.0\t±0.8\t3.9\t±0.7\t0.718ns\t\nRange (min-max)\t2.7\t, 6.0\t2.9\t, 5.2\t\t\nProthrombin time (s)\t21.6\t±3.4\t21.3\t±3.1\t0.802ns\t\nRange (min-max)\t18\t, 28.9\t18.5\t, 28.8\t\t\nINR\t1.84\t±0.27\t1.80\t±0.27\t0.688ns\t\nRange (min-max)\t1.51\t, 2.45\t1.5\t, 2.4\t\t\nSerum albumin (gm/dl)\t2.5\t±0.5\t2.3\t±0.5\t0.282ns\t\nRange (min-max)\t1.5\t, 3.4\t0.93\t, 3.0\t\t\nSerum creatinine (mg/dl)\t1.1\t±0.4\t2.3\t±0.5\t0.001s\t\nRange (min-max)\t0.4\t, 1.9\t0.93\t, 3.0\t\t\nSerum bilirubin (mg/dl)\t19.3\t±7.1\t17.9\t±7.9\t0.613ns\t\nRange (min-max)\t9\t, 32.1\t9.1\t, 35.3\t\t\nCTP score\t12.2\t±0.8\t12.1\t±0.8\t0.734ns\t\nRange (min-max)\t11\t, 14\t11\t, 14\t\t\nMELD score\t25.3\t±2.7\t25.6\t±5.4\t0.848ns\t\nRange (min-max)\t21\t, 29\t21\t, 39\t\t\nEsophageal varix\t9 (60.0%)\t11 (73.3%)\t0.438ns\t\nns=not significant, s=significant, CTP=Child-Turcotte Pugh. P-value reached from unpaired t-test\n\nTable 4i Distribution of the study patients by HBeAg, anti-HBe and anti-HBc IgM\n\nVariables\tTenofovir group (n=15)\tTelbivudine group (n=15)\tP\t\n\t\t\nn\t%\tn\t%\t\nHBeAg\t\t\t\t\t\t\n Positive\t7\t46.7\t10\t66.7\t0.269ns\t\n Negative\t8\t53.3\t5\t33.3\t\t\nAnti-HBe\t\t\t\t\t\t\n Positive\t3\t20.0\t3\t20.0\t1.000ns\t\n Negative\t12\t80.0\t12\t80.0\t\t\nAnti-HBc IgM\t\t\t\t\t\t\n Positive\t9\t60.0\t8\t53.3\t0.704ns\t\n Negative\t6\t40.0\t7\t46.7\t\t\ns=significant, ns=not significant. P-value reached from Chi-square test\n\nTable 4ii Distribution of the study patients by HBV DNA in two groups at baseline\n\n\tMean±SD\tP\t\n\t\nTenofovir group (n=15)\tTelbivudine group (n=15)\t\n*HBV DNA (IU/ml)\t4.1±1.0\t4.8±1.5\t0.143ns\t\nRange (min-max)\t2.3,5.8\t2.2, 7.4\t\t\n*HBV DNA data value changed from LOG transformation. ns=not significant\n\nAll patients in both groups had coagulation failure. Liver failure was seen 86.7% in tenofovir group and 66.7% in telbivudine group, cerebral failure in 26.7% in tenofovir group and 20% in telbivudine group, kidney failure in 26.7% in tenofovir group and 20% in telbivudine group, while circulatory failure seen in 6.7% cases in both groups [Table 5].\n\nTable 5 Distribution of the study patients by organ failure between two groups\n\n\tTenofovir group (n=15)\tTelbivudine group (n=15)\tP\t\n\t\t\nn\t%\tn\t%\t\nLiver failure\t\t\t\t\t\t\n Serum bilirubin >12 mg/dl\t13\t86.7\t10\t66.7\t0.194ns\t\nCoagulation failure\t\t\t\t\t\t\n INR >1.5\t15\t100.0\t15\t100.0\t-\t\nCerebral failure\t\t\t\t\t\t\n HE\t4\t26.7\t3\t20.0\t0.500ns\t\nKidney failure\t\t\t\t\t\t\n Serum creatinine >1.2 mg/dl\t4\t26.7\t3\t20.0\t0.500ns\t\nCirculatory failure\t\t\t\t\t\t\n DBP <70 mm Hg\t1\t6.7\t1\t6.7\t0.758ns\t\ns=significant, ns=not significant, HE=hepatic encephalopathy. P-value reached from Chi-square test\n\nPretreatment CTP score was 12.2 ± 0.8 in tenofovir group and 12.1 ± 0.8 in telbivudine group. After 3 months of therapy, CTP score was 7.5 ± 2.0 in tenofovir group and 7.5 ± 1.9 in telbivudine group. The differences were not statistically significant (P > 0.05) between two groups [Table 6]. On the other hand, pretreatment MELD score was 25.3 ± 2.7 in tenofovir group and 25.6 ± 5.4 in telbivudine group. After 3 months of therapy, MELD score was 12.08 ± 2.84 in tenofovir group and 14.41 ± 1.76 in telbivudine group. MELD score significantly improved in tenofovir group than telbivudine group [Table 7].\n\nTable 6 CTP score at different follow-up two groups\n\nCTP score\tMean±SD\tP\t\n\t\nTenofovir group (n=15)\tTelbivudine group (n=15)\t\nPretreatment\t12.2±0.8\t12.1±0.8\t0.162ns\t\nDay 7\t11.2±1.2\t11.8±1.1\t0.164ns\t\nDay 14\t10.8±1.1\t10.7±1.5\t0.836ns\t\nDay 30\t9.2±1.5\t9.1±1.4\t0.851ns\t\nDay 90\t7.5±2.0\t7.5±1.9\t1.000ns\t\nCTP=Child-Turcotte Pugh, ns=not significant\n\nTable 7 MELD score at different follow-up in both groups\n\nMELD score\tMean±SD\tP\t\n\t\nTenofovir group (n=15)\tTelbivudine group (n=15)\t\nPretreatment\t25.3±2.7\t25.6±5.4\t0.848ns\t\nDay 7\t24.3±4.9\t23.7±4.0\t0.725ns\t\nDay 14\t23.2±3.9\t21.2±4.8\t0.271ns\t\nDay 30\t19.3±3.9\t19.6±4.4\t0.704ns\t\nDay 90\t12.08±2.84\t14.41±1.76\t0.043s\t\nns=not significant, s=significant\n\nHepatic encephalopathy (HE) was the cause of death in 33.3% patients in both groups, hepatorenal syndrome (HRS) in 33.3% patients in tenofovir group and 16.7% in telbivudine group and HE plus HRS was found 33.3% in both groups. HRS and variceal bleeding was the cause of death in 16.7% in telbivudine group [Table 8]. Mean serum albumin was 2.6 gm/dl in the survivors and 2.4 gm/dl in those who died. Difference in serum albumin was statistically significant (P < 0.05) between the two groups.\n\nTable 8 Cause of death of the study patients\n\nOutcome\tTenofovir group (n=3)\tTelbivudine group (n=6)\tP\t\n\t\t\nn\t%\tn\t%\t\nHE\t1\t33.3\t2\t33.3\t0.861ns\t\nHRS\t1\t33.3\t1\t16.7\t0.590ns\t\nHE + HRS\t1\t33.3\t2\t33.3\t1.000ns\t\nHRS + variceal bleeding\t0\t0.0\t1\t16.7\t0.477ns\t\nns=not significant, HE=hepatic encephalopathy, HRS=hepatorenal syndrome\n\nDiscussion\n\nIn this study, there is a significant improvement in CTP and MELD scores after 3 months of tenofovir therapy. Similarly, an Indian study showed significant improvement in MELD score in tenofovir group but not in placebo group in ACLF-B.[7] In our study, telbivudine group also showed a significant improvement in CTP and MELD scores. Although no significant difference was found in CTP score between two groups, MELD score showed a better improvement in tenofovir group than telbivudine, which was statistically significant.\n\nAfter 3 months of antiviral therapy, 80% survived in tenofovir group and 60% in telbivudine group, but there was no statistically significant difference between the groups. A Chinese group has also demonstrated better survival in ACLF-B with telbivudine compared placebo.[8]\n\nThere is also significant clinical improvement (i.e., jaundice, ascites, and HE) in both groups, but not significant between groups. Our study did not observe any adverse event in either group. However, in two patients, renal dose adjustment for tenofovir was required due to HRS. Garg and colleagues have shown in their study that in ACLF-B, none of the patients developed significant renal failure that could be attributed to tenofovir.[7]\n\nVarious baseline parameters were analyzed to predict mortality. Serum bilirubin, INR, creatinine, HBV DNA and MELD score were higher among the dead but none of these were statistically significant. Serum albumin was higher in the survivor group, which was statistically significant.\n\nVarious evolving therapies have recently been shown for the management of chronic liver diseases. The present antiviral therapeutic approach with those novel approaches would be useful for the patients with ACLF.[9101112]\n\nConclusion\n\nThis study was done to compare the outcome with tenofovir and telbivudine in the patients with ACLF-B. It can be concluded that both groups experienced significant improvement of serum bilirubin, albumin, INR, and CTP and MELD scores. Both groups also have HBV DNA suppression. However, tenofovir therapy significantly improved MELD score compared to telbivudine therapy. Survival rate was also higher in tenofovir group than telbivudine group at 3 months, but this was not statistically significant.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\nAcknowledgement\n\nThe study was conducted at Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.\n==== Refs\n1 Jalan R Gines P Olson JC Mookerjee RP Moreau R Arroyo V Acute-on chronic liver failure J Hepatol 2012 57 1336 48 22750750\n2 Sarin SK Kedarisetty CK Abbas Z Amarapukar D Bihari C Chan AC Acute-on-chronic liver failure: Consensus recommendations of the Asian Pacific Association for the study of the liver (APASL) Hepatol Int 2014 8 453 71 26202751\n3 Perz JF Armstrong GL Farringto LA Hutin YJ Bell BP The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide J Hepatol 2006 45 529 38 16879891\n4 Shi Y He Y Wu W Huang J Yang Y Garcia-Tsao G Efficacy and safety of nucleos(t)ide analogue in the treatment of HBV-related acute-on-chronic liver failure: A meta-analysis Ann Hepatol 2013 12 364 72 23619252\n5 Philips CA Sarin SK Potent antiviral therapy improves survival in acute on chronic liver failure due to hepatitis B virus reactivation World J Gastroenterol 2014 20 16037 52 25473156\n6 Lin B Pan CQ Xie D Xie J Xie S Zhang X Entecavir improves the outcome of acute-on-chronic liver failure due to the acute exacerbation of chronic hepatitis B Hepatol Int 2013 7 460 7 26201778\n7 Garg H Sarin SK Kumar M Garg V Sharma BC Kumar A Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure Hepatology 2011 53 774 80 21294143\n8 Zhang Y Xi Q Dai X Guo Y Xu X Yang Q A modified MELD model for Chinese Pre-ACLF and ACLF patients and it reveals poor prognosis in pre-ACLF patients PLoS One 2013 8 e64379 23755119\n9 Al Mahtab M Mohammad Fazle Akbar S Chandra Podder D Kumar Saha P Jahan M Begum L Relationship between hepatitis B viral deoxyribonucleic acid load and hepatocellular carcinoma Euroasian J Hepatogastroenterol 2014 4 66 7 29264325\n10 Hussain M Al Mahtab M Islam S Ahmed N Rahman S Khan M Therapy targeting stem cell in patients with decompensated cirrhosis of liver in a tertiary treatment care center of Bangladesh Euroasian J Hepatogastroenterol 2017 7 111 2 29201789\n11 Al Mahtab M Akbar SM Begum Mf Islam Md A Rahim Md A Alam SM Stem cell therapy for cirrhosis of liver in Bangladesh: Specific design compatible for developing country Euroasian J Hepatogastroenterol 2018 8 121 5 30828553\n12 Mf Akbar S Al-Mahtab M I Khan S Nature of host immunity during hepatitis B virus infection and designing immune therapy Euroasian J Hepatogastroenterol 2018 8 42 6 29963460\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2249-4863",
"issue": "10(6)",
"journal": "Journal of family medicine and primary care",
"keywords": "ACLF-B; HBV; telbivudine; tenofovir",
"medline_ta": "J Family Med Prim Care",
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"nlm_unique_id": "101610082",
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"pages": "2381-2385",
"pmc": null,
"pmid": "34322442",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": "25473156;21294143;16879891;30828553;29963460;26202751;22750750;29201790;26201778;23619252;23755119",
"title": "Role of tenofovir and telbivudine in treatment of hepatitis B related acute on chronic liver failure.",
"title_normalized": "role of tenofovir and telbivudine in treatment of hepatitis b related acute on chronic liver failure"
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"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
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"abstract": "We report the death of a 22-year-old woman, with a 3½ year history of cyclic vomiting and cannabis use since age 14, who developed torsades de pointes cardiac arrythmia while being treated in the emergency room for nausea and vomiting. Resuscitation restored spontaneous cardiac circulation, however, due to post-cardiac arrest anoxic brain injury, she never regained consciousness and was declared brain dead 4 days later. Postmortem examination confirmed hypoxic-ischemic encephalopathy, in keeping with the in-hospital diagnosis of brain death. The heart was anatomically normal but showed signs of acute post-cardiopulmonary arrest reperfusion injury. As a consequence of limited survival in hospital in a neuro-vegetative state, early bronchopneumonia and isolated pulmonary thromboemboli were seen. Toxicological studies confirmed cannabis use, in addition to the presence of haloperidol and ondansetron. Genetic studies were performed to rule out a possible channelopathy and revealed a mutation in the MYBPC3 and RYR2 genes. Death in this woman with cannabinoid hyperemesis syndrome was attributed to a fatal cardiac arrhythmia complicating vomiting-induced hypokalemia and treatment with QT interval prolonging and potentially arrhythmogenic medications, with the identified cardiac genetic mutations listed as contributing factors. The emphasis of this report is a) to raise awareness that death can occur due to cyclic vomiting, b) provide a brief but practical overview of cannabinoid hyperemesis syndrome, c) describe the findings from our postmortem examination and come to the most reasonable cause and mechanism of death, d) comment on the risk factors associated with torsades de pointes cardiac arrythmia, and e) conclude that a complete postmortem examination is needed to exclude an anatomical or toxicological cause of death in cannabinoid hyperemesis syndrome, a disabling but preventable disorder.",
"affiliations": "Provincial Forensic Pathology Unit, Department of Laboratory Medicine & Pathobiology, Ontario Forensic Pathology Service, University of Toronto, 25 Morton Shulman Avenue, Toronto, ON, M3M 0B1, Canada. ingo.vonboth@gmail.com.;Provincial Forensic Pathology Unit, Department of Laboratory Medicine & Pathobiology, Ontario Forensic Pathology Service, University of Toronto, 25 Morton Shulman Avenue, Toronto, ON, M3M 0B1, Canada.",
"authors": "von Both|Ingo|I|;Santos|Brittini|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12024-021-00410-z",
"fulltext": null,
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"issn_linking": "1547-769X",
"issue": "17(4)",
"journal": "Forensic science, medicine, and pathology",
"keywords": "Autopsy; Cannabinoid hyperemesis syndrome; Cannabis; Forensic pathology; Hypokalemia; Marijuana; Nausea/vomiting; Postmortem examination; QT prolongation; QT prolonging drugs; Torsades de pointes",
"medline_ta": "Forensic Sci Med Pathol",
"mesh_terms": null,
"nlm_unique_id": "101236111",
"other_id": null,
"pages": "715-722",
"pmc": null,
"pmid": "34735682",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "8145089;19368653;15479672;18371009;18042112;10520833;10959442;31702939;27147122;28672431;29768651;16197488;24184696;11606489;28571820;16157354;25516874;32656345;31568081;25903855;28000146;22169581;29747789;9196697;11228282;20585227;3706349;30159612;15213787;29473523;20394022;29560069;29543555;25393073;27597918;23716032;20130993;22480624",
"title": "Death of a young woman with cyclic vomiting: a case report.",
"title_normalized": "death of a young woman with cyclic vomiting a case report"
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"companynumb": "CA-Fresenius Kabi-FK202114212",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HALOPERIDOL LACTATE"
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"abstract": "A 48-year-old woman who is a contact lens wearer presented with unilateral ACANTHAMOEBA keratitis, confirmed by PCR, which responded initially to topical polyhexamethylene biguanide (PHMB) and brolene. Three months later, despite continued treatment, she developed diffuse anterior scleritis with severe pain and marked scleral injection but without evidence of recurrence keratitis. Oral non-steroidal anti-inflammatories and oral high-dose corticosteroids were added without success. Subsequent treatment with intravenous methylprednisolone and high-dose cyclosporine led to a temporary improvement. Re-presenting with signs of recurrent scleritis and severe pain, the antitumor necrosis factor monoclonal antibody adalimumab, and later oral cyclophosphamide, were added. This led to complete quiescence of the scleritis. Unfortunately, frequent recurrences of ACANTHAMOEBA keratitis and anterior uveitis occurred on immunosuppression requiring continued treatment with PHMB, brolene and topical corticosteroids. This is the first case of severe refractory ACANTHAMOEBA scleritis requiring the concomitant use of four immunosuppressive agents to achieve continued disease control. The challenges in managing this case are discussed.",
"affiliations": "Ophthalmology Department, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.;Ophthalmology Department, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.",
"authors": "Igras|Estera|E|;Murphy|Conor|C|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000048:Acanthamoeba; D015823:Acanthamoeba Keratitis; D003261:Contact Lenses; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012008:Recurrence; D015423:Scleritis; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25878227",
"pubdate": "2015-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19660733;21658877;7787645;8154529;18210154;3753282;19321727;24828345;12045063;18843498;17893557",
"title": "Use of multiple immunosuppressive agents in recalcitrant ACANTHAMOEBA scleritis.",
"title_normalized": "use of multiple immunosuppressive agents in recalcitrant acanthamoeba scleritis"
} | [
{
"companynumb": "IE-MYLANLABS-2015M1043759",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "POLIHEXANIDE HYDROCHLORIDE"
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"abstract": "Adrenal vein development in utero occurs concurrently with the development of the inferior vena cava, the renal veins, and the gonadal veins. The embryologic formation of these veins involves communication of various venous systems. Although the left adrenal-renal vein complex is most commonly described as a shared emptying of the left adrenal vein and the left inferior phrenic vein into the left renal vein, there have been reports of numerous anatomic variations of this complex. In this report, we present a case of a rare variant of the left adrenal vein, in which the left adrenal vein empties into the left gonadal vein, which takes an atypical course superolateral to the left kidney.",
"affiliations": "Frank H. Netter SOM, Quinnipiac University, 370 Bassett Rd, North Haven, CT 06473 USA.;Department of Interventional Radiology, Yale New Haven Hospital, New Haven, CT, USA.;Department of Interventional Radiology, Yale New Haven Hospital, New Haven, CT, USA.",
"authors": "Ford|Kaitlin M|KM|;Smolinski|Sara|S|;Perez Lozada|Juan Carlos|JC|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2017.09.010",
"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(17)30301-110.1016/j.radcr.2017.09.010Interventional RadiologyAnomalous adrenal vein anatomy complicating the evaluation of primary hyperaldosteronism Ford Kaitlin M. BSkmford13@gmail.coma*Smolinski Sara MDbPerez Lozada Juan Carlos MDba Frank H. Netter SOM, Quinnipiac University, 370 Bassett Rd, North Haven, CT 06473 USAb Department of Interventional Radiology, Yale New Haven Hospital, New Haven, CT, USA* Corresponding author. kmford13@gmail.com20 10 2017 2 2018 20 10 2017 13 1 139 141 16 7 2017 8 9 2017 8 9 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Adrenal vein development in utero occurs concurrently with the development of the inferior vena cava, the renal veins, and the gonadal veins. The embryologic formation of these veins involves communication of various venous systems. Although the left adrenal-renal vein complex is most commonly described as a shared emptying of the left adrenal vein and the left inferior phrenic vein into the left renal vein, there have been reports of numerous anatomic variations of this complex. In this report, we present a case of a rare variant of the left adrenal vein, in which the left adrenal vein empties into the left gonadal vein, which takes an atypical course superolateral to the left kidney.\n\nKeywords\nLeft adrenal vein variantLeft gonadal vein variantAdrenal vein sampling\n==== Body\nIntroduction\nVariable venous drainage of the adrenal-renal vein complex has been described on the left adrenal gland in 1%-5% of cadaveric studies [1] and in 9% of patients in a retrospective review after laparoscopic adrenalectomy [2]. In this report, we present a case of a rare variant of the left adrenal vein in which the left gonadal vein drains into the left adrenal vein after taking an atypical course superolateral to the left kidney. The left adrenal vein itself drained into a left phrenicoadrenal vein and the azygos vein via 2 tributaries. Knowledge of the anomalies of the adrenal-renal vein complex can help radiologists and surgeons in the recognition and protection of these veins during procedures of the abdomen and the pelvis.\n\nCase\nA 58-year-old Caucasian woman with no significant medical history presented to a tertiary care facility with new-onset hypertension. This condition had been discovered during visits to a podiatrist for an unrelated complaint. After monitoring at home, the patient was found to consistently have blood pressures of 150-160 and 90-100 despite exercise, adhering to a low-sodium diet and limiting caffeine intake. The patient was initiated on therapy with lisinopril 10 mg daily, which was increased incrementally to 40 mg daily with hydrochlorothiazide 12.5 mg over the course of 8 weeks, at which time the therapy was changed to amlodipine 5 mg daily with losartan, given the presence of a cough. The patient was also started on potassium supplementation due to hypokalemia (potassium level of 2.9 mmol/L). The serum aldosterone level was within normal limits at 15 ng/dL, the plasma renin activity was low at 0.23 ng/mL/h, and the aldosterone-to-plasma renin activity ratio was elevated at 65.2. A sodium suppression test was indicative of primary hyperaldosteronism. A computed tomography of the abdomen was then performed, which showed a 1.5-cm left adrenal mass with an absolute washout greater than 60% and a relative washout greater than 40%, consistent with an adrenal adenoma. A cortisol suppression test and subsequent adrenal vein sampling were performed, which lateralized aldosterone hypersecretion to the left adrenal gland (aldosterone levels of 4700 ng/dL on the left compared with 63 ng/dL on the right and 50 ng/dL in the inferior vena cava [IVC]). As one might expect, a sample obtained using a microcatheter directly into the vein communicating with the draining gonadal vein had a reduced aldosterone level at 345 ng/dL. Together, these findings confirmed the presence of a primary hyperaldosteronism in the setting of a functioning left adrenal adenoma, although if the variant had not been identified, this diagnosis might have been missed altogether.\n\nThe patient went for a subsequent left retroperitoneoscopic adrenalectomy, which took place without complication. Post procedure, the patient's blood pressure improved, such that she was discharged on only 1 antihypertensive medication. A final diagnosis of an adrenal cortical adenoma was found on surgical pathology. Three months later, all antihypertensives were discontinued and the patient was found to have a blood pressure within normal limits.\n\nDiscussion\nThe adrenal-renal vein complex arises via a complex series of development, anastomosis, regression, and replacement of various venous systems [1]. This process begins in early development at which time the paired subcardinal, supracardinal, and inferior cardinal veins form an anastomotic net. From this net arise the paired renal, adrenal, and gonadal veins [1], [3]. The suprarenal veins, in particular, arise from both the subcardinal vein proximal to the IVC and the inferior cardinal vein more distal to the IVC [3]. This complicated embryogenesis of the adrenal veins occurs concurrently with that of the gonadal and renal veins, which contributes to adrenal vein variations and their relationship with the gonadal and renal veins [1].\n\nThe left adrenal vein most commonly originates at the hilum of the left adrenal gland and travels inferomedially, connecting with the left inferior phrenic vein, to drain into the superior border of the left renal vein. Adrenal vein variants include the left adrenal vein entering the renal vein without receiving the inferior phrenic nerve, the bifid left adrenal vein, the double adrenal veins, the left adrenal vein joined by one of the duplicated gonadal veins, the adrenal vein draining directly into the IVC, the adrenal vein receiving gonadal and second lumbar before draining into the renal vein, and the 2 inferior phrenic veins merging with left adrenal vein [1], [2]. The variant described in our patient may be a remnant of the embryonic inferior cardinal venous system. A failure of regression of its communication with the median sacral vein might have resulted in this anomalous branching pattern.Adrenal-gonadal vein variant.\n\nUnlabelled imageNormal adrenal vein anatomy.\n\nUnlabelled image\n\nKnowledge of adrenal and gonadal vein variants is important for the surgeon and the interventional radiologist. For the surgeon, this knowledge might be significant in assessing bleeding risk during an abdominal procedure. During left adrenalectomy in this patient, the left adrenal vein branches, including this gonadal vein, were clipped with no adverse effect (Fig. 1, Fig. 2). For the interventional radiologist, knowledge of variants can aid in accurate technique during an adrenal vein sampling procedure. In addition, in the male patient with a varicocele, knowing this variant can assist in the timely identification of the gonadal vein for embolization.Fig. 1 Digital imaging during contrast injection into the origin of the left adrenal vein (white arrow) demonstrating an aberrant vein (black arrow) coursing lateral and then superior to the left kidney and draining in the adrenal vein, demonstrated on prolonged injection to represent the gonadal vein. The left adrenal vein shares a common origin with the left L2 lumbar vein (blue arrow).\n\nFig. 1Fig. 2 Digital imaging of the pelvis performed during contrast injection into the origin of the left adrenal vein demonstrating an opacification of the left gonadal vein (white arrow).\n\nFig. 2\n\nAcknowledgments\nThe authors would like to thank Dennis A. Barbon, RN for his illustrative contributions to this case report.\n==== Refs\nReferences\n1 Cesmebasi A. Du Plessis M. Iannatuono M. Shah S. Tubbs R.S. Loukas M. A review of the anatomy and clinical significance of adrenal veins Clin Anat 27 8 2014 1253 1263 24737134 \n2 Scholten A. Cisco R.M. Vriens M.R. Shen W.T. Duh Q. Variant adrenal venous anatomy in 546 laparoscopic adrenalectomies JAMA Surg 148 4 2013 378 383 23715888 \n3 Gupta R. Gupta A. Aggarwal N. Variations of gonadal veins: embryological prospective and clinical significance J Clin Diagn Res 9 2 2015 AC8 A10\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1930-0433",
"issue": "13(1)",
"journal": "Radiology case reports",
"keywords": "Adrenal vein sampling; Left adrenal vein variant; Left gonadal vein variant",
"medline_ta": "Radiol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101467888",
"other_id": null,
"pages": "139-141",
"pmc": null,
"pmid": "29487649",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": "23715888;24737134;25859438",
"title": "Anomalous adrenal vein anatomy complicating the evaluation of primary hyperaldosteronism.",
"title_normalized": "anomalous adrenal vein anatomy complicating the evaluation of primary hyperaldosteronism"
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"companynumb": "US-TEVA-2018-US-876414",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
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{
"abstract": "BACKGROUND\nTargeting the vascular endothelial growth factor (VEGF) signaling pathway has become an important approach to current cancer therapy. Anti-VEGF therapy-related renal adverse effects may present as hypertension, non-nephrotic proteinuria, and rarely as nephrotic syndrome (NS) and acute kidney injury.\n\n\nMETHODS\nIn this report, we present a 15-year-old boy who had developed nephrotic syndrome and thrombotic microangiopathy 26 months after administration of anti-VEGF therapy. Treatment was discontinued and nephrotic syndrome remitted spontaneously within 3 months.\n\n\nCONCLUSIONS\nNephrologists should be aware of the side effects of anti-VEGF therapy. Early diagnosis and prompt management with withdrawal of the agents will result in spontaneous remission.",
"affiliations": "Department of Pediatrics, Division of Pediatric Nephrology, Ankara University School of Medicine, Ankara, Turkey. songulyilmaz23@gmail.com.;Department of Pediatrics, Division of Pediatric Nephrology, Ankara University School of Medicine, Ankara, Turkey.;Department of Pediatric Nephrology, Ankara Child Health Hematology and Oncology Education Research Hospital, Ankara, Turkey.;Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.;Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.;Department of Pediatrics, Division of Pediatric Oncology, Ankara University School of Medicine, Ankara, Turkey.;Department of Pediatrics, Division of Pediatric Nephrology, Ankara University School of Medicine, Ankara, Turkey.",
"authors": "Yılmaz|Songül|S|;Özçakar|Z Birsin|ZB|;Taktak|Aysel|A|;Kiremitçi|Saba|S|;Ensari|Arzu|A|;Dinçaslan|Handan|H|;Yalçınkaya|Fatoş|F|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; D004317:Doxorubicin; D000077157:Sorafenib; D002945:Cisplatin; D007069:Ifosfamide; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-016-3355-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "31(6)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Anti-VEGF; Bevacizumab; Child; Nephrotic syndrome; Thrombotic microangiopathy",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001859:Bone Neoplasms; D002945:Cisplatin; D004317:Doxorubicin; D006801:Humans; D007069:Ifosfamide; D008297:Male; D008727:Methotrexate; D009404:Nephrotic Syndrome; D009536:Niacinamide; D012516:Osteosarcoma; D010671:Phenylurea Compounds; D011507:Proteinuria; D012075:Remission, Spontaneous; D000077157:Sorafenib; D057049:Thrombotic Microangiopathies; D042461:Vascular Endothelial Growth Factor A; D028761:Withholding Treatment",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "1029-32",
"pmc": null,
"pmid": "26928310",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25480873;24104527;24067439;17324579;18669456;18596824;22760023;18852116;12890841;19828679;17660022;18337603;20538785;20006922;15090854",
"title": "Anti-VEGF-related thrombotic microangiopathy in a child presenting with nephrotic syndrome.",
"title_normalized": "anti vegf related thrombotic microangiopathy in a child presenting with nephrotic syndrome"
} | [
{
"companynumb": "TR-BAYER-2016-155030",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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"drugadditional": n... |
{
"abstract": "A 7-month-old baby girl with acute lymphoblastic leukemia (ALL) presented with bulging anterior fontanelle after completing the first and second courses of high-dose methotrexate (HD-MTX) chemotherapy. Between courses, the infant recovered and was discharged. Prior to the third and fourth HD-MTX courses, the baby girl was administered infusions of dexamethasone, which prevented recurrence of neurological side effects observed after the first and second courses of HD-MTX. To our knowledge, this is the first reported case of HD-MTX-induced idiopathic intracranial hypertension in infants, and that prophylactic use of dexamethasone can be applied to prevent acute intracranial hypertension following HD-MTX infusion.",
"affiliations": "Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.;Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, United States.;Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"authors": "Zhang|Yazhi|Y|;Qiu|Yining|Y|;Wang|Zhujun|Z|;Wang|Ran|R|;Jin|Runming|R|;Hinkle|Louis Edward|LE|;Wu|Xiaoyan|X|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2020.00839",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812 Frontiers Media S.A. \n\n10.3389/fphar.2020.00839\nPharmacology\nCase Report\nHigh-Dose Methotrexate-Induced Idiopathic Intracranial Hypertension in Infant Acute Lymphoblastic Leukemia\nZhang Yazhi \n1\n\n†\n Qiu Yining \n1\n\n†\n Wang Zhujun \n1\n Wang Ran \n1\n Jin Runming \n1\n Hinkle Louis Edward \n2\n\n*\n Wu Xiaoyan \n1\n\n*\n \n1\nDepartment of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China\n\n\n2\nDepartment of Nanomedicine, Houston Methodist Research Institute, Houston, TX, United States\n\nEdited by: Judith Ann Smith, University of Texas Health Science Center at Houston, United States\n\nReviewed by: Kathleen Job, The University of Utah, United States; Caren Lee Hughes, Mayo Clinic, United States\n\n*Correspondence: Louis Edward Hinkle, lehinkle@houstonmethodist.org; Xiaoyan Wu, xwu@hust.edu.cn\n†These authors have contributed equally to this work\n\nThis article was submitted to Obstetric and Pediatric Pharmacology, a section of the journal Frontiers in Pharmacology\n\n\n17 6 2020 \n2020 \n11 83904 3 2020 21 5 2020 Copyright © 2020 Zhang, Qiu, Wang, Wang, Jin, Hinkle and Wu2020Zhang, Qiu, Wang, Wang, Jin, Hinkle and WuThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.A 7-month-old baby girl with acute lymphoblastic leukemia (ALL) presented with bulging anterior fontanelle after completing the first and second courses of high-dose methotrexate (HD-MTX) chemotherapy. Between courses, the infant recovered and was discharged. Prior to the third and fourth HD-MTX courses, the baby girl was administered infusions of dexamethasone, which prevented recurrence of neurological side effects observed after the first and second courses of HD-MTX. To our knowledge, this is the first reported case of HD-MTX-induced idiopathic intracranial hypertension in infants, and that prophylactic use of dexamethasone can be applied to prevent acute intracranial hypertension following HD-MTX infusion.\n\nhigh-dose methotrexateneurotoxicityidiopathic intracranial hypertensiondexamethasoneacute lymphoblastic leukemia\n==== Body\nIntroduction\nA 7-month-old female patient with B-cell acute lymphoblastic leukemia (ALL) developed recurring anterior fontanelle bulging after completing both of her first and second courses of high-dose methotrexate (HD-MTX) induction. She did not, however, show any other abnormal neurological examinations, abnormal laboratory investigations, or abnormal brain CT. She recovered completely with mannitol and dexamethasone treatment. It appears that she benefited from prophylactic dexamethasone since she did not experience neurotoxicity following her third and fourth HD-MTX courses. Our clinical team concluded that the baby girl likely experienced idiopathic intracranial hypertension (IIH) induced by HD-MTX, which is characterized by increased intracranial pressure in the absence of any intracranial space-occupying lesion. Interestingly, we found that prophylactic use of dexamethasone could prevent foreseeable side effects of HD-MTX infusion, which has not been previously reported.\n\nBackground\nMethotrexate (MTX) is one of the most effective and widely used medications for the treatment and targeting of extramedullary leukemia (Pui et al., 2004). Although MTX is essential to pediatric ALL therapy, MTX therapy-induced toxicity remains a concern. MTX can cause multiple side effects including myelosuppression, hepatotoxicity, and neurotoxicity. MTX administration causes central nervous system neurotoxicity in 3.8 to 7.8% of ALL patients and manifests with transient stroke-like phenomena, which include altered mental status, seizures or seizure-like activity, and/or aphasia (Mahoney et al., 1998; Kishi et al., 2003; Bhojwani et al., 2014). Clinical symptoms of MTX-induced neurotoxicity are often associated with leukoencephalopathy, while the mechanisms underlying the pathogenesis are not fully understood. Acute intracranial hypertension is noticed as a low incidence and unpredictable consequence of MTX, occurring rarely in pediatric ALL patients (Inaba et al., 2007; Thon and Gittinger, 2016). Although MTX-related clinical neurotoxicity is transient, all symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy. It is considered that prompt diagnosis and prevention of these side effects are crucial and that the outcome is favorable if the neurotoxicity is detected early (Weid and Popovic, 2006; Bhojwani et al., 2014).\n\nIn this case, we noticed that an infant presented idiopathic intracranial hypertension after receiving HD-MTX infusion, and we also found that dexamethasone might be used to prevent neurotoxicity in infants.\n\nCase\nA 7-month-old female infant was diagnosed with B-cell ALL with an initially high WBC count. This baby girl was stratified into a moderate-risk group based on complicated findings and received the relevant courses of chemotherapy according to Chinese Children's Cancer Group ALL 2015 (CCCG-ALL-2015) protocol (Cai et al., 2019). This baby girl received timely induction therapies including Dexamethasone-preliminary induction, a VDLP course consisting of vindesine (VDS), daunorubicin (DNR), Pegasparagase (PEG-Asp), and prednisone, and the following CAM course of cyclophosphamide (CTX), cytarabine (Ara-C), and mercaptopurine (6-MP) with intrathecal therapy (I.T.). For this baby girl, there was no evidence of central nervous system (CNS) infiltration, and early assessment of minimal residual disease was negative. Genotype analysis for Methylenetetrahydrofolate reductase (MTHFR) variant C677T revealed high risk of MTX toxicity in this patient (Vagace et al., 2011).\n\nSubsequently, this baby girl started a total of four courses of HD-MTX, with each course given every two weeks according to the CCCG-ALL-2015 protocol. The infusion in each course of HD-MTX lasted for 24 h. The first dose of HD-MTX was reduced to 3.5 g/m2 because of the patient's low creatinine clearance rate (CrCl). Forty-four hours after the start of MTX infusion, MTX serum level was 1.29 µmol/l and renal function was normal. Three days later, she presented symptoms of acute intracranial hypertension of tense and bulging anterior fontanelle and frequent vomiting. The baby girl also had a fever with 100 F (37.8°C) with normal neutrophil count. She was conscious and did not show discomfort from a headache. Blood pressure was normal and neurological examination was unremarkable. In laboratory investigation, the cerebrospinal fluid (CSF) showed no pleocytosis with normal protein and glucose concentrations, and brain CT was normal. The ophthalmologic exam and cranial MRI failed several times because she was too young to cooperate. The patient was given mannitol (1g/kg, 3 times daily IV) as soon as she developed symptoms and dexamethasone (0.25 mg/kg/d, 2 times daily IV) three days later because of persistent fontanelle bulging and vomiting. Her symptoms improved one day after dexamethasone treatment. Three days later she completely recovered, and we gradually reduced mannitol and dexamethasone over one week.Two weeks after the first MTX infusion, this infant patient received the second course of HD-MTX, which was decreased to 2.8g/m2. Forty-four hours after infusion, MTX serum level reached 6.60 µmol/l with normal renal function. Interestingly, she showed the same symptoms with high intracranial pressure and low-grade fever three days after completing the second course of HD-MTX chemotherapy. There was no evidence of intracranial infection or damage at this time. She received mannitol on the first day after symptoms and dexamethasone on the second day, with both treatments at the same dosages as before. After three days of treatment, the baby recovered completely and medications were gradually reduced.\n\nOur clinical team considered that this infant's the disorder might have resulted from HD-MTX because she developed the same symptoms at the same point in time after each infusion of HD-MTX. Additionally, glucocorticoids like dexamethasone were found to be effective in quelling these side effects. Prior to the third and fourth infusion of HD-MTX, she was given the dexamethasone in advance to prevent intracranial hypertension, and, indeed, she did not present the same symptoms after the remaining infusions of HD-MTX. The process of chemotherapy is shown in \nFigure 1\n.\n\nFigure 1 The chemotherapy process of the patient based on the Chinese Children's Cancer Group ALL 2015 (CCCG-2015-ALL) protocol. The red rectangle represents the symptoms after high-dose maintenance(HD-MTX) induction; The orange describes dexamethasone(DEX) and the other drugs therapy when symptoms where noticed. The blue refers to performances after therapy. AFU is short for anterior fontanelle uplift. The red triangle indicates the start of HD- MTX treatment.\n\nDiscussion\nHere, we describe the case of an infant with elevated intracranial pressure at similar points in time after the first and second courses of HD-MTX infusion. MTX is an antimetabolite chemotherapeutic agent that is given intravenously, orally, and intrathecally. It has been a vital component of pediatric ALL therapy strategy for over 70 years, but it has the potential to cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy, particularly when delivered intravenously (Ko and Liu, 2010). Side effect symptoms can include stroke-like phenomena, altered mental status, and seizures or seizure-like activity that occur up to 2 weeks after MTX exposure. However, acute intracranial hypertension is an unexpected adverse drug reaction for our infant patient since this side effect has mostly been described in adults cases (Phillips and Sheldon, 2017).\n\nIn the above infant patient, bulging anterior fontanelle presented after MD-MTX infusion without an identified etiology, such as an intracranial lesion, central nervous system infection, or other causes of elevated intracranial pressure. We examined and managed her condition with the suspicion that she had developed idiopathic IIH, which is a rare neurological disorder characterized by increased intracranial pressure in the absence of any intracranial space-occupying lesion. IIH, previously known as pseudotumor cerebri, may be a primary or secondary consequence to certain conditions (Warner et al., 2002). Over the past few decades, several medications have been described to be associated with IIH. There have been only a few reports of IIH associated with MTX in ALL children (Phillips and Sheldon, 2017). To our knowledge, this is the first case of MTX-induced IIH in infants.\n\nA genetic predisposition may also play a role in susceptibility to the development of neurotoxicity following HD-MTX. Polymorphisms that contribute to MTX sensitivity have been identified in GSTP1, MTHFR, and SHMT1. Additionally, a recent genome-wide study has identified single nucleotide polymorphisms in genes involved in neuronal development pathways that contribute to MTX sensitivity (Bhojwani et al., 2014). The infant in our case was confirmed to have MTHFR (C677T) gene variant, and this potentially contributed to her MTX sensitivity. MTX Drug dosage was reduced according to her CrCl for the first infusion, and MTX dose was further decreased for the second infusion based on her 44 h MTX serum level, but she still experienced neurotoxicity.\n\nThe pathophysiology of IIH is incompletely characterized. Recent trials suggested that underpinning mechanisms of IIH include cerebrospinal fluid dysregulation as well as metabolic and endocrinological factors (Mollan et al., 2016). We hypothesize that HD-MTX might induce intracranial cell edema leading to increased intracranial pressure. Alternatively, HD-MTX could result in altered cerebrospinal fluid flow dynamics or hormone changes with ALL children (Donaldson, 1981; Burkett and Ailani, 2018). In the case presented here, the 7-month-old infant with intracranial hypertension showed recurring anterior fontanelle bulging because of her unclosed anterior fontanelle, which might help early detection and timely treatment of acute intracranial hypertension in infants.\n\nIt should be noted that dexamethasone might be an effective tool to treat and prevent such adverse reactions to MTX. We found that prophylactic dexamethasone was able to prevent IIH symptoms that would otherwise consistently appear in the infant patient following HD-MTX. This is a surprising finding when compared to previous research that showed corticosteroids used for treatment of autoimmune diseases like JIA and Crohn's disease could cause IIH after prolonged use in children and adults (Friedman et al., 2014; Kwon et al., 2016). There is a paucity of pediatric data to guide the use of medications in IIH, so there is much debate surrounding treatment of IIH in children. While in adults, acetazolamide was found to yield better outcomes and quality of life in the treatment of IIH (Bruce et al., 2016; Mollan et al., 2016). In the case we describe here, mannitol and dexamethasone were applied to the infant, and it was found that prophylactic dexamethasone was able to prevent IIH in the third and fourth HD-MTX infusions. Prophylactic use of dexamethasone to mitigate or prevent IIH is a novel concept and needs further investigation.In summary, since HD-MTX is a common drug for pediatric ALL patients to prevent extramedullary leukemia, caretakers of infant patients treated with HD-MTX should be warned against potential adverse effects, and prophylactic use of dexamethasone could prevent foreseeable acute intracranial hypertension resulting from HD-MTX infusion.\n\nData Availability Statement\nAll datasets generated for this study are included in the article/supplementary material.\n\nEthics Statement\nWritten informed consent was obtained from the parents of this patient for the publication of this case report and accompanying images. The Medical Ethics Committee of Union Hospital affiliated with Tongji Medical College of Huazhong University of Science and Technology approved this study, and the institutional review board gave us the permission to publish this case report and accompanying images.\n\nAuthor Contributions\nYZ and YQ contributed to our collection of this patient's medical history. YZ and XW wrote the manuscript. XW approved of conceiving the report and edited the manuscript. LH helped to correct and improve the manuscript. RW and ZW collected the information during the follow-up period. RJ agreed to final approval of the version to be published. All authors reviewed and approved the manuscript.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\nBhojwani D. Sabin N. D. Pei D. Yang J. J. Khan R. B. Panetta J. C. (2014 ). Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia\n. J. Clin. Oncol. \n32 (9 ), 949 –959\n. 10.1200/jco.2013.53.0808 \n24550419 \n\nBruce B. B. Digre K. B. Mcdermott M. P. Schron E. B. Wall M. (2016 ). Quality of life at 6 months in the Idiopathic Intracranial Hypertension Treatment Trial\n. Neurol . 87 (18 ), 1871 –1877\n. 10.1212/WNL.0000000000003280 \n\n\nBurkett J. G. Ailani J. (2018 ). An Up to Date Review of Pseudotumor Cerebri Syndrome\n. Curr. Neurol. Neurosci. Rep . 18 (6 ), 33 . 10.1007/s11910-018-0839-1 \n29721718 \n\nCai J. Yu J. Zhu X. Hu S. Zhu Y. Jiang H. (2019 ). Treatment abandonment in childhood acute lymphoblastic leukaemia in China: a retrospective cohort study of the Chinese Children's Cancer Group\n. Arch. Dis. Child \n104 (6 ), 522 –529\n. 10.1136/archdischild-2018-316181 \n30705079 \n\nDonaldson J. O. (1981 ). Pathogenesis of Pseudotumor Cerebri Symptoms\n. Neurol . 31 (7 ), 877 –880\n. 10.1212/WNL.31.7.877 \n\n\nFriedman D. I. McDermott M. P. Kieburtz K. Kupersmith M. Stoutenburg A. Keltner J. L. (2014 ). The idiopathic intracranial hypertension treatment trial: design considerations and methods\n. J. Neuroophthalmol. \n34 (2 ), 107 –117\n. 10.1097/wno.0000000000000114 \n24739993 \n\nInaba H. Khan R. B. Laningham F. H. Crews K. R. Pui C. H. Daw N. (2007 ). Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer\n. Ann. Oncol . 19 (1 ), 178 –184\n. 10.1093/annonc/mdm466 \n17947226 \n\nKishi S. Griener J. Cheng C. Das S. Relling M. V. (2003 ). Homocysteine, Pharmacogenetics, and Neurotoxicity in Children With Leukemia\n. J. Clin. Oncol. Res . 21 (16 ), 3084 –3091\n. 10.1200/JCO.2003.07.056 \n\n\nKo M. W. Liu G. T. (2010 ). Pediatric Idiopathic Intracranial Hypertension (Pseudotumor Cerebri)\n. Horm. Res. Paediatr . 74 (6 ), 381 –389\n. 10.1159/000321180 \n20962512 \n\nKwon Y. J. Allen J. L. Liu G. T. Mccormack S. E. (2016 ). Presumed Pseudotumor Cerebri Syndrome After Withdrawal of Inhaled Glucocorticoids\n. Pediatr . 137 (6 ), e20152091. 10.1542/peds.2015-2091 \n\n\nMahoney D. H. Shuster J. J. Nitschke R. Lauer S. J. Steuber C. P. Winick N. (1998 ). Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy–a Pediatric Oncology Group study\n. J. Clin. Oncol. Res. \n16 (5 ), 1712 –1722\n. 10.1200/JCO.1998.16.5.1712 \n\n\nMollan S. P. Ali F. Hassan-Smith G. Botfield H. Sinclair A. (2016 ). Evolving evidence in adult idiopathic intracranial hypertension: Pathophysiology and management\n. Neurol. Neurosurg. Psychiatry \n87 , (9 ) 982 –992\n. 10.1136/jnnp-2015-311302 \n\n\nPhillips P. H. Sheldon C.A.J.J.N. (2017 ). Pediatric Pseudotumor Cerebri Syndrome\n. J. Neuroophthalmol . 37 , S33 –S40\n. 10.1097/WNO.0000000000000548 \n28806347 \n\nPui C. H. Relling M. V. Downing J. R. (2004 ). Acute Lymphoblastic Leukemia\n. N. Engl. J. Med . 350 (15 ), 1535 –1548\n. 10.1056/NEJMra023001 \n15071128 \n\nThon O. R. Gittinger J. W. (2016 ). Medication-Related Pseudotumor Cerebri Syndrome\n. Semin. Ophthalmol . 32 (1 ), 1 –10\n. 10.1080/08820538.2016.1228415 \n27748640 \n\nVagace J. M. Caceres-Marzal C. Jimenez M. Casado M. S. Murillo S. G. D. Gervasini G. (2011 ). Methotrexate-induced subacute neurotoxicity in a child with acute lymphoblastic leukemia carrying genetic polymorphisms related to folate homeostasis\n. Am. J. Hematol . 86 (1 ), 98 –101\n. 10.1002/ajh.21897 \n21064136 \n\nWarner J. E. A. Bernstein P. S. Yemelyanov A. Alder S. C. Digre K. B. (2002 ). Vitamin A in the cerebrospinal fluid of patients with and without idiopathic intracranial hypertension\n. Ann. Neurol . 52 (5 ), 647 –650\n. 10.1002/ana.10377 \n12402264 \n\nWeid N. X. V. D. Popovic M.B.J.R.M.S. (2006 ). [Acute lymphoblastic leukemia in children and adolescents]\n. Rev. Med. Suisse \n2 (59 ), 873 –876\n. 10.3238/arztebl.2012.0652 \n16646372\n\n",
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"title": "High-Dose Methotrexate-Induced Idiopathic Intracranial Hypertension in Infant Acute Lymphoblastic Leukemia.",
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"abstract": "An intriguing area of research in thyroidology is the recently discovered association of insulin resistance with thyroid functional and morphological abnormalities. Individuals with hyperinsulinemia have larger thyroid gland and a higher prevalence of thyroid nodules and cancer. Accordingly, patients treated with metformin have a smaller thyroid volume and a lower risk of incident goiter, thyroid nodule and cancer. Multiple studies in vitro and in vivo have demonstrated that metformin can inhibit the growth of thyroid cells and different types of thyroid cancer cells by affecting the insulin/IGF1 and mTOR pathways. Besides, metformin treatment was associated with a decrease in the levels of serum thyroid-stimulating hormone (TSH) in diabetic patients possibly by enhancing the effects of thyroid hormones in the pituitary and activating the adenosine monophosphate-activated protein kinase (AMPK). Based on this evidence, metformin appears to be a promising therapeutic tool in patients with thyroid disease. More clinical studies are necessary to evaluate the clinical significance of metformin for the treatment of thyroid diseases.",
"affiliations": "Chinese Medicine Hospital in Linyi CityLinyi, China.;Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China.;Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China.;Division of EndocrinologyDepartment of Medicine, St. Hedwig Hospital, Berlin, Germany.;Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China liuchao@nfmcn.com.",
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"abstract": "This is a case report of a 42-year-old man who underwent suboccipital craniectomy and C-1 laminoplasty under general anesthesia. His weight and height were 32 kg and 110 cm, respectively. The patient had short limbs, a protruding forehead, a large tongue, and a short neck. Preoperative magnetic resonance imaging showed marked stenosis of the foramen magnum and cervicomedullary compression and malacia, with the smallest anteroposterior diameter of 4.5 mm. Mask ventilation and tracheal intubation were not feasible; therefore, an Airtraq® laryngoscope and a bronchial fiberscope were used. Anesthesia was maintained with propofol, remifentanil, and fentanyl. After intubation and postural change, the patient was awakened, and we confirmed the absence of any limb movement disorder. Intraoperative motor evoked potentials were normal. After extubation, he experienced numbness of the limbs. Postoperative magnetic resonance imaging revealed an enlargement of the foramen magnum and the foramen of the atlas. However, the cervicomedullary malacia remained unchanged. The cause of numbness was unknown. After rehabilitation, he became ambulatory and could walk continuously for about 300 m at a slow pace.",
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"title": "Anesthetic Management for Cervicomedullary Decompression in a Patient with Achondroplasia--A Case Report.",
"title_normalized": "anesthetic management for cervicomedullary decompression in a patient with achondroplasia a case report"
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"abstract": "Antiepileptic drug monotherapy is the mainstay of treatment for epilepsy; however, the efficacy of different antiepileptic drugs in reducing the incidence of seizure-related hospitalization among older adults, who are at higher risk of developing epilepsy compared to their younger counterparts, has not been examined.\nThe objective of the present study was to compare the rate of seizure-related hospitalization among older adults on levetiracetam compared to different antiepileptic drugs (AEDs).\nThis was a retrospective cohort study of older adults (≥60 years) in two tertiary care hospitals. Patients who are 60 years of age and older, have a confirmed diagnosis of epilepsy, and are taking a single and the same antiepileptic drug for at least 36 months were included. The patients were followed up for 24 months after 12 months of treatment with no incidence of seizure-related hospitalization via their health records. Multiple Poisson regression with robust error variance was used to estimate the relative risk of hospitalization for patients on levetiracetam compared to different antiepileptic drugs controlling for age, gender, number of prescription medications, dosage strengths, and Charlson Comorbidity Index (CCI) score.\nOne hundred and thirty-six patients met the inclusion criteria and were included in the study. The recruited patients were on one of the following four antiepileptic drugs: carbamazepine (n=44), levetiracetam (n=39), phenytoin (n=31), and valproic acid (n=22). Patients on levetiracetam were more than twice as likely to be hospitalized due to seizures within the 24 months of follow-up compared to their counterparts on other AEDs (RR=2.76, 95% CI=1.16-6.53, P=0.021).\nThis study suggests that older adults on old generation AEDs such as phenytoin, carbamazepine, and valproic acid appear to have a lower risk of seizure-related hospitalization compared to their counterparts on levetiracetam.",
"affiliations": "Department of Pharmacy, King Saud University Medical City, Riyadh, Saudi Arabia.;Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.;Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.;Department of Medicine, Neurology Division, College of Medicine, King Saud University, Riyadh, Saudi Arabia.;Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.;Department of Pharmacy, King Saud University Medical City, Riyadh, Saudi Arabia.;Department of Pharmaceutical Care, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Department of Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.;Department of Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.;Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.",
"authors": "Alzahrani|Huda|H|;Almalag|Haya Mohammad|HM|;AlRuthia|Yazed|Y|0000-0002-0029-5924;Al-Hussain|Fawaz|F|0000-0001-6041-6241;Balkhi|Bander|B|;Almutairi|Lama|L|;Algasem|Reem|R|;De Vol|Edward B|EB|;Almarzouqi|Manal Rashed|MR|;Alsemari|Abdulaziz|A|0000-0002-4196-3239",
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"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNDTneurodistNeuropsychiatric Disease and Treatment1176-63281178-2021Dove 22140310.2147/NDT.S221403Original ResearchThe Risk Of Seizure-Related Hospitalization Among Older Adults On Levetiracetam Monotherapy: A Retrospective Comparative Cohort Study Alzahrani et alAlzahrani et alAlzahrani Huda 1Almalag Haya Mohammad 2http://orcid.org/0000-0002-0029-5924AlRuthia Yazed 23http://orcid.org/0000-0001-6041-6241Al-hussain Fawaz 4Balkhi Bander 23Almutairi Lama 1Algasem Reem 5De Vol Edward B 6Almarzouqi Manal Rashed 6http://orcid.org/0000-0002-4196-3239Alsemari Abdulaziz 71 Department of Pharmacy, King Saud University Medical City, Riyadh, Saudi Arabia2 Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia3 Pharmacoeconomics Research Unit, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia4 Department of Medicine, Neurology Division, College of Medicine, King Saud University, Riyadh, Saudi Arabia5 Department of Pharmaceutical Care, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia6 Department of Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia7 Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi ArabiaCorrespondence: Yazed AlRuthia Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaTel +996 11 4677483Fax +966 11 4677480 Email yazeed@ksu.edu.sa24 9 2019 2019 15 2781 2788 30 6 2019 09 9 2019 © 2019 Alzahrani et al.2019Alzahrani 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).Background\nAntiepileptic drug monotherapy is the mainstay of treatment for epilepsy; however, the efficacy of different antiepileptic drugs in reducing the incidence of seizure-related hospitalization among older adults, who are at higher risk of developing epilepsy compared to their younger counterparts, has not been examined.\n\nPurpose\nThe objective of the present study was to compare the rate of seizure-related hospitalization among older adults on levetiracetam compared to different antiepileptic drugs (AEDs).\n\nPatients and methods\nThis was a retrospective cohort study of older adults (≥60 years) in two tertiary care hospitals. Patients who are 60 years of age and older, have a confirmed diagnosis of epilepsy, and are taking a single and the same antiepileptic drug for at least 36 months were included. The patients were followed up for 24 months after 12 months of treatment with no incidence of seizure-related hospitalization via their health records. Multiple Poisson regression with robust error variance was used to estimate the relative risk of hospitalization for patients on levetiracetam compared to different antiepileptic drugs controlling for age, gender, number of prescription medications, dosage strengths, and Charlson Comorbidity Index (CCI) score.\n\nResults\nOne hundred and thirty-six patients met the inclusion criteria and were included in the study. The recruited patients were on one of the following four antiepileptic drugs: carbamazepine (n=44), levetiracetam (n=39), phenytoin (n=31), and valproic acid (n=22). Patients on levetiracetam were more than twice as likely to be hospitalized due to seizures within the 24 months of follow-up compared to their counterparts on other AEDs (RR=2.76, 95% CI=1.16–6.53, P=0.021).\n\nConclusion\nThis study suggests that older adults on old generation AEDs such as phenytoin, carbamazepine, and valproic acid appear to have a lower risk of seizure-related hospitalization compared to their counterparts on levetiracetam.\n\nKeywords\nseizureshospitalizationlevetiracetamcarbamazepinephenytoinvalproic acid\n==== Body\nIntroduction\nOlder adults are more likely to develop seizures compared to their younger counterparts.1 This can be attributable to a multitude of risk factors that older adults are usually presented with such as stroke, head injuries, and dementia.2–4 The incidence of epilepsy is reported to be as high as 60 per 100,000 people in those aged between 40 and 59 years,5 though it can be more than 135 per 100,000 people in those aged 80 years and older.3 Additionally, the rate of epilepsy-related mortality is two to three times higher among older adults (e.g., ≥60 years) than their younger counterparts.6 The World Health Organization (WHO) estimated that epilepsy may represent 1% of the global burden of disease since its lifetime prevalence could be as large as 70 million people worldwide.7,8 The rates of mortality and hospitalization have increased within the last decade, especially among newly diagnosed patients.9 However, age was not found to be associated with healthcare services utilization according to a study that explored the predictors of healthcare resources utilization among a sample of epileptic patients in the United States,10 though the cost of healthcare services utilization is believed be significantly higher among older adults with epilepsy than those without epilepsy.11\n\nEpilepsy management is largely based on pharmacotherapy. Many antiepileptic drugs (AEDs) used in epilepsy treatment have variable efficacy and safety profiles.12 Currently, there are two generations of AEDs. The first generation of AEDs, such as phenobarbital, phenytoin, valproic acid, ethosuximide, and carbamazepine, are still used extensively in the management of epilepsy across different age groups; however, the risk of adverse events is generally higher with those AEDs compared to the second generation of AEDs, such as levetiracetam, lamotrigine, oxcarbazepine, zonisamide, and topiramate.13–16 It is known that appropriate selection of an AED can result in effective management of epilepsy and long-term remission shortly after the initiation of treatment, and approximately 70% of the patients can achieve seizure-freedom with a single AED.17 Therefore, different professional organizations, such as the International League against Epilepsy, have published guidelines that assist clinicians in choosing the right AED for their patients.18,19\n\nMultiple studies have compared the efficacy and tolerability of several AEDs. Brodie et al,20 compared the efficacy and tolerability of levetiracetam vs controlled-release carbamazepine in a sample of adult patients with newly diagnosed focal or generalized tonic-clonic seizures in a randomized, multicenter, double-blind trial. Although the withdrawal rate due to adverse events between the two drugs was higher among patients on carbamazepine, the percentage of patients who achieved seizure-freedom was slightly higher among patients on carbamazepine compared to their counterparts on levetiracetam (58.5% vs 56.6%).20 Similarly, in another multicentre randomized controlled trial that investigated the safety and efficacy of levetiracetam vs sustained-release carbamazepine in a sample of 106 older adults (>65 years) with post-stroke seizure, levetiracetam was non-inferior to carbamazepine in achieving seizure-freedom for 52 weeks, but patients on levetiracetam had a significantly lower rate of adverse events overall compared to patients on carbamazepine.21 However, this was not the case with the risk of fracture in which patients on levetiracetam, carbamazepine, or valproic acid had the same risk of fracture after 15 months of follow-up.22 Additionally, the new AEDs, such as levetiracetam and lamotrigine, do not appear to lower the rate of adverse events compared to old AEDs, such as phenytoin and carbamazepine, according to another study that compared the self-reported rates of AED adverse events in a sample of older adults.23 The SANAD study group has conducted an unblinded randomized clinical trial to compare the efficacy of carbamazepine against lamotrigine, oxcarbazepine, gabapentin, and topiramate for controlling seizures in patients with focal seizures. Lamotrigine was found to be non-inferior to carbamazepine and clinically better than other AEDs in the study for focal seizures.24 For generalized and unclassified seizures, the SANAD study group conducted another study to compare the efficacy of valproic acid vs lamotrigine and topiramate for controlling seizures. Although valproic acid was significantly better than topiramate for controlling generalized seizures, it was not better than lamotrigine.25 The findings of the SANAD study group’s unblinded randomized clinical trials for focal and generalized seizures were confirmed in the latest network meta-analysis by the Cochrane group, which suggests that carbamazepine and lamotrigine should be considered as first-line treatment options for patients with focal seizures while levetiracetam can be considered as an alternative. In contrast, valproic acid and lamotrigine should be considered first-line treatment options for generalized seizures with levetiracetam being considered as an alternative.17\n\nAlthough multiple randomized controlled studies have compared the efficacy of different AED monotherapies,17 very few studies have examined their efficacy in elderly patients (≥60 years).26–29 Moreover, these clinical trials have looked into the efficacy of different AEDs among older adults in terms of retention time as well as seizure-freedom over a 12-month period at most following the initiation of AED treatment.17,30,31 However, the efficacy of different AED monotherapies in terms of preventing seizure-related hospitalization, which is defined as inpatient hospital admissions due to uncontrolled seizures, following 12 months of stabilization with no incidence of seizure-related hospitalization has not been examined before in older adults with epilepsy. Therefore, the aim of this study was to compare the rates of seizure-related hospitalizations among older adults with epilepsy on levetiracetam, which is the most commonly used new AED among epileptic elderly patients in Saudi Arabia, compared to different AED monotherapies over a 24-month period following 12 months of treatment with no incidence of seizure-related hospitalization.\n\nMaterials And Methods\nStudy Design\nThis study was a retrospective review of medical charts of older adults visiting outpatient neurology clinics at two tertiary care hospitals in Riyadh, Saudi Arabia. Patient medical charts were reviewed by two neurologists to confirm their diagnosis with epilepsy prior to their inclusion in the study. We identified 556 consecutive elderly epileptic patients who were at least 12 months free from a seizure-related hospitalization, from patients seen in outpatient neurology clinics from Jan 2015 to Jan 2016. Retrospective data were collected from Jan 2014 to Jan 2018 using both paper and electronic patient medical records. Patients who were on more than one AED or not on a single AED for at least 36 months or who did not have complete data on prescription medications, and other comorbidities were excluded. Patients’ age, gender, education level, nationality, marital status, type of seizure, number of prescription medications, and name and dosage of AED were collected. The burden of illness was assessed using the Charlson Comorbidity Index (CCI), which assigns weighted scores to 17 different medical conditions depending on the severity and nature of the medical condition that patient has; higher CCI scores are associated with worse rates of morbidity and mortality.32 The study was approved by the institutional review boards of King Saud University Medical City and King Faisal Specialist Hospital and Research Center in Riyadh, Saudi Arabia (project numbers E16-1933 and 2161160) were the data collection took place. The patient population in these two public tertiary care hospitals is mostly Saudi citizens who have been referred by the ministry of health. The study was granted a waiver of the consent form by the institutional review boards of the two hospitals since no personal identifiers (e.g., name, address, and national identification number) were collected. The ethical principles for medical research involving human subjects as stated in the declaration of Helsinki were adhered to.\n\nParticipants\nOlder adults aged 60 years or over with focal or generalized seizures and on a single AED were recruited to the study. Patients had to be on the same AED for at least 36 months and must not have had any seizure-related hospitalizations in the first 12 months of treatment prior to their follow-up for an additional 24 months. Cancer patients, and those with missing observations on prescription drugs and other comorbidities as well as those with no neurology outpatient clinic visits for regular check-up, and those with no electronic medical record were excluded from the study. Furthermore, patients who did not fill their medications on a regular basis were also excluded.\n\nStatistical Analysis\nThe chi-square test or Fisher’s exact test was used as appropriate to compare the percentages of categorical variables, such as gender, across the different AEDs. Analysis of variance (ANOVA) was used to compare the means of continuous variables across the patients on different AEDs. Multiple Poisson regression with robust error variance was used to estimate the relative risk of hospitalization for patients on different antiepileptic drugs controlling for age, gender, number of prescription medications, and Charlson Comorbidity Index (CCI) score. Furthermore, the dosage strengths of AEDs were controlled for using the interaction terms between the utilization of each AED and its dosage. The minimum sample size was estimated to be 68 patients based on α=0.05, power of 0.8, and medium effect size (F2=0.15).\n\nResults\nOf 556 elderly epileptic patients who were identified between Jan 2015 and Jan2018, only 136 met the study’s inclusion criteria and were included in the analysis, as is shown in Figure 1. The patients’ sociodemographic and medical characteristics are summarized in Table 1. More than two-thirds of the patients (71%) were on old AEDs, such as carbamazepine (32%), phenytoin (23%), and valproic acid (16%), while approximately 29% of the patients were on levetiracetam. The mean ages of the patients on each AED were comparable, and their overall mean age was approximately 70 years. Most of the patients were married (84%), with no formal education (57%), male (54%), and from Saudi Arabia (93%). Approximately 47% of the patients had generalized seizures, 26.47% had focal seizures, and 26.47% had unclassified seizures. The mean number of prescription medications and the CCI scores for the patients were approximately six and three, respectively. The mean dosages of patients on levetiracetam, carbamazepine, phenytoin, and valproic acid were approximately 1011, 456, 245, and 934 mg, respectively. Approximately 51% of the patients on levetiracetam, 39% on carbamazepine, 36% on valproic acid, and 19% on phenytoin had an incidence of seizure-related hospitalization within the 24 months of follow-up as is shown in Figure 2. The utilization of levetiracetam was associated with almost a 3-fold higher risk of hospitalization due to seizure within the 24 months of follow-up (RR=2.76, 95% CI=1.16–6.53, P=0.021) compared to other AEDs controlling for age, gender, education level, number of prescription medications, dosage strength, and CCI score, as shown in Table 2.Table 1 Baseline Characteristics Of Patients\n\nCharacteristic\tAntiepileptic Drug (AED)\t\nLevetiracetam (N=39)\tCarbamazepine (N=44)\tPhenytoin (N=31)\tValproic Acid (N=22)\tTotal (N=136)\t\nAge (years), mean ± SD\t69.12 ± 5.6\t69.02 ± 7.75\t72.06 ± 8.88\t69.36 ± 9.13\t69.80 ± 7.75\t\nGender, n (%)\t\t\t\t\t\t\n Male\t21 (51.28)\t23 (52.27)\t16 (51.61)\t14 (63.63)\t74 (54.41)\t\n Female\t18 (46.15)\t21 (47.72)\t15 (48.38)\t8 (36.36)\t62 (45.59)\t\nMarital status, n (%)\t\t\t\t\t\t\n Married\t33 (84.61)\t40 (90.9)\t23 (74.19)\t18 (81.81)\t114 (83.82)\t\n Widowed\t6 (15.38)\t4 (9.09)\t2 (6.45)\t3 (13.63)\t15 (11.03)\t\n Divorced\t0 (0.00%)\t0 (0.00%)\t4 (12.9)\t0 (0.00%)\t4 (2.94)\t\n Single\t0 (0.00%)\t0 (0.00%)\t2 (6.45)\t1 (4.54)\t3 (2.21)\t\nNationality, n (%)\t\t\t\t\t\t\n Saudi\t35 (89.74)\t41 (93.18)\t30 (96.77)\t20 (90.9)\t126 (92.65)\t\n Non-Saudi\t4 (10.25)\t3 (6.81)\t1 (3.22)\t2 (9.09)\t10 (7.35)\t\nEducation, n (%)\t\t\t\t\t\t\n No formal education\t21 (53.84)\t27 (61.36)\t19 (61.29)\t10 (45.45)\t77 (56.62)\t\n Elementary school\t6 (15.38)\t5 (11.36)\t5 (16.12)\t2 (9.09)\t18 (13.24)\t\n Intermediate school\t1 (2.56)\t3 (6.81)\t0 (0.00%)\t2 (9.09)\t6 (4.41)\t\n High school\t3 (7.69)\t3 (6.81)\t2 (6.45)\t0 (0.00%)\t8 (5.88)\t\n Associate degree\t3 (7.69)\t4 (9.09)\t2 (6.45)\t2 (9.09)\t11 (8.09)\t\n Bachelor degree\t5 (12.82)\t2 (4.54)\t3 (9.67)\t6 (27.27)\t16 (11.76)\t\nNumber of Prescription Medications, mean ± SD\t5.79 ± 2.86\t5.38 ± 3.13\t6.32 ± 3.07\t6.31 ± 3.06\t5.86 ± 3.02\t\nCCI, mean ±SD\t3.35 ± 2.09\t2.54 ± 1.86\t3.7 ± 2.9\t3.04 ± 1.88\t3.12 ± 2.23\t\nTypes of seizures, n (%)\t\t\t\t\t\t\n Focal\t10 (25.64)\t15 (34.09)\t8 (25.8)\t3 (13.63)\t36 (26.47)\t\n Generalized\t17 (43.58)\t18 (40.9)\t13 (41.9)\t16 (72.72)\t64 (47.06)\t\n Unclassified\t12 (30.76)\t11 (25)\t10 (32.25)\t3 (13.63)\t36 (26.47)\t\nMean AED dosage in milligrams ±SD\t1011.72 ± 384.29\t465.22 ± 224.32\t244.89 ± 73.77\t933.87 ± 395.26\t-\t\nAbbreviations: AED, antiepileptic drug, LEV, levetiracetam; CBZ, carbamazepine; PHT, phenytoin; VPA, valproic acid; CCI, Charlson comorbidity index.\n\n\nTable 2 The Risk Of Hospitalization For Patients On Levetiracetam, Carbamazepine, Phenytoin, And Valproic Acid\n\nVariable\tRelative Risk (95% Confidence Interval)\tP-value\t\nLevetiracetam utilization§\t2.76 (1.16–6.53)\t0.021\t\nEducation\t0.96 (0.85–1.09)\t0.599\t\nCCI\t0.91 (0.81−1.02)\t0.106\t\nGender\t0.69 (0.43–1.10)\t0.119\t\nAge\t0.99 (0.96–1.03)\t0.961\t\nNumber of prescription medications\t1.1 (1.03–1.20)\t0.009\t\nNotes:\n§The utilization of different antiepileptic drugs (AEDs) was adjusted for dosage strengths. The bold data signify statistical significant (P<0.05).\n\nAbbreviation: CCI, Charlson comorbidity index.\n\n\nFigure 1 Patients’ recruitment scheme.\n\nFigure 2 Rate of seizure-related hospitalization for different antiepileptic drugs.\n\n\n\nDiscussion\nThe current study examined the rate of seizure-related hospitalizations among older adults with seizure disorders on levetiracetam monotherapy compared to different old AED monotherapies, such as carbamazepine, phenytoin, and valproic acid, over a 24-month period. Although several randomized trials and observational studies have shown preferable therapeutic efficacy and favourable safety and drug interaction profiles of levetiracetam in the management of both focal and generalized seizures in comparison to different AED monotherapies,17 few of these studies were designed to examine the efficacy of levetiracetam among older adults.28,30,31 Furthermore, these studies have assessed the efficacy of different AED monotherapies using 12-month seizure-freedom rates;28,30,31 however, our current study examined the efficacy of levetiracetam and other AED monotherapies by comparing the rates of seizure-related hospitalizations between levetiracetam and other AED monotherapies for 24 months after 12 months of treatment stabilization with no incidence of seizure-related hospitalization. Interestingly, the findings of this study are at odds with the results of previous studies among older adults.30,31 Elderly patients on levetiracetam had a significantly higher risk of hospitalization due to seizures compared to phenytoin, valproic acid, and carbamazepine controlling for their age, gender, number of prescription medications, AED dosage strength, burden of illness as measured by CCI, and education level. Patients on levetiracetam had the highest rate of seizure-related hospitalization, while patients on phenytoin had the lowest rate. Although phenytoin utilization for seizure disorders has been reduced over the last two decades largely because of its adverse effects profile, it appeared to perform better than most AEDs for both generalized and focal onset seizures.17 This study’s results question the value of levetiracetam among elderly patients for controlling seizures and reducing the rate of seizure-related hospitalization, which is associated with significantly higher healthcare utilization costs11 in the long term. Moreover, these findings may partially lend support to the authors’ conclusions in the Cochrane review on the efficacy of AED monotherapies, in which carbamazepine and sodium valproate are considered suitable as first-line treatments for focal onset and generalized tonic-clonic seizures, respectively, however it questions the suitability of levetiracetam as first-line treatment for the aforementioned types of seizures among elderly patients with epilepsy.17 Besides the higher likelihood of seizure-related hospitalization among elderly patients on levetiracetam, the number of prescription medications was associated with higher likelihood of seizure-related hospitalization which is consistent with previously published studies that linked higher number of prescription medications among elderly patients with epilepsy to poor medication adherence and higher risk of hospitalization.33\n\nAlthough this study has investigated the rate of seizure-related hospitalization among older adults on levetiracetam monotherapy in comparison to old AEDs, such as phenytoin, carbamazepine, and valproic acid over a 24-month period, its findings have multiple limitations. First, the study design was a retrospective medical chart review, which has multiple limitations such as information bias.34 Furthermore, a significant number of patients were excluded due to missing information. Despite the fact that the patients in this study should not have any issues with their possession of AEDs given that prescription medications are dispensed for all patients without any charge in the medical centres in which the study took place, medication adherence was not controlled for. However, the authors have controlled for multiple variables that are believed to influence adherence, such as the number of prescription medications and the burden of illness as measured by the CCI,32 gender,35 and patients’ level of education.36 Moreover, the study did not control for the frequency of seizures at baseline as well as the duration of illness which can influence the findings of this study. However, a 12-month period of stabilization on the same AED with no incidence of seizure-related hospitalization was chosen to reduce the impact of such confounding factors. Additionally, although the likelihood of patients being hospitalized in other hospitals due to seizures cannot be excluded, it is very unlikely given the structure of the public health system in Saudi Arabia in which patients can only be admitted in hospitals where their medical files are in. Emergency department (ED) visits were also not controlled for, however, all of the patients who were admitted were seen and evaluated in the ED before their admission. Finally, the study took place in only two tertiary care centers, which limits the generalizability of the study findings.\n\nConclusion\nThe management of epilepsy among older adults with levetiracetam may not be as effective as other old AEDs for ensuring seizure freedom in the long term, as the findings of this study suggest. Seizure-related hospitalizations are associated with immense direct medical costs and unfavourable clinical outcomes. Therefore, future studies should examine the rate of seizure-related hospitalizations among different AED monotherapies including levetiracetam on a large scale and with more robust research designs.\n\nAcknowledgments\nThe authors thank Muhammad Alshehri and Saleh Alageel for their data collection efforts. The authors also acknowledge financial support from the Researchers Supporting Project number (RSP-2019/16), King Saud University, Riyadh, Saudi Arabia.\n\nAbbreviations\nAED, antiepileptic drug; CCI, Charlson comorbidity index; WHO, world health organization.\n\nData Sharing Statement\nStudy data are available from the authors upon request.\n\nAuthor Contributions\nAll authors contributed to data analysis, drafting or revising the article, gave final approval for the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Acharya \nJN , Acharya \nVJ . Epilepsy in the elderly: special considerations and challenges . Ann Indian Acad Neurol . 2014 ;17 (Suppl 1 ):S18 –S26 . doi:10.4103/0972-2327.128645 24791083 \n2. Picot \nMC , Baldy-Moulinier \nM , Daures \nJP , Dujols \nP , Crespel \nA . 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A randomized, double-blind comparison of antiepileptic drug treatment in the elderly with new-onset focal epilepsy . Epilepsia . 2015 ;56 (3 ):450 –459 . doi:10.1111/epi.12926 25684224 \n31. Arif \nH , Buchsbaum \nR , Pierro \nJ , et al. Comparative effectiveness of 10 antiepileptic drugs in older adults with epilepsy . Arch Neurol . 2010 ;67 (4 ):408 –415 . doi:10.1001/archneurol.2010.49 20385905 \n32. Charlson \nME , Pompei \nP , Ales \nKL , MacKenzie \nCR . A new method of classifying prognostic comorbidity in longitudinal studies: development and validation . J Chronic Dis . 1987 ;40 (5 ):373 –383 . doi:10.1016/0021-9681(87)90171-8 3558716 \n33. Zelko \nE , Klemenc-Ketis \nZ , Tusek-Bunc \nK . Medication adherence in elderly with polypharmacy living at home: a systematic review of existing studies . Mater Sociomed . 2016 ;28 (2 ):129 –132 . doi:10.5455/msm .27147920 \n34. Vassar \nM , Holzmann \nM . The retrospective chart review: important methodological considerations . 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"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6328",
"issue": "15()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "carbamazepine; hospitalization; levetiracetam; phenytoin; seizures; valproic acid",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "2781-2788",
"pmc": null,
"pmid": "31576133",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "27382285;15329080;19800848;24324853;20067507;25114785;18339521;17283312;17382827;16322020;25684224;17561956;3558716;30765980;28661008;23128439;29414554;15955935;26842957;10515178;27147920;25625087;24791083;18363709;27421539;21075011;25083209;21384700;20385905;29859697;20196795;23350722;17382828",
"title": "The Risk Of Seizure-Related Hospitalization Among Older Adults On Levetiracetam Monotherapy: A Retrospective Comparative Cohort Study.",
"title_normalized": "the risk of seizure related hospitalization among older adults on levetiracetam monotherapy a retrospective comparative cohort study"
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"companynumb": "SA-UCBSA-2019043645",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
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"activesubstancename": "LEVETIRACETAM"
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{
"abstract": "OBJECTIVE\nTo evaluate the activity of imatinib in treating advanced, life-threatening malignancies expressing one or more imatinib-sensitive tyrosine kinases.\n\n\nMETHODS\nThis was a phase II, open-label, single arm study. Patients > or = 15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinib-sensitive tyrosine kinases were enrolled. Patients were treated with 400 or 800 mg/d imatinib for hematologic malignancy and solid tumors, respectively. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was to identify evidence of imatinib activity with tumor response as the primary end point.\n\n\nRESULTS\nOne hundred eighty-six patients with 40 different malignancies were enrolled (78.5% solid tumors, 21.5% hematologic malignancies). Confirmed response occurred in 8.9% of solid tumor patients (4 complete, 9 partial) and 27.5% of hematologic malignancy patients (8 complete, 3 partial). Notable activity of imatinib was observed in only five tumor types (aggressive fibromatosis, dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myeloproliferative disorders, and systemic mastocytosis). A total of 106 tumors were screened for activating mutations: five KIT mutations and no platelet-derived growth factor receptor mutations were found. One patient with systemic mastocytosis and a partial response to therapy had a novel imatinib-sensitive KIT mutation (D816T). There was no clear relationship between expression or activation of wild-type imatinib-sensitive tyrosine kinases and clinical response.\n\n\nCONCLUSIONS\nClinical benefit was largely confined to diseases with known genomic mechanisms of activation of imatinib target kinases. Our results indicate an important role for molecular characterization of tumors to identify patients likely to benefit from imatinib treatment.",
"affiliations": "Department of Hematology and Medical Oncology, Oregon Health & Science University Cancer Institute and Portland VA Medical Center, Portland, Oregon 97239-3098, USA. heinrich@ohsu.edu",
"authors": "Heinrich|Michael C|MC|;Joensuu|Heikki|H|;Demetri|George D|GD|;Corless|Christopher L|CL|;Apperley|Jane|J|;Fletcher|Jonathan A|JA|;Soulieres|Denis|D|;Dirnhofer|Stephan|S|;Harlow|Amy|A|;Town|Ajia|A|;McKinley|Arin|A|;Supple|Shane G|SG|;Seymour|John|J|;Di Scala|Lilla|L|;van Oosterom|Allan|A|;Herrmann|Richard|R|;Nikolova|Zariana|Z|;McArthur|And Grant|AG|;|||",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta",
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-07-4575",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
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"abstract": "Abiotrophia defectiva, also known as nutritionally variant streptococcus, is part of the normal flora of the oral cavity and urogenital and intestinal tracts and is a rare cause of infective endocarditis. It is fastidious or difficult to culture and associated with high rates of septic embolization, treatment failure and mortality. We describe an unusual presentation of infective endocarditis with severe mitral valve regurgitation due to Abiotrophia defectiva in an immunocompetent patient. After a complicated hospital course, surgical replacement of both the mitral and aortic valves was performed. We suggest that this patient likely had subacute infective endocarditis before diagnosis and treatment of her urinary tract infection, and following treatment failure, she developed life-threatening infective endocarditis. This case report highlights that patients with Abiotrophia defectiva infections are at high risk for infective endocarditis and that the clinical progression from this infection can be slow, with difficulty isolating the pathogen, which can significantly impact patient outcome.",
"affiliations": "Division of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.;Division of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.;Division of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.;Division of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.",
"authors": "Foley|Edward D|ED|;Ben Omran|Mohamed|M|;Bora|Vaibhav|V|;Castresana|Manuel R|MR|",
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"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1878770010.1177_2050313X18787700Case ReportCardiogenic and septic shock associated with aortic and mitral valve infective endocarditis caused by Abiotrophia Defectiva from a urinary tract infection Foley Edward D Ben Omran Mohamed Bora Vaibhav Castresana Manuel R Division of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USAEdward D Foley, Division of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, BIW-2144 1120 15th Street, Augusta, GA 30912, USA. Email: efoley@augusta.edu13 7 2018 2018 6 2050313X187877009 3 2018 18 6 2018 © The Author(s) 20182018SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Abiotrophia defectiva, also known as nutritionally variant streptococcus, is part of the normal flora of the oral cavity and urogenital and intestinal tracts and is a rare cause of infective endocarditis. It is fastidious or difficult to culture and associated with high rates of septic embolization, treatment failure and mortality. We describe an unusual presentation of infective endocarditis with severe mitral valve regurgitation due to Abiotrophia defectiva in an immunocompetent patient. After a complicated hospital course, surgical replacement of both the mitral and aortic valves was performed. We suggest that this patient likely had subacute infective endocarditis before diagnosis and treatment of her urinary tract infection, and following treatment failure, she developed life-threatening infective endocarditis. This case report highlights that patients with Abiotrophia defectiva infections are at high risk for infective endocarditis and that the clinical progression from this infection can be slow, with difficulty isolating the pathogen, which can significantly impact patient outcome.\n\nCardiovascularAbiotrophia defectivainfective endocarditisseptic shockcover-dateJanuary-December 2018\n==== Body\nIntroduction\nAbiotrophia defectiva (AD) infections are associated with high rates of septic embolization, treatment failure and mortality.1–3 We describe an unusual presentation of infective endocarditis (IE) due to AD, complicated by sepsis, severe valvulopathy and pulmonary hypertension, with characteristic septic embolization to the spleen and lower extremity. Surgical replacement of both the mitral and aortic valves was required. Intensivists and cardiac anesthesiologists, as well as other clinical providers and specialists involved in the management of these complicated cases, should be aware of this rare but potentially fatal infection and consider it as a cause of acute deterioration and organ failure in at-risk patients.\n\nCase report\nA 53-year-old immunocompetent female presented with a 1-week history of dizziness, worsening shortness of breath and increasing chest pressure. Prior to admission, she was diagnosed with a urinary tract infection, culture positive for AD. This was initially treated with sulfamethoxazole-trimethoprim 800/160 mg twice per day for a week followed by an intramuscular injection of ceftriaxone and oral ciprofloxacin 500 mg twice per day for 7 days.\n\nOn admission to hospital, she was lethargic, vital signs recorded were temperature of 36.7°C, blood pressure of 104/88 mmHg, heart rate of 175 beats per minute, respiratory rate of 21 breaths per minute and oxygen saturation of 98% on room air. Chest radiography was unremarkable and electrocardiogram showed atrial fibrillation with a rapid ventricular rate to 180 beats per minute. Brain natriuretic peptide was elevated at 819 pg/mL, initial troponin I value was 0.1 ng/mL with a repeat value of 0.34 ng/mL and a heparin infusion was started for presumed acute coronary syndrome as well as a diltiazem infusion, with improvement in heart rate control. Further workup revealed a lactic acidosis, acute kidney injury with creatinine 1.62 mg/dL (baseline 0.8 mg/dL) and thrombocytopenia to 29,000/mm3. Transthoracic echocardiogram showed a thickened and restricted mitral valve with a large vegetation (21 mm × 19 mm) on the posterior leaflet (Figure 1), with partial flail and severe regurgitation. The vegetation was seen to be obstructing inflow into the left ventricle with associated stenotic physiology. The aortic valve was also thickened with perforation of the non-coronary cusp and the ejection fraction was normal. Right ventricular systolic pressure was severely elevated at 70–80 mmHg with evidence of right ventricular overload.\n\nFigure 1. Transthoracic echocardiographic image with large vegetation attached to the posterior leaflet of the mitral valve.\n\nEmpiric vancomycin and piperacillin/tazobactam were started and subsequently changed within 24 h to ampicillin 2 g every 4 h and gentamycin 3 mg/kg every 24 h, in view of blood cultures growing gram-positive bacilli. Surgical intervention was deferred due to severe thrombocytopenia and bacteremia.\n\nOne week after admission, she developed acute heart failure, requiring emergent intubation and mechanical ventilation. Ampicillin was switched to ampicillin/sulbactam 3 g every 6 h with gentamycin and daptomycin 6 mg/kg, for better anerobic and resistant gram-positive coverage. This was followed by sudden onset septic embolization to the left lower limb causing critical ischemia, as well as new splenic infarcts (Figure 2), managed with left lower extremity thrombectomy and four-compartment fasciotomy. Blood cultures continued to show no definitive pathogen. Given the severe valvulopathy and metastatic septic embolization, surgical replacement of both the mitral and aortic valves was performed.\n\nFigure 2. Computer tomographic image with splenic infarct due to septic embolization.\n\nIntraoperative transesophageal echocardiogram showed an enlarged left atrium measuring 5.7 cm with thrombi present in both left and right atrial appendages (Figure 3). The aortic valve appeared thinned with evidence of severe aortic insufficiency. The posterior leaflet of the mitral valve was eroded by the large vegetation, and there were micro-abscesses in the posterior annulus and nodular extension up the endocardium into the left atrium. As pulmonary artery pressures remained elevated after mitral valve replacement, inhaled epoprostenol was initiated with good effect and weaned slowly.\n\nFigure 3. Photograph of thrombus removed from left atrial appendage.\n\nPostoperative course was uncomplicated. Blood culture pathogen identification showed AD in addition to Gram-positive bacilli (cereus/thuringiensis, magaterium and subtilis) from initial blood cultures on admission. The patient was discharged from the intensive care unit after 2 weeks on broad spectrum antibiotics for a total of 6 weeks.\n\nDiscussion\nOrganisms of the genus Abiotrophia were first classified as nutritionally variant streptococci (NVS) in 1961.3\nabiotrophia defectiva has been associated with life-threatening infections such as bacteremia, osteomyelitis, brain abscess, pancreatic abscess, septic arthritis and crystalline keratopathy.2,4\n\nA 2001 study of 97 patients, by Christensen and Facklam,5 showed that IE was reported in 58% of patients, while in 26% of patients, septicemia or bacteremia was given as the clinical diagnosis. Endocarditis caused by NVS is implicated in 5%–6% of all streptococcal endocarditis cases, with <1% of all cases caused by abiotrophia defectiva.3,6\n\nThe reason that this pathogen has a higher affinity for the endocardium is due to its ability to secrete exopolysaccharide, enabling it to adhere to fibronectin in the extracellular matrix.7 In these cases, IE progresses slowly, but despite its sensitivity to antimicrobials, approximately 50% of patients need surgical management, as was the case with our patient.8\n\nThe identification of Abiotrophia is difficult because of its growth requirement and its confusing Gram stain appearance. It needs a high clinical suspicion and may be a diagnostic challenge that may require more advanced diagnostics modalities such as polymerase chain reaction (PCR) and/or matrix-assisted laser desorption ionization time-of-flight mass spectrophotometry (MALDI-TOF-MS). MALDI-TOF-MS is a relatively simple and inexpensive method of identification.2 At our institution, we do not offer these testing procedures, and therefore, this was a “send out” test to another institution which used MALDI-TOF-MS method of identification. Given that this identification was from two different blood samples, this was a hematogenous infection rather than merely colonization. If the identification had been from just one sample, it more likely would have been less significant and thus merely represented colonization. Also, the Bacillus cereus, Bacillus thuringiensis, Bacillus magaterium and Bacillus subtilis identification was from a single sample, and therefore, it was interpreted as probably caused by contamination from skin or perhaps an uncleaned sample bottle top.\n\nTreatment failure rates as high as 41% occur despite the use of appropriate antibiotics.9 A mortality rate of up to 17% has been reported in the literature, which is high when compared to mortality rates from endocarditis caused by Viridans streptococci (0%–12%) and other pathogens.10 Most reported deaths are due to acute heart failure or major systemic embolization, both of which were manifested in our patient.\n\nAD endocarditis predominantly occurs in the setting of pre-existing heart disease (90% of cases), and prosthetic heart valves are involved in 10% of patients.3,8 However, neither of these risk factors were present in our patient.\n\nThe American Heart Association guidelines recommend use of the same treatment as for Enterococcus endocarditis, that is, a combination of ampicillin or benzylpenicillin plus gentamycin for a period of 4–6 weeks.9 Alternatively, vancomycin can be used alone for 6 weeks in patients with a penicillin allergy. Ceftriaxone combined with gentamycin is an alternative option.10–12\n\nSpecific therapeutic dosing guidelines recommend 18–30 million units of penicillin per 24 h divided into six doses or 12 g of ampicillin per 24 h intravenously, divided into six doses, in addition to intravenous gentamycin at 3 mg/kg/24 h divided into three doses for 4–6 weeks. Vancomycin represents a good therapeutic choice in patients who have shown a poor response to penicillin/aminoglycoside combination therapy.13,14\n\nThe portal of entry for systemic bacteremia in our patient was most likely the genitourinary tract. Abiotrophia species are generally considered to be part of the normal flora of the urogenital and oropharyngeal tracts and can also be found in the gastrointestinal tract.11 Our patient was diagnosed with a urinary tract infection caused by abiotrophia defectiva in the weeks preceding presentation and acute deterioration with signs and symptoms of IE and cardiogenic and septic shock. Given that workup for her clinical deterioration showed hematogenous spread of her known Abiotrophia urinary tract infection and that IE was found to be the cause of her hemodynamic decompensation, it is a logical conclusion that the urinary presence of the bacterium was the primary cause of the IE. Although as stated previously, Abiotrophia species is also considered normal flora of the oropharyngeal tract, and there were no clinical signs or symptoms to suggest an oropharyngeal source (e.g. dental abscess, tonsillitis, upper respiratory tract infection). Also, this patient was not immunocompromised and did not have any history of congenital heart disease such as bicuspid aortic valve or prosthetic heart valve placement at the time of initial presentation. In our case, open heart surgery with complex anesthesia management due to sepsis and hemodynamic deterioration was required for definitive treatment, which was followed by an uncomplicated postoperative course.\n\nConclusion\nThis case report highlights that patients with known AD infections are at high risk for IE with severe cardiorespiratory compromise, even in the absence of known risk factors. Cardiac anesthesiologists and clinical specialists involved in the care of these patients, such as neurologists, hospitalists and infectious disease consultants, should be aware of this rare but potentially fatal infection, which may present a significant anesthetic challenge, and consider it as a cause of acute deterioration and organ failure in at-risk patients in the intensive care unit.\n\nPresented at the 47th Annual Congress Society of Critical Care Medicine, Sepsis Research Snapshot Theater, Henry B Gonzalez Convention Center, San Antonio, Texas (February 2018). Published in abstract form as Foley ED, Castresana MR, et al. Abiotrophia defectiva a rare cause of infective endocarditis of the mitral valve. Crit Care Med 2018; 46(1): 716.\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\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed consent: Written informed consent was obtained from the patient for their anonymized information to be published in this article\n==== Refs\nReferences\n1 \nRuoff KL. \nNutritionally variant streptococci . Clin Microbiol Rev \n1991 ; 4 : 184 –190 .2070344 \n2 \nHoller JG Pedersen LK Calum H et al \nUsing MALDI-TOF mass spectrometry as a rapid and accurate diagnostic tool in infective endocarditis: a case report of a patient with mitral valve infective endocarditis caused by Abiotrophia defective . Scand J Inf Dis \n2011 ; 43 : 234 –237 .21091125 \n3 \nFrenkel A Hirsch W. \nSpontaneous development of L forms of streptococci requiring secretions of other bacteria or sulphydryl compounds for normal growth . Nature \n1961 ; 191 : 728 –730 .13701753 \n4 \nRoberts RB Krieger AG Schiller NL et al \nViridans streptococcal endocarditis: The role of various species, including pyridoxal-dependent streptococci . Rev Infect Dis \n1979 ; 1 : 955 –966 .551516 \n5 \nChristensen JJ Facklam RR. \nGranulicatella and Abiotrophia species from human clinical specimens . J Clin Microbiol \n2001 ; 39 (10 ): 3520 –3523 .11574566 \n6 \nHeath CH Bowen SF McCarthy JS et al \nVertebral osteomyelitis and discitis associated with Abiotrophia adiacens (nutritionally variant streptococcus) infection . Aust N Z J Med \n1998 ; 28 : 663 .9847960 \n7 \nCarle MA Giudice AD Viglietti R et al \nAortic valve endocarditis caused by Abiotrophia defectiva: case report and literature overview . In Vivo \n2015 ; 29 : 515 –518 .26359407 \n8 \nKiernan TJ O’Flaherty N Gilmore R et al \nAbiotrophia defective endocarditis and associated hemophagocytic syndrome—a first case report and review of the literature . Int J Infect Dis \n2008 ; 12 : 478 –482 .18539495 \n9 \nBaddour LM Wilson WR Bayer AS et al \nInfective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association . Circulation \n2015 ; 132 (15 ): 1435 –1486 .26373316 \n10 \nTuazon CU Gill V Gill F. \nStreptococcal endocarditis: single vs combination antibiotic therapy and role of various species . Rev Infect Dis \n1986 ; 8 (1 ): 54 –60 .3952425 \n11 \nAlberti MO Hindler JA Humphries RM. \nAntimicrobial susceptibilities of Abiotrophia defectiva, Granulicatella adiacens, and Granulicatella elegans . Antimicrob Agents Chemother \n2015 ; 1460 (3 ): 1411 –1420 .\n12 \nZheng X Freeman AF Villafranca J et al \nAntimicrobial susceptibilities of invasive pediatric Abiotrophia and Granulicatella isolates . J Clin Microbiol \n2004 ; 42 (9 ): 4323 –4326 .15365035 \n13 \nBouvet A. \nHuman endocarditis due to nutritionally variant streptococci: streptococcus adjacens and Streptococcus defectivus . Eur Heart J \n1995 ; 16 (Suppl. B ): 24 –27 .\n14 \nPrasidthrathsint K Fisher MA. \nAntimicrobial susceptibility patterns among a large, nationwide cohort of Abiotrophia and Granulicatella clinical isolates . J Clin Microbiol \n2017 ; 55 (4 ): 1025 –1031 .28077699\n\n",
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"title": "Cardiogenic and septic shock associated with aortic and mitral valve infective endocarditis caused by Abiotrophia Defectiva from a urinary tract infection.",
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"abstract": "The diagnosis of histoplasmosis in patients with human immunodeficiency virus in southern Africa is complicated by the nonspecific presentation of the disease in this patient group and the unavailability of sensitive diagnostics including antigen assays. Treatment options are also limited due to the unavailability of liposomal amphotericin and itraconazole, and the inability to perform therapeutic drug monitoring further confounds management. We present 3 clinical cases to illustrate the limits of diagnosis and management in the southern African context, and we highlight the need for additional diagnostic tools and treatment options in resource-limited settings.",
"affiliations": "Médecins Sans Frontières/Doctors Without Borders ; Albert Einstein College of Medicine , Bronx, New York, New York.;Department of Infectious Diseases , Nelson R. Mandela School of Medicine.;Department of Infectious Diseases , Nelson R. Mandela School of Medicine.;Department of Anatomical Pathology , University of KwaZulu-Natal , Durban , South Africa.;New York University School of Medicine.;Department of Infectious Diseases , Nelson R. Mandela School of Medicine.",
"authors": "Murphy|Richard A|RA|;Gounder|Lilishia|L|;Manzini|Thandekile C|TC|;Ramdial|Pratistadevi K|PK|;Castilla|Carmen|C|;Moosa|Mahomed-Yunus S|MY|",
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"fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidofidsOpen Forum Infectious Diseases2328-8957Oxford University Press 2603477410.1093/ofid/ofv025ofv025Brief ReportsChallenges in the Management of Disseminated Progressive Histoplasmosis in Human Immunodeficiency Virus-Infected Patients in Resource-Limited Settings Murphy Richard A. 12Gounder Lilishia 3Manzini Thandekile C. 3Ramdial Pratistadevi K. 4Castilla Carmen 5Moosa Mahomed-Yunus S. 31 Médecins Sans Frontières/Doctors Without Borders2 Albert Einstein College of Medicine, Bronx, New York, New York3 Department of Infectious Diseases, Nelson R. Mandela School of Medicine4 Department of Anatomical Pathology, University of KwaZulu-Natal, Durban, South Africa5 New York University School of MedicineCorrespondence: Richard A. Murphy, MD, MPH, Médecins Sans Frontières-Doctors Without Borders, 333 7th Ave, New York, NY (ramurphy@gmail.com).1 2015 23 3 2015 2 1 ofv0253 10 2014 16 1 2015 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.The diagnosis of histoplasmosis in patients with human immunodeficiency virus in southern Africa is complicated by the nonspecific presentation of the disease in this patient group and the unavailability of sensitive diagnostics including antigen assays. Treatment options are also limited due to the unavailability of liposomal amphotericin and itraconazole, and the inability to perform therapeutic drug monitoring further confounds management. We present 3 clinical cases to illustrate the limits of diagnosis and management in the southern African context, and we highlight the need for additional diagnostic tools and treatment options in resource-limited settings.\n\nAIDSdeveloping countriesdisseminated progressive histoplasmosisfluconazoleHIVitraconazoleliposomal amphotericin Blow- and middle-income countryopportunistic infectionresource-limited settings cover-dateWinter 2015\n==== Body\nHistoplasmosis, although not endemic in southern Africa, has emerged, in the context of the human immunodeficiency virus (HIV) epidemic, as an opportunistic infection (OI) of potential importance [1–3]. Histoplasmosis in patients with advanced HIV most commonly manifests as disseminated progressive disease (DPH), usually with a subacute presentation [4], but it can also present fulminantly with shock and altered mental status [5]. In the absence of skin or mucus membrane lesions, the presenting symptoms and signs of DPH closely mimic OIs such as tuberculosis which because of its high prevalence is often treated empirically in the developing world. Importantly, unless DPH is promptly diagnosed and treated, in persons with HIV it is associated with a high mortality [4].\n\nThe actual burden of histoplasmosis in patients infected with HIV in southern Africa remains largely unknown, owing to at least 2 factors: (1) the often nonspecific presentation when skin lesions are absent and (2) the lack of access to sensitive diagnostic tests, notably the Histoplasma capsulatum antigen assay [6]. As a result, DPH is an OI that is likely underrecognized [7]. To underscore the challenges associated with the diagnosis and management of DPH among patients with HIV in southern Africa, we present cases encountered in routine clinical care.\n\nPatient 1\nA 36-year-old male with advanced HIV (CD4 cell count 14 cells/mm3) was admitted to a hospital in KwaZulu-Natal, South Africa with skin lesions for 4 weeks and altered mental status and vomiting for 1 week. The patient began antiretroviral therapy (ART) 12 weeks before admission, when he was clinically well. In the hospital, he was disorientated, febrile, and had oral candidiasis. His skin exam revealed flesh-colored nodules. Smaller nodules were scattered throughout his chin and chest, and 1 erosive lesion was on his forehead (Figure 1A). An abdominal ultrasound revealed abdominal lymphadenopathy and hepatosplenomegaly. Cerebrospinal fluid (CSF) pressure, chemistry, and cell count were normal, and a CSF cryptococcal antigen test was negative. The patient was placed on 200 mg daily dose of fluconazole (for candidiasis), and he received high-dose cotrimoxazole as treatment for suspected central nervous system toxoplasmosis. A skin biopsy was obtained. The patient deteriorated rapidly within 24 hours of admission, with the development of hypotension and worsening mental status, and he died. A shave biopsy later revealed an infiltrate of histiocytes containing innumerable small ovoid yeast-like organisms measuring 2–4 µm in diameter. Clear halos surrounded many of the organisms both within histiocytes and free in the dermis. Admixed lymphocytes and plasma cells were also noted (Figure 1B).\nFigure 1. A, Profile and forehead upon hospital presentation. B, A shave biopsy later revealed a diffuse infiltrate of histiocytes within which innumerable small ovoid yeast-like organisms measuring 2–4 µm in diameter. Clear halos surrounded many of the organisms both within histiocytes and free in the dermis. Admixed lymphocytes and plasma cells were noted.\n\n\n\nPatient 2\nA 35-year-old male was admitted to a teaching hospital in KwaZulu-Natal with a 2-month history of pruritic skin ulcerations. At admission, the patient was in his fourth month of therapy for tuberculous lymphadenitis. Exam revealed oral candidiasis, an ulcer involving the tongue, several ulcerated nodules over the face, legs, and hands, and destructive lesions of the nasal septum and nostrils (Figure 2A). He was found to have a CD4 cell count of 14 cells/µL. Liver function tests showed an alkaline phosphatase of 172 U/I and γ-glutamyl transpeptidase of 118 U/I. Cerebrospinal fluid was normal. Histology of the skin biopsy showed intracellular yeast forms (Figure 2C–E). Gram stain of the skin biopsy demonstrated yeast cells identified as H capsulatum var. duboisii by culture. The patient was commenced on itraconazole 200 mg/day 3 times daily. Rifampicin was stopped due to the potential interaction with itraconazole. He completed 1 year of itraconazole at 200 mg twice daily after which he was switched to fluconazole 200 mg twice daily. He initiated stavudine, lamivudine, and efavirenz 2 months after HIV diagnosis. The cutaneous lesions healed within 9 months (Figure 2B).\nFigure 2. A and B, Front profile before (A) and after (B) antifungal treatment sections of the skin biopsy demonstrate a diffuse infiltrate of histiocytes with voluminous cytoplasm and scattered uninucleate and multinucleate giant cells (C, haematoxylin & eosin). Conspicuous intracellular yeast forms, measuring approximately 8–12 µm with prominent, refractile cell walls were conspicuous on haematoxylin and eosin stains (arrows, C) and were highlighted on periodic acid Schiff staining (arrows, D). Gomori Grocott methenamine silver staining confirmed budding yeast forms with a ‘figure-of-eight’ configuration (arrows, E).\n\n\n\nPatient 3\nA 45-year-old male with HIV (CD4 cell count 29 cells/µL) was admitted to a teaching hospital in Durban, KwaZulu-Natal, South Africa for management of biopsy-proven histoplasmosis. Five months earlier, the patient had presented to a local hospital with epigastric pain, vomiting, and bloody diarrhea and an endoscopy had revealed a perforated duodenal ulcer. The current examination was notable for cervical lymphadenopathy, hepatomegaly, and splenomegaly. There were no oral or skin lesions. Ultrasound of the abdomen revealed left paraortic and splenic hilar lymphadenopathy. In addition, there were multiple splenic hypodensities. A solid mass was noted in the hepatic flexure of the colon. These findings were believed to be suggestive of extrapulmonary tuberculosis, and the patient began empiric antituberculous therapy followed by combination ART. To confirm the diagnosis, the left cervical lymph node was biopsied and a colonoscopy was performed, revealing a 1.5 cm deep ulcer with hypertrophic edges in the hepatic flexure. The biopsy showed ulcerated colonic mucosa with the lamina propria expanded by histiocytes, containing yeasts compatible with histoplasmosis. Lymph node biopsy revealed a histiocyte-rich inflammatory cell infiltrate with numerous fungi morphologically consistent with histoplasmosis. The patient was given amphotericin B for 14 days followed by maintenance therapy with oral fluconazole 800 mg/daily for a period of 30 days. Antituberculous treatment was continued. However, the patient died before treatment completion from sepsis, reportedly from Acinetobacter baumannii bacteremia.\n\nDISCUSSION\nFor febrile patients with advanced HIV in southern African—with or without characteristics skin lesions—DPH must be considered as a potentially lethal systemic infection. However, as a result of major gaps in diagnostics, DPH is likely an underrecognized cause of death in this region, as it is in many parts of the world. According to some authors, a vicious cycle has emerged in resource-limited settings whereby the absence of diagnostics and clinical awareness of histoplasmosis in the setting of acquired immune deficiency syndrome has led to under diagnosis and missed opportunities to treat this potentially important OI [7].\n\nWithout characteristic skin lesions, the diagnosis of DPH is particularly challenging, because the presentation is nonspecific and difficult to distinguish from more common OIs such as extrapulmonary tuberculosis, a disease which may also be present as a copathogen [8]. Mucocutaneous manifestations of DPH, although common in some series, are not a sensitive sign in DPH and may be present in as few as 10% of patients. This makes the diagnosis of DPH highly reliant on laboratory investigations that are not readily available. Furthermore, low autopsy rates may allow many cases of HIV-associated DPH to go unrecognized, further contributing to the underestimation of the burden of DPH as an OI in resource-limited settings. Most importantly, although histopathology and culture are the diagnostic gold standards, delays in obtaining positive laboratory confirmation impact negatively on patient management.\n\nHistoplasma capsulatum antigen detection assays, which are inaccessible in southern Africa, are central to the rapid diagnosis of DPH in patients infected with HIV. These assays can be applied to urine or serum and, among patients with HIV infection, have reported sensitivities of more than 85% [9]. Antigen detection assays offer a rapid turnaround time (usually 24 hours) compared with histology or culture, which allows for early initiation of treatment [6]. Additional advantages of quantitative antigen assays include avoiding invasive biopsies, monitoring response to treatment, and determining the timing of treatment termination. Advantages also include the early detection of relapse, which is of particular concern in patients with HIV.\n\nIn resource-limited settings, an additional challenge is that key agents in the optimal treatment of moderate or severe DPH are not readily available, specifically liposomal amphotericin and itraconazole. The treatment of choice for moderate to severe DPH in patients with HIV is liposomal amphotericin for at least 14 days, with some experts advocating a longer course in patients with a slow clinical response [10]. Although liposomal amphotericin B is associated with a faster clinical response and less toxicity than amphotericin B deoxycholate (0.7–1 mg/kg per day), outcomes with deoxycholate are comparable. Due to its accessibility, amphotericin B deoxycholate is the drug of choice for moderate to severe disease in southern Africa. For mild to moderate disease, the current recommendation places itraconazole above fluconazole. Itraconazole demonstrated an 85% response in 1 study whereas fluconazole showed a 74% response in a separate study [11, 12]. In the absence of a head-to-head comparison, and considering the excellent pharmacokinetic properties of fluconazole, which eliminates the need for therapeutic drug monitoring, fluconazole arguably becomes a reasonable choice in resource-constrained settings.\n\nMaintenance antifungal therapy is important to prevent relapse in HIV-associated DPH and should be provided in combination with ART. As maintenance therapy, fluconazole is inferior to itraconazole with drug resistance accounting for some fluconazole treatment failure [13]. Nonetheless, because it is less costly and more readily availability, fluconazole is used as maintenance therapy in resource-limited settings. In the absence of itraconazole, it might be prudent to consider higher doses of fluconazole, up to 800 mg/daily, as maintenance therapy given the reassuring experience with the use of high-dose fluconazole in the treatment of cryptococcal meningitis [14].\n\nMonitoring the response of DPH to treatment in patients infected with HIV in resource-limited settings involves careful attention to clinical parameters (such as weight gain) and resolution of clinical signs attributable to the disease. Guidelines recommend that serum or urine histoplasma antigen levels be used as sensitive measures of response to treatment and to detect early relapse [15, 16]. In the absence of these tools, discontinuation of treatment and early detection of relapse become extremely challenging.\n\nCONCLUSIONS\nIn conclusion, although HIV-associated DPH has been described in southern Africa and other resource-limited settings, the unavailability of sensitive diagnostic tools make the actual burden of HIV-associated DPH unknown. Difficulty in differentiating DPH from more common OIs, such as tuberculosis, potentially leads to misdiagnosis and inappropriate treatment. The lack of optimal treatment options should encourage critical interrogation of guidelines to facilitate optimal treatment within resource constraints. There is an urgent need to make diagnostic, therapeutic, and monitoring tools available for this disease in areas of the world where histoplasmosis is known to be an HIV-associated OI of potential importance. Finally, studies are required to evaluate the benefit of high-dose fluconazole in management of DPH.\n\nAcknowledgments\nWe gratefully acknowledge the generosity of the patients who participated in this research.\n\nAuthor contributions. R. A. M. and M.-Y. S. M. conceived the study. R. A. M., L. G., T. C. M., and C. C. collected the primary data. P. K. R. and M.-Y. S. M. provided the pathological descriptions. R. A. M. and C. C. drafted the manuscript. R. A. M. and M.-Y. S. M. critically revised the manuscript for intellectual content. All authors read and approved the final manuscript. R. A. M. and M.-Y. S. M. are guarantors of the paper.\n\nPotential conflicts of interest. All authors: No reported conflicts.\n\nAll authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1 K Ramdial P Mosam A Dlova NC \nDisseminated cutaneous histoplasmosis in patients infected with human immunodeficiency virus . J Cutan Pathol \n2002 ; 29 :215 –25 .12028154 \n2 Pillay T Pillay DG Bramdev A \nDisseminated histoplasmosis in a human immunodeficiency virus-infected African child . Pediatr Infect Dis J \n1997 ; 16 :417 –8 .9109150 \n3 Gumbo T Just-Nubling G Robertson V \nClinicopathological features of cutaneous histoplasmosis in human immunodeficiency virus-infected patients in Zimbabwe . Trans R Soc Trop Med Hyg \n2001 ; 95 :635 –6 .11816437 \n4 Wheat LJ Kauffman CA \nHistoplasmosis . Infect Dis Clin North Am \n2003 ; 17 :1 –19 , vii .12751258 \n5 Vathesatogkit P Goldenberg R Parsey M \nA 27-year-old HIV-infected woman with severe sepsis and pulmonary infiltrates. Disseminated histoplasmosis with severe sepsis and acute respiratory failure . Chest \n2003 ; 123 :272 –3 , 274–276 .12527630 \n6 Durkin MM Connolly PA Wheat LJ \nComparison of radioimmunoassay and enzyme-linked immunoassay methods for detection of Histoplasma capsulatum var. capsulatum antigen . J Clin Microbiol \n1997 ; 35 :2252 –5 .9276396 \n7 Nacher M Adenis A Mc Donald S \nDisseminated histoplasmosis in HIV-infected patients in South America: a neglected killer continues on its rampage . PLoS Negl Trop Dis \n2013 ; 7 :e2319 .24278485 \n8 Agudelo CA Restrepo CA Molina DA \nTuberculosis and histoplasmosis co-infection in AIDS patients . Am J Trop Med Hyg \n2012 ; 87 :1094 –8 .23128292 \n9 Williams B Fojtasek M Connolly-Stringfield P \nDiagnosis of histoplasmosis by antigen detection during an outbreak in Indianapolis, Ind . Arch Pathol Lab Med \n1994 ; 118 :1205 –8 .7979915 \n10 Kaplan JE Benson C Holmes KH \nGuidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America . MMWR Recomm Rep \n2009 ; 58 :1 –207 ; quiz CE201–204 .\n11 Wheat J MaWhinney S Hafner R \nTreatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group . Am J Med \n1997 ; 103 :223 –32 .9316555 \n12 Wheat J Hafner R Korzun AH \nItraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trial Group . Am J Med \n1995 ; 98 :336 –42 .7709945 \n13 Wheat LJ Connolly P Smedema M \nEmergence of resistance to fluconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome . Clin Infect Dis \n2001 ; 33 :1910 –3 .11692303 \n14 Pappas PG Chetchotisakd P Larsen RA \nA phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis . Clin Infect Dis \n2009 ; 48 :1775 –83 .19441980 \n15 Goldman M Zackin R Fichtenbaum CJ \nSafety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy . Clin Infect Dis \n2004 ; 38 :1485 –9 .15156489 \n16 Hay RJ \nMycotic Infections . In: Cook GC Alimuddin IZ , eds. Manson's Tropical Diseases . 22nd ed \nSaunders ; 2009 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "2(1)",
"journal": "Open forum infectious diseases",
"keywords": "AIDS; HIV; developing countries; disseminated progressive histoplasmosis; fluconazole; itraconazole; liposomal amphotericin B; low- and middle-income country; opportunistic infection; resource-limited settings",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofv025",
"pmc": null,
"pmid": "26034774",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article",
"references": "23128292;24278485;15156489;12751258;7709945;9109150;12527630;19441980;9276396;11692303;19357635;11816437;9316555;12028154;7979915",
"title": "Challenges in the management of disseminated progressive histoplasmosis in human immunodeficiency virus-infected patients in resource-limited settings.",
"title_normalized": "challenges in the management of disseminated progressive histoplasmosis in human immunodeficiency virus infected patients in resource limited settings"
} | [
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"abstract": "BACKGROUND\nNeurological manifestations of COVID-19 infection are well recognized. Seizures and status epilepticus (SE) have been reported as possible manifestations and/or complications of SARS-CoV-2 infection at different disease stages, but few data are known about the type, severity, treatment response, and recurrence.\n\n\nMETHODS\nSingle-center retrospective case series.\n\n\nRESULTS\nThis case series describes four COVID-19-positive patients admitted to an Italian University Hospital, who developed status epilepticus during the active phase of disease, independently from the severity of respiratory symptoms. Two of them presented a relapse after resolution of the acute viral infection, a feature that has not been previously reported.\n\n\nCONCLUSIONS\nAlthough a possible association between SE and COVID-19 has been reported, the exact etiopathogenetic mechanism remains still not understood. Our series adds new insights to shed further light on this controversial issue.",
"affiliations": "Neurology Unit, Department of Neurosciences, S. Maria Della Misericordia University Hospital, Piazzale S. Maria della Misericordia, 15, 33100, Udine, Italy. marco.belluzzo@hotmail.com.;Clinical Neurology Unit, Department of Neurosciences, S. Maria Della Misericordia University Hospital, Udine, Italy.;Clinical Neurology Unit, Department of Neurosciences, S. Maria Della Misericordia University Hospital, Udine, Italy.;Clinical Neurology Unit, Department of Neurosciences, S. Maria Della Misericordia University Hospital, Udine, Italy.",
"authors": "Belluzzo|Marco|M|http://orcid.org/0000-0003-2797-5142;Nilo|Annacarmen|A|;Valente|Mariarosaria|M|;Gigli|Gian Luigi|GL|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-021-05536-0",
"fulltext": null,
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"issn_linking": "1590-1874",
"issue": null,
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": "EEG; Epilepsy; Recurrent SE; SARS-CoV-2 infection; Status epilepticus",
"medline_ta": "Neurol Sci",
"mesh_terms": null,
"nlm_unique_id": "100959175",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34398369",
"pubdate": "2021-08-16",
"publication_types": "D016428:Journal Article",
"references": "33709220;32418288;32454137;33860395;33743344;32688169;32422085;32944929;32637987;32944946;33006723;15007130;31326280;26092326",
"title": "New-onset status epilepticus in SARS-CoV-2 infection: a case series.",
"title_normalized": "new onset status epilepticus in sars cov 2 infection a case series"
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"companynumb": "IT-MYLANLABS-2022M1029993",
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"abstract": "Awareness of the need for prevention of glucocorticoid-induced fractures is growing, but glucocorticoid administration is often overlooked as the most common cause of nontraumatic osteonecrosis. Glucocorticoid-induced osteonecrosis develops in 9-40% of patients receiving long-term therapy although it may also occur with short-term exposure to high doses, after intra-articular injection, and without glucocorticoid-induced osteoporosis. The name, osteonecrosis, is misleading because the primary histopathological lesion is osteocyte apoptosis. Apoptotic osteocytes persist because they are anatomically unavailable for phagocytosis and, with glucocorticoid excess, decreased bone remodeling retards their replacement. Glucocorticoid-induced osteocyte apoptosis, a cumulative and unrepairable defect, uniquely disrupts the mechanosensory function of the osteocyte-lacunar-canalicular system and thus starts the inexorable sequence of events leading to collapse of the femoral head. Current evidence indicates that bisphosphonates may rapidly reduce pain, increase ambulation, and delay joint collapse in patients with osteonecrosis.",
"affiliations": "Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA. weinsteinroberts@uams.edu",
"authors": "Weinstein|Robert S|RS|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D050071:Bone Density Conservation Agents; D005938:Glucocorticoids; D003907:Dexamethasone; D019386:Alendronate",
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-011-9580-0",
"fulltext": null,
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"issue": "41(2)",
"journal": "Endocrine",
"keywords": null,
"medline_ta": "Endocrine",
"mesh_terms": "D000328:Adult; D019386:Alendronate; D000818:Animals; D000893:Anti-Inflammatory Agents; D017209:Apoptosis; D050071:Bone Density Conservation Agents; D003907:Dexamethasone; D005938:Glucocorticoids; D006801:Humans; D010011:Osteocytes; D010020:Osteonecrosis",
"nlm_unique_id": "9434444",
"other_id": null,
"pages": "183-90",
"pmc": null,
"pmid": "22169965",
"pubdate": "2012-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D016454:Review",
"references": "15930417;14873721;20047574;10990229;13588963;14774102;11431303;1574093;10946902;7837896;21938549;13702268;16881128;20421485;10562298;4326745;16030164;11289593;19895917;20101428;14691012;16935844;21771887;19802682;9664068;21119943;11181552;13712871;2882300;21732837;21710604;19547906;21557780;20844158;19091998;21493380;21148812;21256699;11956241;20593167;20302963;16203877;15568539;20576660;21602181;3279040;12054173;14381192",
"title": "Glucocorticoid-induced osteonecrosis.",
"title_normalized": "glucocorticoid induced osteonecrosis"
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"companynumb": "GR-VIANEX-20211110",
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"abstract": "Immune check point inhibitors (ICIs) are now increasingly used for cancer therapy. At the same time, by activating the immune system, ICIs induce unique side effects, termed immune-related adverse events (irAEs). Renal irAEs, although uncommon, result in acute tubulointerstitial nephritis. Recently, because of an increase in ICI administration, renal irAEs, including glomerulonephritis, are being increasingly reported. A 69-year-old man presented with nephrotic syndrome after use of the ICI nivolumab. He underwent renal biopsy and was diagnosed with membranous nephropathy (MN) without acute tubulointerstitial nephritis. Immunofluorescence staining was negative for IgG4 and phospholipase A2 receptor (PLA2R), suggesting a malignancy-associated pattern. Oral glucocorticoid therapy was started as the standard treatment for irAEs, which resulted in complete remission of the nephrotic syndrome in 20 months. We suggest his MN was induced or accelerated by immune activation due to nivolumab. It means that ICIs possibly induce not only acute tubulointerstitial nephritis but also nephrotic syndrome due to MN as renal irAEs which is treatable with glucocorticoid.",
"affiliations": "Department of Nephrology, Osaka University Hospital, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan.;Department of Internal Medicine, Division of Nephrology, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Toyonaka, Osaka, 560-8565, Japan.;Department of Diagnostic Pathology, Kobe City Medical Center General Hospital, 2-1-1, Minamimachi, Minatojima, Chuo Ward, Kobe, Hyogo, 650-0047, Japan.;Department of Internal Medicine, Division of Nephrology, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Toyonaka, Osaka, 560-8565, Japan.;Department of Internal Medicine, Division of Nephrology, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Toyonaka, Osaka, 560-8565, Japan.;Department of Internal Medicine, Division of Nephrology, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Toyonaka, Osaka, 560-8565, Japan.;Department of Internal Medicine, Division of Nephrology, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Toyonaka, Osaka, 560-8565, Japan.;Department of Internal Medicine, Division of Nephrology, Toyonaka Municipal Hospital, 4-14-1 Shibahara-cho, Toyonaka, Osaka, 560-8565, Japan. mtakeji@zeus.eonet.ne.jp.",
"authors": "Wakabayashi|Keiko|K|;Yamamoto|Satoko|S|;Hara|Shigeo|S|;Okawara|Momoko|M|;Teramoto|Kumie|K|;Ikeda|Natsuko|N|;Kusunoki|Yasuo|Y|;Takeji|Masanobu|M|http://orcid.org/0000-0002-3813-9484",
"chemical_list": null,
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"journal": "CEN case reports",
"keywords": "IgG subclass; Immune check point inhibitors (ICIs); Immune-related adverse events (irAEs); Membranous nephropathy (MN); Nephrotic syndrome; Nivolumab; Phospholipase A2 receptor (PLA2R)",
"medline_ta": "CEN Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101636244",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34524642",
"pubdate": "2021-09-15",
"publication_types": "D016428:Journal Article",
"references": "33243934;32257470;28781794",
"title": "Nivolumab-induced membranous nephropathy in a patient with stage IV lung adenocarcinoma.",
"title_normalized": "nivolumab induced membranous nephropathy in a patient with stage iv lung adenocarcinoma"
} | [
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"companynumb": "JP-PFIZER INC-202200780381",
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{
"abstract": "Negative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation. Although atypical antipsychotics have been associated with higher efficacy on negative symptoms than typical agents, not all of them are equally effective. Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several adverse events (e.g., extrapyramidal symptoms or hyperprolactinemia), and also for increasing this drug's efficacy over negative symptoms. This case series presents three young adults with predominantly negative symptoms during treatment with an atypical antipsychotic, administered in stable dose within the therapeutic range, and for at least 4 weeks prior to the cariprazine switch. These patients (two male and one female, mean age 35.7 years) were diagnosed with schizophrenia, according to the DSM-5 criteria. They were evaluated using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and Global Assessment of Functioning (GAF). Their mean initial values were 80.3 on PANSS, 4.3 on CGI-S, and 48 on GAF. All these patients were already on a treatment with stable doses of atypical antipsychotics (olanzapine 10 mg/day, n = 1, risperidone 6 mg/day, n = 1, and quetiapine 600 mg/day, n = 1). Cross-titration to cariprazine was initiated, from 1.5 mg qd up to 6 mg qd, during a mean period of 2.7 weeks. After 12 weeks of cariprazine 6 mg/day, the positive scale of PANSS was relatively stable compared to baseline, while the negative mean score decreased by 22%. Also, the mean CGI-S improvement was 15.4% and the GAF mean score increased by 17%. The overall tolerability was good, without severe adverse events being reported. Conclusions: Cariprazine is well tolerated and efficient for patients diagnosed with schizophrenia who have significant negative symptoms that impair daily functioning. After 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression.",
"affiliations": "Department of Psychiatry, Dr. Carol Davila University Emergency Central Military Hospital, Bucharest, Romania.",
"authors": "Vasiliu|Octavian|O|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fpsyt.2021.786171",
"fulltext": "\n==== Front\nFront Psychiatry\nFront Psychiatry\nFront. Psychiatry\nFrontiers in Psychiatry\n1664-0640\nFrontiers Media S.A.\n\n10.3389/fpsyt.2021.786171\nPsychiatry\nCase Report\nCase Report: Cariprazine Efficacy in Young Patients Diagnosed With Schizophrenia With Predominantly Negative Symptoms\nVasiliu Octavian *\n\nDepartment of Psychiatry, Dr. Carol Davila University Emergency Central Military Hospital, Bucharest, Romania\nEdited by: György Németh, Gedeon Richter, Hungary\n\nReviewed by: Uma Suryadevara, University of Florida, United States; Georgios Demetrios Kotzalidis, Sapienza University of Rome, Italy\n\n*Correspondence: Octavian Vasiliu octavvasiliu@yahoo.com\nThis article was submitted to Psychopharmacology, a section of the journal Frontiers in Psychiatry\n\n22 11 2021\n2021\n12 78617129 9 2021\n22 10 2021\nCopyright © 2021 Vasiliu.\n2021\nVasiliu\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nNegative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation. Although atypical antipsychotics have been associated with higher efficacy on negative symptoms than typical agents, not all of them are equally effective. Cariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several adverse events (e.g., extrapyramidal symptoms or hyperprolactinemia), and also for increasing this drug's efficacy over negative symptoms. This case series presents three young adults with predominantly negative symptoms during treatment with an atypical antipsychotic, administered in stable dose within the therapeutic range, and for at least 4 weeks prior to the cariprazine switch. These patients (two male and one female, mean age 35.7 years) were diagnosed with schizophrenia, according to the DSM-5 criteria. They were evaluated using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), and Global Assessment of Functioning (GAF). Their mean initial values were 80.3 on PANSS, 4.3 on CGI-S, and 48 on GAF. All these patients were already on a treatment with stable doses of atypical antipsychotics (olanzapine 10 mg/day, n = 1, risperidone 6 mg/day, n = 1, and quetiapine 600 mg/day, n = 1). Cross-titration to cariprazine was initiated, from 1.5 mg qd up to 6 mg qd, during a mean period of 2.7 weeks. After 12 weeks of cariprazine 6 mg/day, the positive scale of PANSS was relatively stable compared to baseline, while the negative mean score decreased by 22%. Also, the mean CGI-S improvement was 15.4% and the GAF mean score increased by 17%. The overall tolerability was good, without severe adverse events being reported. Conclusions: Cariprazine is well tolerated and efficient for patients diagnosed with schizophrenia who have significant negative symptoms that impair daily functioning. After 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression.\n\nnovel atypical antipsychotics\nnegative symptoms\nschizophrenia\ncariprazine\ntolerability\nquality of life\nsocial reintegration\n==== Body\npmcIntroduction\n\nNegative symptoms of schizophrenia are among the most invalidating clinical manifestations of this disorder, and they are correlated with poorer prognosis, lower quality of life, and fewer chances for successful social reintegration and professional rehabilitation (1–3). Targeting negative symptoms (e.g., apathy, alogia, flat affect) can lead to significant improvements of daily functional and quality of life (4). Although atypical antipsychotics have been associated with higher efficacy over the negative symptoms than typical agents, not all the atypicals are equally effective. According to a meta-analysis of placebo-controlled and head-to-head randomized controlled trials (n = 402 studies, N = 53,463 participants) that compared 32 antipsychotics, only clozapine, amisulpride, olanzapine, and, to a lesser degree, zotepine and risperidone decreased negative symptoms severity more than other agents, while the differences between the remaining drugs were less supported by evidence (5). An important problem that may lead to uncertainty in the interpretation of negative symptoms improvement in clinical trials is represented by lack of discrimination using standard measurements between primary and secondary negative symptoms (6). Therefore, the clinician should address this problem during the psychiatric interview, and to take into account any other sources of information available (medical personnel, family members or other caregivers), in order to differentiate between primary and secondary negative symptoms. This is not of scholastic importance, but it has practical utility, due to the different treatment approaches for the two groups of symptoms.\n\nCariprazine is a new D3 and D2 receptor partial agonist, and its high D3 affinity may be useful for decreasing several dopamine-related adverse events, and, in the same time, for increasing this drug's efficacy over negative symptoms (7). The efficacy and safety of cariprazine have been demonstrated in adults with schizophrenia during four short-term randomized, double-blind, placebo-controlled trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study vs. the active comparator risperidone (8). Post-hoc analyses supported efficacy of cariprazine across individual symptoms and domains of schizophrenia, and in areas like cognition, functioning, negative symptoms, hostility, and global well-being (8).\n\nCariprazine was generally well tolerated in clinical trials in patients with schizophrenia, and the most frequently reported adverse events were of mild to moderate severity (7). Cariprazine may reduce side effects when switching a patient from other antipsychotic because of its lower anticholinergic, anti-adrenergic, antihistaminergic, and metabolic effects, with a better cardiovascular safety profile (9, 10).\n\nIn a multicentric, randomized, double-blind, phase 3b trial (N = 533 patients with predominant negative symptoms), cariprazine (3–6 mg/day) was superior to risperidone (3–6 mg/day) in leading to significant greater least squares mean change in Positive and Negative Syndrome Scale- factor score for negative symptoms (PANSS-FSNS) after 26 weeks of treatment (11). This trial was well-controlled for secondary negative symptoms, but it was sponsored by the manufacturer of cariprazine (6, 11).\n\nAccording to the recommendations from an International Panel for the management of schizophrenia, cariprazine is useful in patients with first episode of psychosis, predominant negative symptoms (maintenance/acute phase) and significant side effects (e.g., metabolic syndrome, sedation, hyperprolactinemia) with onset during the administration of other antipsychotics (9). If the weight is placed on the long-term efficacy and tolerability, cariprazine may become one of the first-line medications in schizophrenia, not only for prominent negative symptoms, but also for relatively severe positive symptoms (9). An overlap of at least 2–3 weeks is usually recommended in clinical practice when switching from other antipsychotics to cariprazine, in order to avoid a dopaminergic, antihistaminergic and/or muscarinic rebound (9).\n\nThis case series presents three young adults with persistent negative symptoms during treatment with an atypical antipsychotic, administered in stable doses within the therapeutic range and for at least 4 weeks, prior to the cariprazine switch.\n\nCase Presentation\n\nThe first patient was a male, diagnosed with schizophrenia according to the DSM-5 criteria, age 37.5, who received treatment for the last 6 weeks prior to baseline with risperidone 6 mg daily. He was evaluated because of persistent negative symptoms, consisting mainly of anhedonia, alogia and avolition. This patient had a history of schizophrenia of more than 5 years, and received in the past olanzapine (10 mg qd, for almost 2 years) and amisulpride (800 mg daily, for 2 years), to which he responded partially, because several negative symptoms were still present. The patient accused tolerability issues, namely sedation to olanzapine, and extrapyramidal symptoms to amisulpride. The initial psychiatric examination detected residual positive symptoms- ideas of reference, mild suspiciousness and conceptual disorganization, as well as general symptoms- anxiety, insomnia, social withdrawal, poor attention and low memory performances. This patient had no family history of psychiatric disorder and no somatic comorbidity could be identified during the initial visit.\n\nThe first evaluation detected a total PANSS score of 80, with a negative scale score of 32, a CGI-S (Clinical Global Impression- Severity) value of 4 and a GAF (Global Assessment of Functioning) score of 52. Cariprazine was initiated based on this antipsychotic pharmacodynamics profile and its presumed efficacy over the negative symptoms. Risperidone was gradually tapered off, while cariprazine was initiated with 1.5 mg and titrated up to 6 mg qd, during a period of 15 days. No incident was reported during the cross-over period.\n\nAfter 12 weeks of stable dose, the PANSS total score decreased to 66, with the negative scale showing a value of 26, the CGI-S score remained stable, and the GAF score increased to 60. The positive PANSS score decreased minimally, from 21 to 19. This patient reported no adverse events during the 12 weeks of the 6 mg qd cariprazine regimen.\n\nThe second patient was a male, age 33.5, diagnosed with schizophrenia for 11 years, who received treatment with olanzapine 10 mg qd for the last 8 weeks. He was previously on treatment with risperidone 8 mg/day for multiple periods of 6–12 months, interrupted by lack of adherence. Also, the patient received treatment with risperidone microspheres, up to 50 mg every 2 weeks, but after more than 1 year he declined the need for any injectable treatment and was switched back on oral medication. This patient had a family history of psychiatric disorder, as his father also had schizophrenia. No somatic comorbidity could be identified during the initial visit.\n\nDuring the initial psychiatric evaluation this patient presented with fragmentary persecutory delusions without significant behavioral impact and prominent negative symptoms, especially flat affect, avolition, and anhedonia. His baseline PANSS total score was 78, with negative subscale score of 29, positive subscale score of 18, CGI-S score of 4, and GAF score=44. Olanzapine was gradually tapered off, while cariprazine was slowly titrated up to 6 mg qd, during 20 days. No clinical signs of positive or negative symptoms worsening was reported during the titration period.\n\nAfter 12 weeks of cariprazine administered 6 mg qd, the PANSS total score decreased to 62, with the negative scale showing a value of 22, and the positive scale a value of 16. The CGI-S score decreased to three, while the GAF score improved by eight points, reaching a value of 52.\n\nThe third patient was a female, age 36, diagnosed with schizophrenia for 6 years, and she received treatment with quetiapine 600 mg qd for the last month. This patient had no family history of psychiatric disorder and no somatic disease could be identified during the initial visit. She had a personal history of multiple antipsychotics prior to the baseline treatment, including typical (haloperidol, zuclopentixol) and atypical (olanzapine, ziprasidone) agents. Her response to quetiapine was initially good, because it alleviated insomnia and anxiety, but the impact over the negative symptoms was less significant. Therefore, she was switched on cariprazine, starting from 1.5 mg, up to 6 mg qd, during a period of 22 days.\n\nThe initial psychiatric evaluation detected mainly negative symptoms, consisting of anhedonia, flat affect, avolition, low attention and memory performances. Her baseline PANSS total score was 83, with negative subscale score of 35 and positive subscale score of 23, CGI-S=5, and GAF=57. After 12 weeks of cariprazine stable dose treatment, PANSS total score decreased to 65, with negative score reaching a value of 27, while the positive score was relatively stable (22, final visit score). The CGI-S score at endpoint was 4, and the GAF improved to 60.\n\nAll these patients were screened for psychiatric comorbidities at baseline using Mini-International Neuropsychiatric Interview (MINI), but no specific diagnoses were detected except for schizophrenia. None of them required hospitalization during their switch and up to the final visit. Cross-titration to cariprazine was well tolerated in all cases, and all the other antipsychotics were tapered slowly in order to avoid antihistaminergic/antidopaminergic rebound. After 12 weeks of cariprazine 6 mg/day, the positive subscale of PANSS showed a relatively stable level, but the negative subscale mean score decreased with 22% (Figure 1). The overall PANSS mean score decreased by 19.5% (Figure 2), the CGI-S mean scores improved by 15.4% (Figure 3), while the mean GAF scores increased by 17%. The overall results are presented in Table 1. No severe adverse events was reported throughout the monitoring period.\n\nFigure 1 Evolution of the PANSS negative subscale scores during cariprazine treatment.\n\nFigure 2 Evolution of the PANSS total scores during cariprazine treatment.\n\nFigure 3 Evolution of the CGI-S scores during cariprazine treatment.\n\nTable 1 The results of the cariprazine switch during 12 weeks of monitoring.\n\n\tPatient 1\tPatient 2\tPatient 3\t\nPrevious medication, dosage, and duration of its administration\tRisperidone, 6 mg/day, 6 weeks\tOlanzapine, 10 mg/day, 8 weeks\tQuetiapine 600 mg/day, 4 weeks\t\nSwitch to cariprazine duration\t15 days\t20 days\t22 days\t\nPANSS total score- initial visit\t80\t78\t83\t\nPANSS total score- final visit\t66\t62\t65\t\nPANSS Negative scale score- initial visit\t32\t29\t35\t\nPANSS Negative scale score- final visit\t26\t22\t27\t\nPANSS Positive scale score- initial visit\t21\t18\t23\t\nPANSS positive scale score- final visit\t19\t16\t22\t\nCGI-S initial score\t4\t4\t5\t\nCGI-S final score\t4\t3\t4\t\nGAF initial score\t52\t44\t57\t\nGAF final score\t60\t52\t60\t\nSelf-reported/clinician-detected severe adverse events throughout the monitoring period\tNone\tNone\tNone\t\n\nDiscussion\n\nThese patients presented a relatively long history of schizophrenia, between 2 and 11 years (mean value 6.3 years), although their mean age was 35.7 years. They all received multiple treatments before the initiation of cariprazine and presented negative symptoms under their current antipsychotic (olanzapine, quetiapine, or risperidone). Cariprazine is a distinctive antipsychotic agent due to its D3-preferential dopamine partial agonism, which make it preferable for patients with prominent negative symptoms. Patients tolerated well the antipsychotic switch from various antipsychotics to cariprazine. In this case series, after 12 weeks cariprazine succeeded in improving negative symptoms, global functioning, and clinical global impression. The positive symptoms were quite stable, but their low level of severity at baseline may have precluded the observation of a therapeutic effect.\n\nRegarding the limitations of this case series, it must be taken into account the short period of monitoring, which may have prevented the observation of other, long-term, treament effects. Also, variables related to the antipsychotic's adverse events were not monitored in a structured manner, as we only collected patients' reports about tolerability and data from clinical exams during each visit. It is also important to mention that patients included in this case series were relatively stable, based on their initial PANSS, GAF, and CGI-S scores, without severe positive or behavioral symptoms and they did not require hospitalization.\n\nPatient Perspective\n\n“I was unable to take care of myself because I had no energy. No interest, either. And I was feeling scared or even frightened. I feel now I can go outside if I have to do something. I feel less blocked from within” (Patient number 1).\n\n“I feel less tension inside me now than before. My thoughts are more synchronized with what I do… I can watch a TV movie, which I couldn't do before because I was sort of numb” (Patient number 2).\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nThe author confirms being the sole contributor of this work and has approved it for publication.\n\nConflict of Interest\n\nThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n==== Refs\nReferences\n\n1. Correll CU Schoolder NR . Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat. (2020) 16 :519–34. 10.2147/NDT.S225643 32110026\n2. Foussias G Remington G . Negative symptoms in schizophrenia: avolition and occam's razor. Schizophr Bull. (2010) 36 :359–69. 10.1093/schbul/sbn094 18644851\n3. Vasiliu O Vasile D Făinărea AF . Analysis of risk factors for antipsychotic-resistant schizophrenia in young patients- a retrospective analysis. Rom J Military Med. (2018) CXXI:25–9.\n4. Remington G Foussias G Fervaha G Agid O Takeuchi H Lee J . Treating negative symptoms in schizophrenia : an Update. Curr Treat Options Psychiatry. (2016) 3 :133–50. 10.1007/s40501-016-0075-8 27376016\n5. Huhn M Nikolakopoulou A Schneider-Thoma S Krause M Samara M Peter N . Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. (2019) 394 :939–51. 10.1016/S0140-6736(19)31135-3 31303314\n6. Krause M Zhu Y Huhn M Schneider-Thoma J Bighelli I Nikolakopoulou A . Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci. (2018) 268 :625–39. 10.1007/s00406-018-0869-3 29368205\n7. Garnock-Jones KP . Cariprazine: a review in schizophrenia. CNS Drugs. (2017) 31 :513–25. 10.1007/s40263-017-0442-z 28560619\n8. Laszlovsky I Barabassy A Nemeth G . Cariprazine, a broad-spectrum antipsychotic for the treatment of schizophrenia: pharmacology, efficacy, and safety. Adv Ther. (2021) 38 :3652–6373. 10.1007/s12325-021-01797-5 34091867\n9. Fagiolini A Alcala JA Aubel T Bienkiewicz W Bogren MMK Gago J . Treating schizophrenia with cariprazine: from clinical research to clinical practice. Real world experiences and recommendations from an International Panel. Ann Gen Psychiatry. (2020) 19 :55. 10.1186/s12991-020-00305-3 32999683\n10. Nasrallah HA Earley W Cutler AJ Wang Y Lu K Laszlovszky I . The safety and tolerability of cariprazine in long-term treatment of schizophrenia : a post-hoc pooled analysis. BMC Psychiatry. (2017) 17 :305. 10.1186/s12888-017-1459-z 28836957\n11. Nemeth G Laszolovsky I Czobor P Szalai E Szatmári B Harsányi J . Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomized, double-blind, controlled trial. Lancet. (2017) 389 :1103–13. 10.1016/S0140-6736(17)30060-0 28185672\n\n",
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"keywords": "cariprazine; negative symptoms; novel atypical antipsychotics; quality of life; schizophrenia; social reintegration; tolerability",
"medline_ta": "Front Psychiatry",
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"title": "Case Report: Cariprazine Efficacy in Young Patients Diagnosed With Schizophrenia With Predominantly Negative Symptoms.",
"title_normalized": "case report cariprazine efficacy in young patients diagnosed with schizophrenia with predominantly negative symptoms"
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"abstract": "METHODS\nAn otherwise healthy 25-year-old patient with heavy cannabis-abuse suffered from an undiagnosed cannabis hyperemesis syndrome (CHS) over years, which characteristically was resistant to usual antiemetics. In an apparently last attempt at healing, opiates (morphine, methadone) were administrated and improved the CHS, however, this led to an at least as equally distressing and painful opiate withdrawal syndrome.\n\n\nMETHODS\nIn the controlled cannabis abstinence during the 2-week inpatient treatment of opiate addiction syndrome the CHS has not recurred.\n\n\nCONCLUSIONS\nOpiates are not suited for the treatment of CHS because they are addictive and lead to respiratory depression in overdose.",
"affiliations": "Klinik für Psychiatrie, Psychotherapie und Psychosomatik, Evangelisches Krankenhaus Castrop-Rauxel, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen.;Klinik für Psychiatrie, Psychotherapie und Psychosomatik, Evangelisches Krankenhaus Castrop-Rauxel, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen.;Klinik für Psychiatrie, Psychotherapie und Psychosomatik, Evangelisches Krankenhaus Castrop-Rauxel, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen.",
"authors": "Bonnet|U|U|;Stratmann|U|U|;Isbruch|K|K|",
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"mesh_terms": "D000328:Adult; D000932:Antiemetics; D013759:Dronabinol; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005858:Germany; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D002189:Marijuana Abuse; D008691:Methadone; D009020:Morphine; D009293:Opioid-Related Disorders; D016320:Substance Abuse Treatment Centers; D013375:Substance Withdrawal Syndrome; D014839:Vomiting",
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"title": "No opiates against cannabis hyperemesis syndrome.",
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"abstract": "OBJECTIVE\nTo determine functional connectivity of the default mode network in patients with sensorineural hearing loss (SNHL) in resting state.\n\n\nMETHODS\nThe posterior cingulate cortex was selected as a seed for assessment of functional connectivity of the activated brain areas in resting state by using a seed-based correlation analysis of the resting state functional magnetic resonance imaging (fMRI) data.\n\n\nRESULTS\nThe fMRI results demonstrated that, the healthy volunteers and the patients with NSHL shared certain activated brain areas with positive functional connectivity with region of interest (ROI). However, the healthy volunteers also had positive functional connectivity with ROI in bilateral middle temporal gyrus, left anterior cingulate cortex, right inferior parietal lobule and left medial superior frontal gyrus. While the patients with SNHL did with bilateral inferior parietal lobule, left medial superior frontal gyrus, right supramarginal gyrus, and left middle temporal gyrus. Compared to controls, patients with SNHL showed increased functional connectivity in the right posterior frontal lobe, right precentral gyrus, right supramarginal gyrus and left posterior cingulate cortex, and had decreased functional connectivity in the left lingual gyrus, right cuneus lobe and right superior frontal gyrus.\n\n\nCONCLUSIONS\nThe posterior cingulate cortex, precuneus lobe, medial frontal gyrus, anterior cingulate cortex, temporal lobe, angular gyrus and inferior parietal lobule constitute a default mode of network in normal resting status. And patients with SNHL have abnormal functional connectivity of default mode network and cortical reorganisation in resting status.",
"affiliations": "Department of Radiology, Second Hospital of Hebei Medical University Shijiazhuang, China ; Department of Radiology, Hebei Armed Police Hospital Shijiazhuang, China.;Department of Radiology, Second Hospital of Hebei Medical University Shijiazhuang, China.;Department of Radiology, Second Hospital of Hebei Medical University Shijiazhuang, China.;Department of Radiology, Second Hospital of Hebei Medical University Shijiazhuang, China.;Department of Radiology, Second Hospital of Hebei Medical University Shijiazhuang, China.;Department of Radiology, Second Hospital of Hebei Medical University Shijiazhuang, China.",
"authors": "Li|Zhengliang|Z|;Zhu|Qingfeng|Q|;Geng|Zuojun|Z|;Song|Zhenhu|Z|;Wang|Lixin|L|;Wang|Ya|Y|",
"chemical_list": null,
"country": "United States",
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"issue": "8(1)",
"journal": "International journal of clinical and experimental medicine",
"keywords": "Resting-status; functional connectivity; functional magnetic resonance imaging; sensorineural hearing loss",
"medline_ta": "Int J Clin Exp Med",
"mesh_terms": null,
"nlm_unique_id": "101471010",
"other_id": null,
"pages": "569-78",
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"references": "10504190;12960757;21493243;18372048;20083773;15110032;15350243;7535489;11459765;10808145;9448260;10718312;17533167;11756728;9882090;4038669;9740361;11069306;1000279;16996009;11584306;20057496;15770152;11209064;2660775;5545728;12506194;11788197;12355013",
"title": "Study of functional connectivity in patients with sensorineural hearing loss by using resting-state fMRI.",
"title_normalized": "study of functional connectivity in patients with sensorineural hearing loss by using resting state fmri"
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"abstract": "We report the case of a 65-year-old Coronavirus disease 2019 (COVID-19) patient with pneumonia and subsequent end-stage pulmonary failure who required 63 days of mechanical ventilation (MV) and 62 days of extracorporeal membrane oxygenation (ECMO).\n\n\n\nOn Day 45, a comprehensive interdisciplinary discussion on the best course of treatment resulted in the general consensus that his lungs would not recover. As such, he was evaluated and listed for a lung transplant.\n\n\n\nWe performed a bilateral lung transplant, and the patient was weaned off ECMO and MV postoperatively. This is the first report of lung transplants in patients with COVID-19 in Wuhan.\n\n\n\nWe suggest that a lung transplantation may be a viable treatment for patients with end-stage pulmonary failure secondary to COVID-19 in selected situations.",
"affiliations": "Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.;Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.;Department of Cardiothoracic Surgery, Queen Mary Hospital, Hong Kong, China.;Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu, China.;Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China.",
"authors": "Wang|Bo|B|0000-0001-6520-6809;Huang|Jie|J|;Hsin|Micheal|M|;Chen|Jingyu|J|;Lin|Huiqing|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/iid3.501",
"fulltext": "\n==== Front\nImmun Inflamm Dis\nImmun Inflamm Dis\n10.1002/(ISSN)2050-4527\nIID3\nImmunity, Inflammation and Disease\n2050-4527\nJohn Wiley and Sons Inc. Hoboken\n\n34469048\n10.1002/iid3.501\nIID3501\nOriginal Article\nOriginal Articles\nFirst lung transplant in Wuhan for a critical and elderly COVID‐19 patient\nWANG et al.\nWang Bo http://orcid.org/0000-0001-6520-6809\n1\nHuang Jie 1\nHsin Micheal 2\nChen Jingyu 3 chenjy@wuxiph.com\n\nLin Huiqing 1 huiqing.lin@whu.edu.cn\n\n1 Department of Thoracic Surgery Renmin Hospital of Wuhan University Wuhan Hubei Province China\n2 Department of Cardiothoracic Surgery Queen Mary Hospital Hong Kong China\n3 Wuxi Lung Transplant Center Wuxi People's Hospital Affiliated to Nanjing Medical University Wuxi Jiangsu China\n* Correspondence Huiqing Lin, Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China.\nEmail: huiqing.lin@whu.edu.cn\nJingyu Chen, Wuxi Lung Transplant Center, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, Jiangsu 214023, China.\nEmail: chenjy@wuxiph.com\n\n01 9 2021\n12 2021\n9 4 10.1002/iid3.v9.4 15001507\n25 6 2021\n18 2 2021\n22 7 2021\n© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nIntroduction\n\nWe report the case of a 65‐year‐old Coronavirus disease 2019 (COVID‐19) patient with pneumonia and subsequent end‐stage pulmonary failure who required 63 days of mechanical ventilation (MV) and 62 days of extracorporeal membrane oxygenation (ECMO).\n\nMethods\n\nOn Day 45, a comprehensive interdisciplinary discussion on the best course of treatment resulted in the general consensus that his lungs would not recover. As such, he was evaluated and listed for a lung transplant.\n\nResults\n\nWe performed a bilateral lung transplant, and the patient was weaned off ECMO and MV postoperatively. This is the first report of lung transplants in patients with COVID‐19 in Wuhan.\n\nConclusions\n\nWe suggest that a lung transplantation may be a viable treatment for patients with end‐stage pulmonary failure secondary to COVID‐19 in selected situations.\n\nLung transplantation provided an opportunity for this very severe selected patient a chance to survival, which is meaningful\n\nCOVID‐19\nlung transplant\npulmonary failure\nChina Organ Transplantation Development Foundation2020HX0011 National Natural Science Foundation of China 10.13039/501100001809 81800343 source-schema-version-number2.0\ncover-dateDecember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:12.11.2021\nWang B , Huang J , Hsin M , Chen J , Lin H. . First lung transplant in Wuhan for a critical and elderly COVID‐19 patient. Immun Inflamm Dis. 2021;9 :1500‐1507. 10.1002/iid3.501\n\nBo Wang and Jie Huang are cofirst authors.\n\nHuiqing Lin and Jingyu Chen contributed equally to this study.\n==== Body\npmc1 INTRODUCTION\n\nOn December 31, 2019, the World Health Organization (WHO) China Country Office was informed about cases of pneumonia of unknown etiology detected in Wuhan, the capital city of the Hubei province in China. Wuhan became the center of a pneumonia outbreak of unknown origin. 1 In 2020, a pandemic novel coronavirus (2019‐nCoV) outbreak was declared by the WHO. During the first 2 months of the outbreak, 67 (6.1%) of 1099 patients with laboratory‐confirmed Coronavirus disease 2019 (COVID‐19) from 552 hospitals in 30 provinces in China were critically ill. Of this, 5.0% were admitted to the intensive care unit (ICU), 2.3% underwent invasive mechanical ventilation (MV), and 1.4% died. 2 The complications of COVID‐19 are primarily manifested in the respiratory system culminating with end‐stage pulmonary failure and patients with end‐stage COVID‐19 have a higher risk of complications. 3 Lung transplantation (LT) is an established treatment for end‐stage pulmonary failure. However, little is known about LT in cases of virus‐related diseases such as COVID‐19. Furthermore, bilateral LT in patients with end‐stage COVID‐19 disease has been reported in only a few anecdotal case. Herein, we report the case of a successful bilateral LT in a COVID‐19 patient with end‐stage pulmonary failure. The patient was on life support, namely, MV for 63 days and extracorporeal membrane oxygenation (ECMO) for 62 days before transplantation. We hope this report provides useful information regarding the management of elderly patients with COVID‐19 who are deemed to be in a critical condition.\n\n2 CASE REPORT\n\nA 65‐year‐old male who presented with a high temperature for 9 days and was admitted to his local hospital on February 1, 2020. A nasal swab specimen tested positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) nucleic acid, and chest computed tomography (CT) revealed bilateral consolidation and ground‐glass opacities. His symptoms and radiographic manifestations worsened despite antiviral treatment with oral oseltamivir, intravenous cefuroxime, and proprietary Chinese medicine. He was transferred to a COVID‐19 designated hospital on February 7 for further treatment. On February 16, he was admitted to the intensive care unit (ICU) for noninvasive respiratory support, which was escalated to MV on February 17. Venovenous (VV)‐ECMO support commenced on February 18. The patient was transferred to our hospital on March 18 for comprehensive treatment. From March 18 to April 9, his diagnoses included sepsis, coagulation disorders, gastrointestinal bleeding, pneumothorax, and hemothorax. Coagulation disorders were corrected with intravenous blood products and, somatostatin, and pleural complications were treated with tube thoracostomy chest. On March 20, the patient was diagnosed with septic shock due to carbapenem‐resistant Acinetobacter baumannii (CRAB). Following antiviral, anti‐infective, immunosupportive, and life support therapy, produced five consecutive negative results for nucleic acid detection by the reverse transcriptase polymerase chain reaction (RT‐PCR) test for SARS‐CoV‐2, and three results of negative Immunoglobulin (Ig)M and positive IgG antibodies since February 28. Despite these efforts, his pulmonary function continued to deteriorate. The lung volume was only 220 ml and the static compliance 13 ml/cmH2O. As such, we judged that the patient could not be weaned off VV‐ECMO and MV despite prolonged support. Following a discussion among professionals from multidisciplinary teams at the hospital, it was concluded that a LT should be considered. After we told the outcome of our discussion to the patient and his family, they requested aggressive treatment. The case was approved by the ethics committee of the Renmin Hospital of Wuhan University and the patient was registered with the China Organ Transplant Response System (COTRS).\n\nAfter 2 weeks on the waiting list, a suitable donor was allocated by Chinese Donor Allocation System COTAS with the following characteristics: 32‐year‐old male; weight, 58 kg; height, 167 cm; matching blood type; clear chest radiograph; no history of smoking, malignancy; and PaO2/FiO2 ratio of 578 mmHg. Left LT was performed first with an ischemic time of 7.5 h followed by right LT with an ischemic time of 10 h. When suitable donor lungs became available, surgeons performed a clamshell thoracotomy for bilateral sequential LT. The incision connected the bilateral anterolateral thoracotomy incisions across the midline by dividing the sternum. The bilateral thoracic cavity contained approximately 1000 ml of yellow pleural effusion. Both mammary arteries are divided in this approach, and this incision provides added exposure during a concomitant cardiac procedure. A prior CT scan indicated that the right lung function was better than the left. Therefore, the left single LT was performed first via a standard procedure. After blocking the left main pulmonary artery before resecting the left lung, the heart rate and blood pressure decreased suddenly. The patient developed hemodynamic instability following occlusion of the left pulmonary artery, and central VA‐ECMO was established. We then instituted venoarterial (VA)‐ECMO (3 L/min) via an ascending aortic cannula (21F) and a single‐stage cannula in the right atrium, and downregulated the VV‐ECMO to 1.5 L/min. We administered 500 mg methylprednisolone before opening the pulmonary artery. The left donor lung expanded well without obvious edema. The surgeons proceeded to right pneumonectomy and implantation of the second donor lung. Right LT was performed via a standard procedure. On the left LT, perform the bronchial anastomosis with a 4‐0 polydioxanone running suture. Cover the anastomosis with local pericardial and parabronchial connective tissues. Next, anastomose the pulmonary artery using a running suture of 5‐0 polypropylene (Prolene). Take care to ensure that this graft is not too long or twisted. Retract the two tied pulmonary veins away from the heart, and place the Satinsky clamp at the base of the pulmonary veins. The postoperative blood pressure and heart rate were stable. The cold ischemia time for the left and right lung were 7.5 and 10 h, respectively. On gross inspection, the native lungs had alternating areas of black, gray, and dark red discoloration, and were firm on palpation (Figure 1A, B). The patient was weaned off VA‐ECMO support at the end of the procedure, and the VV‐ECMO support was retained while the patient was transferred to the ICU. The VV‐ECMO was successfully weaned off 44 h postoperatively. Propofol and sufentanil were administered postoperatively to maintain the Richmond Agitation‐Sedation Scale (RASS) score from −3 to −2 as the patient was cannulated with ECMO, an endotracheal tube, a central line, and a Foley catheter. After the patient was weaned off ECMO, sedation with propofol and sufentanil was gradually reduced and dexmedetomidine was used to maintain the RASS score from −1 to 0 to facilitate early rehabilitation. The patient was diagnosed with Acinetobacter baumannii bacteremia in the early postoperative stage. He then contracted Pseudomonas aeruginosa and subsequently Klebsiella isolated from bronchoalveolar lavage (BAL) fluid. With each infection, the causative pathogens were detected, by appropriate laboratory testing, bacterial susceptibility tests were performed promptly, and the anti‐infective treatment adjusted accordingly. We closely monitored procalcitonin (PCT), C‐reactive protein, body temperature, and other infection markers daily.\n\nFigure 1 Gross and hematoxylin‐eosin staining photos of patients. Resected left (A) and right (B) lungs of the patient. (C, D) Pathological manifestations of lung tissue in the patient with severe pneumonia caused by SARS‐CoV‐2. Diffuse Alveoli collapses and fibrosis were showed in figures C and D (H&E ×100). The septa of the remained alveoli were slightly thickened with inflammatory cells and fibroblasts, and marked fibrin exudation (at the left upper margin) was observed in figure C. Fibrin exudatation could also be observed in the right upper field of figure D. H&E, hematoxylin‐eosin stain; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2\n\nThe patient was extubated on the 16th day after the LT. The pre‐ and posttransplant chest CT scans are shown in Figure 2. The patient was placed on a immunosuppression protocol of cyclosporin and prednisone. He started to receive a double regimen on the day before surgery (tacrolimus 0.1 mg/kg po bid), and prednisone (0.5 mg/kg po qd, tapering down by 5 mg/week to 0.25 mg/kg/day). The postoperative chest CT revealed clear lung fields with no infiltrates.\n\nFigure 2 Chest CT and X‐ray image of patients. (A, B) The patient's chest CT before lung transplantation. (C, D) The patient's chest X‐ray on the fifth day after lung transplantation. CT, computed tomography\n\nA rehabilitation program that included neuromuscular electrical stimulation, proprioceptive stimulation, joint activity training, limb movement, sitting, balance training, and muscle strength training was initiated to recover physical function. Breathing training was added to rehabilitation regimen following intermittent weaning of MV. Finally, the patient recovered to nearly Grade 4 muscle strength at discharge (Table 1). The patient died 4 months after discharge at last. As a result of prolonged supportive treatment, the patient had multiple organ impairments and eventually died of renal failure and its associated complications.\n\nTable 1 Timeline from onset of illness, to transplant, to discharge from hospital\n\n\t\nJohn Wiley & Sons, Ltd.\n\n2.1 RT‐PCR test and histological results for SARS‐CoV‐2 in lung tissue\n\nThe explanted native lungs were sent to the Physical Containment Level 3 Laboratory. Pathological sections of the lungs from each lobe submitted for RT‐PCR for the detection of SARS‐CoV‐2 were negative. Histological examination indicated bilateral diffuse alveolar damage with fibrosis (Figure 1C, D). The septa of the remained alveoli were slightly thickened with inflammatory cells and fibroblasts, and marked fibrin exudation (at the left upper margin) was observed in Figure 1C. In Figure 1D, Fibrin exudatation could also be observed in the right upper field.\n\n3 DISCUSSION\n\nLT has been an established treatment for end‐stage pulmonary failure since the first successful case in 1983. 4 However, cases of LT in virus‐related diseases are rare. 5 , 6 , 7 , 8 , 9 In this report, we present the case of a successful bilateral LT for end‐stage pulmonary failure secondary to pneumonia as a result of COVID‐19 in a patient who required pretransplant support, with 63 days of MV and 62 of VV‐ECMO.\n\nWhen the COVID‐19 pandemic occurred in Wuhan, the city entered a state of lockdown, and all organ donation and transplantation activities were postponed because of the high risk of potential infection. Transplants were expected to overwhelm the already understaffed public health system, especially in ICUs. This LT was performed when COVID‐19 was well controlled in Wuhan and considered as a low‐risk epidemic area. The IgM–IgG test is an accurate and sensitive diagnostic method. A combination of nucleic acid and IgM–IgG testing is a more sensitive and accurate approach for diagnosis and early treatment of COVID‐19. A positive IgM antibody indicates that the duration of infection is short, in this period we think is not suit for surgery. The coronavirus lockdown ended and Wuhan reopened on April 8, 2020, following which medical resources in Wuhan became sufficient to consider organ transplantation.\n\nLT may be a viable alternative for patients with end‐stage pulmonary failure secondary to COVID‐19 in selective situations. We considered the following criteria as suitable for selecting LT recipients for end‐stage pulmonary failure secondary to COVID‐19 at our center 1 : no serious pre‐existing medical conditions; 2 the course of clinical diagnosis and treatment of COVID‐19 infection exceeds 2 months, with proven recovery; 3 the presence of irreversible pulmonary fibrosis and respiratory failure secondary to COVID‐19; 4 dependence on ECMO and/or MV for at least 1 month, with no signs of improvement to aid weaning; 5 three consecutive negative RT‐PCR nucleic acid tests for SARS‐CoV‐2 from a nasopharyngeal swab, an anal swab, sputum, BAL and blood; 6 normal immunological function; 7 normal neurological examination after discontinuation of sedatives; 8 major organs (heart, liver, and kidneys) are functioning; 9 normal coagulation function; 10 no bacteremia or infection with drug‐resistant bacteria before surgery; and 11 general condition deemed to have adequate rehabilitation potential following LT.\n\nNotably, the real‐time RT‐PCR for SARS‐CoV‐2 was an important diagnostic indicator and was performed pretransplantation on samples from nasopharyngeal swabs and BAL. The WHO guidelines define laboratory confirmation of SARS‐CoV‐2 as a positive RT‐PCR of a nasal or pharyngeal swab. 10 Cypel and Keshavjee suggest that the patient should have a recent negative SARS‐CoV‐2 PCR result, or infectivity assays using deep respiratory tract samples that show the absence of a viable virus before LT. 11 Lang et al. 12 reported the first case of a LT for a patient with a persistently positive SARS‐CoV‐2 real‐time RT‐PCR result. However, the viral culture was negative and the real‐time RT‐PCR C t values were high. Chen et al. 13 have reported the first case series on LT for COVID‐19 patients. They stipulated that at least three consecutive negative RT‐PCR nucleic acid tests for SARS‐CoV‐2 from a nasopharyngeal swab, an anal swab, sputum, BAL, and blood should be obtained owing to the potential of a negative RT‐PCR nucleic acid test to return to positive. The criteria proposed for patient selection and timing of LT in this study require validation in future studies. Furthermore, the current criteria should include confirmation of the absence of viable virus from nasopharyngeal and anal swabs, sputum, BAL specimens, and blood. A combination of nucleic acid and IgM–IgG testing is a more sensitive and accurate approach for diagnosis and early treatment of COVID‐19.\n\nOur patient met the above criteria. The COVID‐19 infection was confirmed for over 80 days before assessing his suitability for a LT. His CT image revealed presumptive evidence of pulmonary fibrosis. The patient was supported by VV‐ECMO for 62 days and MV for 63 days and we were satisfied that he could not be weaned off. Three consecutive SARS‐CoV‐2 nucleic acid tests were negative. The patient had normal cellular and humoral immunity and a normal neurological examination. Bacteremia and other organ damage were absent (Table 2).\n\nTable 2 Clinical and laboratory characteristics in the recipients before lung transplant and transfer while on ECMO\n\n\tPatient\t\t\t\nClinical characteristics\t\t\t\t\nAge\t65\t\t\t\nGender\tMale\t\t\t\nEpidemiological history\tYes (exposure to relevant environment)\t\t\t\nDate of admission\tFebruary 1\t\t\t\nEF（%）\t60\t\t\t\nSigns and symptoms\t\t\t\t\nFever on admission\n\nCough\n\nSore throat\n\nDiarrhoea\n\nChest pain\n\nMyalgia\n\nDyspnoea\n\nPRA‐I\n\nPRA‐II\n\nHLA‐A\n\nHLA‐B\n\nHLA‐DR\n\n\tYes\n\nYes\n\nYes\n\nYes\n\nYes\n\nNo\n\nYes\n\n10.7%\n\n5.5%\n\nA1A11\n\nB37B55\n\nDR12DR15\n\n\t\t\t\nLaboratory characteristics\tBefore LTx\tTransfer while on ECMO\tRange\t\nALT (U/L)\t12\t26\t0–40\t\nAST (U/L)\n\nPRO‐BNP (pg/ml)\n\nCK‐MB (ng/ml)\n\nMyoglobin (μg/L)\n\nTNI (ng/ml)\n\nUr (mmol/L)\n\nCre (μmmol/L)\n\nGFR (ml/min)\n\nPT (sec)\n\nINR\n\nDimer (mg/L)\n\nCD3 (%)\n\nCD4 (%)\n\nCD8 (%)\n\nCD19 (%)\n\nCD16+56 (%)\n\nIgG (g/L)\n\nIgM (g/L)\n\nIgA (g/L)\n\nIgE (IU/ml)\n\nC3 (g/L)\n\nC4 (g/L)\n\n\t15\n\n1683\n\n0.75\n\n39.88\n\n0.017\n\n13.1\n\n98\n\n69.42\n\n13.4\n\n1.15\n\n9.24\n\n76.76\n\n46.86\n\n28.44\n\n4.89\n\n17.79\n\n7.35\n\n0.561\n\n0.975\n\n55.6\n\n0.667\n\n0.207\n\n\t35\n\n2000\n\n0.93\n\n43.52\n\n0.023\n\n28.5\n\n75\n\n92\n\n15.2\n\n1.32\n\n1.35\n\n65.9\n\n34.94\n\n31.01\n\n2.53\n\n31.31\n\n6.88\n\n0.638\n\n0.728\n\n19.2\n\n0.552\n\n0.198\n\n\t0–40\n\n0–450\n\n0–5\n\n0–110\n\n0–0.04\n\n3.6–9.5\n\n57–111\n\n>90\n\n9–13\n\n0.76–1.24\n\n0–0.55\n\n56–86\n\n33–58\n\n13–39\n\n5–22\n\n5–26\n\n8.6–17.4\n\n0.3–2.2\n\n1.0–4.2\n\n<100\n\n0.7–1.4\n\n0.1–0.4\n\n\t\nAbbreviations: ALT, Alanine aminotransferase; ARDS, acuterespiratrydistresssyndrme; AST, Aspartate aminotransferase; CK‐MB, creatine phosphokinase‐MB; Cre, Creatinine; ECMO, extracorporeal membrane oxygenation; EF, ejection fraction; GFR, Glomerular filtration rate; HLA, Human leukocyte antigen; IgA, immunoglobulin A; INR, International normalized ratio; PRA, panel reactive antibodies; PRO‐BNP, pro brain natriuretic peptide; PT, Prothrombin time; TNI, Troponin I; Ur, Urea.\n\nJohn Wiley & Sons, Ltd.\n\nRecognizing the limitations of testing and the possibility of atypical symptoms, we applied an even higher clinical index of suspicion. Utilization of Grade 3 personal protective equipment (PPE), including an intraoperative positive pressure mask, presented a challenge for surgeons, anesthesiologists, and nurses, whose range of motion was limited. Additionally, the health workers were unable to communicate effectively during the operative process, which made the operation more difficult and required tacit understanding. Sign language and preoperative rehearsals were also utilized to ensure clear understanding by all team members of the different scenarios. Reassuringly, the RT‐PCR results for SARS‐CoV‐2 taken from different lung lobes were negative, demonstrating that there was no virus replication. Decreasing the level of PPE when operating on a known SARS‐CoV‐2 patient with negative nucleic acid tests warrants further investigation.\n\nPatients with severe COVID‐19 often progress to acute respiratory failure, and ongoing inflammation often inflammation results in pulmonary damage and subsequent multiple organ failure. 14 Protecting the function of multiple organs is essential during the course of treatment. Intraoperative ECMO and postoperative continuous renal replacement therapy (CRRT) were used to protect the cardiac and renal function. The cardiac function by echocardiography was normal preoperatively. However, it was considered that concomitant cardiovascular procedure might be required. ECMO is believed to contribute to lung function recovery in severely infected patients and serves as an interim treatment and bridge before LT to prevent mortality. LT in SARS patients with ARDS has been reported in anecdotal case reports. However, LT has been performed for patients receiving ECMO for >45 days after H1N1 infection. 15 Several reports suggest that LT should not be considered before 4–6 weeks of ECMO support after the initial clinical signs of respiratory failure. The VA‐ECMO was utilized during LT to reduce cardiac load and to facilitate gas exchange. ECMO was chosen instead of cardiopulmonary bypass for intraoperative support because 1 ECMO results in less damage to red blood cells; 2 No additional anticoagulation is required during ECMO; and 3 so that we can continue to use ECMO to support cardiac dysfunction and hypoxemia when the patient returns to the ICU after LT. Meticulous attention to enteral nutrition, physical therapy, deep vein thrombosis prophylaxis, and daily evaluation of organ functions is essential for patients requiring prolonged ECMO support. 8 VV‐ECMO was weaned off 44 h after the LT in our case. CRRT was used for nonrenal indications during the LT, and helped to remove inflammatory mediators such as cytokines and maintain a negative fluid balance, 16 thereby reducing the occurrence of primary graft dysfunction (PGD). The 62 days of preoperative ECMO and the influence of COVID‐19 impaired the patient's coagulation ability. As a result, he lost nearly 7000 ml of blood intraoperatively. We infused over 10,000 ml of fluid including crystalloids, colloids, and blood products. Postoperatively, we detected severe pulmonary edema and decreased lung compliance. To maintain the negative fluid balance we initiated CRRT, which is very effective for improving pulmonary edema and lung compliance. Following the procedure rehabilitation commenced to facilitate earlier recovery. This included physical exercise, neuromuscular electrical stimulation, and oral tactile stimulation.\n\nPatients with viral infections are usually at risk of multiorgan damage, as well as immune system impairment. 17 COVID‐19 can attack the immune system, creating a characteristically low lymphocyte count. As such, immunosuppressed patients are at increased risk of severe disease from COVID‐19. 18 Furthermore, it can be difficult to determine an appropriate balance between immunosuppressive and anti‐infectious measures. Given that such COVID‐19 patients may be sensitive to immunosuppressive drugs, we selected our immunosuppressive protocol prudently and used them at a lower dosage. Cyclosporin A (CsA) is a well‐known immunosuppressive drug that binds to cellular cyclophilins to inhibit calcineurin 19 and reportedly inhibits the replication of coronaviruses. 20 CsA is easily adjusted according to immune status due to its wide therapeutic range; thus, we used CsA and prednisone for immunosuppression.\n\nIn conclusion, to our knowledge, we reported the first successful LT for an elderly and critical COVID‐19 patient with end‐stage pulmonary fibrosis secondary to pneumonia in Wuhan. This patient received ECMO support for 62 days indicating a high risk of mortality. ECMO was weaned off 44 h after LT and MV was weaned off after the 16th postoperative day. As LT is not routinely performed in pulmonary failure occurring secondary to pneumonia, we do not yet know the long‐term outcome in this group of COVID‐19 patients, however, our patient remains well at the time of writing. Despite the limited evidence of case reports from a similar situation, it is important to emphasize that LT provided an opportunity for recovery and survival in this patient.\n\nAUTHOR CONTRIBUTIONS\n\nBo Wang, Jie Huang contributed to conception, designed experiments and were responsible for the whole work; Micheal Hsin, Jingyu Chen, Huiqing Lin analyzed experimental results and wrote the manuscript. All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval for the version to be published, and agree to be accountable for all aspects of the work.\n\nACKNOWLEDGEMENTS\n\nThe authors thank Dr. Ying Chen and Dr. Rendi Jiang for their academic and technical support. This study was supported by the National Natural Science Foundation of China (81800343) and the China Organ Transplantation Development Foundation(2020HX0011).\n\nDATA AVAILABILITY STATEMENT\n\nAll data included in this study are available upon request by contact with the corresponding author.\n==== Refs\nREFERENCES\n\n1 Zhou F , Yu T , Du R , et al. Clinical course and risk factors for mortality of adult inpatients with COVID‐19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395 :1054‐1062.32171076\n2 Guan WJ , Ni ZY , Hu Y , et al. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med. 2020;382 :1708‐1720.32109013\n3 Gattinoni L , Chiumello D , Rossi S . COVID‐19 pneumonia: ARDS or not? Crit Care. 2020;24 :154.32299472\n4 Toronto Lung Transplant Group . Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med. 1986;314 :1140‐1145.3515192\n5 Bertani A , Grossi P , Vitulo P , et al. Successful lung transplantation in an HIV‐ and HBV‐positive patient with cystic fibrosis. Am J Transplant. 2009;9 :2190‐2196.19656132\n6 Al Aklabi MM , Weinkauf JG , Humar A , Ghorpade N . Successful bilateral lung transplantation in a patient with end‐stage lung disease and positive novel influenza virus (H1N1). J Heart Lung Transplant. 2010;29 :898‐899.20538489\n7 Mason DP , Murthy SC , Yun JJ , et al. Lung transplantation in a recipient with novel 2009 H1N1 influenza: lessons learned. Thorac Cardiovasc Surg. 2011;59 :126‐127.21384312\n8 Wang Q , Pan S , Zhang S , Shen G , Huang M , Wu M . Lung transplantation in pulmonary fibrosis secondary to influenza A pneumonia. Ann Thorac Surg. 2019;108 :e233‐e235.30910653\n9 Han W , Zhu M , Chen J , et al. Lung transplantation for elderly patients with end‐stage COVID‐19 pneumonia. Ann Surg. 2020;272 :e33‐e34.32301803\n10 Covid‐19 . Why test? Who to test? How to test? Bull Acad Natl Med. 2020;204 :9.\n11 Cypel M , Keshavjee S . When to consider lung transplantation for COVID‐19. Lancet Respir Med. 2020;8 :944‐946.32857989\n12 Lang C , Jaksch P , Hoda MA , et al. Lung transplantation for COVID‐19‐associated acute respiratory distress syndrome in a PCR‐positive patient. Lancet Respir Med. 2020;8 :1057‐1060.32857987\n13 Chen JY , Qiao K , Liu F , et al. Lung transplantation as therapeutic option in acute respiratory distress syndrome for coronavirus disease 2019‐related pulmonary fibrosis. Chin Med J. 2020;133 :1390‐1396.32251003\n14 Wang T , Du Z , Zhu F , et al. Comorbidities and multi‐organ injuries in the treatment of COVID‐19. Lancet. 2020;395 :e52.32171074\n15 Hoetzenecker K , Benazzo A , Stork T , et al. Bilateral lung transplantation on intraoperative extracorporeal membrane oxygenator: an observational study. J Thorac Cardiovasc Surg. 2020;160 :320‐327.e1.31932054\n16 Oda S , Sadahiro T , Hirayama Y , et al. Non‐renal indications for continuous renal replacement therapy: current status in Japan. Contrib Nephrol. 2010;166 :47‐53.20472991\n17 Borrow P , Evans CF , Oldstone MB . Virus‐induced immunosuppression: Immune system‐mediated destruction of virus‐infected dendritic cells results in generalized immune suppression. J Virol. 1995;69 :1059‐1070.7815484\n18 Ritchie AI , Singanayagam A . Immunosuppression for hyperinflammation in COVID‐19: a double‐edged sword? Lancet. 2020;395 :1111.\n19 de Wilde AH , Zevenhoven‐Dobbe JC , van der Meer Y , et al. Cyclosporin A inhibits the replication of diverse coronaviruses. J Gen Virol. 2011;92 :2542‐2548.21752960\n20 Ma‐Lauer Y , Zheng Y , Malešević M , von Brunn B , Fischer G , von Brunn A . Influences of cyclosporin A and non‐immunosuppressive derivatives on cellular cyclophilins and viral nucleocapsid protein during human coronavirus 229E replication. Antiviral Res. 2020;173 :104620.31634494\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-4527",
"issue": "9(4)",
"journal": "Immunity, inflammation and disease",
"keywords": "COVID-19; lung transplant; pulmonary failure",
"medline_ta": "Immun Inflamm Dis",
"mesh_terms": "D000368:Aged; D000086382:COVID-19; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D012121:Respiration, Artificial; D000086402:SARS-CoV-2",
"nlm_unique_id": "101635460",
"other_id": null,
"pages": "1500-1507",
"pmc": null,
"pmid": "34469048",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "30910653;32109013;32171076;32299472;31932054;19656132;32857987;32406424;21752960;32251003;21384312;32220278;31634494;32857989;7815484;20538489;32301803;32171074;34469048;3515192;20472991",
"title": "First lung transplant in Wuhan for a critical and elderly COVID-19 patient.",
"title_normalized": "first lung transplant in wuhan for a critical and elderly covid 19 patient"
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"abstract": "Nephrogenic adenoma is a rare, benign lesion that can be encountered anywhere along the urinary tract. It is associated with genitourinary trauma, chronic inflammation, genitourinary surgery, renal transplant, urolithiasis, and radiation. In children, these lesions are almost exclusively found in the bladder. However, we report an unusual case of a 15-year-old boy with no prior urologic history who presented with an obstructing right ureteral nephrogenic adenoma that required an ileal ureter interposition and right ureterectomy.",
"affiliations": "Department of Urology, Wake Forest University, Winston Salem, NC.;Department of Urology, Wake Forest University, Winston Salem, NC.;Department of Urology, Wake Forest University, Winston Salem, NC.;Department of Pathology, Wake Forest University, Winston Salem, NC.;Department of Urology, Wake Forest University, Winston Salem, NC. Electronic address: shodges@wakehealth.edu.",
"authors": "Peak|Taylor C|TC|;Kogan|Stanley J|SJ|;Atala|Anthony J|AJ|;Fenu|Elena M|EM|;Hodges|Steve J|SJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.urology.2020.05.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4295",
"issue": "143()",
"journal": "Urology",
"keywords": null,
"medline_ta": "Urology",
"mesh_terms": null,
"nlm_unique_id": "0366151",
"other_id": null,
"pages": "231-233",
"pmc": null,
"pmid": "32439556",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Case Report of an Obstructing Ureteral Nephrogenic Adenoma in a Child Managed With Open Ileal Ureter.",
"title_normalized": "a case report of an obstructing ureteral nephrogenic adenoma in a child managed with open ileal ureter"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-04977",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
... |
{
"abstract": "Tako-Tsubo cardiomyopathy (TTC) occurs particularly in post-menopausal women, being precipitated in many cases by severe emotional stress. We describe six patients in whom TTC occurred in association with therapeutic ingestion or overdose of the serotonin/noradrenaline reuptake inhibitor venlafaxine, or its metabolite desvenlafaxine. Importantly, two of the six cases were not post-menopausal women. An increased risk of TTC may account for some of the reported cardiovascular adverse effects of venlafaxine and similar agents.",
"affiliations": "Department of Cardiology, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA 5011, Australia.",
"authors": "Neil|Christopher J A|CJ|;Chong|Cher-Rin|CR|;Nguyen|Thanh H|TH|;Horowitz|John D|JD|",
"chemical_list": "D003511:Cyclohexanols; D010446:Peptide Fragments; D017367:Serotonin Uptake Inhibitors; C109794:pro-brain natriuretic peptide (1-76); D009647:Normetanephrine; D020097:Natriuretic Peptide, Brain; D000069470:Venlafaxine Hydrochloride; D000069468:Desvenlafaxine Succinate",
"country": "Australia",
"delete": false,
"doi": "10.1016/j.hlc.2011.12.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1443-9506",
"issue": "21(4)",
"journal": "Heart, lung & circulation",
"keywords": null,
"medline_ta": "Heart Lung Circ",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003511:Cyclohexanols; D000069468:Desvenlafaxine Succinate; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D009647:Normetanephrine; D010446:Peptide Fragments; D017367:Serotonin Uptake Inhibitors; D054549:Takotsubo Cardiomyopathy; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "100963739",
"other_id": null,
"pages": "203-5",
"pmc": null,
"pmid": "22285074",
"pubdate": "2012-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Occurrence of Tako-Tsubo cardiomyopathy in association with ingestion of serotonin/noradrenaline reuptake inhibitors.",
"title_normalized": "occurrence of tako tsubo cardiomyopathy in association with ingestion of serotonin noradrenaline reuptake inhibitors"
} | [
{
"companynumb": "US-DEXPHARM-20191159",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
"drugadditional": "1... |
{
"abstract": "Isoniazid (INH) therapy is associated with a significant incidence of idiosyncratic liver failure. We recently reported eight cases of INH-induced liver failure in which patients had antidrug and anticytochrome P450 antibodies. However, it was unclear what role these antibodies play in the mechanism of INH-induced liver injury. Here, we report that the dominant isotype of anti-INH antibodies was IgG, with IgG3 being the dominant subtype. IgG3 antibodies are associated with a Th1-type immune response and fix complement. IgG3 antibodies have been associated with other forms of liver injury and may play a pathogenic role in INH-induced liver injury.",
"affiliations": "Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto , Toronto, Ontario M5S 1A8, Canada.",
"authors": "Metushi|Imir G|IG|;Lee|William M|WM|;Uetrecht|Jack|J|",
"chemical_list": "D000995:Antitubercular Agents; D007074:Immunoglobulin G; D007538:Isoniazid",
"country": "United States",
"delete": false,
"doi": "10.1021/tx500108u",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0893-228X",
"issue": "27(5)",
"journal": "Chemical research in toxicology",
"keywords": null,
"medline_ta": "Chem Res Toxicol",
"mesh_terms": "D000995:Antitubercular Agents; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D007074:Immunoglobulin G; D007538:Isoniazid; D008099:Liver; D017093:Liver Failure",
"nlm_unique_id": "8807448",
"other_id": null,
"pages": "738-40",
"pmc": null,
"pmid": "24786179",
"pubdate": "2014-05-19",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "IgG3 is the dominant subtype of anti-isoniazid antibodies in patients with isoniazid-induced liver failure.",
"title_normalized": "igg3 is the dominant subtype of anti isoniazid antibodies in patients with isoniazid induced liver failure"
} | [
{
"companynumb": "PHHY2015CA076126",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": null,
"druga... |
{
"abstract": "We report the case of an 11-year-old boy brought to our emergency department 2 hours after a viper bite to his right hand. He suffered severe pain and rapidly progressive swelling with signs of haemodynamic compromise in keeping with distributive shock. The oedema progressed from his right wrist upwards to his forearm and upper arm with compartment syndrome ultimately resulting. He underwent fasciotomy of the right upper limb and antivenom serum was given. The patient required vasopressors for 48 hours and a total of nine surgical interventions were necessary. In the event of a snakebite, it is essential to promptly recognise the signs of severity, complications and indications for the administration of antivenom serum. We intend to highlight this rare shock aetiology and the need for emergency management if severe clinical signs are present. Early administration of antivenom serum is essential and it should be available in all emergency departments.",
"affiliations": "Pediatric Department, Unidade Local de Saude de Matosinhos EPE, Senhora da Hora, Portugal joana.teixeiracarvalho@gmail.com.;Pediatric Intensive Care Unit, Centro Hospitalar e Universitario de Coimbra EPE Hospital Pediatrico de Coimbra, Coimbra, Coimbra, Portugal.;Pediatric Emergency Service, Centro Hospitalar e Universitario de Coimbra EPE Hospital Pediátrico de Coimbra, Coimbra, Coimbra, Portugal.;University Clinic of Pediatrics, Universidade de Coimbra Faculdade de Medicina, Coimbra, Coimbra, Portugal.",
"authors": "Carvalho|Joana|J|http://orcid.org/0000-0001-6561-2153;Moinho|Rita|R|;Macao|Patricia|P|;Oliveira|Guiomar|G|",
"chemical_list": "D000997:Antivenins; D014757:Viper Venoms",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240206",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "emergency medicine; neonatal and paediatric intensive care; paediatrics",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000818:Animals; D000997:Antivenins; D002648:Child; D003161:Compartment Syndromes; D006230:Hand Injuries; D006801:Humans; D008297:Male; D012769:Shock; D012909:Snake Bites; D014757:Viper Venoms; D017819:Viperidae",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33563677",
"pubdate": "2021-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "When snakebites complicate: a paediatric case with shock and compartment syndrome.",
"title_normalized": "when snakebites complicate a paediatric case with shock and compartment syndrome"
} | [
{
"companynumb": "PT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-310286",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"dru... |
{
"abstract": "Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation.",
"affiliations": "Departments of Adult and Pediatric Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Children's Hospital, Boston, MA, USA.",
"authors": "Richardson|P G|PG|;Elias|A D|AD|;Krishnan|A|A|;Wheeler|C|C|;Nath|R|R|;Hoppensteadt|D|D|;Kinchla|N M|NM|;Neuberg|D|D|;Waller|E K|EK|;Antin|J H|JH|;Soiffer|R|R|;Vredenburgh|J|J|;Lill|M|M|;Woolfrey|A E|AE|;Bearman|S I|SI|;Iacobelli|M|M|;Fareed|J|J|;Guinan|E C|EC|",
"chemical_list": "D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; D018047:Receptors, Purinergic P1; C036901:defibrotide; D006493:Heparin; D010959:Tissue Plasminogen Activator; D001663:Bilirubin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "92(3)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001663:Bilirubin; D002648:Child; D002675:Child, Preschool; D004341:Drug Evaluation; D005240:Feasibility Studies; D005260:Female; D005343:Fibrinolytic Agents; D018380:Hematopoietic Stem Cell Transplantation; D006470:Hemorrhage; D006493:Heparin; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure; D009369:Neoplasms; D010166:Palliative Care; D011089:Polydeoxyribonucleotides; D018047:Receptors, Purinergic P1; D012189:Retrospective Studies; D012306:Risk; D013789:Thalassemia; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "737-44",
"pmc": null,
"pmid": "9680339",
"pubdate": "1998-08-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.; D016454:Review",
"references": null,
"title": "Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population.",
"title_normalized": "treatment of severe veno occlusive disease with defibrotide compassionate use results in response without significant toxicity in a high risk population"
} | [
{
"companynumb": "US-JAZZ-2016-US-008946",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEFIBROTIDE SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Botulism is a rare, life-threatening paralytic illness. Equine-derived heptavalent botulinum antitoxin (HBAT), the only currently available treatment for noninfant botulism in the United States, was licensed in 2013. No reports have systematically examined safety and clinical benefit of HBAT among botulism patients.\n\n\n\nFrom March 2010 through March 2013, we collected data prospectively and through medical record reviews of patients with confirmed or suspected botulism who were treated with HBAT under an expanded-access Investigational New Drug program.\n\n\n\nAmong 249 HBAT-treated patients, 1 (<1%) child experienced an HBAT-related serious adverse event (hemodynamic instability characterized by bradycardia, tachycardia, and asystole); 22 (9%) patients experienced 38 nonserious adverse events reported by physicians to be HBAT related. Twelve (5%) deaths occurred; all were determined to be likely unrelated to HBAT. Among 104 (42%) patients with confirmed botulism, those treated early (≤2 days) spent fewer days in the hospital (median, 15 vs 25 days; P < .01) and intensive care (10 vs 17 days; P = .04) than those treated later. Improvements in any botulism sign/symptom were detected a median of 2.4 days and in muscle strength a median of 4.8 days after HBAT.\n\n\n\nHBAT was safe and provided clinical benefit in treated patients. HBAT administration within 2 days of symptom onset was associated with shorter hospital and intensive care stays. These results highlight the importance of maintaining clinical suspicion for botulism among patients presenting with paralytic illness to facilitate early HBAT treatment before laboratory confirmation might be available. Clinical consultation and, if indicated, HBAT release, are available to clinicians 24/7 through their state health department in conjunction with CDC.",
"affiliations": "Regulatory Affairs, Centers for Disease Control and Prevention, Atlanta, Georgia.;Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases (DFWED), Centers for Disease Control and Prevention, Atlanta, Georgia.;Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases (DFWED), Centers for Disease Control and Prevention, Atlanta, Georgia.;DFWED, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia.;Regulatory Affairs, Centers for Disease Control and Prevention, Atlanta, Georgia.;Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases (DFWED), Centers for Disease Control and Prevention, Atlanta, Georgia.;Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases (DFWED), Centers for Disease Control and Prevention, Atlanta, Georgia.;Regulatory Affairs, Centers for Disease Control and Prevention, Atlanta, Georgia.;Regulatory Affairs, Centers for Disease Control and Prevention, Atlanta, Georgia.;Enteric Diseases Epidemiology Branch, Division of Foodborne, Waterborne, and Environmental Diseases (DFWED), Centers for Disease Control and Prevention, Atlanta, Georgia.",
"authors": "Yu|Patricia A|PA|;Lin|Neal H|NH|;Mahon|Barbara E|BE|;Sobel|Jeremy|J|;Yu|Yon|Y|;Mody|Rajal K|RK|;Gu|Weidong|W|;Clements|Jennifer|J|;Kim|Hye-Joo|HJ|;Rao|Agam K|AK|",
"chemical_list": "D001904:Botulinum Antitoxin; C578223:botulism antitioxin (Equine) Heptavalent (A,B,C,D,E,F,G)",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/cix816",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "66(suppl_1)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "BAT; HBAT; botulism; equine-derived heptavalent botulinum antitoxin",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001904:Botulinum Antitoxin; D001906:Botulism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "S57-S64",
"pmc": null,
"pmid": "29293928",
"pubdate": "2017-12-27",
"publication_types": "D016428:Journal Article",
"references": "26615088;22257488;24106296;17690419;17051488;29293931;7191633;28770820;16163636;26068781;8842274;14744243;19435432;19435438;6720725;28603554;18834318;4925448",
"title": "Safety and Improved Clinical Outcomes in Patients Treated With New Equine-Derived Heptavalent Botulinum Antitoxin.",
"title_normalized": "safety and improved clinical outcomes in patients treated with new equine derived heptavalent botulinum antitoxin"
} | [
{
"companynumb": "US-PFIZER INC-2019031473",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": "3",
... |
{
"abstract": "Hydroxychloroquine (HQ) has been used for the treatment of novel coronavirus disease (COVID-19) even though there is no clear evidence for its effectiveness yet. In contrary, HQ has major side effects like QTc prolongation and subsequent development of ventricular arrhythmias. Such side effects may possess additional risks on end-stage renal disease (ESRD) patients who have higher cardiovascular risks than general population. We herein present 2 cases of sudden cardiac death in 2 ESRD patients with COVID-19 for whom a treatment regimen including HQ was preferred. Both patients were clinically stable at the time of arrest. Death could not be attributed to worsening of the COVID-19 since the patients' clinical picture and laboratory values were improving. The cardiac events coincided with the end of routine haemodialysis sessions of both patients. Electrocardiography controls upon admission and on the 24 and 48 h of treatment showed normal QTc intervals. Potential risks contributing to sudden cardiac death during HQ treatment of ESRD patients are discussed.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey, ahmet.murt@istanbul.edu.tr.;Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.;Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey.",
"authors": "Murt|Ahmet|A|;Dincer|Mevlut Tamer|MT|;Karaca|Cebrail|C|",
"chemical_list": "D006495:Heparin, Low-Molecular-Weight; D006886:Hydroxychloroquine; D017963:Azithromycin; D006493:Heparin; D008274:Magnesium; D011188:Potassium",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000511392",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-5068",
"issue": "50(3)",
"journal": "Blood purification",
"keywords": "Coronavirus disease-19; End-stage renal disease; Haemodialysis; Hydroxychloroquine; Sudden death",
"medline_ta": "Blood Purif",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D017963:Azithromycin; D000086382:COVID-19; D016757:Death, Sudden, Cardiac; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D006329:Heart Conduction System; D006493:Heparin; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D006886:Hydroxychloroquine; D007676:Kidney Failure, Chronic; D008274:Magnesium; D008297:Male; D011188:Potassium; D006435:Renal Dialysis; D000086402:SARS-CoV-2",
"nlm_unique_id": "8402040",
"other_id": null,
"pages": "402-404",
"pmc": null,
"pmid": "33032282",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Sudden Cardiac Death in Haemodialysis Patients under Hydroxychloroquine Treatment for COVID-19: A Report of Two Cases.",
"title_normalized": "sudden cardiac death in haemodialysis patients under hydroxychloroquine treatment for covid 19 a report of two cases"
} | [
{
"companynumb": "TR-ACCORD-206042",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Immune check point inhibitors (ICIs) have emerged as a new therapeutic paradigm for a variety of malignancies including metastatic melanoma. As the use of ICIs expand, immune-mediated adverse events are becoming a common occurrence.\n\n\n\nWe describe the first reported patient with small vessel vasculitis, manifested by digital ischemia, following treatment with high dose Ipilimumab for resected stage IIIB/C melanoma. This patient received high dose steroids, five-day intravenous (IV) Epoprostenol protocol, botulinum toxin injections, and Rituximab 375 mg/m2 weekly for four cycles. With this treatment regimen, the digital ischemia did not progress proximally, but she did require multiple distal digit amputations about six months after the onset of her symptoms.\n\n\n\nPrompt identification and management of immune related adverse events (IRAEs) are critical to optimal patient management. This patient's vasculitis did not reverse, but was likely halted and stabilized with multiple immunosuppressive medications.",
"affiliations": "Division of Rheumatology, Department of Internal Medicine, University of Michigan, Floor 3, Reception A, 1500 E Medical Center Drive, SPC 5342, Ann Arbor, MI, 48109, USA. rithydpu@gmail.com.;Division of Rheumatology, Department of Internal Medicine, University of Michigan, Floor 3, Reception A, 1500 E Medical Center Drive, SPC 5342, Ann Arbor, MI, 48109, USA.;Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.;Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.;Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.;Division of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.",
"authors": "Padda|Amrita|A|0000-0001-8186-1096;Schiopu|Elena|E|;Sovich|Justin|J|;Ma|Vincent|V|;Alva|Ajjai|A|;Fecher|Leslie|L|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000074324:Ipilimumab",
"country": "England",
"delete": false,
"doi": "10.1186/s40425-018-0321-2",
"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 32110.1186/s40425-018-0321-2Case ReportIpilimumab induced digital vasculitis http://orcid.org/0000-0001-8186-1096Padda Amrita 419-654-2259rithydpu@gmail.comamritapa@med.umich.edu 1Schiopu Elena eschiopu@med.umich.edu 1Sovich Justin jsovich@med.umich.edu 2Ma Vincent vma@med.umich.edu 2Alva Ajjai ajjai@med.umich.edu 3Fecher Leslie lfecher@med.umich.edu 31 0000000086837370grid.214458.eDivision of Rheumatology, Department of Internal Medicine, University of Michigan, Floor 3, Reception A, 1500 E Medical Center Drive, SPC 5342, Ann Arbor, MI 48109 USA 2 0000000086837370grid.214458.eDepartment of Internal Medicine, University of Michigan, Ann Arbor, MI USA 3 0000000086837370grid.214458.eDivision of Hematology Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI USA 12 2 2018 12 2 2018 2018 6 121 8 2017 23 1 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nImmune check point inhibitors (ICIs) have emerged as a new therapeutic paradigm for a variety of malignancies including metastatic melanoma. As the use of ICIs expand, immune-mediated adverse events are becoming a common occurrence.\n\nCase presentation\nWe describe the first reported patient with small vessel vasculitis, manifested by digital ischemia, following treatment with high dose Ipilimumab for resected stage IIIB/C melanoma. This patient received high dose steroids, five-day intravenous (IV) Epoprostenol protocol, botulinum toxin injections, and Rituximab 375 mg/m2 weekly for four cycles. With this treatment regimen, the digital ischemia did not progress proximally, but she did require multiple distal digit amputations about six months after the onset of her symptoms.\n\nConclusions\nPrompt identification and management of immune related adverse events (IRAEs) are critical to optimal patient management. This patient’s vasculitis did not reverse, but was likely halted and stabilized with multiple immunosuppressive medications.\n\nKeywords\nIpilimumabImmune related adverse events (IRAEs)Vasculitisissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nIpilimumab (Yervoy®) is approved by the Food and Drug Administration (FDA) for the treatment of resected stage III melanoma and advanced unresectable melanoma. It is a fully human monoclonal antagonistic antibody which targets cytotoxic T lymphocyte antigen 4 (CTLA-4) on T cells and blocks the CTLA-4 interaction with its ligand CD80. CTLA-4 is an immune check point molecule which downregulates pathways of T cell activation. Therefore, when CTLA-4 is blocked with Ipilimumab, the T lymphocyte inhibitory pathway is hindered, and the immune response is enhanced, allowing T lymphocytes to destroy cancer cells [1]. Melanoma incidence continues to rise and metastatic melanoma results in approximately 53,000 deaths per year worldwide as estimated by the World Health Organization [2]. Ipilimumab was the first therapeutic agent to demonstrate an overall survival benefit in the treatment of advanced, unresectable melanoma [3]. It is currently approved by the FDA at a dose of 3 mg/kg in the metastatic setting. More recently, Ipilimumab 10 mg/kg demonstrated an improved median relapse free survival of 26.1 months compared to 17.1 months for placebo in resected stage III cutaneous melanoma in the European Organization for Research and Treatment of Cancer (EORTC)18,071; this study led to its approval by the FDA for this indication [4]. An update for this study was recently published and reported a five year relapse free survival of 40.8% in the Ipilimumab group compared to 30.3% in the placebo group, with a median follow up of 5.3 years [5]. Five-year overall survival in the Ipilimumab group was 65.4% versus 54.4% in the placebo group. No vascular toxicities of any grade were reported. Please see Table 1 for adverse events.Table 1 Grade 3/4/5 toxicities from the E1609 trial and EORTC trial. These studies are in the setting of resected patients (adjuvant)\n\n\tE1609 triala (Safety Data n = 1019)\n(Total Enrollment = 1673)\tEORTC 18071 trial (n = 945)\t\nTreatment type\tIpi 3 mg/kg\tIpi 10 mg/kg\tIpi 10 mg/kg\tPlacebo\t\nNumber of patients\t516\t503\t471\t474\t\nAdverse event of any grade\t98.4%\t100%\t(465 99%)\t432 (91%)\t\nTreatment-related AE (any grade)\t96%\t98.8%\t\t\t\n Grade 3 adverse eventsb\t37%\t57%\t\t\t\n Grade 4 adverse eventsb\t\t\t\nImmune related adverse events (grade 3/4)\t18.8%\t34%\t196 (41.6%)\t13 (2.7%)\t\n Gastrointestinal adverse eventb\t12.0%\t18.5%\t76 (16%)\t4 (< 1%)\t\n Hepatic adverse eventsb\t3.1%\t7.8%\t51 (11%)\t1 (< 1%)\t\n Endocrine adverse eventsb\t6.6%\t12.4%\t37 (8%)\t1(< 1%)\t\n Neurologic adverse eventsb\t2.0%\t1.6%\t9 (1.9%)\t0 (0%)\t\nTreatment related Adverse event leading to discontinuation of treatment\t35%\t54%\t240 (51%)\t22(4.6%)\t\nDeath due to treatment related adverse events\t2 (0.4%)\t8 (1.6%)\t5 (1.1%)\t0\t\naAbstract available only for the E1609 trial\n\nbGrade 3/4 adverse events\n\n\n\nPreliminary safety data from an unplanned interim analysis for Ipilimumab-treated subjects was recently presented from the 1609 trial sponsored by the Eastern Cooperative Oncology Group at the American Society for Clinical Oncology [6]. This phase III study in subjects with resected stage III and IV melanoma randomized 1673 patients to high dose interferon (HDI), Ipilimumab 3 mg/kg, or Ipilimumab 10 mg/kg, with co-primary endpoints of relapse free survival and overall survival. They reported safety data for 1019 subjects treated at either dose of Ipilimumab, as well as relapse free survival data for 773 concurrently randomized subjects with a median follow up of 3.1 years. There were two deaths (0.4%) in the lower dose Ipilimumab arm due to colitis and eight (1.6%) in the higher dose Ipilimumab arm: five subjects with colitis, one pneumonitis, one thromboembolic event with hypophysitis, and one cardiac event. This unplanned exploratory analysis showed no difference in relapse free survival between the low dose and high dose Ipilimumab, however additional follow up is needed. Of note, the Ipilimumab 10 mg/kg arm accrual was suspended for approximately 2 months due to toxicity (Table 1). These adjuvant toxicity rates are at least equivalent and possibly greater than those reported in the advanced, unresectable melanoma setting with grade 3/4 rates reported at 27-58% for 10 mg/kg [7–10].\n\nCase presentation\nWe report a case of a 52-year-old Caucasian woman who was diagnosed with stage IIIB/C melanoma from a regressed primary of the abdomen when she presented with a bulky left groin mass. Imaging demonstrated a 6.5 cm lobulated mass in the left groin involving soft tissue and probable lymph nodes. Excisional biopsy revealed two lymph nodes with metastatic melanoma; tumor cells were positive for Melan-A and SOX-10, and negative for CD45, Cytokeratin AE1/AE3. The patient reported a long standing black skin lesion at the lower abdomen that had previously grown and bled, but more recently had started to fade. This lesion was biopsied and demonstrated superficial dermal fibrosis with tumoral melanosis and pigment laden macrophages (melanophages), consistent with a regressed melanocytic lesion. She had no distant metastases on staging and underwent a wide local excision of the regressed primary site and radical resection of the inguinal mass with complete lymph node dissection, followed by reconstruction of the left groin with a sartorius flap. Pathology of the 8.9 cm subcutaneous mass revealed a spindle cell (sarcomatoid) melanoma involving lymph node tissue, possible aggregate of matted lymph nodes with extranodal extension, and multiple additional lymph nodes without melanoma. She had no known history of autoimmune conditions or prior Raynaud’s phenomenon.\n\nThe first high dose Ipilimumab of 10 mg/kg was administered at an outside hospital followed by limited loose bowel movements and mouth soreness. One week after the second Ipilimumab infusion (at 3-week intervals), she developed myalgias, arthralgias, rash, vision changes, jaw pain, and discoloration of several upper and lower limb digits. Initially, the digital symptoms included intermittent red and blue color changes, worse in the cold, and better with warmth. Two weeks after the second infusion, her oncologist initiated Amlodipine 10 mg daily, Aspirin 81 mg daily, and Prednisone 10 mg daily for suspected immune-mediated Raynaud’s phenomenon. Serologic workup at the initial presentation included a negative antinuclear antibody, rheumatoid factor, anti-cyclic citrullinated peptide antibody, cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies, cryoglobulins, and hepatitis C antibody and ribonucleic acid (RNA); serum and urine protein electrophoresis were within normal limits. She reported immediate improvement of the myalgias, rash, arthralgias and jaw pain, but she had progression of digital pain and discoloration, therefore her oncologist administered 500 mg of IV Methylprednisolone and increased her daily Prednisone to 60 mg for a presumed Ipilimumab immune related adverse event (IRAE). Her digits did not improve, and she received a second 500 mg dose of IV Methylprednisolone three days later. The lower extremity digital pain resolved, but the upper extremity digital pain became so severe that she required high doses of morphine.\n\nShe was admitted for inpatient management two days after her outpatient steroid infusions. Physical exam revealed acrocyanosis of all upper extremity digits (Fig. 1a & 1b). She was initiated on 2 mg/kg of IV Methylprednisolone and calcium channel blockade. Lower extremity digits were less affected and demonstrated the greatest improvement. The upper extremity digital pain and acrocyanosis persisted. She was treated with one dose of 1000 mg of IV Methylprednisolone with limited benefit, and thus continued daily 2 mg/kg dosing. Arterial duplex dopplers of upper and lower extremities were normal. Transthoracic echocardiogram was negative for thrombus or mass. Conventional angiogram was performed on the left upper extremity; it revealed severely diminished blood flow in the digital arteries beyond the proximal interphalangeal joints, and the Verapamil challenge did not increase blood flow (Fig. 2). Findings on the conventional angiogram were consistent with small vessel occlusive disease. Extensive autoantibody panels (inclusive of myeloperoxidase, proteinase 3, antinuclear, anti-centromere, anti-topoisomerase I, Beta-2-glycoprotein 1, anti-cardiolipin, anti-neutrophil cytoplasmic) and viral panels (human immunodeficiency virus, hepatitis panels) were negative. A full coagulopathy work-up was unrevealing. Given concern for ongoing immune-mediated vasculitis, the patient also received a 5-day course, 6-h per day, of Epoprostenol at a rate of 3 ng/kg/min. Fifty units of botulinum toxin A in 10 mL of normal saline was injected into each hand via palmar approach focusing on the proximal aspect of each digital artery. After six days of IV steroids, she was transitioned to oral Prednisone 100 mg (1 mg/kg) daily. She received four cycles of Rituximab at 375 mg/m2, at approximately one-week intervals. Her Prednisone was tapered to 10 mg daily over the course of seven weeks. She then developed an IRAE of pneumonitis, which quickly improved when the Prednisone was increased to 50 mg daily. During steroid treatment, she was also on Alendronate and calcium for osteoporosis prophylaxis, Bactrim for pneumocystis pneumonia prophylaxis, and Omeprazole for gastrointestinal protection.Fig. 1 (Panel a and b). This picture was taken four weeks after her second Ipilimumab infusion (week 26 on timeline). Physical exam reveals acrocyanosis of all digits with small ulcers of the right second and fourth fingertips\n\nFig. 2 Conventional angiogram of the left arm was performed five weeks after her second Ipilimumab infusion (end of week 26 on timeline). There is severely diminished flow in the digital arteries of the left hand beyond the level of all proximal interphalangeal joints (black arrow), consistent with small vessel occlusive disease\n\n\n\nAfter the four cycles of Rituximab, we believe that the vasculitic process and additional damage were halted, as she did not develop further proximal digital ischemia or other systemic symptoms. The exam appeared worse with dry gangrene of the fingertips, consistent with the natural evolution of skin changes with distal digital ischemia, as shown in Fig. 3a & b (Taken 5 weeks after Fig. 1), likely reflecting consequences of the initial injury. She did ultimately require distal digit amputations. See Table 2 for the chronological outline of the case presentation.Fig. 3 (Panel a and b) This picture was taken nine weeks after her second Ipilimumab infusion (week 31 on timeline). The patient is status-post high dose steroids and four cycles of Rituximab. The exam appeared worse with dry gangrene of the fingertips, secondary to the natural evolution of skin changes with distal digital ischemia. We believe that the vasculitic process was halted, as she did not develop further proximal digital ischemia\n\nTable 2 Summarized timeline of case presentation\n\nWeek 0\tPresented with left groin mass. Excisional lymph node biopsy was consistent with metastatic melanoma.\t\nWeek 4\tRadical resection of melanoma with wide local excision of regressed primary and complete lymph node dissection.\t\nWeek 19\tFirst cycle of Ipilimumab 10 mg/kg. Side effects included mild diarrhea and mouth soreness.\t\nWeek 22\tSecond cycle of Ipilimumab 10 mg/kg.\t\nWeek 23\tSymptoms of myalgias, arthralgias, rash, vision changes, jaw pain, and discoloration of several upper and lower limb digits.\t\nWeek 24\tAmlodipine 10 mg daily, Aspirin 81 mg daily, and Prednisone 10 mg daily initiated for suspected Raynaud’s phenomenon. Digital pain and discoloration progressed.\t\nWeek 25\tShe received Methylprednisolone 500 mg IV followed by oral Prednisone 60 mg daily. Additional dose of 500 mg Methylprednisolone IV given later in the week. Lower extremity digital pain resolved, upper extremity digital pain progressed.\t\nWeek 26\tAdmitted. Initiated on Methylprednisolone 2 mg/kg/day IV, calcium channel blockade, and nitropaste. Administered an additional Methylprednisolone 1000 mg dose. Epoprostenol initiated for a 5-day course. Botulinum toxin A was injected into each hand. Refer to Fig. 1 for the physical exam and Fig. 2 for the conventional angiogram.\t\nWeek 27\tTransitioned to oral Prednisone 100 mg (1 mg/kg) daily and Sildenafil 20 mg BID.\t\nWeek 27-30\tInitiated on weekly Rituximab 375 mg/m2. Refer to Fig. 3 for the physical exam at week 31.\t\nWeek 32\tPrednisone was tapered down to 10 mg daily.\t\nWeek 34\tDeveloped IRAE of pneumonitis, prednisone was increased to 50 mg daily and symptoms improved.\t\nWeek 48-52\tSurgical amputation of multiple distal digits.\t\nWeek 49\tPrednisone completely weaned off.\t\n\n\nDiscussion and conclusions\nImmune related adverse events (IRAEs) are common with checkpoint inhibitors, and can range from mild to severe and life threatening [11, 12]. While there are common patterns in presentation, it is not possible to predict specific toxicities at this time. Skin, gastrointestinal tract, liver and endocrine glands are commonly affected. In general, IRAEs are treated with steroids which can require high doses with slow tapers at least over one month. Some IRAEs can be refractory and require additional immunosuppressive or immune-modulating agents including Infliximab or Mycophenolate [11–13]. Immune-related toxicities have been reported involving nearly all organ systems, including rare cardiac and neurologic toxicities [14]. Inflammatory arthritis mimicking rheumatoid arthritis and sicca syndrome have frequently been described in Ipilimumab use [15]. However, IRAEs involving blood vessels, such as vasculitides are quite rare and reported at a less than 1% incidence [16]. The most common vascular IRAE reported to date is giant cell arteritis/temporal arteritis [17]. A recent review addresses the molecular mechanism of how immune checkpoint inhibitors increase anti-vascular immunity risk, specifically in causing medium and large cell vasculitis, like giant cell arteritis [18]. In a search across PubMed, there have only been three case reports of vasculitis in Ipilimumab use. One case was isolated lymphocytic uterine vasculitis [19]. The other two cases were polymyalgia rheumatica with giant cell arteritis, both patients highly responsive to prednisone [20].\n\nTo our knowledge, this is the first reported case of an Ipilimumab IRAE causing small vessel vasculitis manifesting as digital ischemia. This case illustrates the current debate in melanoma oncology regarding the risk-benefit profile of adjuvant high dose Ipilimumab. Multiple studies of programmed death receptor-1 inhibitors in the adjuvant setting are completed with preliminary data or ongoing with pending data and further data from ECOG 1609 trial is forthcoming. This case highlights the importance of close monitoring of patients on immune checkpoint inhibitor therapy and prompt diagnosis and management of immune related adverse events.\n\nAbbreviations\nCTLA-4Cytotoxic T-lymphocyte antigen 4\n\nICIImmune checkpoint inhibitor\n\nIRAEImmune related adverse event\n\nIVIntravenous\n\nAcknowledgements\nN/A\n\nFunding\nN/A\n\nAvailability of data and materials\nN/A\n\nAuthors’ contributions\nAP, LF, JS, VM, AA all provided care to this patient. AP, LF, ES all made significant contributions to drafting the manuscript. JS, AA, and VM revised and edited the manuscript multiple times. Each author has given final approval of the version to be published. All authors have agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNo formal ethics approval was needed since we were only reporting an observational case report. Consent was obtained from the patient.\n\nConsent for publication\nConsent was obtained from the patient. She signed a biomed generic consent for this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Melero I Hervas-Stubbs S Glennie M Pardoll DM Chen L Immunostimulatory monoclonal antibodies for cancer therapy Nat Rev Cancer 2007 7 95 106 10.1038/nrc2051 17251916 \n2. World Health Organization. Skin cancers. (Accessed 1 May 2017, at http://www.who.int/uv/faq/skincancer/en/index1.html.)\n3. Hodi FS O'Day SJ McDermott DF Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 2010 363 8 711 723 10.1056/NEJMoa1003466 20525992 \n4. Eggermont AM Chiarion-Sileni V Grob JJ Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomized, double-blind, phase 3 trial Lancet Oncol. 2015 16 5 522 530 10.1016/S1470-2045(15)70122-1 25840693 \n5. Eggermont AM Chiarion-Sileni V Grob JJ Prolonged survival in stage III melanoma with Ipilimumab adjuvant therapy N Engl J Med 2016 375 19 1845 1855 10.1056/NEJMoa1611299 27717298 \n6. Tarhini AA, Lee SJ, Hodi FS, et al. A phase III randomized study of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk melanoma (U.S. Intergroup E1609): Preliminary safety and efficacy of the ipilimumab arms. J Clin Oncol. 2017 (suppl; abstr 9500).\n7. Wolchok JD Neyns B Linette G Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomized, double-blind, multicenter, phase 2, dose-ranging study Lancet Oncol. 2010 11 2 155 164 10.1016/S1470-2045(09)70334-1 20004617 \n8. Ascierto PA Del Vecchio M Robert C Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomized, double-blind, multicenter, phase 3 trial Lancet Oncol 2017 18 5 611 622 10.1016/S1470-2045(17)30231-0 28359784 \n9. Hodi FS Lee S McDermott DF Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial JAMA 2014 312 17 1744 1753 10.1001/jama.2014.13943 25369488 \n10. Weber J Thompson JA Hamid O A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma Clin Cancer Res 2009 15 17 5591 5598 10.1158/1078-0432.CCR-09-1024 19671877 \n11. Fecher LA Agarwala SS Hodi FS Weber JS Ipilimumab and its toxicities: a multidisciplinary approach Oncologist 2013 18 6 733 743 10.1634/theoncologist.2012-0483 23774827 \n12. Weber JS Postow M Lao CD Schadendorf D Management of Adverse Events Following Treatment with Anti-Programmed Death-1 agents Oncologist 2016 21 10 1230 1240 10.1634/theoncologist.2016-0055 27401894 \n13. Weber J Ipilimumab: controversies in its development, utility and autoimmune adverse events Cancer Immunol Immunother 2009 58 5 823 830 10.1007/s00262-008-0653-8 19198837 \n14. Michot JM Bigenwald C Champiat S Immune-related adverse events with immune checkpoint blockade: a comprehensive review Eur J Cancer 2016 54 139 148 10.1016/j.ejca.2015.11.016 26765102 \n15. Cappelli LC Gutierrez AK Baer AN Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab Ann Rheum Disease 2017 76 1 43 50 10.1136/annrheumdis-2016-209595 27307501 \n16. Ipilimumab FDA label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf.\n17. O'Day SJ Maio M Chiarion-Sileni V Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study Ann Oncol 2010 21 8 1712 1717 10.1093/annonc/mdq013 20147741 \n18. Watanabe R Zhang H Berry G Goronzy JJ Weyand CM Immune checkpoint dysfunction in medium and large vessel Vasculitis Am J Physiol Heart Circ Physiology 2017 312 5 H1052 H1059 10.1152/ajpheart.00024.2017 \n19. Minor DR, Bunker SR, Doyle J. Lymphocytic Vasculitis of the Uterus in a Patient with Melanoma Receiving Ipilimumab. J Clin Oncol. 2013;31(20):e356.\n20. Goldstein BL Gedmintas L Todd DJ Drug associated Polymyalgia Rheumatica/Giant cell Arteritis occurring in two patients after treatment with Ipilimumab, an antagonist of CTLA-4 Arthritis & Rheumatology 2014 66 3 768 769 10.1002/art.38282 24574239\n\n",
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"issue": "6(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "Immune related adverse events (IRAEs); Ipilimumab; Vasculitis",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008545:Melanoma; D008875:Middle Aged; D012878:Skin Neoplasms; D014657:Vasculitis",
"nlm_unique_id": "101620585",
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"title": "Ipilimumab induced digital vasculitis.",
"title_normalized": "ipilimumab induced digital vasculitis"
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"abstract": "OBJECTIVE\nTo determine the safety and efficacy of enteral naloxone for the treatment of opioid-induced constipation in the medical intensive care unit (MICU).\n\n\nMETHODS\nThis descriptive study included patients aged 18 to 89 years admitted to the MICU between July 1, 2007, and June 30, 2012, who received scheduled opioids and at least 1 dose of enteral naloxone. All data were obtained from electronic charting systems. Efficacy was assessed by evaluating time to bowel movement (BM), number of naloxone doses until BM, and ability to tolerate tube feeds after receipt of enteral naloxone. Safety was assessed by comparing opioid requirements, heart rates, and systolic blood pressures before and during naloxone treatment.\n\n\nRESULTS\nFifteen of the 16 patients included in the final analysis passed BMs during the study period. The median time to BM was 24.4 hours. The median number of naloxone doses received prior to passing a BM was 3. Seventy-eight percent of patients who were not receiving tube feeds at the time of naloxone administration received continuous tube feeds after naloxone initiation. No adverse effects associated with use of enteral naloxone were noted.\n\n\nCONCLUSIONS\nEnteral naloxone appears safe for the treatment of opioid-induced constipation in the MICU. Enteral naloxone may be effective in treating opioid-induced constipation; however, further studies are warranted.",
"affiliations": "Veterans Affairs North Texas Health Care System/Texas Tech University Health Sciences Center School of Pharmacy, Dallas, TX.;Veterans Affairs North Texas Health Care System/Texas Tech University Health Sciences Center School of Pharmacy, Dallas, TX. Electronic address: steven.pass@ttuhsc.edu.",
"authors": "Gibson|Caitlin M|CM|;Pass|Steven E|SE|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone",
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"issue": "29(5)",
"journal": "Journal of critical care",
"keywords": "Constipation; ICU analgesia; Intensive care units; Naloxone; Opioid-induced constipation; Opioids",
"medline_ta": "J Crit Care",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D003248:Constipation; D065187:Controlled Before-After Studies; D003672:Defecation; D004750:Enteral Nutrition; D005260:Female; D006339:Heart Rate; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D012189:Retrospective Studies; D013997:Time Factors",
"nlm_unique_id": "8610642",
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"pages": "803-7",
"pmc": null,
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"pubdate": "2014-10",
"publication_types": "D016428:Journal Article",
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"title": "Enteral naloxone for the treatment of opioid-induced constipation in the medical intensive care unit.",
"title_normalized": "enteral naloxone for the treatment of opioid induced constipation in the medical intensive care unit"
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"abstract": "Anticholinergic toxicity is a relatively uncommon occurrence. When it does occur, it is usually attributed to an overdose of anticholinergic agents, especially in the elderly population. In younger patients, anticholingeric toxicity is usually due to an intentional overdose in a suicide attempt, accidental exposure to jimson weed or deadly nightshade plant, or the combination of anticholinergic drugs with recreational drugs (psilocybin mushroom). Over-the-counter cold medicines are well known to contain a variety of anticholinergic substances, the most well-known being diphenhydramine. Uncommonly, these readily available substances can produce anticholinergic toxicity in elderly patients, even when appropriate dosages are consumed. Younger patients are less likely to develop this clinical picture, due to higher renal clearance and lower drug volume of distribution. Nonetheless, clinical suspicion should remain high in the younger population. Patients can present with fever, tachycardia, diplopia, urinary retention, dry mucous membranes, and altered mental status. This case provides awareness to the unlikely complication of over-the-counter cold medicines in a young 19-year-old patient, while highlighting the need for diligent history taking and deliberate use of physostigmine in patients with altered mental status.",
"affiliations": "Internal Medicine, University of Connecticut School of Medicine, Farmington, USA.;Internal Medicine, Hartford Hospital, Hartford, USA.;Internal Medicine, Hartford Hospital, Hartford, USA.",
"authors": "Khan|Ahsum|A|;Singh|Gagan|G|;Jacob|Jason|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.13919",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13919\nEmergency Medicine\nInternal Medicine\nMedical Education\nA Rare Presentation of Anticholinergic Toxicity in a Young Patient Due to Over-The-Counter Cold Medicines\nMuacevic Alexander\nAdler John R\nKhan Ahsum 1\nSingh Gagan 2\nJacob Jason 2\n1 Internal Medicine, University of Connecticut School of Medicine, Farmington, USA\n2 Internal Medicine, Hartford Hospital, Hartford, USA\nAhsum Khan ahsumk@gmail.com\n16 3 2021\n3 2021\n13 3 e1391916 3 2021\nCopyright © 2021, Khan et al.\n2021\nKhan et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/44414-a-rare-presentation-of-anticholinergic-toxicity-in-a-young-patient-due-to-over-the-counter-cold-medicines\nAnticholinergic toxicity is a relatively uncommon occurrence. When it does occur, it is usually attributed to an overdose of anticholinergic agents, especially in the elderly population. In younger patients, anticholingeric toxicity is usually due to an intentional overdose in a suicide attempt, accidental exposure to jimson weed or deadly nightshade plant, or the combination of anticholinergic drugs with recreational drugs (psilocybin mushroom).\n\nOver-the-counter cold medicines are well known to contain a variety of anticholinergic substances, the most well-known being diphenhydramine. Uncommonly, these readily available substances can produce anticholinergic toxicity in elderly patients, even when appropriate dosages are consumed. Younger patients are less likely to develop this clinical picture, due to higher renal clearance and lower drug volume of distribution. Nonetheless, clinical suspicion should remain high in the younger population. Patients can present with fever, tachycardia, diplopia, urinary retention, dry mucous membranes, and altered mental status. This case provides awareness to the unlikely complication of over-the-counter cold medicines in a young 19-year-old patient, while highlighting the need for diligent history taking and deliberate use of physostigmine in patients with altered mental status.\n\nanticholinergic overdose\nanticholingeric delerium\naltered mental state\notc medication\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nAnticholinergic toxicity is usually attributed to an overdose of anticholinergic agents, although mild toxicity can be noted as a side effect of these drugs. Most of these anticholinergic agents are ingested by mouth, such as atropine, scopolamine, jimson weed, tricyclic antidepressants (TCAs), and overactive bladder antimuscarinics (oxybutynin, tolterodine, and solifenacin) [1]. Importantly, the anticholinergic effects of these medications are synergistic, meaning the use of multiple agents results in a greater risk for anticholinergic toxicity [1,2].\n\nIn terms of pathophysiology, anticholinergic agents compete with acetylcholine at the postganglionic parasympathetic muscarinic receptors. Muscarinic receptors can be found in the salivary glands, smooth muscle, heart, eye, and central nervous system. As a result, during anticholinergic toxicity, patients can present with anhidrosis, tachycardia, fever, altered mental status (confusion, hallucinations, agitation, or delirium), urinary retention, mydriasis, diplopia, and dry mucous membranes [2,3]. In particular, toxicity due to diphenhydramine can present with cardiovascular findings, due to binding with calcium and sodium channels, leading to prolonged QT and QRS complexes [1,2].\n\nIn 2018, the American Association of Poison Control Centers reported 3613 single exposures to anticholinergics, 74,698 single exposures to antihistamines, with 30,883 specific to diphenhydramine [4,5]. And of these exposures, diphenhydramine was responsible for 22 out of 24 deaths attributable to antihistamines. In 2017, the sales of cold medications totaled over 150 million units accounting for almost 900 million dollars in sales [4,5]. These medications commonly contain antihistamines, particularly diphenhydramine, which can be an unrecognized cause of delirium in patients.\n\nIn this report, we describe the case of a 19-year-old male with a past medical history of asthma who presented to the emergency department (ED) with altered mental status and slurring of speech in the context of frequent intake of over-the-counter (OTC) cold medicine due to an upper respiratory infection. He was found to be tachycardic to 110 beats per min, hypertensive to 160/110 mmHg, with a prolonged QTc of 545 ms, and responded with a rapid improvement in mental status, following a dose of physostigmine for suspected anticholinergic toxicity.\n\nPresentation of anticholinergic toxicity in the general population can vary greatly. Although it is more commonly seen in the elderly, due to decreased renal clearance, and body fat composition, younger patients can also be affected [2,3]. In this younger cohort, toxicity can commonly present as an intentional suicide attempt, accidental ingestion of drugs or plants (jimson weed (Datura stramonium) or deadly nightshade (Atropa belladonna)) by children, or combination of anticholinergic medicines and recreational drugs (psilocybin mushrooms) [1,3]. However, an important, often overlooked cause in both young and elderly populations is the use of OTC cold medications. Diligence during history taking can be critical, in teasing out the intake of multiple cold medications, quantity, and frequency. \n\nCase presentation\n\nA 19-year-old male with a past medical history of asthma presented to the ED with suspicion for altered mental status due to slurred speech and decreased alertness. He was completely alert and oriented the evening prior to presentation, but was complaining of increased fatigue and viral-like symptoms (cough, congestion, and rhinorrhea) that had been present for over six days.\n\nAt 3 AM, his mother heard him walking around his room and subsequently heard a loud noise. She quickly went to investigate the noise, and found her son confused, lying face down in bed, and slurring his speech. Emergency Medical Service was called, and he was found to be hypertensive to 160/110 mmHg, tachycardic to 110 beats per minute, and his fasting glucose was found to be 49 mg/dl. A bolus of D50 was given, but produced no positive impact on his clinical state. Salicylate, ammonia, acetaminophen, and thyroid hormone levels were all within normal limits. A complete metabolic panel, complete blood count, venous blood gas, carboxyhemoglobin, urine toxicology, CT scan of the head, chest x-ray, and lumbar puncture were all checked, all of which were non-significant. An EKG revealed sinus tachycardia, with prolonged QTc to 545 ms. Patient was also found to be hypertensive. After these investigations yielded no results, a more detailed physical and history was obtained.\n\nThe patient’s mother stated that the patient had been ingesting the OTC cold medications Nyquil and Simply Sleep, both containing diphenhydramine, quite frequently. She also noted that the patient had taken a full 16 oz bottle of Nyquil, over the course of 6 hours preceding the hospital presentation. Closer physical exam revealed 6 mm dilated pupils, flushing of his skin, altered mental status, all consistent with anticholinergic toxicity. In the context of the patient’s presentation, 2 mg of physostigmine was given over 5 min, and the patient became fully alert and oriented within 30 min. He was monitored in the intensive care unit, but did not require further physostigmine. He was discharged with close follow-up the next day.\n\nDiscussion\n\nThis case describes an unusual complication of OTC cold medicine usage in a relatively young patient. Anticholinergic delirium is a relatively rare phenomenon in the younger population. Younger individuals tend to have a greater resilience to the anticholinergic toxicity, so accidental overdose on OTC cold medications is rare [6,7]. Our patient’s combination of Simply Sleep and NyQuil introduced the H1 antagonists, doxylamine and diphenhydramine, into his system. Together, even in relatively low doses, these drugs can produce a dramatic anticholinergic effect [1]. It was evident that this patient had not been taking the appropriate doses of these medications, which led to the enhanced depression of his muscarinic activity, and the corresponding clinical picture.\n\nIn regard to clinical picture, classical anticholinergic toxicity can be remembered using the phrase “red as a beet, hot as a hare, dry as a bone, mad as a hatter, blind as a bat, and full as a flask” [1]. Therefore, the typical patient will present with flushing, fever, dry mucous membranes, altered mental status/delirium, mydriasis, diplopia, and urinary retention. Rarely, patients can present with seizures, jerking movements, and rhabdomyolysis [1]. As aforementioned, diphenhydramine has been associated with QT and QTC prolongation due to action on sodium and calcium channels [1,2].\n\nDiagnosis of anticholinergic toxicity should follow a systematic approach, one that is consistent with workup of any patient suspected poisoning. The patient’s airway, breathing, and circulation should all be initially assessed. Vital signs should be obtained and evaluated, including heart rate, respiratory rate, pulse oximetry, and blood pressure. The patient should be placed on continuous cardiac monitoring, and have intravenous (IV) access in place [1,2]. Diagnostic testing, including liver panel, urine toxicology screen, creatine kinase, basic metabolic panel, salicylate and acetaminophen level, should all be obtained. The diagnosis is largely based upon clinical findings and history of presentation, as other diagnoses are excluded as mentioned above [2,3].\n\nManagement of this presentation is largely supportive. However, in cases where presentation is severe, or signs of altered mental status are observed (central nervous system effects), as was the case in our patient, physostigmine can be used. Physostigmine is an acetylcholinesterase inhibitor that demonstrates peripheral central nervous system activity. The recommended dose is 0.5 to 2 mg IV for adults [1,3]. If symptoms do not respond within 30 min, a second dose may be warranted. In cases of severe diphenhydramine poisoning that does not respond to physostigmine, IV fat emulsion therapy has been proven to be useful. If the patient demonstrates seizure activity, benzodiazepines and correcting electrolyte disturbances may be indicated. Activated charcoal can be used, if indigestion of the anticholinergic drug is within 1 h of presentation. Finally, the hyperthermia in anticholinergic poisoning is classified as an anhidrotic hyperthermia. Sweat glands are innervated by muscarinic receptors [1]. Blockade of these receptors by anticholinergic medications leads to interference with normal heat dissipation methods (sweating), potentially leading to hyperthermia. Hyperthermia in anticholinergic poisoning should be treated with active cooling measures, as antipyretics will not be helpful as this fever is not cytokine based (as opposed to infectious etiology of fever) [1,2,6]. Additionally, atypical antipsychotics should be used with caution, when dealing with encephalopathy due to the risk of hyperthermia and prolonged QTc. A TCA level should be checked in the urine prior to giving physostigmine, due to risk of asystole [2,3].\n\nConclusions\n\nThis report described the case of anticholinergic toxicity secondary to OTC cold medicine usage in a relatively young patient. Outright delirium is rare in young patients secondary to OTC cold medicine usage, due to increased resilience. This resilience stems from a combination of higher renal clearance of drugs, less volume of distribution, and increased brain reserve. However, it is still possible, and clinical suspicion is still warranted in these cases. Management of severe cases may include the use of physostigmine. If seizures are present, correcting electrolyte disturbances and abortive therapy with benzodiazepines are indicated. With decisive clinical judgment, quick disbursement of acetylcholinesterase inhibitor medication, and supportive measures, prognosis is good overall.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Anticholinergic Toxicity. StatPearls [Internet] Broderick ED Metheny H Crosby B Treasure Island, FL StatPearls Publishing 2020 https://www.ncbi.nlm.nih.gov/books/NBK534798/\n2 Toxicity of over-the-counter cough and cold medications Pediatrics Gunn VL Taha SH Liebelt EL Serwint JR 0 108 2001\n3 The latest update on over-the-counter cough and cold product use in children J Pediatr Pharmacol Ther Briars LA 127 131 14 2009 23055900\n4 2015 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd annual report Clin Toxicol (Phila) Mowry JB Spyker DA Brooks DE Zimmerman A Schauben JL 924 1109 54 2016 28004588\n5 2016 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th annual report Clin Toxicol (Phila) Gummin DD Mowry JB Spyker DA Brooks DE Fraser MO Banner W 1072 1252 55 2017 29185815\n6 Understanding older adults' medication decision making and behavior: a study on over-the-counter (OTC) anticholinergic medications Res Social Adm Pharm Holden RJ Srinivas P Campbell NL 53 60 15 2019 29559218\n7 Dextromethorphan, chlorphenamine and serotonin toxicity: case report and systematic literature review Br J Clin Pharmacol Monte AA Chuang R Bodmer M 794 798 70 2010 21175434\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(3)",
"journal": "Cureus",
"keywords": "altered mental state; anticholinergic overdose; anticholingeric delerium; otc medication",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e13919",
"pmc": null,
"pmid": "33880270",
"pubdate": "2021-03-16",
"publication_types": "D002363:Case Reports",
"references": "11533370;23055900;28004588;21175434;29185815;29559218",
"title": "A Rare Presentation of Anticholinergic Toxicity in a Young Patient Due to Over-The-Counter Cold Medicines.",
"title_normalized": "a rare presentation of anticholinergic toxicity in a young patient due to over the counter cold medicines"
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"activesubstancename": "DIPHENHYDRAMINE HYDROCHLORIDE"
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"abstract": "Osteopetrosis (OP) is a rare disease caused by defective osteoclast differentiation or function. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available in the infantile \"malignant\" form of OP. Improved clinical and genetic diagnosis of OP has seen the emergence of a cohort of patients with less severe and heterogeneous clinical presentations. This intermediate form of OP does not call for urgent intervention, but patients accumulate debilitating skeletal complications over years and decades, which are severe enough to require curative treatment and may also require intermittent transfusion of blood products. Here we present data from 7 patients with intermediate OP caused by mutations in TCIRG1 (n = 2), CLCN7 (n = 2), RANK (n = 1), SNX10 (n = 1), and CA2 (n = 1), who were transplanted between the ages of 5 to 30 years (mean, 15; median, 12). Donors were matched siblings or family (n = 4), matched unrelated (n = 2), or HLA haploidentical family donors (n = 1). Conditioning was fludarabine and treosulfan based. All 6 patients transplanted from matched donors are currently alive with a follow-up period between 1 and 8 years at time of publication (median, 4 years) and have demonstrated a significant improvement in symptoms and quality of life. Patients with intermediate OP should be considered for HSCT.",
"affiliations": "Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.;Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.;Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.;Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.;Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel.;Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem, Israel; and.;Department of Pediatrics and Adolescent Medicine.;Department of Pediatrics and Adolescent Medicine.;Department of Pediatrics and Adolescent Medicine.;Department of Pediatrics and Adolescent Medicine.;Department of Radiology, and.;Department of Internal Medicine III, University Medical Center Ulm, Ulm, Germany.;Department of Internal Medicine III, University Medical Center Ulm, Ulm, Germany.;Department of Pediatrics and Adolescent Medicine.;Department of Pediatrics and Adolescent Medicine.",
"authors": "Stepensky|Polina|P|;Grisariu|Sigal|S|;Avni|Batia|B|;Zaidman|Irina|I|;Shadur|Bella|B|;Elpeleg|Orly|O|;Sirin|Mehtap|M|;Hoenig|Manfred|M|;Schuetz|Catharina|C|;Furlan|Ingrid|I|;Beer|Meinrad|M|;von Harsdorf|Stephanie|S|;Bunjes|Donald|D|;Debatin|Klaus-Michael|KM|;Schulz|Ansgar S|AS|0000-0002-7798-7996",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/bloodadvances.2018025890",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2473-9529",
"issue": "3(6)",
"journal": "Blood advances",
"keywords": null,
"medline_ta": "Blood Adv",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009154:Mutation; D010022:Osteopetrosis; D011788:Quality of Life; D014019:Tissue Donors; D019172:Transplantation Conditioning; D055815:Young Adult",
"nlm_unique_id": "101698425",
"other_id": null,
"pages": "862-868",
"pmc": null,
"pmid": "30885997",
"pubdate": "2019-03-26",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22499339;14584882;26485304;10587979;24535816;26012570;14675409;16953210;18606301;19172990;25879376;15625335;23113501;23877423",
"title": "Stem cell transplantation for osteopetrosis in patients beyond the age of 5 years.",
"title_normalized": "stem cell transplantation for osteopetrosis in patients beyond the age of 5 years"
} | [
{
"companynumb": "IL-ADIENNEP-2019AD000206",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TREOSULFAN"
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"drugadditional": "3",
... |
{
"abstract": "We present a patient with hepatitis C virus (HCV) and cirrhosis who was treated with eltrombopag for idiopathic thrombocytopenic purpura and was incidentally found to have a right atrial thrombus with extension into the left internal jugular vein. Eltrombopag was discontinued and the patient was treated with thrombectomy and anticoagulation. Given the proposed use of eltrombopag in HCV-associated thrombocytopenia, we advise caution when treating cirrhotics who are at higher intrinsic risk of thrombosis.",
"affiliations": "Department of Internal Medicine, Albert Einstein Medical Center, Philadelphia, PA.;Department of Internal Medicine, Albert Einstein Medical Center, Philadelphia, PA.;Division of Hematology and Oncology, Albert Einstein Medical Center, Philadelphia, PA.;Division of Hepatology, Albert Einstein Medical Center, Philadelphia, PA.",
"authors": "Baumann|Alexandra J|AJ|;Wheeler|David S|DS|;Varadi|Gabor|G|;Feyssa|Eyob|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.2016.20",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2016.2010.14309/crj.2016.20Case ReportLiverSevere Thrombotic Complication of Eltrombopag in a Cirrhotic Patient Baumann Alexandra J. DO1Wheeler David S. MD, PhD1Varadi Gabor MD2Feyssa Eyob MD31 Department of Internal Medicine, Albert Einstein Medical Center, Philadelphia, PA2 Division of Hematology and Oncology, Albert Einstein Medical Center, Philadelphia, PA3 Division of Hepatology, Albert Einstein Medical Center, Philadelphia, PACorrespondence: Alexandra J. Baumann, Department of Internal Medicine, Albert Einstein Medical Center, 5401 Old York Road, Klein 363, Philadelphia, PA 19141 (baumanna@einstein.edu).1 2016 20 1 2016 3 2 121 123 21 4 2015 16 11 2015 Copyright © Baumann et al.2016This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/We present a patient with hepatitis C virus (HCV) and cirrhosis who was treated with eltrombopag for idiopathic thrombocytopenic purpura and was incidentally found to have a right atrial thrombus with extension into the left internal jugular vein. Eltrombopag was discontinued and the patient was treated with thrombectomy and anticoagulation. Given the proposed use of eltrombopag in HCV-associated thrombocytopenia, we advise caution when treating cirrhotics who are at higher intrinsic risk of thrombosis.\n==== Body\nIntroduction\nThe incidence of chronic idiopathic thrombocytopenic purpura (ITP) in hepatitis C virus (HCV) is estimated to be very low.1 Eltrombopag, a thrombopoietin receptor agonist, is FDA approved to treat thrombocytopenia in chronic ITP and in HCV patients, so that interferon-based therapy may be initiated and maintained.2\n\n\nCase Report\nA 52-year-old woman with chronic HCV and chronic ITP stable on eltrombopag presented with decompensated liver disease. She had failed to complete interferon-based therapy due to thrombocytopenia and subsequently developed cirrhosis and portal hypertension. Initial abdominal/pelvic computed tomography (CT) scan incidentally found a 2.75 x 2.46 cm right atrial thrombus. Chest CT revealed extension of the thrombus to the superior vena cava, brachiocephalic, left subclavian, and left internal jugular vein (Figure 1).\n\nFigure 1 Imaging of an extensive eltrombopag-induced thrombus extending from the right atria to left internal jugular vein. Chest CT demonstrated a right atrial thrombus extending into the (A) superior vena cava (arrow), brachiocephalic vein (arrowhead), and (B) left internal jugular vein (arrow).\n\nShe had no prior history of thromboembolic events or identifiable thrombotic risk factors other than 3 years of intermittent eltrombopag use due to bleeding and platelet counts lower than 30,000/mm3. At eltrombopag initiation, giant platelets on peripheral blood smear consistent with ITP were noted, but no portal hypertension or hepatosplenomegaly. Her platelet count on current admission was 81,000/mm3, and this strong platelet response to eltrombopag supported an autoimmune origin over bone marrow dysfunction or sequestration.\n\nEltrombopag was discontinued and the patient underwent cardiothoracic surgery to remove the thrombus in the right atrium and some of its extension into the superior vena cava. Intravenous heparin therapy and warfarin was started immediately following surgery. Follow-up imaging showed improved vascular patency. Prior surveillance imaging with ultrasound revealed no evidence for hepatocellular carcinoma. The patient tested negative for anti-B2-glycoprotein and lupus anticoagulant; further hypercoaguable work-up could not be performed due to cirrhosis and anticoagulation use.\n\nDiscussion\nThromboembolic events are reported to occur in 2-5% of noncirrhotic patients receiving eltrombopag.3,4 The safety in cirrhotic patients is less clear. An initial study in cirrhosis was discontinued due to higher rates of thrombotic events; however, a more recent study found the risk to be similar to that of noncirrhotic patients.5,6 This may reflect the complex coagulation system in cirrhosis, in which antithrombin III and protein C promote coagulation simultaneously as factor VIII and von Willebrand factor deficiencies prevent coagulation; hemorrhage or thrombosis can result.7 Further studies are needed to understand the mechanism behind eltrombopag’s effect on this delicately balanced coagulation system. Elevation of platelet counts are one consideration, and one study showed increased thrombotic risk with platelet counts equal or greater than 200,000/mm3.5\n\nAtrial thrombus has occurred in cirrhotic patients, usually in the setting of hepatocellular carcinoma, which likely shifts the tenuous coagulation balance toward thrombosis.8,9 Our patient did not have evidence of liver nodules or masses on ultrasound or CT. We hypothesize that our patient’s extensive clot with atypical location was caused by the procoagulant effects of eltrombopag. Prior to using eltrombopag in cirrhosis, the potential benefits must be weighed against the risks of thrombosis. While no evidence-based guidelines exist, it may be advisable to screen for portal vein patency with imaging prior to initiating therapy. Additionally, maintenance of platelet counts between 50,000/mm3 (a count adequate for hemostasis) and 150,000/mm3 (a count above which there is increased thrombotic risk) is advisable according to expert consensus.\n\nDisclosures\nAuthor contributions: All authors approved the final manuscript. AJ Baumann performed the literature review, drafted the manuscript, and is the article guarantor. DS Wheeler contributed to the literature review and drafting of the manuscript. G. Varadi and E. Feyssa critically revised the manuscript for important intellectual content.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n\nPrevious Presentation: This case was presented as a poster at a the American College of Physicians Regional Conference; October 2013; Philadelphia, Pennsylvania.\n==== Refs\nReferences\n1 Chiao EY , Engels EA , Kramer JR , et al. \nRisk of immune thrombocytopenic purpura and autoimmune hemolytic anemia among 120 908 US veterans with hepatitis C virus infection . Arch Intern Med . 2009 ;169 (4 ): 357 –63 .19237719 \n2 McHutchison JG , Dusheiko G , Shiffman ML , et al. \nEltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C . N Engl J Med . 2007 ;357 (22 ):2227 –36 .18046027 \n3 Cheng G , Saleh MN , Marcher C , et al. \nEltrombopag for management of chronic immune thrombocytopenia (RAISE): A 6-month, randomised, phase 3 study . Lancet . 2011 ;377 (9763 ):393 –402 .20739054 \n4 Saleh MN , Bussel JB , Cheng G , et al. \nSafety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: Results of the long-term, open-label EXTEND study . Blood . 2013 ;121 (3 ):537 –45 .23169778 \n5 Afdhal NH , Giannini EG , Tayyab G , et al. \nEltrombopag before procedures in patients with cirrhosis and thrombocytopenia . N Engl J Med . 2012 ;367 (8 ):716 –24 .22913681 \n6 Afdhal NH , Dusheiko GM , Giannini EG , et al. \nEltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy . Gastroenterology . 2014 ;146 (2 ):442 –52 .24126097 \n7 Tripodi A , Mannucci PM \nThe coagulopathy of chronic liver disease . N Engl J Med . 2011 ;365 (2 ):147 –56 .21751907 \n8 Kato Y , Tanaka N , Kobayashi K , et al. \nGrowth of hepatocellular carcinoma into the right atrium: Report of five cases . Ann Intern Med . 1983 ;99 (4 ):472 –4 .6312861 \n9 Agelopoulou P , Kapatais A , Varounis C , et al. \nHepatocellular carcinoma with invasion into the right atrium: Report of two cases and review of the literature . Hepatogastroenterology . 2007 ;54 (79 ):2106 –8 .18251169\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "3(2)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "121-3",
"pmc": null,
"pmid": "26958566",
"pubdate": "2016-01",
"publication_types": "D002363:Case Reports",
"references": "21751907;6312861;19237719;18251169;20739054;24126097;22913681;23169778;18046027",
"title": "Severe Thrombotic Complication of Eltrombopag in a Cirrhotic Patient.",
"title_normalized": "severe thrombotic complication of eltrombopag in a cirrhotic patient"
} | [
{
"companynumb": "PHHY2016US032391",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ELTROMBOPAG"
},
"drugadditional": null,
"dru... |
{
"abstract": "Still considered a new ASD, teratogenicity from lacosamide (LCM) exposure during pregnancy is unknown. LCM metabolism through several cytochrome P450 enzymes and minor glucuronidation metabolism in the liver may increase during pregnancy and theoretically lead to lower LCM levels during pregnancy and the risk of increased seizures. Our objective was to determine the impact of pregnancy on serum LCM levels in a series of women with epilepsy (WWE). We identified seven pregnancies with exposure to LCM with at least one level drawn during pregnancy. Patient ages ranged from 18 to 38 years (mean 26.4 years) and total daily doses of LCM ranged from 200 to 600 mg/day. Two patients had increased dose adjustments in response to breakthrough seizures. Dose normalized concentrations (DNC) showed an overall decrease over time through each trimester (p = 0.002) and significantly lower during trimester 2 and 3 (p = 0.001 and p = 0.004, respectively) compared to pre-pregnancy levels. There were no significant changes in seizure frequency and none of the neonates had teratogenic findings at time of birth. We are the first to report a case series on the changes in LCM levels during pregnancy with significant decreased LCM DNC levels during the second and third trimesters in comparison to pre-pregnancy values.",
"affiliations": "Comprehensive Epilepsy Center, Department of Neurology, Wayne State University, Detroit, MI, USA. Electronic address: dzutshi@med.wayne.edu.;Department of Physical Medicine and Rehabilitation, Wayne State University, Detroit, MI, USA.;Comprehensive Epilepsy Center, Department of Neurology, Wayne State University, Detroit, MI, USA.;Comprehensive Epilepsy Center, Department of Neurology, Wayne State University, Detroit, MI, USA.;Comprehensive Epilepsy Center, Department of Neurology, Wayne State University, Detroit, MI, USA.",
"authors": "Zutshi|Deepti|D|;Millis|Scott R|SR|;Basha|Maysaa M|MM|;Daimee|Maha A|MA|;Srinivas|Meghana|M|",
"chemical_list": "D000927:Anticonvulsants; D000078334:Lacosamide",
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"doi": "10.1016/j.yebeh.2021.108253",
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"journal": "Epilepsy & behavior : E&B",
"keywords": "All Epilepsy/seizures [60]; Antiepileptic drugs [61]; Pregnancy",
"medline_ta": "Epilepsy Behav",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D004827:Epilepsy; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D000078334:Lacosamide; D011247:Pregnancy; D012640:Seizures; D055815:Young Adult",
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"title": "Lacosamide serum concentrations during pregnancy.",
"title_normalized": "lacosamide serum concentrations during pregnancy"
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"abstract": "A review of the literature reflects numerous instances of acute pancreatitis developing in patients while being treated with drugs. The causative relation is not yet definitively established but, in several instances, there appears to be a probable relation. The literature records at least 112 patients with drug-induced acute pancreatitis. Fifty-one instances were caused by steroids or adrenocorticotropic hormone, six by estrogen, two by azathioprine, 16 by diurectics, two by hypercalcemia, 24 by chemotherapy, three by clonidine and phenformin, two by warfarin and one each by salicylate, 1-asparaginase and d-propoxyphene. In addition, many patients have experienced acute pancreatitis while receiving immunosuppressive therapy after renal transplantation.",
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"authors": "Nakashima|Y|Y|;Howard|J M|JM|",
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"mesh_terms": "D000208:Acute Disease; D000305:Adrenal Cortex Hormones; D000324:Adrenocorticotropic Hormone; D000328:Adult; D000367:Age Factors; D001379:Azathioprine; D002648:Child; D004232:Diuretics; D004967:Estrogens; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D008297:Male; D010195:Pancreatitis",
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"title": "Drug-induced acute pancreatitis.",
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"abstract": "Identification of the cause of hypotension after induction of anesthesia is critical as treatment differs. We describe a case of anaphylaxis in a patient with severe cardiac disease, diagnosed by echocardiography and successfully treated with immediate cardiovascular resuscitation, epinephrine, vasopressors and antihistamines.",
"affiliations": null,
"authors": "Bhatt|Himani V|HV|;Frost|Elizabeth A M|EA|",
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"issue": "22(6)",
"journal": "Middle East journal of anaesthesiology",
"keywords": null,
"medline_ta": "Middle East J Anaesthesiol",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000758:Anesthesia; D005260:Female; D006333:Heart Failure; D006801:Humans; D007022:Hypotension",
"nlm_unique_id": "8604187",
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"pages": "623-6",
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"pubdate": "2014-10",
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"title": "Hypotension on induction: anaphylaxis or cardiac failure?",
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"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2015US-95500",
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"abstract": "BACKGROUND\nAnterior uveitis secondary to topical brimonidine administration is rare and not well-defined. In glaucoma patients using brimonidine, one must consider this phenomenon to avoid mis-diagnosis and over-treatment with topical steroids which in turn may increase intraocular pressure (IOP). This is the largest case series including the longest patient follow-up in the current literature.\n\n\nMETHODS\nSixteen patients (26 eyes) with consultant diagnosed brimonidine-associated anterior uveitis in a tertiary referral glaucoma clinic presenting between 2015 and 2019 were included in this retrospective case series. Clinical records were taken for descriptive analysis. Main outcome measures were the key clinical features, and disease course (therapy, IOP control, patient outcome).\n\n\nRESULTS\nKey features were conjunctival ciliary injection and mutton fat keratic precipitation in all eyes. The findings were bilateral in 10 patients. Time between initiation of brimonidine treatment and presentation was 1 week to 49 months. Glaucoma sub-types were mostly pseudo-exfoliative and primary open angle glaucoma. Brimonidine treatment was stopped immediately. Additionally, topical corticosteroids were prescribed in 18 eyes and tapered down during the following 4 weeks. Thirteen eyes did not need surgical or laser treatment (median follow-up time 15 months). No patient showed recurrence of inflammation after cessation of brimonidine.\n\n\nCONCLUSIONS\nThis type of anterior uveitis is an uncommon but important manifestation which should always be considered in glaucoma patients on brimonidine treatment. Although treatable at its root cause, problems may persist, especially with respect to IOP control. The latter may necessitate glaucoma surgery after the resolved episode of the uveitis.",
"affiliations": "Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany. susanne.hopf@unimedizin-mainz.de.;Manchester University Hospitals NHS Trust, Manchester Royal Eye Hospital, M13 9WH, Manchester, UK.;Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.;Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.",
"authors": "Hopf|Susanne|S|https://orcid.org/0000-0002-7989-9420;Mercieca|Karl|K|;Pfeiffer|Norbert|N|;Prokosch-Willing|Verena|V|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D000959:Antihypertensive Agents; D009883:Ophthalmic Solutions; D000068438:Brimonidine Tartrate",
"country": "England",
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"doi": "10.1186/s12886-020-01762-w",
"fulltext": "\n==== Front\nBMC Ophthalmol\nBMC Ophthalmol\nBMC Ophthalmology\n1471-2415 BioMed Central London \n\n1762\n10.1186/s12886-020-01762-w\nResearch Article\nBrimonidine-associated uveitis – a descriptive case series\nhttps://orcid.org/0000-0002-7989-9420Hopf Susanne susanne.hopf@unimedizin-mainz.de 1 Mercieca Karl 23 Pfeiffer Norbert 1 Prokosch-Willing Verena 1 1 grid.410607.4Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany \n2 grid.416375.20000 0004 0641 2866Manchester University Hospitals NHS Trust, Manchester Royal Eye Hospital, M13 9WH, Manchester, UK \n3 grid.5379.80000000121662407Faculty of Biology, Medicine and Health School of Health Sciences, University of Manchester, Manchester, UK \n17 12 2020 \n17 12 2020 \n2020 \n20 48928 9 2020 8 12 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\nAnterior uveitis secondary to topical brimonidine administration is rare and not well-defined. In glaucoma patients using brimonidine, one must consider this phenomenon to avoid mis-diagnosis and over-treatment with topical steroids which in turn may increase intraocular pressure (IOP). This is the largest case series including the longest patient follow-up in the current literature.\n\nMethods\nSixteen patients (26 eyes) with consultant diagnosed brimonidine-associated anterior uveitis in a tertiary referral glaucoma clinic presenting between 2015 and 2019 were included in this retrospective case series. Clinical records were taken for descriptive analysis. Main outcome measures were the key clinical features, and disease course (therapy, IOP control, patient outcome).\n\nResults\nKey features were conjunctival ciliary injection and mutton fat keratic precipitation in all eyes. The findings were bilateral in 10 patients. Time between initiation of brimonidine treatment and presentation was 1 week to 49 months. Glaucoma sub-types were mostly pseudo-exfoliative and primary open angle glaucoma. Brimonidine treatment was stopped immediately. Additionally, topical corticosteroids were prescribed in 18 eyes and tapered down during the following 4 weeks. Thirteen eyes did not need surgical or laser treatment (median follow-up time 15 months). No patient showed recurrence of inflammation after cessation of brimonidine.\n\nConclusions\nThis type of anterior uveitis is an uncommon but important manifestation which should always be considered in glaucoma patients on brimonidine treatment. Although treatable at its root cause, problems may persist, especially with respect to IOP control. The latter may necessitate glaucoma surgery after the resolved episode of the uveitis.\n\nSupplementary Information\nThe online version contains supplementary material available at 10.1186/s12886-020-01762-w.\n\nKeywords\nBrimonidine-associated uveitisGlaucomaBrimonidineAnterior uveitisDrug-induced uveitisissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nBrimonidine tartrate, a selective α2-agonist, is often administered as second line therapy or as part of a combined topical regime in glaucoma and ocular hypertension [1]. The granulomatous anterior uveitis associated with its use was first described by Byles in 2000 [2]. A cumulative total of 39 cases (68 eyes) within 15 reports [1–16] have been published since then, the greatest number previously reported being 12 cases (19 eyes) in 2015 [4]. To the best of our knowledge, this is the largest case series of brimonidine associated uveitis, including the longest patient follow-up in the literature.\n\nBrimonidine-induced uveitis with corneal endothelial inflammatory deposits (keratic precipitations or KPs) and usually cells and flare, occurs in elderly patients, mostly above the age of 75 years, and following several years of brimonidine application [10]. Most authors recommend stopping brimonidine use with or without the administration of steroid [12] and/or non-steroidal anti-inflammatory eye drops.\n\nVery little is known about the specific characteristics of patients developing this uncommon type of drug-induced anterior uveitis. However, one must consider this phenomenon to avoid mis-diagnosis and over-treatment with topical steroids which in turn may increase intraocular pressure. The aim of our study was to try and identify the key clinical features of this condition and to look for possible co-factors such as duration of brimonidine treatment and sub-type of glaucoma. In view of the paucity of evidence on how to treat this type of uveitis, our second aim was to report on the disease course with respect to therapy whilst also focusing on intraocular pressure (IOP) control and clinical outcomes.\n\nMethods\nThis is a retrospective descriptive case series of 16 consecutive patients (26 eyes) diagnosed with brimonidine-associated anterior uveitis in a tertiary referral glaucoma clinic presenting between 2015 and 2019. The diagnosis was made by a consultant glaucoma sub-specialist, and any unconfirmed or doubtful cases with regards to uveitis causation were excluded.\n\nClinical records were accessed for descriptive analysis. We annotated anterior segment examination (including the evaluation of inflammation according to the SUN grading system), initiation of brimonidine, current topical medication, IOP and visual acuity, type of glaucoma and further ocular diseases, previous surgeries, history of systemic inflammatory disease (e.g. rheumatoid arthritis), subsequent therapy regimens, and clinical outcome (IOP, eventually surgery, inflammation). Patient characteristics were categorized as absolute and relative frequencies for categorical variables, and as mean and standard deviations for continuous variables.\n\nCriteria for the diagnosis were: anterior uveitis in one or both eyes for no other reason than the use of brimonidine or brinzolamide-brimonidine fixed combination topical therapy. Keratic precipitation and eventually cells or flare in association with these drops, in the absence of systemic inflammatory or infectious disease, were considered as suspicious, even more so in combination with elevated IOP. The selected cases did not undergo a conjunctival biopsy prior to diagnosis as this is not pathognomonic [5]. Serologic and radiological workup was performed in cases where it was deemed indicated (for example bilateral involvements), and included routine laboratory testing, c-reactive protein, differential blood count, antinuclear antibodies, angiotension converting enzyme, soluble IL-2 receptor, HLA B 27, infectious laboratory (tuberculosis, syphilis, borrelia), and chest x-ray.\n\nResults\nWe identified 26 eyes in 16 consecutive patients with brimonidine-associated uveitis, with a male-to-female ratio of 7:9 and a mean patient age of 76 years (standard deviation (SD) +/− 10 years). The brimonidine ‘exposure time’ spanned from 1 week to 49 months (median 15 months) and was defined as the time between the documented start of brimonidine treatment and the clinical diagnosis of the drug-induced anterior uveitis. The exposure time was based on available data from 10 patients (14 eyes), and was unknown for 6 patients (12 eyes). Detailed patient data is provided in the Table 1.\nTable 1 Characteristics of the case series: Predisposing factors and presenting symptoms\n\nID\tAge, Gender\tEyes affected\tUveitis signs (conjunctival hyperemia present in all affected eyes)\tGlaucoma therapy\tBrimonidine Use\tType of glaucoma\tPrior surgery\tAuto- immune or rheumatoid disease\tIris pigmentation\tlogMAR visual acuity R/ L\t\n1\t80’s-90’s, f\tBoth\tKP, cells 1+ (R + L), Synechia (R)\tBoth: Br\t13 mo.\tNTG\tNo\tNo **\tDark\t0.6\n\n0.4\n\n\t\n2\t60’s-70’s, m\tBoth\tKP, cells 1+ (R + L), synechia (R)\tBoth: Br, DoTim, Tra\t> 4 mo.\tOHT\tTE, N, 4x CPC, Psph (14 mo.) (R); 4x CPC (L)\tCrohn’s disease *\tDark\t0.0\n\n0.0\n\n\t\n3\t80’s-90’s, f\tBoth\tunpigm. KP and cells 1+ (R + L), synechia in the chamber angle (L)\tBoth: Br, BzTim\tn.a.\tNTG\tPsph (8 mo.) (R); Psph (7 mo.) (L)\tNo *\t–\t0.5\n\n0.1\n\n\t\n4\t70’s-80’s, f\tBoth\tKP, flare 2+ (R + L)\tBoth: Br, Do, BimTim, Pil, Acet\tn.a.\tPOAG\tPsph (3 years) (R); Psph (3 years) (L)\tNo\tDark\t0.6\n\n0.5\n\n\t\n5\t60’s-70’s, m\tLeft\tKP (L), flare 2+ (R + L)\tBoth: Br, BimTim\t> 24 mo.\tPOAG\tLTP(R); LTP(L)\tHay fever\tPale\t0.0\n\n0.1\n\n\t\n6\t70’s-80’s, f\tBoth\tKP (L)\tBoth: Br, DoTim, Taf, Pil, pred\tn.a.\tPXG\tPsph (n.a.), XEN, 2x N (R); Psph (n.a.), 2x XEN, PPV, cyclocryocoagulation (L)\tIntermediate uveitis 2 years earlier\tPale\t0.22\n\n0.7\n\n\t\n7\t80’s-90’s, f\tLeft\tKP (L)\tBoth: Lat; Left: BzBrim\t2 mo.\tPOAG\tPsph (n.a.), cyclocryocoagulation (R); Psph (n.a.) (L)\tNo\tPale\t0.5\n\n0.6\n\n\t\n8\t80’s-90’s, m\tBoth\tKP (R > L)\tBoth Br, DoTim\t6 mo.\tPXG (R); PXG - > sec. Glaucoma ^^ (L)\tPsph (4 mo.) (R)\tNo\tPale\t0.22\n\n3\n\n\t\n9\t80’s-90’s, m\tLeft\tKP (L)\tBoth: Do, Taf; Left: Br\t31 mo.\tPXG\tPsph (3 years), TE, multiple AntiVEGF-IVOMs (R); TE, TE-Revision, Psph (3 years) (L)\tNo\tPale\t0.22\n\n0.22\n\n\t\n10\t70’s-80‘s, m\tRight\tKP, DF, cells 2+, flare 2+ (R)\tBoth: Br, DoTim\t18 mo.\tPOAG - > sec. Glaucoma ^ (R); POAG (L)\tPsph (1 year) (R); Psph (1 year) (L)\tNo **\tPale\t0.6\n\n0.4\n\n\t\n11\t40’s-50’s, m\tLeft\t–\tBoth: Br, BzTim\t> 49 mo.\tsec. Glaucoma\tAC-IOL (R); AC-IOL, 2x PPV, AC-IOL-Expl. + Psph (4 years), 2x steroidal IVOMs, CPC (L)\tNo *\t–\t0.4\n\n1.0\n\n\t\n12\t70’s-80’s, f\tRight\twhitish KP (R), vascularized cornea (L)\tBoth: BzBrim, BimTim\t24 mo.\tPOAG\tPsph (n.a.) (R); Aphak (n.a.) (L)\tNo\tPale\t0.3\n\n3\n\n\t\n13\t70’s-80’s, f\tBoth\tlarge whitish KP (R + L)\tBoth: BzBrim, Lat\tn.a.\tPXG\tNo (R); Psph+iStent+TA (9 mo.) (L)\tn.a.\t–\t0.4\n\n1.8\n\n\t\n14\t70’s-80’s, f\tBoth\tKP (R < L), cells 1+, flare 2+\tBoth: Br, LatTim\t0.25 mo.\tPXG\tPsph (n.a.) (R); Psph (n.a.), TE (L)\tHay fever, allergic asthma **\tDark\t0.6\n\n3\n\n\t\n15\t80’s-90’s, f\tBoth\tKP (R + L), cells 2+, flare 2+\tBoth: Br, DoTim, Lat, BzTim\tn.a.\tPXG\tPsph (1 year) (R); Psph (1 mo.), TE, N (L)\tNo\tDark\t0.3\n\n0.22\n\n\t\n16\t80’s-90’s, m\tBoth\tKP (R + L)\tBoth: Br, BzTim\tn.a.\tPXG\tPsph (1.5 years) (R); Psph (4 years) (L)\tNo\t–\t2.3\n\n2.3\n\n\t\nAcet acetazolamide, AC-IOL anteror chamber intraocular lens implantation, BimTim bimatoprost/ timolol fixed combination, Br brimonidine, BzBrim brinzolamide/ brimonidine fixed combination, BzTim brinzolamid/ timolol fixed combination, CPC Cyclophotocoagulation, Do dorzolamide, DoTim dorzolamide/ timolol fixed combination, Expl. Explantation, iStent iStent® implantation, IVOM intravitreal operative medication, Lat latanoprost, LatTim latanoprost/timolol fixed combination, LTP lasertrabeculoplasty, mo. month(s), N Needling, n.a. not applicable, NTG normal tension glaucoma, OHT ocular hypertension, Pil pilocarpine, POAG primary open angle glaucoma, PPV pars plana vitrectomy, pred prednisolone acetate, Psph cataract surgery, PXG pseudoexfoliative glaucoma, TA trabecular meshwork aspiration, Taf tafluprost, TE trabeculectomy, Tra travoprost, XEN XEN® stent implantation. (*) medical evaluation (completely **) done (routine, infectious, and autoimmune laboratory). (^) initial differential diagnosis was phacomorphic keratopathy, in follow-ups after 2 months hyperemic iris vessels were classified as determined by uveitis, after 4 months rubeosis was identified correctly to be due to (^^) the development of ocular ischemia\n\n\n\nGlaucoma sub-types were pseudo-exfoliative glaucoma (7), primary open angle glaucoma (5), normal tension glaucoma (2), and secondary glaucoma (1) while one patient had ocular hypertension. Two patients subsequently developed ocular ischemia, one case in the affected eye, the other on the contralateral side. The key features documented for all 26 eyes were ciliary injection and pigmented (brownish) (Supplemental Fig. 1) or unpigmented (Supplemental Fig. 2), granulomatous type, “mutton fat” KPs. Intraocular inflammation with cells were detected in 11 eyes (42%), flare in 8 eyes (31%) and posterior synechiae in 3 eyes (12%). Posterior segment involvement was not present.\n\nSerological diagnostic workups were performed in six patients (three of them received a complete workup as mentioned above) (see Table 1, marked by an asterisk) but did not give indications of any underlying pre-disposing inflammatory conditions. No relevant systemic illness such as inflammatory conditions etc. were present in our cohort, although four patients (25%) did have previous history of had hay fever, asthma, Crohn’s disease or intermediate uveitis. All bilateral cases (10) were on brimonidine treatment to both eyes. In one patient, the fellow eye could not be assessed for uveitis due to corneal scarring and vascularization and this patient was classified as a unilateral case. Two of the six unilateral cases were treated with brimonidine solely to the affected eye while the remaining four were having bilateral brimonidine application but did not develop uveitis in the fellow eye during the study period. Cataract surgery had been performed 1 month to 4 years prior to onset of uveitis in 20 out of 26 eyes (77%) (Table 1). None of those patients had evidence of iris transillumination. A dark iris was present in five patients while a pale (blue/green) iris was described in seven patients. The remaining four patients had no specific description of their iris pigmentation. At the time of diagnosis, median logMAR visual acuity in affected eyes was 0.45 (min. 0.0, max. 3.0), and mean IOP was 26.6 (SD +/− 11.3) mmHg. 62% (16 out of 26) of the affected eyes showed IOP above 20 mmHg. Thirteen patients (81%) were on brimonidine 0.2% (Alphagan®, Allergan) as a stand-alone drug with the other three using brimonidine within a fixed combination of brinzolamide 1.0% and brimonidine 0.2% (Simbrinza®, Alcon). Prostaglandins were being used by 10 patients in 17 eyes (65%).\n\nAll patients were told to stop brimonidine treatment in the affected eye(s), and 11 patients (18 eyes, 69%) were additionally advised treatment with a short course of topical steroids (4 times daily initially) tapering it down over the following 4 weeks (i.e. 69% of the affected eyes received steroids); see Table 2. Re-challenges to confirm the cause of uveitis were not performed as per the patients’ wishes. At a minimum follow-up time of at least 1 month (median 15 months), uveitis resolution was rapid and complete in all affected eyes, with no recurrence after the investigated follow-up time.\nTable 2 Characteristics of the case series: IOP course and management\n\nID\tAge\tType of glaucoma\tEyes affected\tManagement: (All stopped Brimonidine)\tIOP R/L (mmHg)\tIOP R/ L (mmHg) course and surgical management if needed at follow-up\tFollow-up time\t\n1\t80’s-90’s\tNTG\tBoth\tsteroids (pred)\t20\n\n15\n\n\t14\n\n15\n\n\t84 mo.\t\n2\t60’s-70’s\tOHT\tBoth\tsteroids (dexa, flu)\t21\n\n22\n\n\t18\n\n14\n\n\t14 mo.\t\n3\t80’s-90’s\tNTG\tBoth\tsteroids (dexa)\t42\n\n35\n\n\t6 with Acet\n\n6 with Acet\n\n\t1 mo.\t\n4\t70’s-80’s\tPOAG\tBoth\tsteroids (dexa)\t35\n\n41\n\n\t34 - > TE –> 13 after 2x N\n\n34 - > TE –> 7\n\n\t28 mo.\t\n5\t60’s-70’s\tPOAG\tLeft\tsteroids (dexa)\t(13)\n\n15\n\n\t(12–16) 12–16\t2 mo.\t\n6\t70’s-80’s\tPXG\tBoth\t–\t41\n\n24\n\n\t12 after TE - > 10\n\n34 –> 34\n\n\t1 mo.\t\n7\t80’s-90’s\tPOAG\tLeft\tsteroids (dexa)\t(13)\n\n17\n\n\t(15 - > CPC - > 10)\n\n24 - > CPC 10\n\n\t1 mo.\t\n8\t80’s-90’s\tPXG (R);\n\nPXG - > rubeotic secondary glaucoma ^^ (L)\n\n\tBoth\t–\t31\n\n59\n\n\t10–18\n\n26–45 with Acet\n\n\t3 mo.\t\n9\t80’s-90’s\tPXG\tLeft\tsteroids (dexa)\t(15)\n\n22\n\n\t(22 - > 12)\n\n31 –> CPC - > 16\n\n\t9 mo.\t\n10\t70’s-80’s\tPOAG - > rubeotic secondary glaucoma ^ (R); POAG (L)\tRight\tsteroids (pred)\t24\n\n(10)\n\n\t13 - > 45 - > 2x CPC - > 36\n\n(10 - > 20 - > 19)\n\n\t7 mo.\t\n11\t40’s-50’s\tsecondary glaucoma\tLeft\t–\t(18)\n\n29\n\n\t(18 - > 10)\n\nCPC - > 23 - > 21\n\n\t12 mo.\t\n12\t70’s-80’s\tPOAG\tRight\t–\t28\n\n(20)\n\n\t19–22\n\n(6–16)\n\n\t1 mo.\t\n13\t70’s-80’s\tPXG\tBoth\t–\t13\n\n27\n\n\tCPC 16\n\n16 (with Acet)\n\n\t0.5 mo. (lost to follow-up)\t\n14\t70’s-80’s\tPXG\tBoth\tsteroids (dexa)\t15\n\n15\n\n\t\t(lost to follow-up)\t\n15\t80’s-90’s\tPXG\tBoth\tsteroids (flu)\t30\n\n17\n\n\t30 - > TE - > 8\n\n17 - > 17\n\n\t1 mo.\t\n16\t80’s-90’s\tPXG\tBoth\tsteroids (dexa)\t18\n\n15\n\n\t5\n\n9\n\n\t1 mo.\t\nAcet acetazolamide, CPC Cyclophotocoagulation, dexa dexamethasone, flu fluorometholone, mo. month(s), N Needling, n.a. not applicable, NTG normal tension glaucoma, OHT ocular hypertension, POAG primary open angle glaucoma, pred prednisolone acetate, PXG pseudoexfoliative glaucoma, TE trabeculectomy. (^) initial differential diagnosis was phakomorphic keratopathy, in follow-ups after 2 months iris hyperemia was classified as determined by uveitis, after 4 months rubeosis was identified correctly to be due to (^^) the development of ocular ischemia\n\n\n\nIn 13 eyes, IOP was well regulated without surgical intervention (see Table 2); another 2 eyes were lost to follow up. Surgery for IOP control was eventually required in 9 eyes (4 eyes underwent subsequent trabeculectomy and 5 eyes a cyclodestructive procedure), while 2 eyes were untreated for elevated IOP due to the poor prognosis (visual acuity was No Light Perception in one case and in the other case the fellow eye had already previously undergone trabeculectomy as this was the better seeing eye).\n\nDiscussion\nTo the best of our knowledge, this study presents the largest case series and longest follow-up of brimonidine-associated anterior uveitis in the literature. With regard to our investigated cohort, four key findings may be highlighted, but may change within a larger population: Firstly, the time between initiation of brimonidine treatment and uveitis presentation varied widely between 1 week and 49 months. Secondly, the clinical features were mainly ciliary injection and mutton fat keratic precipitates while cells, flare and posterior synechiae were less frequent; IOP was elevated in the majority of patients (two thirds of eyes). Thirdly, glaucoma sub-types were primarily pseudoexfoliative and primary open angle glaucoma. Finally, within a month of follow-up, IOP was well-controlled in half of the affected eyes (which included 6 of the 16 eyes which had prior IOP elevation above 20 mmHg), without the need for surgery or laser treatment. A procedure was eventually needed in nine eyes, four undergoing trabeculectomy and 5 a cyclodestructive procedure.\n\nThe time interval between initiation of brimonidine treatment and presentation varied widely. The patients in our case series had been using brimonidine from just over one week up to four years prior to onset of symptoms and diagnosis. This is in line with the indicated 1 week to 5 years interval in the report from Beltz et al. [4]. Based on the lengthy spell of time between first administration and appearance of the uveitis in many cases, it is presumed that besides a primary toxic reaction, a secondary cell-mediated immune response may also be involved in the patho-physiology with the drug acting as a potential antigen or immune modulator [17]. In patients on long-term treatment, it has been postulated that inflammatory cytokines within the vitreous humor may contribute to granulomatous uveitis [18].\n\nIn our series, an elevated IOP accompanied the anterior segment reaction in the majority of cases (62% of eyes). In contrast, eight eyes (42%) in the cases from Beltz et al. showed an IOP rise of 5 mmHg or more from baseline and seven eyes (36%) were estimated too high necessitating further glaucoma therapy [4]. In our series, 9 out of 26 (35%) eyes underwent laser or surgical intervention.\n\nClinical signs may differ and there is no pathognomonic appearance as one finds, for example, in Fuch’s uveitis syndrome. The previously described clinical spectrum of brimonidine-associated uveitis ranges from simple conjunctival congestion [13], severe follicular conjunctivitis, blepharitis [11, 14, 15], and punctate corneal epithelial erosions [5], to the full extent of anterior uveitis with corneal endothelial deposition (mutton fat KPs) [4, 6], significant anterior chamber activity (cells and flare) [3, 4, 9] and posterior synechiae (PS) [1, 2, 7]. PS were present in only three of our patients, while Beltz et al. did not find any in their series, despite reporting cells and flare in most cases [4]. We detected scattered and mostly small mutton fat KPs in nearly all cases with large whitish KPs in only one case; Beltz et al. mostly found stellate KPs [4]. Our cases had a mean age of 76 years (SD +/− 10 years), and were thereby comparable with Beltz et al.’s series where mean age was 74 years (SD (+/− 9 years) [4].\n\nIn our cohort brimonidine-associated uveitis seemed to occur mostly in patients with pseudoexfoliative and primary open angle glaucoma. Although this may be a simple reflection of the relative frequency of these two sub-types, pseudoexfolation syndrome may itself occasionally present with keratic precipitates as well, masquerading as uveitis. The appearance was reported as white dandruff-like flakes diffusely distributed over the endothelial surface which do not disappear after topical corticosteroid administration and which are not accompanied by intraocular inflammation [19].\n\nThe coexistent elevated IOP could be a result of a hypertensive uveitic response but could also be due to an overall sub-optimal IOP control which necessitated the use of brimonidine in the first place. It remains unclear whether previous surgery (particularly cataract surgery) might play a role in the development of brimonidine-associated uveitis. Beltz et al. included 16 pseudophakic eyes (out of 19 total eyes) and postulated that patients undergoing cataract surgery were often in the same age as patients with glaucoma. According to them, one could hypothesize that the damaged corneal integrity due to phaco-incisions with drugs penetrating or diffusing into the anterior chamber resulting in intraocular reaction [4]. We find this concept unlikely, especially the longer the time lapses from the surgery, as wound healing and corneal recovery would have occurred. It is more likely that previous cataract surgery may have weakened the blood-aqueous barrier resulting in a lower anterior chamber inflammatory threshold. The calculation of statistical associations was not possible due to the small and heterogenous sample size.\n\nAs brimonidine accumulates in pigmented tissues, one could expect eyes with dark irides to be more prone to this type of drug-induced uveitis [5]. However, a larger proportion of patients in our study exhibited pale irides, thus counteracting this argument. Possible confounding factors for acute anterior uveitis in our cohort could include other local agents such as prostaglandin analogues (used in 16/26 eyes), benzalkonium chloride (present in brimonidine eye drops), topical beta-blockers and carbonic anhydrase inhibitors, and systemic drugs [20–22]. Previous operations might have also predisposed to hypersensitivities to various agents, lowering the sensitivity threshold for the inflammatory trigger caused by brimonidine. In one case, we diagnosed a case of brimonidine-associated uveitis which subsequently developed secondary neovascular glaucoma due to ocular ischemia. The latter can also present clinically with signs of anterior ocular inflammation although in our case the uveitis had occurred prior to and had completed subsided by the time neovascularization developed. Oli and Joshi presented one case of neovascular glaucoma due to central retinal vein occlusion developing brimonidine-associated ‘uveitis’ with conjunctival congestion and mild chemosis but without intraocular inflammation [13]. We therefore recommend to look carefully for iris/angle neovascularization, and if necessary retinal ischemia, in any patient with suspected brimonidine-associated uveitis. The second patient with ocular ischemia in our cohort presented with KPs predominantly on his right eye, while the ischemia affected his left eye only.\n\nOur analysis showed complete and rapid resolution of uveitis when brimonidine itself was stopped in isolation (one third) or when this was combined with a short administration of topical steroid (two thirds). Our treatment strategy in managing uveitis with coexistent elevated IOP was correlated with the severity of inflammation and degree of glaucomatous optic nerve damage. In cases of corneal changes in isolation (i.e. KPs), we stopped brimonidine alone, especially when pseudoexfoliation syndrome was present and might contribute to the corneal abnormalities, while topical steroid might be considered when a more diffuse and/or severe inflammatory element was present.\n\nThe potential effects of steroid administration may of course include the masking of other etiologies such as autoimmune or viral uveitis. Steroids can also further increase IOP, although this commonly increases over weeks rather than days. In our cohort, steroid administration did not further increase IOP. As none of the patients reported steroid response in the history, and IOP was elevated before steroid commencement, we conclude that the reason in most cases with persistent uncontrolled IOP was not a steroid response.\n\nAlthough inflammation was resolved in all eyes, nine eyes needed surgical IOP control. The elevated IOPs were not exclusively due to the uveitis but probably more due to sub-optimal IOP beforehand which could represent an uncontrolled course of the glaucomatous process, partly due to the adverse effect of brimonidine itself. In patients who required surgery, the IOP was managed early and effectively after the resolution of the uveitis.\n\nOphthalmologists should consider brimonidine-associated uveitis as reversible uveitis syndrome. Conscious acquaintance with this condition enables waiving needless tests and therapies [4]. In unclear cases of uveitis with KPs and eventually cells and flare in glaucoma patients on topical brimonidine, the manifestation of brimonidine-associated uveitis should be always considered. Stopping brimonidine usually resolves and prevents recurrence of the inflammation; however, the subsequent management of high IOP may result in the need for surgery.\n\nSupplementary Information\n\nAdditional file 1: Supplemental Figure 1. Anterior segment photograph showing pigmented keratic precipitates (ID 15).\n\n Additional file 2: Supplemental Figure 2. Anterior segment photograph showing scattered, mostly depigmented keratic precipitates (ID 14).\n\n \n\nAbbreviations\nKPKeratic precipitations\n\nIOPIntraocular pressure\n\nPSPosterior synechiae\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank C. Bornscheuer MD (Duderstadt, Germany) for his drive to pursue this interesting topic.\n\nAuthors’ contributions\nSH and KM drafted the manuscript. SH and VP collected, analysed and interpreted the data. VP designed the study and made substantial contributions to conception and revising critically the manuscript for important intellectual content. NP enabled data collection, and revised substantively the work. All authors read and approved the final manuscript.\n\nAuthors’ information\nNot applicable.\n\nFunding\nNo funding was obtained for this work. Open Access funding enabled and organized by Projekt DEAL.\n\nAvailability of data and materials\nAll data generated or analysed during the current study are included in this published article (presented in Tables 1 and 2).\n\nEthics approval and consent to participate\nThe study was conducted according to the recommendations of the Declaration of Helsinki, and was authorized by the local ethics committee of Rhineland-Palatinate, Mainz (Germany). The patients gave informed written consent for data collection and analysis.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Nguyen EV Azar D Papalkar D McCluskey P Brimonidine-induced anterior uveitis and conjunctivitis: clinical and histologic features J Glaucoma 2008 17 40 42 10.1097/IJG.0b013e3181132188 18303383 \n2. Byles DB Frith P Salmon JF Anterior uveitis as a side effect of topical brimonidine Am J Ophthalmol 2000 130 287 291 10.1016/S0002-9394(00)00491-8 11020406 \n3. Becker HI Walton RC Diamant JI Zegans ME Anterior uveitis and concurrent allergic conjunctivitis associated with long-term use of topical 0.2% brimonidine tartrate Arch Ophthalmol Chic Ill 1960 2004 122 1063 1066 10.1001/archopht.122.7.1063 \n4. Beltz J Zamir E Brimonidine induced anterior uveitis Ocul Immunol Inflamm 2016 24 128 133 10.3109/09273948.2015.1037845 26399160 \n5. Carrasco MA Schlaen BA Zárate JO Brimonidine-timolol fixed combination induced granulomatous inflammation of the eye Int Ophthalmol 2013 33 557 560 10.1007/s10792-012-9688-0 23224363 \n6. Casado A Cabarga C de la Fuente MA Muñoz-Negrete FJ Suspected granulomatous anterior uveitis associated with brimonidine tartrate 0.2% and timolol maleate 0.5% ophthalmic solution Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol 2013 251 2659 2660 10.1007/s00417-013-2415-3 \n7. Cates CA Jeffrey MN Granulomatous anterior uveitis associated with 0.2% topical brimonidine Eye Lond Engl 2003 17 670 671 \n8. Clemente-Tomás R Arciniegas-Perasso CA Hervás-Hernandis JM García-Ibor F Ruiz-Del Río N Duch-Samper AM Hypertensive acute granulomatous anterior uveitis as a side effect of topical brimonidine Arch Soc Espanola Oftalmol 2018 93 511 514 10.1016/j.oftal.2018.05.005 \n9. Goyal R Ram AR Brimonidine tartarate 0.2% (Alphagan) associated granulomatous anterior uveitis Eye Lond Engl 2000 14 Pt 6 908 910 \n10. Hondeghem K, Augustinus B, De Smet MD. Bilateral granulomatous uveitis as a side effect of topical brimonidine: two case reports. Bull Soc Belge Ophtalmol. 2009:51–2.\n11. Kahana A Marcet MM Albert DM Thliveris AT Drug-induced cicatrising granulomatous conjunctivitis Br J Ophthalmol 2007 91 691 692 10.1136/bjo.2006.099085 \n12. McKnight CM Richards JC Daniels D Morgan WH Brimonidine (Alphagan) associated anterior uveitis Br J Ophthalmol 2012 96 766 768 10.1136/bjophthalmol-2011-300872 \n13. Oli A Joshi D Interesting case of severe anterior uveitis caused by brimonidine eye drops Med J Armed Forces India 2015 71 Suppl 1 S285 S286 10.1016/j.mjafi.2014.09.009 26265860 \n14. Velasque L Ducousso F Pernod L Vignal R Deral V Anterior uveitis and topical brimonidine: a case report J Fr Ophtalmol 2004 27 1150 1152 10.1016/S0181-5512(04)96285-7 15687926 \n15. Comet A Donnadieu B Courjaret J-C Gascon P Denis D Matonti F Brimonidine and acute anterior granulomatous uveitis: a case report and literature review J Fr Ophtalmol 2017 40 e127 e129 10.1016/j.jfo.2016.01.016 28336279 \n16. Kattige J Konana VK Babu K Bilateral granulomatous uveitis in an elderly female Indian J Ophthalmol 2019 67 1391 10.4103/ijo.IJO_1427_19 31436179 \n17. Moorthy RS London NJS Garg SJ Cunningham ET Drug-induced uveitis Curr Opin Ophthalmol 2013 24 589 597 10.1097/01.icu.0000434534.32063.5c 24100371 \n18. Shin H-Y Lee H-S Lee YC Kim S-Y Effect of Brimonidine on the B cells, T cells, and cytokines of the ocular surface and aqueous humor in rat eyes J Ocul Pharmacol Ther Off J Assoc Ocul Pharmacol Ther 2015 31 623 626 10.1089/jop.2015.0067 \n19. Chern KC Meisler DM Rockwood EJ Lowder CY Pseudoexfoliation syndrome masquerading as uveitis Am J Ophthalmol 1994 118 392 393 10.1016/S0002-9394(14)72966-6 8085598 \n20. Beck RW Moke P Blair RC Nissenbaum R Uveitis associated with topical beta-blockers Arch Ophthalmol Chic Ill 1960 1996 1181 114 112 \n21. London NJ Garg SJ Moorthy RS Cunningham ET Drug-induced uveitis J Ophthalmic Inflamm Infect 2013 3 43 10.1186/1869-5760-3-43 23522744 \n22. Moorthy RS Moorthy MS Cunningham ET Drug-induced uveitis Curr Opin Ophthalmol 2018 29 588 603 10.1097/ICU.0000000000000530 30222658\n\n",
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"issue": "20(1)",
"journal": "BMC ophthalmology",
"keywords": "Anterior uveitis; Brimonidine; Brimonidine-associated uveitis; Drug-induced uveitis; Glaucoma",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D060433:Administration, Ophthalmic; D058647:Adrenergic alpha-2 Receptor Agonists; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents; D000068438:Brimonidine Tartrate; D005260:Female; D005500:Follow-Up Studies; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D009798:Ocular Hypertension; D009883:Ophthalmic Solutions; D012189:Retrospective Studies; D014606:Uveitis, Anterior",
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"title": "Brimonidine-associated uveitis - a descriptive case series.",
"title_normalized": "brimonidine associated uveitis a descriptive case series"
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"abstract": "OBJECTIVE\nNo studies have evaluated the use of sorafenib with the direct-acting antiviral ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV).\n\n\nMETHODS\nThree hepatitis C virus genotype 1b-infected patients with well-preserved liver function were included in this prospective case series. The patients were taking sorafenib for advanced hepatocellular carcinoma and received OBV/PTV/r+DSV for 12 weeks. One patient discontinued sorafenib while concomitant treatment due to grade 2 fatigue and muscular pain. The other two patients reported only grade 1 adverse effects. Sustained virologic response at 24 weeks was achieved, and no tumour recurrences were found.\n\n\nCONCLUSIONS\nThe concurrent use of OBV/PTV/r+DSV with sorafenib was considered safe and effective.",
"affiliations": "Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;Gastroenterology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.;Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.",
"authors": "Revuelta-Herrero|J L|JL|http://orcid.org/0000-0003-2071-8928;Giménez-Manzorro|A|A|;Matilla-Peña|A|A|;Herranz-Alonso|A|A|;Sanjurjo-Sáez|M|M|",
"chemical_list": "D000813:Anilides; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D011392:Proline; D000077157:Sorafenib; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
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"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "antiviral agents; drug interaction; hepatitis C; hepatocellular carcinoma; sorafenib",
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"mesh_terms": "D015081:2-Naphthylamine; D000368:Aged; D000813:Anilides; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002219:Carbamates; D006528:Carcinoma, Hepatocellular; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D008113:Liver Neoplasms; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D011446:Prospective Studies; D019438:Ritonavir; D000077157:Sorafenib; D013449:Sulfonamides; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine",
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"references": null,
"title": "Concomitant use of sorafenib with ombitasvir/paritaprevir/ritonavir and dasabuvir: Effectiveness and safety in clinical practice.",
"title_normalized": "concomitant use of sorafenib with ombitasvir paritaprevir ritonavir and dasabuvir effectiveness and safety in clinical practice"
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"abstract": "Topiramate has a wide array of pharmacologic effects, including proximal renal tubular acidosis (RTA). Clinicians must be wary of the possibility for development of somnolence due to compensatory hyperventilation and cardiac dysrhythmias.",
"affiliations": "Department of Internal Medicine University of Florida College of Medicine - Jacksonville Jacksonville FL USA.;Department of Internal Medicine University of Florida College of Medicine - Jacksonville Jacksonville FL USA.;Department of Internal Medicine University of Florida College of Medicine - Jacksonville Jacksonville FL USA.;Department of Internal Medicine University of Florida College of Medicine - Jacksonville Jacksonville FL USA.;Department of Internal Medicine University of Florida College of Medicine - Jacksonville Jacksonville FL USA.",
"authors": "Chahin|Michael|M|https://orcid.org/0000-0001-9371-0252;Oye|Monique|M|https://orcid.org/0000-0002-0725-2716;Jadeja|Sonal|S|;Sanders|Kimberly|K|;Reddy|Pramod|P|",
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"doi": "10.1002/ccr3.2733",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.2733\nCCR32733\nCase Report\nCase Reports\nTopiramate causing type II renal tubular acidosis: A case and review of the mechanism\nCHAHIN et al.Chahin Michael https://orcid.org/0000-0001-9371-0252\n1\nmichael.chahin@jax.ufl.edu Oye Monique https://orcid.org/0000-0002-0725-2716\n1\n Jadeja Sonal \n1\n Sanders Kimberly \n1\n Reddy Pramod \n1\n \n1 \nDepartment of Internal Medicine\nUniversity of Florida College of Medicine ‐ Jacksonville\nJacksonville\nFL\nUSA\n\n* Correspondence\n\nMichael Chahin, Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, 653‐1 W 8th St, L18, Jacksonville, FL 32209, USA.\n\nEmail: michael.chahin@jax.ufl.edu\n\n18 2 2020 \n4 2020 \n8 4 10.1002/ccr3.v8.4731 733\n14 10 2019 27 12 2019 26 1 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nTopiramate has a wide array of pharmacologic effects, including proximal renal tubular acidosis (RTA). Clinicians must be wary of the possibility for development of somnolence due to compensatory hyperventilation and cardiac dysrhythmias.\n\nTopiramate has a wide array of pharmacologic effects, including proximal renal tubular acidosis (RTA). Clinicians must be wary of the possibility for development of somnolence due to compensatory hyperventilation and cardiac dysrhythmias.\n\n\ncarbonic anhydrase inhibitorproximal renal tubular acidosistopiramate source-schema-version-number2.0cover-dateApril 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.9 mode:remove_FC converted:08.04.2020\n\n\nChahin \nM \n, \nOye \nM \n, \nJadeja \nS \n, \nSanders \nK \n, \nReddy \nP \n. Topiramate causing type II renal tubular acidosis: A case and review of the mechanism\n. Clin Case Rep . 2020 ;8 :731 –733\n. 10.1002/ccr3.2733\n==== Body\n1 INTRODUCTION\nTopiramate is an under‐recognized cause of proximal renal tubular acidosis. Our patient was started on topiramate and developed a normal anion gap metabolic acidosis that was discovered after an overdose attempt. The diagnosis was confirmed by bicarbonate challenge. Patients taking topiramate may become somnolent, and respiratory failure has been reported.\n\nType II, or proximal, renal tubular acidosis (RTA) occurs due to loss of bicarbonate (HCO3‐) reabsorption in the proximal tubule.1 Type II RTA is frequently attributed to etiologies such as hyperparathyroidism and multiple myeloma.2 Topiramate is an anticonvulsant with a wide range of pharmacological activity, including reduction in voltage‐sensitive sodium channel activity, increased γ‐aminobutyric acid (GABA)A receptor activity, and inhibition of carbonic anhydrase.3 We present a patient who developed type II RTA after being initiated on this medication.\n\n2 CASE REPORT\nAn 18‐year‐old female with past medical history of asthma and bipolar depression presented to the emergency department after an overdose attempt with topiramate and atomoxetine. In addition to suicidal ideation, she complained of headache and fatigue. Her physical examination was significant for somnolence, lateral nystagmus, and increased respirations. She was not in respiratory distress. Her QTc interval was 508 ms Acetaminophen, aspirin, ethanol, and ketone levels were negative. Her serum osmolality was normal, and her topiramate level was 70.5 ug/mL. She had reportedly been taking lamotrigine, but testing was negative. Serum bicarbonate was 16 mmol/L, with a normal anion gap, and potassium was 3.3 mmol/L. Urine pH was 5.5.\n\nRenal function testing revealed elevated creatinine (1.02‐1.23 mg/dL) from a baseline of 0.71 mg/dL and a normal anion gap metabolic acidosis with respiratory compensation. Over the past year, serum bicarbonate ranged from 15 to 18 mmol/L and potassium was 3.3‐3.8 mmol/L. She had been started on topiramate 200 mg daily for weight loss just prior to this period. During an admission two months before this one, also after a topiramate overdose, she was treated with sodium bicarbonate tablets for normal anion gap metabolic acidosis with no improvement in her serum bicarbonate and resulting in alkalotic urine pH. Urine pH at that time was 7, whereas it was 5.5 before. She reported having continued to take the medication, this was confirmed by the pharmacy.\n\nOver several hours, her symptoms resolved. Repeat electrocardiogram revealed QTc interval of 460 ms She was advised to stop taking topiramate and trialed on bicarbonate supplementation for several days. She did not have recurrence of somnolence, or other symptoms, during the remainder of the admission. Repeat laboratories two months later revealed resolution of the metabolic acidosis, after cessation of topiramate.\n\n3 DISCUSSION\nType II (Proximal) renal tubular acidosis is caused by decreased HCO3‐ reabsorption in the proximal tubule, which is the primary site of its reabsorption in the kidney.4 Etiologies can be divided between causes of selective and diffuse type II RTA, which depend on the defects present in the proximal tubule. For example, Fanconi syndrome causes the diffuse type, as evidenced by the presence of glycosuria despite normal serum glucose and amino aciduria. Acetazolamide is a classic example of selective impairment of HCO3‐ reabsorption since there this is the only defect and there is no loss of glucose or amino acids.5 Topiramate also causes selective type II RTA by inhibiting carbonic anhydrase II, the predominant renal isoenzyme of carbonic anhydrase.4, 6\n\n\nIn type II RTA, the reabsorption of HCO3‐ in the distal tubule is unaffected. Ordinarily, the threshold for HCO3‐ loss in adults in the proximal tubule is 26 mmol/L. However, in these patients there is a compensatory excretion of ammonium (NH4+) to match the decreased serum HCO3‐.1 Thus, the threshold for HCO3‐ release is approximately 15 mmol/L. Type II RTA can be divided into active and maintenance phases, which is not frequently mentioned in the literature. The active phase occurs during this equalization, which leads to a hyper‐chloremic metabolic acidosis. HCO3‐ loss leads to volume contraction causing the development of a hyper‐aldosterone state and chloride reabsorption.7\n\n\nThe maintenance phase occurs once the lower HCO3‐ threshold is established.7 The diagnosis can be made with bicarbonate loading, such as seen in our patient.8 Her urine pH became alkalotic and the serum bicarbonate was relatively unchanged, as a result of this compensation. Between the two admissions for topiramate overdose, she had two confirmatory bicarbonate challenge tests. Had it been measured her urine bicarbonate would have been elevated.\n\nIndications for topiramate include the treatment of epilepsy and migraine prophylaxis.9 However, it has been used off‐label, such as in our patient, for weight loss.10 Type II RTA due to topiramate has been demonstrated in the literature but is still likely an underreported issue.\n\nClinicians must be wary of the effects of this metabolic acidosis, which can include hyperventilation, fatigue, cardiac dysrhythmias, and poor bone health. In addition to proximal RTA, topiramate causes hypocitraturia and thus increased risk for nephrolithiasis.11 Zonisamide and acetazolamide have also been identified as causing decreased urine citrate, and this is a unique characteristic from other causes of proximal RTA.12\n\n\nA case series demonstrated the symptoms of topiramate overdose include somnolence, agitation, vertigo, and mydriasis, whereas some patients were asymptomatic. The asymptomatic patient ingested a relatively low dose, 10.7 mg/kg, compared to the others in the series, and was treated with gastric lavage within one hour.13 There is another case of a woman who was on topiramate for several months who presented with dyspnea and ultimately required intubation for respiratory fatigue. She was found to have a normal anion gap metabolic acidosis, and her condition improved after cessation of the medication.14\n\n\nOur patient had also taken atomoxetine in excess, which likely contributed to her drowsiness and lateral nystagmus. However, the acidosis exhibited by tricyclic antidepressant consumption has been attributed to lactic acidosis and respiratory depression.15\n\n\n4 CONCLUSION\nTopiramate is a commonly prescribed medication that has demonstrated efficacy in epilepsy and migraines. As further uses are elucidated, it is crucial that prescribers are aware of the development of metabolic acidosis due to carbonic anhydrase impairment. Routine metabolic and urine testing is essential when starting patients on this medication as it may cause severe adverse effects.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHORS' CONTRIBUTIONS\nMC: described and formatted the case. MC and MO: collaborated on the literature review. KS and SJ: edited the manuscript. PR: served as the advisor and was the clinician who treated the patient.\n==== Refs\nREFERENCES\n1 \n\nSoriano \nJR \n. Renal tubular acidosis: the clinical entity\n. J Am Soc Nephrol . 2002 ;13 :2100 ‐2170\n.\n2 \n\nGolembiewska \nE \n, \nCiechanowski \nK \n. Renal tubular acidosis – underrated problem?\n\nActa Biochim Pol . 2012 ;59 (2 ):213 ‐217\n.22693689 \n3 \n\nMula \nM \n, \nCavanna \nAE \n, \nMonaco \nF \n. Psychopharmacology of topiramate: from epilepsy to bipolar disorder\n. Neuropsychiatr Dis Treat . 2006 ;2 (4 ):475 ‐488\n.19412496 \n4 \n\nSinha \nA \n, \nOo \nP \n, \nAsghar \nM \n, et al. Type II renal tubular acidosis secondary to topiramate: A Review\n. Cureus . 2018 ;10 (11 ):e3635.30755834 \n5 \n\nEmmett \nM \n, \nPalmer \nBF \n. Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis. UpToDate\n. https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis?. Accessed June 15, 2019.\n6 \n\nPuckerson \nJM \n, \nSchwartz \nGJ \n. The role of carbonic anhydrases in renal physiology\n. Med Res Rev . 2009 ;71 :103 ‐115\n.\n7 \n\nReddy \nP \n. Clinical approach to renal tubular acidosis in adult patients\n. Int J Clin Pract . 2011 ;65 (3 ):350 ‐360\n.21314872 \n8 \n\nYaxley \nJ \n, \nPirrone \nC \n. Review of diagnostic evaluation of renal tubular acidosis\n. Ochsner J . 2016 ;16 (4 ):525 ‐530\n.27999512 \n9 \nTopiramate (Topamax) . [package insert]. Titusville, NJ : Janssen Pharmaceuticals, Inc ; 2017 .\n10 \n\nMoradi \nS \n, \nKerman \nSRJ \n, \nMollabashi \nM \n. The effect of topiramate on weight loss in patients with type 2 diabetes\n. J Res Med Sci . 2013 ;18 (4 ):297 ‐302\n.24124426 \n11 \n\nMirza \nN \n, \nMarson \nAG \n, \nPrimohamed \nM \n. Effect of topiramate on acid‐base balance: extent, mechanism, and effects\n. Br J Clin Pharmacol . 2009 ;68 (5 ):655 ‐661\n.19916989 \n12 \n\nCurhan \nGC \n. Nephrolithiasis in Renal Tubular Acidosis In: Sterns R , ed. UpToDate . Waltham, MA ; 2019 \nhttps://www.uptodate.com/contents/nephrolithiasis-in-renal-tubular-acidosis?\n\n13 \n\nWisniewski \nM \n, \nLukasik‐Glebocka \nM \n, \nAnand \nJS \n. Acute topiramate overdose – clinical manifestations\n. Clin Toxicol (Phila) . 2009 ;47 (4 ):317 ‐320\n.19514879 \n14 \n\nShiber \nJR \n. Severe non‐anion gap metabolic acidosis induced by topiramate: a case report\n. J Emerg Med . 2010 ;38 (4 ):494 ‐496\n.19232874 \n15 \n\nKerr \nGW \n, \nMcGuffie \nAC \n, \nWilkie \nS \n. Tricyclic antidepressant overdose: a review\n. Emerg Med J . 2001 ;18 :236 ‐241\n.11435353\n\n",
"fulltext_license": "CC BY",
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"issue": "8(4)",
"journal": "Clinical case reports",
"keywords": "carbonic anhydrase inhibitor; proximal renal tubular acidosis; topiramate",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
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"pages": "731-733",
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"pmid": "32274047",
"pubdate": "2020-04",
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"references": "27999512;24124426;19916989;19232874;12138150;22693689;30755834;19412496;21314872;19514879;11435353",
"title": "Topiramate causing type II renal tubular acidosis: A case and review of the mechanism.",
"title_normalized": "topiramate causing type ii renal tubular acidosis a case and review of the mechanism"
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"companynumb": "US-GLENMARK PHARMACEUTICALS-2020GMK047705",
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"activesubstancename": "TOPIRAMATE"
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"abstract": "BACKGROUND\nMethemoglobinemia is an uncommon cause of tissue hypoxia, but it can be life threatening if it is not identified and treated promptly.\n\n\nOBJECTIVE\nTo highlight the importance of understanding the potential risks of over-the-counter medications, especially in unsupervised use. Topical benzocaine must be used with caution, even in the healthy population.\n\n\nMETHODS\nWe report a case of methemoglobinemia secondary to topical benzocaine gel. A 6-year-old boy presented to our Pediatric Emergency Department with cyanosis, vomiting, and lethargy after using a gel-type, 7.5% benzocaine (Baby Orajel) for a toothache. Physical examination revealed dusky blue skin, tachycardia, tachypnea, and a normal neurologic examination. His percutaneous oxygen saturation remained 77-83% despite the administration of 100% oxygen. His arterial blood sample had a dark chocolate color appearance, and methemoglobinemia was suspected. His methemoglobin level was 69.9%, which is considered a lethal level. After a single dose of methylene blue (1 mg/kg/dose), cyanosis was reduced and oxygenation improved.\n\n\nCONCLUSIONS\nOver-the-counter topical benzocaine should be used with caution, and the presence of methemoglobinemia must be promptly identified and treated.",
"affiliations": "Department of Pediatrics, Brookdale University Hospital Medical Center, Brooklyn, New York 11212, USA.",
"authors": "Chung|Nam-Young|NY|;Batra|Rajni|R|;Itzkevitch|Myrzia|M|;Boruchov|Donna|D|;Baldauf|Mary|M|",
"chemical_list": "D000700:Analgesics; D004791:Enzyme Inhibitors; D005782:Gels; D008751:Methylene Blue; D001566:Benzocaine",
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"journal": "The Journal of emergency medicine",
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"medline_ta": "J Emerg Med",
"mesh_terms": "D000287:Administration, Topical; D000700:Analgesics; D001566:Benzocaine; D002675:Child, Preschool; D003490:Cyanosis; D004791:Enzyme Inhibitors; D005782:Gels; D006801:Humans; D008297:Male; D008708:Methemoglobinemia; D008751:Methylene Blue",
"nlm_unique_id": "8412174",
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"pages": "601-6",
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"title": "Severe methemoglobinemia linked to gel-type topical benzocaine use: a case report.",
"title_normalized": "severe methemoglobinemia linked to gel type topical benzocaine use a case report"
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"companynumb": "US-PFIZER INC-2017381244",
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"abstract": "Induction therapy with alemtuzumab followed by lower maintenance immunosuppression (IS) has been associated with reduced morbidity and mortality in abdominal and heart transplantation (TX). In the current study, alemtuzumab, in combination with reduced levels of maintenance IS, was compared to thymoglobulin in combination with standard IS. Sixty consecutive patients who underwent lung transplantation (LUTX) at a single center were prospectively randomized in two groups: group A received alemtuzumab in conjunction with reduced doses of tacrolimus, steroids and mycophenolate mofetil. Group B received thymoglobulin in association with standard dose IS. Patient and graft survival, freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, bronchiolitis obliterans syndrome, kidney function, infectious complications and posttransplant lymphoproliferative disorder were analyzed. Alemtuzumab induction therapy resulted in complete the absence of ACR episodes ≥ A2 within the first year post-TX. The difference to thymoglobulin was significant (alemtuzumab 0 vs. ATG 0.33; p = 0.019). All other factors studied did not show any differences between the two groups. Alemtuzumab induction therapy after LUTX in combination with reduced maintenance IS significantly reduces higher-grade rejection rates. This novel therapeutic agent had no impact on survival, infections rates, kidney function and incidence of malignancies.",
"affiliations": "Department of Thoracic Surgery, Medical University of Vienna, Wien, Austria.",
"authors": "Jaksch|P|P|;Ankersmit|J|J|;Scheed|A|A|;Kocher|A|A|;Muraközy|G|G|;Klepetko|W|W|;Lang|G|G|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; C512542:thymoglobulin; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
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"doi": "10.1111/ajt.12824",
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"issue": "14(8)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "Clinical research/practice; immunosuppressive regimens; induction; lung transplantation/pulmonology; lung transplantation: living donor; organ transplantation in general",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D001999:Bronchoscopy; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008171:Lung Diseases; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D011446:Prospective Studies; D016559:Tacrolimus; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100968638",
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"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Alemtuzumab in lung transplantation: an open-label, randomized, prospective single center study.",
"title_normalized": "alemtuzumab in lung transplantation an open label randomized prospective single center study"
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"companynumb": "AT-ROCHE-1138933",
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"activesubstancename": "GANCICLOVIR"
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"abstract": "Low malignant potential serous tumours (LMPSTs) of the ovary represent an indolent disease, with an excellent prognosis in a majority of patients. Patients with recurrent LMPSTs tend to develop widespread disease with a mortality rate as high as 70%. These tumours tend to have a very poor response to standard chemotherapy, and the management of primary and recurrent disease beyond surgical resection is not well defined. The majority of LMPST have been reported to express oestrogen and progesterone hormone receptors. However, only three reported cases of antihormonal treatment in this setting, and only one using aromatase inhibitors (AI), have been previously reported. We herein report long-term complete remission of two patients with relapsed, chemotherapy-resistant LMPSTs, treated with long-term AI (anastrozole 1 mg daily) as per negative MRI and positron emission tomography scans. Our results warrant further investigation for the use of AIs for metastatic recurrent LMPSTs.",
"affiliations": "Department of Medical Oncology, Jewish General Hospital, Montreal, Quebec, Canada.;Department of Medical Oncology, Jewish General Hospital, Montreal, Quebec, Canada.;Department of Medical Oncology, Jewish General Hospital, Montreal, Quebec, Canada.;Department of Medical Oncology, Jewish General Hospital, Montreal, Quebec, Canada.",
"authors": "Esfahani|Khashayar|K|;Ferrario|Cristiano|C|;Le|Philippe|P|;Panasci|Lawrence|L|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D000077384:Anastrozole",
"country": "England",
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009375:Neoplasms, Glandular and Epithelial; D009570:Nitriles; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012074:Remission Induction; D013156:Splenectomy; D013160:Splenic Neoplasms; D014230:Triazoles",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24925537",
"pubdate": "2014-06-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23024155;24219980;24287939;17063075;1869100;16515607;8725765;8631556;8522261;19560192;10836293;11240673;2920945;7837369;20719369;7184889;9061316",
"title": "Aromatase inhibition in relapsing low malignant potential serous tumours of the ovary.",
"title_normalized": "aromatase inhibition in relapsing low malignant potential serous tumours of the ovary"
} | [
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"companynumb": "CA-BAXTER-2014BAX039924",
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"occurcountry": "CA",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
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"abstract": "A 58-year-old man presented with left-sided orbital inflammation, including chemosis and a lateral rectus abduction defect. Initially presumed to represent cellulitis, the condition responded poorly to oral and intravenous antibiotics. CT showed the epicenter of an infiltrate to involve the lateral rectus. The patient improved dramatically when oral prednisone was added. Lateral rectus biopsy displayed intramuscular polyclonal lymphoid infiltrates, rich with eosinophils. Complete resolution of the inflammatory process was confirmed by a follow-up CT. The presumptive diagnosis was idiopathic orbital myositis, an uncommon condition of unknown etiology. However, the patient had taken rosuvastatin, which has been rarely associated with diplopia and ophthalmoplegia, raising the question of whether this case was truly idiopathic.",
"affiliations": "Department of Ophthalmology.;Department of Ophthalmology.;Department of Ophthalmology.;Department of Ophthalmology.;Department of Ophthalmology.",
"authors": "Charles|Norman C|NC|;Rebhun|Carl B|CB|;Lidder|Alcina K|AK|;Coulon|Sara J|SJ|;Kim|Eleanore T|ET|",
"chemical_list": "D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1097/IOP.0000000000001923",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0740-9303",
"issue": "37(4)",
"journal": "Ophthalmic plastic and reconstructive surgery",
"keywords": null,
"medline_ta": "Ophthalmic Plast Reconstr Surg",
"mesh_terms": "D004172:Diplopia; D006801:Humans; D008297:Male; D008875:Middle Aged; D009220:Myositis; D009801:Oculomotor Muscles; D055622:Orbital Myositis; D004364:Pharmaceutical Preparations",
"nlm_unique_id": "8508431",
"other_id": null,
"pages": "e141-e143",
"pmc": null,
"pmid": "33587420",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Myositis of an Extraocular Muscle, a Possible Drug Reaction: Histopathologic and Immunopathologic Analysis.",
"title_normalized": "myositis of an extraocular muscle a possible drug reaction histopathologic and immunopathologic analysis"
} | [
{
"companynumb": "US-APOTEX-2021AP045151",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSuper-refractory status epilepticus (SRSE) is a seizure that continues >24 h after anesthesia, or recurs on the reduction of anesthesia. SRSE is extremely difficult-to-control and associated with poor outcome. To date, optimal therapy and outcome data in children is limited.\n\n\nOBJECTIVE\nTo assess etiology, treatment options and outcome in pediatric SRSE patients.\n\n\nMETHODS\nWe reviewed medical records of children <15 years old with SRSE during 2007-2017 at King Chulalongkorn Memorial Hospital. Demographic data, etiology, treatment, complications and discharge outcome were recorded.\n\n\nRESULTS\nSeventeen patients, aged 1 month-13 years were included. The leading etiology was immune-mediated encephalitis (29.4%) and epilepsy (29.4%). The most common anesthetic agents were midazolam (94.1%) and propofol (52.9%) with the average maximal dose of 1.3 and 6.9 mg/kg/h respectively. Other treatments included immunological therapy (76.5%), ketogenic diet (76.5%), pyridoxine/pyridoxal-5-phosphate (70.5%). The most common complications were hypotension (61.5%), drug hypersensitivity (32.5%). Median length of anesthetic and intensive care were 9 and 23 days. The mortality rate was 17.6%, and 2 of 3 febrile infection-related epilepsy syndrome cases died. At discharge, all survivors were seizure free.\n\n\nCONCLUSIONS\nThe majority of pediatric SRSE does not have epilepsy and the etiology is various. Treatment should expand from antiepileptic drugs to other modalities targeting different possible mechanisms such as immunomodulation or specific metabolic treatment. Multiple anesthetic drugs could be tolerated with close monitoring. Ketogenic diet, via enteral or parenteral route, could be considered early if requiring multiple anesthetic drugs. Initial outcome in children is relatively better than in adults.",
"affiliations": "Department of Pediatrics, King Chulalongkorn Memorial Hospital, Thailand.;Division of Neurology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Thailand. Electronic address: krisnachai.c@chula.ac.th.",
"authors": "Arayakarnkul|Palita|P|;Chomtho|Krisnachai|K|",
"chemical_list": "D000927:Anticonvulsants; D008874:Midazolam; D015742:Propofol",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.braindev.2018.11.011",
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"issn_linking": "0387-7604",
"issue": "41(4)",
"journal": "Brain & development",
"keywords": "Intravenous immunoglobulin; Ketogenic diet; Ketogenic parenteral nutrition; Outcome; Pediatric; Status epilepticus; Super-refractory; Therapeutic hypothermia; Treatment",
"medline_ta": "Brain Dev",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D055423:Diet, Ketogenic; D000069279:Drug Resistant Epilepsy; D004660:Encephalitis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008874:Midazolam; D015742:Propofol; D012008:Recurrence; D012189:Retrospective Studies; D012640:Seizures; D013226:Status Epilepticus; D016896:Treatment Outcome",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "359-366",
"pmc": null,
"pmid": "30528076",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Treatment options in pediatric super-refractory status epilepticus.",
"title_normalized": "treatment options in pediatric super refractory status epilepticus"
} | [
{
"companynumb": "TH-PFIZER INC-2018521153",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "... |
{
"abstract": "We assessed the real-life use of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and exclusion criteria for randomized trials. From 2013 to 2016, 3,578 of 18,853 patients (19%) had exclusion criteria. Irrespective of which anticoagulant was chosen, they had more VTE recurrences (hazard ratio (HR): 3.10; 95% confidence interval (CI): 2.47-3.88), major bleeds (HR: 4.10; 95% CI: 3.38-4.96), and deaths (HR: 9.47; 95% CI: 8.46-10.6) than those without exclusion criteria. During initial therapy, no patient with exclusion criteria on DOACs (n = 115) recurred, but those on rivaroxaban bled less often (adjusted HR: 0.18; 95% CI: 0.04-0.79) than those on unfractionated heparin (n = 224) and similar to those (n = 3,172) on low-molecular-weight (LMWH) heparin. For long-term therapy, patients on rivaroxaban (n = 151) had nonsignificantly fewer VTE recurrences (adjusted HR: 0.74; 95% CI: 0.08-1.32) and major bleeds (adjusted HR: 0.41; 95% CI: 0.15-1.15) than those on LMWH (n = 2,071). The efficacy and safety of DOACs were similar to standard therapy.",
"affiliations": "Department of Emergency, CHU Clermont-Ferrand, Université Clermont Auvergne, Clermont-Ferrand, France.;Department of Medicine-DIMED, 2nd Chair of Internal Medicine, University of Padua, Padua, Italy.;Department of Internal Medicine and Emergency Room, Ospedale Buon Consiglio Fatebenefratelli, Naples, Italy.;Department of Internal Medicine, ALTAHAIA, Xarxa Assistencial de Manresa, Barcelona, Spain.;Department of Medicine 3, Azienda Ospedaliera Universitaria, Parma, Italy.;Department of Internal Medicine, Consorcio Hospitalario Provincial de Castellón, Ceu Cardenal Herrera University, Castellón, Spain.;Department of Internal Medicine, Hospital Universitario Joan XXIII de Tarragona, Tarragona, Spain.;Department of Internal Medicine, CHU de Dijon, Hôpital du Bocage, Dijon, France.;Department of Internal Medicine, Hospital de Can Misses, Ibiza, Spain.;Department of Internal Medicine, Hospital Universitario Germans Trias i Pujol de Badalona, Barcelona, Universidad Católica de Murcia, Spain.",
"authors": "Moustafa|Farès|F|;Pesavento|Raffaele|R|;di Micco|Pierpaolo|P|;González-Martínez|José|J|;Quintavalla|Roberto|R|;Peris|Maria-Luisa|ML|;Porras|José Antonio|JA|;Falvo|Nicolas|N|;Baños|Pilar|P|;Monreal|Manuel|M|;|||",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin; D000069552:Rivaroxaban",
"country": "United States",
"delete": false,
"doi": "10.1002/cpt.781",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9236",
"issue": "103(4)",
"journal": "Clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Clin Pharmacol Ther",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005260:Female; D006470:Hemorrhage; D006493:Heparin; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D000069451:Long Term Adverse Effects; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D000069552:Rivaroxaban; D016896:Treatment Outcome; D054556:Venous Thromboembolism",
"nlm_unique_id": "0372741",
"other_id": null,
"pages": "684-691",
"pmc": null,
"pmid": "28675460",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Real-life Use of Anticoagulants in Venous Thromboembolism With a Focus on Patients With Exclusion Criteria for Direct Oral Anticoagulants.",
"title_normalized": "real life use of anticoagulants in venous thromboembolism with a focus on patients with exclusion criteria for direct oral anticoagulants"
} | [
{
"companynumb": "FR-JNJFOC-20180623442",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "3",
... |
{
"abstract": "A 28-years old patient delivers a daughter by primary caesarian section (41. WOP) in breech presentation after a complication-free pregnancy except increased blood pressure readings at the morning of caesarian section. During the caesarian section a major bleeding of the atonic uterus with hemorrhagic shock appears. Haemostasis is achieved by mechanical tamponade, the application of red blood cell concentrates and the substitution of clotting factors, also tranexamic acid. Because of an anuric renal failure due to the shock hemodialysis is initiated.\n\n\n\nClinical examination and blood tests show the constellation of a thrombotic microangiopathy. There are no hints for a thrombotic thrombocytopenic purpura (TTP) or a hemolytic-uremic syndrome (HUS). In addition, a genetic testing gives no hints for an atypical HUS. After 4 weeks of dialysis duty a renal biopsy is performed. The renal biopsy shows a partly reversible tubular damage with an older ischemic cortical necrosis.\n\n\n\nIn the further course the resumption of the diuresis can be observed. The dialysis treatment has to be continued because of an insufficient excretory renal function. Fortunately a living-donor kidney transplantation (mother) can be carry out successfully already one year after the hemorrhagic shock.\n\n\n\nThe combination of peripartal bleeding with hemorrhagic shock, possibly aggravated by (pre-)eclampsia or HELLP-syndrome, and the application of tranexamic acid with its prothrombotic effect seems to be responsible for the major renal cortical necrosis.",
"affiliations": "Klinik für Nephrologie, Medizinische Fakultät, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland.;Klinik für Nephrologie, Medizinische Fakultät, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland.;Zentrum für Diagnostik, Institut für Pathologie (Sektion Nephropathologie), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland.;Klinik für Anästhesie, Intensivmedizin und Schmerztherapie, Florence-Nightingale-Krankenhaus, Kaiserswerth, Düsseldorf, Deutschland.;Klinik für Gynäkologie, Medizinische Fakultät, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland.;Klinik für Gynäkologie, Medizinische Fakultät, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland.;Klinik für Nephrologie, Medizinische Fakultät, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Deutschland.",
"authors": "Hoch|Henning|H|;Stegbauer|Johannes|J|;Wiech|Thorsten|T|;Barwing|Jürgen|J|;Karbowski|Brigitta|B|;Fehm|Tanja|T|;Rump|Lars Christian|LC|",
"chemical_list": "D014148:Tranexamic Acid",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-0857-8606",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "144(10)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007673:Kidney Cortex Necrosis; D006473:Postpartum Hemorrhage; D011247:Pregnancy; D006435:Renal Dialysis; D014148:Tranexamic Acid",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "678-682",
"pmc": null,
"pmid": "31083737",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal cortical necrosis after application of tranexamic acid in peripartal hemorrhage.",
"title_normalized": "renal cortical necrosis after application of tranexamic acid in peripartal hemorrhage"
} | [
{
"companynumb": "DE-MYLANLABS-2019M1054667",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FIBRINOGEN HUMAN"
},
"drugadditional": "3",
... |
{
"abstract": "In settings where abortion is legally restricted or inaccessible, grassroots feminist networks provide evidence-based information and support to individuals who self-manage abortions-a model of care known as abortion accompaniment. This study aims to fill a gap in existing evidence about out-of-clinic abortion beyond 12 weeks gestation.\n\n\n\nWe conducted a retrospective analysis of anonymized case records from accompaniment groups based in Argentina, Chile, and Ecuador of abortions supported between 13 and 24 weeks gestation. We report on the reproductive histories of individuals who had accompanied abortions, as well as medication regimens, and outcomes.\n\n\n\nBetween 2016 and 2018, 316 individuals received accompaniment support for 318 self-managed medication abortions between 13 and 24 weeks gestation. Individuals most commonly used mifepristone-misoprostol (n = 297, 93%), with sublingual misoprostol administration (n = 288, 88%). Medication alone resulted in 241 complete abortions (76%); 37 (12%) individuals underwent manual vacuum aspiration or dilation and curettage within the formal health system, and 16 people (5%) required an additional medication abortion attempt at a later date, resulted in ongoing pregnancy, or were lost to follow-up. After accounting for additional interventions or monitoring at a healthcare facility, 302 of 318 (95%) abortion attempts completed overall. We had complete information regarding complications only from Chile (n = 78); of these, 12 (15%) experienced potential complications, including delayed placental expulsion and/or heavy bleeding (n = 5, 6%), high fever (n = 3, 4%), and hypotension, panic attack, or vomiting (n = 3, 4%). No abortions resulted in transfusion or hysterectomy.\n\n\n\nSelf-managed medication abortion, with accompaniment network support and linkages to the formal health system in the event that complications arise, may be an effective and safe option for abortion beyond the first trimester - particularly in legally restrictive settings.\n\n\n\nThese results build on an emerging body of evidence suggesting that self-managed medication abortion beyond 12 weeks gestation, conducted with accompaniment support and referrals to formal health care services as needed, can be an effective model of abortion care - and can provide a safe alternative to clandestine surgical procedures.",
"affiliations": "Ibis Reproductive Health, 1736 Franklin St., Oakland, CA 94612, USA. Electronic address: hmoseson@ibisreproductivehealth.org.;Oregon Health Science University, c/o Department of Obstetrics & Gynecology, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA. Electronic address: bullard@ohsu.edu.;Con Las Amigas y en La Casa, Santiago, Chile. Electronic address: leonorapiolini@riseup.net.;La Revuelta Colectiva Feminista, Neuquén, Argentina.;Las Comadres, Quito, Ecuador. Electronic address: vonca@riseup.net.;Ibis Reproductive Health, 1736 Franklin St., Oakland, CA 94612, USA. Electronic address: cgerdts@ibisreproductivehealth.org.",
"authors": "Moseson|Heidi|H|;Bullard|Kimberley A|KA|;Cisternas|Carolina|C|;Grosso|Belén|B|;Vera|Verónica|V|;Gerdts|Caitlin|C|",
"chemical_list": "D016595:Misoprostol; D015735:Mifepristone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.contraception.2020.04.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-7824",
"issue": "102(2)",
"journal": "Contraception",
"keywords": "Accompaniment; Later abortion; Latin America; Medication abortion; Second-trimester abortion; Self-managed abortion",
"medline_ta": "Contraception",
"mesh_terms": "D000028:Abortion, Induced; D000022:Abortion, Spontaneous; D001118:Argentina; D002677:Chile; D004484:Ecuador; D005260:Female; D006801:Humans; D015735:Mifepristone; D016595:Misoprostol; D010920:Placenta; D011247:Pregnancy; D012189:Retrospective Studies",
"nlm_unique_id": "0234361",
"other_id": null,
"pages": "91-98",
"pmc": null,
"pmid": "32360817",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effectiveness of self-managed medication abortion between 13 and 24 weeks gestation: A retrospective review of case records from accompaniment groups in Argentina, Chile, and Ecuador.",
"title_normalized": "effectiveness of self managed medication abortion between 13 and 24 weeks gestation a retrospective review of case records from accompaniment groups in argentina chile and ecuador"
} | [
{
"companynumb": "US-PFIZER INC-2020219273",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MISOPROSTOL"
},
"drugadditional": "3",
... |
{
"abstract": "Two cases of fatalities are reported of which the recreational use of Mitragyna speciosa (\"kratom\") could be confirmed. One of these cases presents with one of the highest postmortem mitragynine concentrations published to date. Our results show that even extremely high mitragynine blood concentrations following the consumption of kratom do not necessarily have to be the direct cause of death in such fatalities as a result of an acute overdose. The two cases are compared with regard to the differences in mitragynine concentrations detected and the role of mitragynine in the death of the subjects. Irrespective of the big differences in mitragynine concentrations in the postmortem blood samples, mitragynine was not the primary cause of death in either of the two cases reported here. Additionally, by rough estimation, a significant difference in ratio of mitragynine to its diastereomers in the blood and urine samples between the two cases could be seen.",
"affiliations": "Institute of Forensic Medicine, Department of Toxicology, University of Munich, 80336 Munich, Germany. Electronic address: Olwen.Groth@med.uni-muenchen.de.;Institute of Forensic Medicine, Department of Toxicology, University of Munich, 80336 Munich, Germany.;Institute of Forensic Medicine, Department of Toxicology, University of Munich, 80336 Munich, Germany.;Institute of Forensic Medicine, Department of Toxicology, University of Munich, 80336 Munich, Germany.;Forensic Toxicological Center (FTC), 80335 Munich, Germany.;Forensic Toxicological Center (FTC), 80335 Munich, Germany.;FTC-Forensic-Toxicological Laboratory, 1120 Vienna, Austria.",
"authors": "Domingo|Olwen|O|;Roider|Gabriele|G|;Stöver|Andreas|A|;Graw|Matthias|M|;Musshoff|Frank|F|;Sachs|Hans|H|;Bicker|Wolfgang|W|",
"chemical_list": "D009294:Narcotics; D010936:Plant Extracts; D011619:Psychotropic Drugs; D046948:Secologanin Tryptamine Alkaloids; C001801:mitragynine",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2016.12.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "271()",
"journal": "Forensic science international",
"keywords": "Concentration dependent effects; Diastereomers; Kratom; Mitragynine; “Legal high”",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D006801:Humans; D008297:Male; D032065:Mitragyna; D009294:Narcotics; D010936:Plant Extracts; D018515:Plant Leaves; D011619:Psychotropic Drugs; D053120:Respiratory Aspiration; D046948:Secologanin Tryptamine Alkaloids; D019966:Substance-Related Disorders; D014474:Unconsciousness; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "e1-e7",
"pmc": null,
"pmid": "28089300",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mitragynine concentrations in two fatalities.",
"title_normalized": "mitragynine concentrations in two fatalities"
} | [
{
"companynumb": "DE-APOTEX-2017AP010378",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ETIZOLAM"
},
"drugadditional": null,
"... |
{
"abstract": "Duodenal polyps have been reported in <1.5% of individuals who undergo esophagogastroduodenoscopy (EGD). We present a case of a 76-year-old male with recurrent hematemesis who was found to have an intestinal-type, pedunculated tubulovillous adenoma in the descending duodenum. An isolated occurrence of nonampullary sporadic duodenal adenoma is a rare finding. Presentation as an upper gastrointestinal hemorrhage is also extremely uncommon. Our patient's polyp was pedunculated, which is atypical, because most sporadic duodenal adenomas are morphologically flat or sessile. The purpose of this case is to present a rare cause of upper gastrointestinal bleeding and to depict characteristics of an isolated duodenal tubulovillous adenoma and its treatment options.",
"affiliations": "Division of Internal Medicine, Memorial Healthcare System, Davie, Florida, USA.;Division of Gastroenterology, Rowan School of Osteopathic Medicine, Jefferson Health System, Stratford, New Jersey, USA.;Division of Internal Medicine, Rowan School of Osteopathic Medicine, Jefferson Health System, Stratford, New Jersey, USA.;Division of Gastroenterology, Rowan School of Osteopathic Medicine, Jefferson Health System, Stratford, New Jersey, USA.;Division of Gastroenterology, Rowan School of Osteopathic Medicine, Jefferson Health System, Stratford, New Jersey, USA.",
"authors": "Khalid|Yaser|Y|;Dasu|Neethi|N|;Suga|Herman|H|;Itidiare|Michael|M|;Walters|Richard|R|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000508436",
"fulltext": "\n==== Front\nCase Rep Gastroenterol\nCase Rep Gastroenterol\nCRG\nCase Reports in Gastroenterology\n1662-0631 S. 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.com \n\n10.1159/000508436\ncrg-0014-0361\nSingle Case\nA Rare Manifestation of a Bleeding Tubulovillous Duodenal Polyp Presenting as an Upper Gastrointestinal Hemorrhage\nKhalid Yaser a Dasu Neethi b* Suga Herman c Itidiare Michael b Walters Richard b aDivision of Internal Medicine, Memorial Healthcare System, Davie, Florida, USA\nbDivision of Gastroenterology, Rowan School of Osteopathic Medicine, Jefferson Health System, Stratford, New Jersey, USA\ncDivision of Internal Medicine, Rowan School of Osteopathic Medicine, Jefferson Health System, Stratford, New Jersey, USA\n*Neethi Dasu, Division of Gastroenterology, Jefferson Health System, 1207 Britton Place Voorhees, NJ 08043 (USA), dasu@rowan.edu\nMay-Aug 2020 \n28 7 2020 \n28 7 2020 \n14 2 361 366\n21 4 2020 1 5 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Duodenal polyps have been reported in <1.5% of individuals who undergo esophagogastroduodenoscopy (EGD). We present a case of a 76-year-old male with recurrent hematemesis who was found to have an intestinal-type, pedunculated tubulovillous adenoma in the descending duodenum. An isolated occurrence of nonampullary sporadic duodenal adenoma is a rare finding. Presentation as an upper gastrointestinal hemorrhage is also extremely uncommon. Our patient's polyp was pedunculated, which is atypical, because most sporadic duodenal adenomas are morphologically flat or sessile. The purpose of this case is to present a rare cause of upper gastrointestinal bleeding and to depict characteristics of an isolated duodenal tubulovillous adenoma and its treatment options.\n\nKeywords\nGastrointestinal hemorrhageAnemiaTubulovillous adenomaDuodenal polypPedunculated polyp\n==== Body\nIntroduction\nDuodenal polyps are a group of polyps that are uncommon to find on endoscopic evaluation. They have been reported in 0.3–1.5% of individuals who undergo upper endoscopy; therefore, they are considered a rare finding [1]. They are histologically classified according to mucin phenotype into intestinal (89.1%) and gastric type (10.9%); the intestinal-type polyps are morphologically subdivided into tubular and tubulovillous adenomas. These polyps grossly present as sessile or pedunculated polyps, nodules, excrescences, or subtle abnormalities of mucosa; they can be located either in the duodenal bulb, ampullary region, or distal duodenum [2]. Duodenal polyps are generally benign and carry a low probability for malignant transformation, and around 90% are nonneoplastic [3]. As endoscopic technology has advanced, the incidence of duodenal polyps has increased. Patients present with symptoms of dyspepsia, abdominal discomfort, mechanical obstruction, and sometimes jaundice. Other atypical and rare symptoms include hematemesis, which was seen in this case [2].\n\nCase Report\nA 76-year-old male from a long-term care facility presented with symptoms of feeling “off” and having increased respiratory secretions. He also complained of coughing, wheezing, and dyspnea. His past medical history included systolic congestive heart failure status-postautomatic implantable cardioverter-defibrillator, chronic kidney disease, chronic obstructive pulmonary disease, paroxysmal atrial fibrillation, hypertension, rheumatoid arthritis, prostate cancer, and a brain mass. On physical examination, he appeared frail and his abdomen was soft and nontender with normal bowel sounds. He also had marked basilar rhonchi on the auscultation of his chest. He was initially placed on bi-level positive airway pressure for respiratory support. However, his mental status continued to decline, and he required intubation with admission to the intensive care unit (ICU) for increasing oxygen requirements and respiratory distress. He was found to have acute hypoxemic respiratory failure secondary to bacterial pneumonia and an acute congestive heart failure exacerbation, which was treated with intravenous diuretics and antibiotics. Gastroenterology was initially consulted because the patient had an episode of coffee-ground hematemesis that was noticed when the nurse was checking his residuals after tube feeding. His hemoglobin was 9.9 g/dL, which was his baseline level. He was hemodynamically stable and thus required no acute endoscopic intervention by gastroenterology. His hematemesis was thought to be secondary to apixaban and aspirin which he was using for coronary artery disease and paroxysmal atrial fibrillation, and thus his apixaban was stopped. Gastroenterology was re-consulted when the patient's hemoglobin decreased to 6.6 g/dL, and orogastric lavage revealed 1 L of coffee-ground emesis. At that time, the patient underwent an emergent esophagogastroduodenoscopy (EGD) which revealed a 10-mm pedunculated polyp in the proximal duodenum with active bleeding (Fig. 1,2). The polyp was resected with hot snare and clipped twice. In addition to this polyp, there was a nonbleeding 4-mm sessile-appearing polyp slightly distally, which was removed with hot snare polypectomy. After EGD, the patient's hematemesis resolved, and his hemoglobin level stabilized back to baseline. However, his acute congestive heart failure and bacterial pneumonia progressed and worsened his respiratory failure. Thus, his family opted for comfort measures and no further interventions. The biopsy of the polyp tissue revealed a tubulovillous adenoma with minute foci of high-grade dysplasia (Fig. 3).\n\nDiscussion\nOur patient had a pedunculated, intestinal-type tubulovillous adenoma. Nonampullary sporadic duodenal adenomas are those which arise in patients without a known polyposis syndrome, such as familial adenomatous polyposis or Gardner's syndrome [4]. Isolated occurrence of such adenomas is a rare finding and presentation as an upper gastrointestinal bleed is even rarer [5]. Most duodenal polyps are benign, but our patient presented with a malignant subtype. Our patient's neoplastic pedunculated polyp was identified in the second portion of the duodenum, which is another atypical and unusual occurrence, because the majority of sporadic duodenal adenomas are flat or sessile [4]. The risk of carcinoma is greater for ampullary adenomas and increases with the size of adenoma [4]. Adenomas that are larger than 20 mm, or those that have high-grade dysplasia, have a higher rate of progression to adenocarcinoma (approximately 54.5%) [4]. This patient's polyp was 10 mm, but with high-grade dysplasia the odds of being malignant are higher, as was seen on biopsy.\n\nDuodenal adenocarcinomas have a significantly higher expression of gastric markers, such as MUC5AC and MUC6 as well as a higher MIB-1 index. Malignant polyps usually have increased depth of mucus invasion. Aside from biopsy, the likelihood of malignancy can be determined while removing the polyp and performing a lift sign, to evaluate if the polyp can be easily lifted from the mucosa's surface. A poor lift sign indicates a higher risk of malignancy; this was seen in this case.\n\nDuodenal polyps typically present with the following symptoms: epigastric pain, jaundice, dyspepsia, and/or weight loss [1]. None of these symptoms were seen in our case so it is unclear how long the patient had this duodenal polyp. Most patients are asymptomatic and very few present primarily with an upper gastrointestinal bleed, as seen in this case.\n\nThere are currently no definitive guidelines on how a duodenal polyp should be resected. Further studies are needed to assess techniques that can decrease mortality and prevent recurrence. Our patient died during the same hospitalization, but if he survived, it would have been essential for him to follow up for a repeat EGD within 6 months, in order to monitor the resection base of the polyp and to determine whether there was any recurrent neoplastic tissue [1].\n\nEGD techniques that are currently used for intervention are endoscopic snare and electrocautery, which were successful in this case as the patient's hematemesis resolved. The use of EGD can also have complications, which include perforation, further bleeding, and sedation from anesthesia. However, no complications were seen following EGD in this case.\n\nConclusion\nDuodenal polyps are a rare occurrence. Most are benign. We presented a case of a 76-year-old male with recurrent hematemesis and anemia who was found to have a duodenal polyp. This is a unique case due to the patient's presenting symptoms of an upper gastrointestinal hemorrhage with findings of a pedunculated tubulovillous duodenal adenoma with high-grade dysplasia. Further guidelines on how to manage malignant tubulovillous adenomas may prove beneficial, but pedunculated polyps should be resected and biopsied. EGD surveillance within 6 months is recommended because nonampullary sporadic adenomas have been linked to an increased risk of colorectal neoplasia [4]. It is also important for practitioners to keep in mind rarer causes of upper gastrointestinal bleeding.\n\nStatement of Ethics\nInformed consent for publication was obtained from the patient's family member/POA (including publication of images).\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThe authors have no funding sources to disclose.\n\nAuthor Contributions\nYaser Khalid and Neethi Dasu: conception of the work, data analysis and interpretation, critical revision of the article, and final approval of the version to be published. Richard Walters: conception of the work, data analysis and interpretation, and critical revision of the article. Michael Itidiare: data collection, data analysis and interpretation, and critical revision of the article. Herman Suga: data collection, data analysis and interpretation, and drafting the article. All authors approved the final version of the manuscript.\n\nFig. 1 EGD revealing a 10-mm pedunculated polyp in the proximal duodenum with active bleeding.\n\nFig. 2 A 10-mm pedunculated polyp in the proximal duodenum with active bleeding.\n\nFig. 3 Focal 20× representation of tubulovillous adenoma with minute foci of high-grade dysplasia.\n==== Refs\nReferences\n1 Jepsen JM Persson M Jakobsen NO Christiansen T Skoubo-Kristensen E Funch-Jensen P Prospective study of prevalence and endoscopic and histopathologic characteristics of duodenal polyps in patients submitted to upper endoscopy Scand J Gastroenterol 1994 6 29 (6) 483 7 8079103 \n2 Collins K Ligato S Duodenal Epithelial Polyps: A Clinicopathologic Review Arch Pathol Lab Med 2019 3 143 (3) 370 85 30354274 \n3 Lee CH Shingler G Mowbray NG Al-Sarireh B Evans P Smith M Surgical outcomes for duodenal adenoma and adenocarcinoma: a multicentre study in Australia and the United Kingdom ANZ J Surg 2018 3 88 (3) E157 61 28122405 \n4 Basford PJ Bhandari P Endoscopic management of nonampullary duodenal polyps Therap Adv Gastroenterol 2012 3 5 (2) 127 38 \n5 Murray MA Zimmerman MJ Ee HC Sporadic duodenal adenoma is associated with colorectal neoplasia Gut 2004 2 53 (2) 261 5 14724161\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "14(2)",
"journal": "Case reports in gastroenterology",
"keywords": "Anemia; Duodenal polyp; Gastrointestinal hemorrhage; Pedunculated polyp; Tubulovillous adenoma",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "361-366",
"pmc": null,
"pmid": "32884511",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "8079103;30354274;14724161;22423261;28122405",
"title": "A Rare Manifestation of a Bleeding Tubulovillous Duodenal Polyp Presenting as an Upper Gastrointestinal Hemorrhage.",
"title_normalized": "a rare manifestation of a bleeding tubulovillous duodenal polyp presenting as an upper gastrointestinal hemorrhage"
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"abstract": "Severe pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration.",
"affiliations": "Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Respiratory Medicine, Kyushu University Hospital, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.;Department of Oncology and Social Medicine, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka 812-8582, Japan.",
"authors": "Ueno|Shohei|S|;Uenomachi|Masato|M|;Kusaba|Hitoshi|H|;Ito|Mamoru|M|;Suzuki|Kunihiro|K|;Ohmura|Hirofumi|H|;Tsuchihashi|Kenji|K|;Ariyama|Hiroshi|H|;Akashi|Koichi|K|;Baba|Eishi|E|",
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"doi": "10.3892/mco.2021.2379",
"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450\n2049-9469\nD.A. Spandidos\n\nMCO-15-4-02379\n10.3892/mco.2021.2379\nArticles\nImprovement in recurring nivolumab-induced pneumonitis with repetitive administration of infliximab in a patient with head and neck cancer: A case report\nUeno Shohei 1\nUenomachi Masato 1\nKusaba Hitoshi 1\nIto Mamoru 1\nSuzuki Kunihiro 2\nOhmura Hirofumi 1\nTsuchihashi Kenji 1\nAriyama Hiroshi 1\nAkashi Koichi 1\nBaba Eishi 3\n1 Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan\n2 Department of Respiratory Medicine, Kyushu University Hospital, Higashi-ku, Fukuoka 812-8582, Japan\n3 Department of Oncology and Social Medicine, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka 812-8582, Japan\nCorrespondence to: Dr Hitoshi Kusaba, Department of Medicine and Biosystemic Sciences, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan hkusaba@intmed1.med.kyushu-u.ac.jp\nAbbreviations: Ab, antibody; CRP, C-reactive protein; CT, computed tomography; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; HNSCC, head and neck squamous cell carcinoma; irAE, immune-related adverse event; ICI, immune checkpoint inhibitor; PD-1, programmed cell death-1; SCC, squamous cell carcinoma; TNF-α, tumor necrosis factor α\n\n10 2021\n25 8 2021\n25 8 2021\n15 4 22114 7 2020\n16 7 2021\nCopyright: © Ueno et al.\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.\nSevere pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration.\n\nhead and neck cancer\nnivolumab\npneumonitis\ninfliximab\nimmunotherapy\nFunding: No funding was received.\n==== Body\npmcIntroduction\n\nHead and neck cancer is the sixth most common cancer worldwide, accounting for ~6% of all cases and an estimated 1-2% of all cancer deaths (1,2). More than 90% of head and neck cancers are squamous cell carcinomas (SCC). In patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), combination therapy with platinum, fluorouracil, and cetuximab as first-line treatment significantly prolongs overall survival (3). Nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody (Ab), shows a significant improvement in overall survival over chemotherapy in patients with HNSCC that is refractory to platinum-based chemotherapy (4). Nivolumab also has durable clinical benefits in patients with various malignant tumors (5-10).\n\nAnti-PD-1 therapies such as nivolumab and pembrolizumab cause immune-related adverse events (irAEs) including endocrine dysfunction, neurological disorders, hepatitis, nephritis, cardiac insufficiency, colitis, and pneumonitis. Among them, pneumonitis is a relatively rare but potentially fatal adverse event (11). The incidence of pneumonitis associated with anti-PD-1 therapies is 2.7% for all-grade and 0.8% for grade ≥3(12). Cancer immunotherapy guidelines recommend an intermediate or high dose of corticosteroids for anti-PD-1 therapy-induced pneumonitis (13,14). In cases of severe pneumonitis that is refractory to corticosteroids, several immune suppressants such as cyclophosphamide, mycophenolate mofetil, and the anti-tumor necrosis factor alpha (TNF-α) Ab, infliximab, are recommended. Infliximab is effective for pneumonitis due to anti-PD-1 therapy (15). However, the efficacy and feasibility of repetitive administration of infliximab for recurrent pneumonitis remain unclear. Here, we present a case in which amelioration of recurrent nivolumab-induced severe pneumonitis was induced by repetitive administration of infliximab.\n\nCase presentation\n\nA 59-year-old female with a heavy smoking (70 pack-years) and drinking history was diagnosed with SCC of the oropharynx (cT2N0M0) and hypopharynx (cT2N0M0) in 201x-3. She was treated with induction chemotherapy consisting of cisplatin and docetaxel followed by concurrent chemoradiotherapy with tegafur/gimeracil/oteracil (S-1), resulting in a complete response. She also had a history of definitive chemoradiotherapy consisting of cisplatin and 5-fluorouracil for locally advanced esophageal SCC (cT3N1M0) in 201x-1. Although she had undergone a complete resection for local recurrence of the hypopharyngeal SCC in August 201x, metastases to the lung and mediastinal lymph nodes were detected in November 201x and histologically confirmed as SCCs. She was then treated with nivolumab monotherapy at a standard dose of 3 mg/kg for metastatic HNSCC. Her Eastern Cooperative Oncology Group performance status was 1. She had no respiratory symptoms. Blood tests and laboratory examinations showed normal values except for anemia (hemoglobin 9.0 g/dl) and a high level of serum C-reactive protein (CRP; 6.3 mg/dl). The antinuclear antibody test was negative. On the 10th day of the first administration of nivolumab, she complained of fever and a dry cough. Oseltamivir was given for 7 days following immunological diagnosis of influenza B virus infection. However, she was admitted to our hospital because of progressive dyspnea on the 14th day of nivolumab administration. Computed tomography (CT) scans of the chest showed ground-glass opacities in the right lung (Fig. 1A). It was difficult for us to determine whether the CT findings were infectious pneumonia such as pulmonary suppuration or round-glass opacities. We consulted with a pulmonologist and a radiologist and diagnosed. Immunological tests for influenza virus were negative. Other infectious diseases were also ruled out by bacterial sputum/blood/urinary culture and fungal antigen tests. Bronchoscopy and bronchoalveolar lavage revealed a high proportion of lymphocytes: Macrophages 27.5%, neutrophils 46.4%, lymphocytes 26.1%, eosinophils 0%. These results suggested drug-induced lung disease or viral infection. The serum concentration of Krebs von den Lungen-6 was normal, but surfactant protein-A was elevated (58.6 ng/ml). She was finally diagnosed with nivolumab-induced pneumonitis. Nivolumab was then discontinued, and intravenous high-dose methylprednisolone (1,000 mg/day for 3 days) was administered. Prophylactic antibiotics were also started. However, on the 17th day, dyspnea worsened to the extent that intubation was required. CT scans showed that the ground-glass opacities in the right lung had worsened (Fig. 1B). Blood tests showed high concentrations of serum CRP (12.4 mg/dl) and serum TNF-α (45.2 pg/ml). She was administered a single dose of infliximab (5 mg/kg) for nivolumab-induced pneumonitis that was refractory to high-dose methylprednisolone. One week after administration of infliximab, serum concentrations of CRP and TNF-α were decreased, and CT scans showed marked regression of pulmonary opacities (Fig. 1C). Subsequently, the dosage of prednisolone was tapered to 30 mg daily after 35 mg daily administration for 2 weeks (Fig. 2). On the 72nd day after nivolumab administration, the patient complained of fever, dyspnea, diarrhea, and joint pain. Blood tests showed that the serum level of CRP (50.0 mg/dl) was elevated again, and CT scans of the chest showed that the pneumonitis had worsened in the right lung (Fig. 3A). Bacterial sputum/blood/urinary culture, the β-D glucan value, and viral antibody tests including influenza virus were all negative. She was thus diagnosed with recurrence of nivolumab-induced pneumonitis. She was administered a single dose of infliximab again on the 70th day because her previous pneumonitis was refractory to high-dose methylprednisolone, and more than 8 weeks had passed since the first dose of infliximab (Fig. 2). The second administration of infliximab improved the pneumonitis (Fig. 3B). Although prednisolone 25 mg daily was continued, pneumonitis relapsed on the 101st day of nivolumab administration without any specific events; nivolumab may have exacerbated the pneumonitis (Fig. 3C). A single dose of infliximab was again administered, and her pneumonitis improved (Fig. 3D). Nivolumab was not re-administered due to severe irAE. We discussed taxanes, S-1, or cetuximab for the next therapy. However, best supportive care was performed because of the poor performance status due to progression of the tumor. The patient died of tumor progression the 121st day after the initial administration of nivolumab. Informed consent was obtained from the patient for publication of a case report.\n\nDiscussion\n\nImmune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) have demonstrated notable antitumor activity across various tumor types. On the other hand, irAEs induced by ICIs have become an important issue. Dermatologic, musculoskeletal, gastrointestinal, hepatic, endocrine, and pulmonary events have been reported (16). Among them, pneumonitis is a serious adverse event that can have a lethal outcome. The incidence of pneumonitis associated with anti-PD-1 Ab is 2.7% for all-grade and 0.8% for grade ≥3(12). Huang et al reported that nivolumab, pembrolizumab, and nivolumab plus ipilimumab therapy are significantly higher risk factors for pneumonitis compared with chemotherapy (17). Generally, the time to onset of pneumonitis associated with anti-PD-1 Ab varies from within a few weeks to months after administration (16).\n\nSeveral retrospective analyses and systematic reviews investigated the risk factors for ICI-related pneumonitis. Pre-existing pulmonary fibrosis increases the risk of anti-PD-1 Ab-related pneumonitis in patients with non-small cell lung cancer (18). A history of radiotherapy of the lung was also thought to be a risk factor for ICI-related pneumonitis (19). In the present case, pneumonitis occurred ~2 weeks after administration of nivolumab. Because infectious pneumonia was carefully ruled out, the patient was diagnosed with nivolumab-induced pneumonitis. Although the patient did not have pre-existing pulmonary fibrosis, a history of radiotherapy for locally advanced esophageal SCC may have affected the development of pneumonitis as reported in a previous study (19). Furthermore, previous influenza B virus infection may trigger or worsen nivolumab-induced pneumonitis. Inflammatory cytokines including TNF-α are induced early after influenza infection (20). Although these factors may be associated with occurrence of ICI-related pneumonitis, the mechanisms of steroid refractoriness of pneumonitis have not been clarified.\n\nRegarding the treatment for ICI-induced pneumonitis, the cancer immunotherapy guidelines recommend corticosteroids for treatment of irAEs (13,14). Immunosuppressive drugs such as infliximab or mycophenolate mofetil are recommended for serious irAEs that are refractory to corticosteroids (13,14). Several studies reported that infliximab is effective for anti-CTLA-4 Ab-induced enterocolitis that is refractory to corticosteroids (21,22). Infliximab also improves ICI-induced pneumonitis that is refractory to corticosteroids (15,23). TNF-α is involved in the onset of pneumonitis associated with autoimmune diseases (24). In the present case, respiratory insufficiency and pulmonary opacities did not improve with intravenous high-dose methylprednisolone but with a single dose of infliximab. After improvement in pneumonitis with infliximab, a maintenance dose of prednisolone was continued. However, reactivation of pneumonitis was observed 2 months after the first administration of infliximab, and 1 month after the second administration of infliximab.\n\nMultiple mechanisms may be associated with recurrence of nivolumab-induced pneumonitis. Activation of CD8+ T cells mediates psoriasis-like dermatitis and hepatotoxicity caused by ICIs (25,26). A specific T cell repertoire such as CD8 that is involved in nivolumab-induced pneumonitis may be decreased after infliximab administration, and then reactivation of the T cell repertoire may induce recurrence of the pneumonitis. Alternatively, the decrease in TNF-α by infliximab administration could induce the T cell repertoire. Thus, serum TNF-α may play a critical role in modulating the activity of nivolumab-induced pneumonitis.\n\nIn the present case, the serum concentration of TNF-α clearly increased in association with exacerbation of the pneumonitis, and it subsequently decreased in association with amelioration of pneumonitis after infliximab therapy. These observations suggested that TNF-α is directly involved in the activity of nivolumab-induced pneumonitis. The dosing schedule of infliximab, including repetitive administration of infliximab, for steroid-refractory ICI-induced pneumonitis has not been clearly described in the current guidelines for cancer immunotherapy (13,14). Recently, a case was reported of ICI-induced pneumonitis demonstrating transient improvement but re-exacerbation 2 weeks after infliximab therapy, suggesting the possible efficacy of repetitive administration of infliximab (23). Immune-related colitis that is refractory to corticosteroids is improved by repetitive administration of infliximab when it relapses (27). Although other cytokines are possibly related to exacerbation of ICI-induced pneumonitis such as interleukin-1 and interleukin-6(28), the recurring nivolumab-induced pneumonitis in the present case is strongly suggested to be mainly dependent on TNF-α. Repetitive infliximab therapy is thought to be effective for nivolumab-induced pneumonitis that worsens in accordance with increased serum concentrations of TNF-α. Steroid-refractory nivolumab-induced pneumonitis was apparently improved with infliximab therapy. One reason for recurrence of the pneumonitis is thought to be an increase in TNF-α caused by reactivation of autoreactive T cells.\n\nA limitation for this study is that TNF-α at the second and third onset of pneumonitis could not be measured due to insufficient blood sample volume.\n\nIn conclusion, repetitive administration of infliximab was effective for the recurring pneumonitis. The present case may provide valuable information to establish an appropriate therapeutic strategy for steroid-refractory ICI-induced pneumonitis.\n\nAcknowledgements\n\nNot applicable.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\n\nSU and HK made substantial contributions to the conception and design of the study. SU, MU, HK, KS and HO made substantial contributions to the acquisition of the data. SU and HK drafted the manuscript. SU and HK confirm the authenticity of all the raw data. SU, HK, MI, KT, HA, KA and EB made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\n\nNot applicable.\n\nPatient consent for publication\n\nWritten informed consent was obtained from the patient for publication of the clinical data and images.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nFigure 1 Images show the lungs before and after infliximab treatment with initial nivolumab-induced pneumonia. (A) CT on the 14th day of nivolumab administration revealed GGO (indicated by arrows) in the right lung. (B) CT on the 17th day of nivolumab administration indicated that the GGO (indicated by arrows) in the right lung were exacerbated. (C) After administration of infliximab, GGO disappeared. CT, computed tomography; GGO, ground-glass opacities.\n\nFigure 2 Clinical course of the patient. Administration of infliximab decreased serum concentrations of CRP and TNF-α. Black column indicates steroid therapy, the downward arrows indicates administration of infliximab (5 mg/kg) and the closed circle indicates CRP (mg/dl). Black cross indicates TNF-α (pg/ml) and the horizontal arrow indicates administration of antibiotics. CRP, C-reactive protein; TNF-α, tumor necrosis factor α.\n\nFigure 3 Lungs before and after infliximab treatment with the second and third nivolumab-induced pneumonia. (A) CT on the 72nd day of nivolumab administration showed that pneumonitis (indicated by arrows) was exacerbated in the right lung. (B) Second administration of infliximab improved the pneumonitis (indicated by arrows). (C) CT on the 101st day of nivolumab administration demonstrated that pneumonitis (indicated by arrows) had relapsed in the right lung. (D) Third administration of infliximab improved the pneumonitis (indicated by arrows). 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Kalinka-Warzocha E Nivolumab in previously untreated melanoma without BRAF mutation N Engl J Med 372 320 330 2015 10.1056/NEJMoa1412082 25399552\n6 Brahmer J Reckamp KL Baas P Crinò L Eberhardt WE Poddubskaya E Antonia S Pluzanski A Vokes EE Holgado E Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer N Engl J Med 373 123 135 2015 10.1056/NEJMoa1504627 26028407\n7 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Chow LQ Vokes EE Felip E Holgado E Nivolumab versus Docetaxel in advanced nonsquamous non-small-cell lung cancer N Engl J Med 373 1627 1639 2015 10.1056/NEJMoa1507643 26412456\n8 Motzer RJ Escudier B McDermott DF George S Hammers HJ Srinivas S Tykodi SS Sosman JA Procopio G Plimack ER Nivolumab versus Everolimus in advanced renal-cell carcinoma N Engl J Med 373 1803 1813 2015 10.1056/NEJMoa1510665 26406148\n9 Kang YK Boku N Satoh T Ryu MH Chao Y Kato K Chung HC Chen JS Muro K Kang WK Nivolumab in patients with advanced gastric or 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blockade of cytotoxic T-lymphocyte-associated antigen 4 J Clin Oncol 24 2283 2289 2006 10.1200/JCO.2005.04.5716 16710025\n22 Johnston RL Lutzky J Chodhry A Barkin JS Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab Dig Dis Sci 54 2538 2540 2009 10.1007/s10620-008-0641-z 19104936\n23 Sawai Y Katsuya Y Shinozaki-Ushiku A Iwasaki A Fukayama M Watanabe K Nagase T Rapid temporal improvement of pembrolizumab-induced pneumonitis using the anti-TNF-α antibody infliximab Drug Discov Ther 13 164 167 2019 10.5582/ddt.2019.01032 31257354\n24 Gosset P Perez T Lassalle P Duquesnoy B Farre JM Tonnel AB Capron A Increased TNF-alpha secretion by alveolar macrophages from patients with rheumatoid arthritis Am Rev Respir Dis 143 593 597 1991 10.1164/ajrccm/143.3.593 2001072\n25 Tanaka R Ichimura Y Kubota N Saito A Nakamura Y Ishitsuka Y Watanabe R Fujisawa Y Kanzaki M Mizuno S Activation of CD8 T cells accelerates anti-PD-1 antibody-induced psoriasis-like dermatitis through IL-6 Commun Biol 3 571 2020 10.1038/s42003-020-01308-2 33060784\n26 Zen Y Yeh MM Hepatotoxicity of immune checkpoint inhibitors: A histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury Mod Pathol 31 965 973 2018 10.1038/s41379-018-0013-y 29403081\n27 Minor DR Chin K Kashani-Sabet M . Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis Cancer Biother Radiopharm 24 321 325 2009 10.1089/cbr.2008.0607 19538054\n28 Fishman JA Hogan JI Maus MV Inflammatory and infectious syndromes associated with cancer immunotherapies Clin Infect Dis 69 909 920 2019 10.1093/cid/ciy1025 30520987\n\n",
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"issue": "15(4)",
"journal": "Molecular and clinical oncology",
"keywords": "head and neck cancer; immunotherapy; infliximab; nivolumab; pneumonitis",
"medline_ta": "Mol Clin Oncol",
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"title": "Improvement in recurring nivolumab-induced pneumonitis with repetitive administration of infliximab in a patient with head and neck cancer: A case report.",
"title_normalized": "improvement in recurring nivolumab induced pneumonitis with repetitive administration of infliximab in a patient with head and neck cancer a case report"
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"abstract": "We encountered two patients with sumatriptan-induced reversible cerebral vasoconstriction syndrome (RCVS). The present patients were taking sumatriptan for the first time because they had been tentatively diagnosed with a migraine. On reviewing the literature, we found nine other cases of triptan-induced RCVS, predominantly among women aged 30 to 40 years. RCVS has been precipitated by triptan at the first ever use, after daily use, and even with long-term use at a normal dose. Patients with acute onset of severe headache should be thoroughly evaluated, and triptan should be administered appropriately. If triptan-induced RCVS is suspected, vascular imaging should be repeated after several days.",
"affiliations": "Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, Japan.",
"authors": "Kato|Yuji|Y|;Hayashi|Takeshi|T|;Mizuno|Satoko|S|;Horiuchi|Yohsuke|Y|;Ohira|Masayuki|M|;Tanahashi|Norio|N|;Takao|Masaki|M|",
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"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.7185Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27904122Case ReportTriptan-induced Reversible Cerebral Vasoconstriction Syndrome: Two Case Reports with a Literature Review Kato Yuji 1Hayashi Takeshi 1Mizuno Satoko 1Horiuchi Yohsuke 1Ohira Masayuki 1Tanahashi Norio 1Takao Masaki 11 Department of Neurology and Cerebrovascular Medicine, Saitama Medical University International Medical Center, JapanCorrespondence to Dr. Yuji Kato, yujik@saitama-med.ac.jp\n\n1 12 2016 55 23 3525 3528 25 1 2016 11 4 2016 The Internal Medicine is an Open Access article 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/).We encountered two patients with sumatriptan-induced reversible cerebral vasoconstriction syndrome (RCVS). The present patients were taking sumatriptan for the first time because they had been tentatively diagnosed with a migraine. On reviewing the literature, we found nine other cases of triptan-induced RCVS, predominantly among women aged 30 to 40 years. RCVS has been precipitated by triptan at the first ever use, after daily use, and even with long-term use at a normal dose. Patients with acute onset of severe headache should be thoroughly evaluated, and triptan should be administered appropriately. If triptan-induced RCVS is suspected, vascular imaging should be repeated after several days. \n\nreversible cerebral vasoconstriction syndrometriptanmigrainethunderclap headache\n==== Body\nIntroduction\nReversible cerebral vasoconstriction syndrome (RCVS) is a clinical entity characterized by severe headaches with or without acute neurological symptoms, the radiological features of which include multifocal segmental constriction of the cerebral arteries that resolves spontaneously within three months (1-4). RCVS is considered a rare syndrome, but the growing use of vasoactive drugs combined with the more frequent use of non-invasive neurovascular imaging has increased the incidence (4). Triptan is one of the drugs that triggers RCVS (2,4), but triptan-induced RCVS cases are relatively rare. We herein describe two cases of sumatriptan-induced RCVS and review the clinical features of triptan-induced RCVS.\n\nCase Reports\nCase 1\nA 43-year-old woman with a history of uncontrolled hypertension began suffering from a bifrontal-throbbing headache every other day, associated with neither nausea, photophobia, nor phonophobia. Three weeks later, she sought medical attention when over-the-counter medications failed to relive the headaches. The results of a computed tomographic (CT) scan of the head were normal, and she was prescribed oral sumatriptan. One hour after taking the drug, she experienced a sudden exacerbation of her headache, followed by a seizure, which caused her to fall and hit her head against the floor. She was subsequently admitted to our institute.\n\nOn admission, her blood pressure was 171/72 mmHg, and she was afebrile. Shortly thereafter, she again experienced a generalized epileptic seizure that was treated by intravenous administration of diazepam and phenytoin. The laboratory findings, including a blood count, coagulation parameters, and the results of liver and renal tests, were normal. Magnetic resonance imaging (MRI) of the brain using fluid-attenuated inversion recovery (FLAIR) revealed a left parietal cortical subarachnoid hemorrhage (SAH) (Fig. 1a, small white arrow) and multiple high-intensity lesions in the bilateral occipital lobes (Fig. 1a, large black arrows). Diffusion-weighted MRI and magnetic resonance angiography (MRA) revealed no abnormalities (Fig. 1b). On Day 6, MRA showed narrowing of the bilateral middle and posterior cerebral arteries (Fig. 1d, white arrows), although the lesions on the occipital lobes had improved (Fig. 1c). Her blood pressure was controlled within a normal range through administration of first amlodipine and then lomerizine. On Day 14, her headache had improved, and findings on MRI and MRA were normal (Fig. 1e and f). She was diagnosed with a headache attributed to arterial hypertension before sumatriptan administration, and RCVS associated with posterior reversible encephalopathy syndrome (PRES). The cortical SAH might have been due either to the head trauma or to RCVS.\n\nFigure 1. a: FLAIR-MRI on admission showing a left parietal cortical subarachnoid hemorrhage (small white arrow), multiple lesions on the bilateral occipital lobes (large black arrows), and traumatic scalp hematoma (black arrowhead). b: MRA on admission showing no abnormalities. c: FLAIR-MRI on Day 6 showing the resolution of the occipital lesions. d: MRA on Day 6 showing a beaded appearance of the bilateral middle and posterior cerebral arteries (white arrows). e: FLAIR-MRI on Day 14 showing no additional findings. f: MRA on Day 14 showing the resolution of the narrowing vessels.\n\nCase 2\nA 30-year-old woman developed a bifrontal-throbbing headache 4 days after spontaneous delivery. The pregnancy had been uneventful, and she never had signs of eclampsia. She had no remarkable medical history. On admission, had blood pressure was 180/104 mmHg. The findings from a neurological examination and initial CT scan were normal. The brain MRI with MRA findings were also normal (Fig. 2a and b). She was treated with nasal sumatriptan, but the headaches initially showed no response. The headaches then gradually resolved following the administration of acetaminophen over a few days, and the patient was discharged. A repeat MRI with MRA performed on Day 6 after her discharge showed narrowing of the bilateral anterior, middle, and posterior cerebral arteries (Fig. 2c and d, white arrows), which were normalized on Day 25 (Fig. 2e and f). In this case, the headache peaked during the first few days following sumatriptan administration and disappeared before the peak of cerebral vasoconstriction. She was retrospectively suspected of having had a postpartum headache before starting sumatriptan administration.\n\nFigure 2. a, b: MRA on admission showing no abnormalities. c, d: MRA on Day 7 showing a diffuse, beaded appearance of the intracranial vasculature (white arrows). e, f: MRA on Day 25 showing the complete resolution of the narrowing vessels.\n\nDiscussion\nSumatriptan is often used to treat migraines and occasionally induces cerebral vasoconstriction. Our two patients were taking sumatriptan for the first time because they had been tentatively diagnosed with a migraine. It was difficult to show any clear evidence of sumatriptan-induced RCVS in both of these cases. Sumatriptan seemed to play a primary role in Case 1, but a secondary role or even an incidental role due to the postpartum period in Case 2. However, sumatriptan likely either induced or exacerbated RCVS in both cases. \n\nThe recent literature reflects a growing interest in RCVS. Four studies including more than 10 cases have been published (5-8). However, only nine cases in the literature have described the association between triptans and RCVS in detail (Table) (7,9-14). The mean age among these 9 cases was 36 years, and 6 (66.7%) were women. Sumariptan, administrated either subcutaneously, orally, or nasally, was the most commonly implicated drug. RCVS was precipitated at the first ever use, or after daily use of one or several drugs, or even after long-term use of triptan at normal doses. Two patients presented with RCVS within the first week after delivery, suggesting that triptans must be used carefully in patients with headache in the postpartum period. The most frequent finding on cerebral imaging was ischemic stroke (four cases). Only two patients presented with thunderclap headache. Most patients had good recovery, but severe stroke seemed to induce poor outcomes.\n\nTable. Case Reports of RCVS and Triptan Use.\n\nReference\tAge/sex\tTrigger drug\tPostpartum \nperiod\tSubarachnoid \nhemorrhage\tStroke\tHeadache characteristics\tClinical outcome\t\n9\t43M\tSumatriptan† (T), Midrin†\tNo\tNo\tIschemic\tBioccipital-throbbing\tRecovery\t\n10\t20F\tSumatriptan* (I), Ergotamine*\tYes\tNo\tIschemic\tSevere frontal and occipitonuchal\tRecovery\t\n11\t37F\tSumatriptan† (I), Ergotamine†\tNo\tNo\tHemorrhage\tFrontal throbbing\tImpairment\t\n12\t34M\tSumatriptan (I) †\tNo\tNo\tIschemic\tNonconscious\tRecovery\t\n13\t12M\tEletriptan (T)\tNo\tYes\tNo\tSevere acute\tRecovery\t\n14\t39F\tNaratriptan (T) †, SNRI, SSRI\tNo\tYes\tNo\tSevere bifrontal-throbbing\tRecovery\t\n7\t68F\tSumatriptan (?)\tNo\tNo\tIschemic\tThunderclap\tDeath\t\nPresent case 1\t44F\tSumatriptan* (T)\tNo\tYes\tPRES\tThunderclap\tRecovery\t\nPresent case 2\t30F\tSumatriptan* (N)\tYes\tNo\tNo\tBifrontal-throbbing\tRecovery\t\n(T) Tablet, (N) Nasal spray, (I) Injection, * First ever use, † Abuse or daily use, SNRI: serotonin norepinephrine reuptake inhibitor, SSRI: selective serotonin reuptake inhibitor, PRES: posterior reversible encephalopathy syndrome\n\nThe underlying mechanisms of RCVS are unknown. Triptan can precipitate RCVS when administered to susceptible patients. An individual's susceptibility to developing RCVS may be influenced by genetic predisposition (e.g., brain-derived neurotrophic polymorphism, female gender) and precipitating factors (e.g., vasoactive substances, pregnancy/postpartum) (15). Triptan-induced RCVS may be more frequent than previously thought. Regardless of the presence of a migraine, patients presenting with acute onset of severe headache should be thoroughly evaluated, and triptan should be administered carefully, as it could precipitate RCVS or aggravate cerebral vasoconstriction. If triptan-induced RCVS is suspected, vascular imaging should be performed after several days.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nCalabrese LH , Dodick DW , Schwedt TJ , Singhal AB \nNarrative review: reversible cerebral vasoconstriction syndromes . Ann Intern Med \n146 : 34 -44 , 2007 .17200220 \n2. \nDucros A \nReversible cerebral vasoconstriction syndrome . Lancet Neurol \n11 : 906 -917 , 2012 .22995694 \n3. \nHeadache Classification Committee of the International Headache Society (IHS) . The International Classification of Headache Disorders, 3rd edition (beta version) . Cephalalgia \n33 : 629 -808 , 2013 .23771276 \n4. \nYancy H , Lee-Iannotti JK , Schwedt TJ , Dodick DW \nReversible cerebral vasoconstriction syndrome . Headache \n53 : 570 -576 , 2013 .23489219 \n5. \nDucros A , Boukobza M , Porcher R , Sarov M , Valade D , Bousser MG \nThe clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients . Brain \n130 : 3091 -3101 , 2007 .18025032 \n6. \nSinghal AB , Hajj-Ali RA , Topcuoglu MA , et al \nReversible cerebral vasoconstriction syndromes: analysis of 139 cases . Arch Neurol \n68 : 1005 -1012 , 2011 .21482916 \n7. \nRobert T , Kawkabani Marchini A , Oumarou G , Uské A \nReversible cerebral vasoconstriction syndrome identification of prognostic factors . Clin Neurol Neurosurg \n115 : 2351 -2357 , 2013 .24021453 \n8. \nKatz BS , Fugate JE , Ameriso SF , et al \nClinical worsening in reversible cerebral vasoconstriction syndrome . JAMA Neurol \n71 : 68 -73 , 2014 .24190097 \n9. \nMeschia JF , Malkoff MD , Biller J \nReversible segmental cerebral arterial vasospasm and cerebral infarction: possible association with excessive use of sumatriptan and Midrin . Arch Neurol \n55 : 712 -714 , 1998 .9605729 \n10. \nGranier I , Garcia E , Geissler A , Boespflug MD , Durand-Gasselin J \nPostpartum cerebral angiopathy associated with the administration of sumatriptan and dihydroergotamine: a case report . Intensive Care Med \n25 : 532 -534 , 1999 .10401952 \n11. \nNighoghossian N , Derex L , Trouillas P \nMultiple intracerebral hemorrhages and vasospasm following antimigrainous drug abuse . Headache \n38 : 478 -480 , 1998 .9664756 \n12. \nSinghal AB , Caviness VS , Begleiter AF , Mark EJ , Rordorf G , Koroshetz WJ \nCerebral vasoconstriction and stroke after use of serotonergic drugs . Neurology \n58 : 130 -133 , 2002 .11781419 \n13. \nYoshioka S , Takano T , Ryujin F , Takeuchi Y \nA pediatric case of reversible cerebral vasoconstriction syndrome with cortical subarachnoid hemorrhage . Brain Dev \n34 : 796 -798 , 2012 .22285527 \n14. \nBa F , Giuliani F , Camicioli R , Saqqur M \nA reversible cerebral vasoconstriction syndrome . BMJ Case Rep \n2012 : bcr0920114841 , 2012 .\n15. \nChen SP , Fuh JL , Wang SJ , Tsai SJ , Hong CJ , Yang AC \nBrain-derived neurotrophic factor gene Val66Met polymorphism modulates reversible cerebral vasoconstriction syndromes . PLoS One \n6 : e18024 , 2011 .21437208\n\n",
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"issue": "55(23)",
"journal": "Internal medicine (Tokyo, Japan)",
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"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D013577:Syndrome; D014057:Tomography, X-Ray Computed; D014363:Tryptamines; D014661:Vasoconstriction; D020301:Vasospasm, Intracranial",
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"title": "Triptan-induced Reversible Cerebral Vasoconstriction Syndrome: Two Case Reports with a Literature Review.",
"title_normalized": "triptan induced reversible cerebral vasoconstriction syndrome two case reports with a literature review"
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"abstract": "OBJECTIVE\nAt the moment there are no standard guidelines for the treatment of autoimmune congenital heart block (CHB). We set out to carry out a prospective cohort study to evaluate the benefits, limits, and safety of a combined therapy protocol to treat antibody-related CHB.\n\n\nMETHODS\nTwelve consecutive pregnant patients positive to anti-SSA/Ro ± anti-SSB/La antibodies in whom CHB was detected were prospectively evaluated from 2009 to 2014. The treatment protocol consisted of: weekly plasmapheresis, fortnightly intravenous immunoglobulins (IVIG), and daily 4 mg betamethasone from CHB detection until delivery; IVIG was administered to the neonates soon after birth.\n\n\nRESULTS\nAt the time CHB was detected, six of the foetuses presented atrioventricular blocks of 2(nd) degree type and six of 3(rd) degree type. Two of the foetuses with a 2(nd) degree block reverted to a 1st degree block and one to a normal atrioventricular conduction. The condition was stable throughout the pregnancy in the other three cases of 2(nd) degree block. All six 3(rd) degree blocks were stable during pregnancy and confirmed at birth. After a mean of 37.6 months ± 19.6 SD post-birth, the infants with 1st, normal sinus rhythm, and 2(nd) degree blocks at birth were all found to be stable. During the follow-up (29 months ± 19.8 SD), pacemakers were implanted in three of the six infants with 3(rd) degree blocks.\n\n\nCONCLUSIONS\nThis combined therapy seems to be effective and safe in treating 2(nd) degree CHB, while its efficacy in treating 3rd degree CHB remains to be established.",
"affiliations": "Rheumatology Unit, Department of Medicine, University of Padua, Italy. amelia.ruffatti@unipd.it.;Paediatric Cardiology Unit, Department of Women's and Children's Health, University of Padua, Italy.;Rheumatology Unit, Department of Medicine, University of Padua, Italy.;Rheumatology Unit, Department of Medicine, University of Padua, Italy.;Rheumatology Unit, Department of Medicine, University of Padua, Italy.;Rheumatology Unit, Department of Medicine, University of Padua, Italy.;Apheresis Unit, Blood Transfusion Service, University Hospital of Padua, Italy.;Cardiology Unit, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Italy.;Paediatric Cardiology Unit, Department of Women's and Children's Health, University of Padua, Italy.",
"authors": "Ruffatti|Amelia|A|;Cerutti|Alessia|A|;Favaro|Maria|M|;Del Ross|Teresa|T|;Calligaro|Antonia|A|;Hoxha|Ariela|A|;Marson|Piero|P|;Leoni|Loira|L|;Milanesi|Ornella|O|",
"chemical_list": "D000974:Antibodies, Antinuclear; D015415:Biomarkers; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; C035356:SS-A antibodies; C035357:SS-B antibodies; D001623:Betamethasone",
"country": "Italy",
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"mesh_terms": "D000328:Adult; D000974:Antibodies, Antinuclear; D001327:Autoimmune Diseases; D001623:Betamethasone; D015415:Biomarkers; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D015150:Echocardiography, Doppler; D005260:Female; D005865:Gestational Age; D005938:Glucocorticoids; D006327:Heart Block; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007231:Infant, Newborn; D008297:Male; D010956:Plasmapheresis; D011247:Pregnancy; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D016216:Ultrasonography, Prenatal",
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"title": "Plasmapheresis, intravenous immunoglobulins and bethametasone - a combined protocol to treat autoimmune congenital heart block: a prospective cohort study.",
"title_normalized": "plasmapheresis intravenous immunoglobulins and bethametasone a combined protocol to treat autoimmune congenital heart block a prospective cohort study"
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"abstract": "Pediatric advanced life support (PALS) is the global standard of pediatric emergency medicine. It depends on the consensus of ILCOR which has been revised every 5 years by the experts worldwide. The concept of PALS is to treat the sick and injured children based on the systematic approach of the evaluation and classification in terms of the respiratory and circulatory status. On the other hand, point of care ultrasound (POCU) has been getting popular worldwide in the field of the emergency and critical care medicine. The PALS approach mainly depends on the physical examination which isn't enough for the decision making of the treatment. Then, POCU has come out as the adjunctive methods to compensate for the physical examination. This article outlines the concept of PALS and POCU.",
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"abstract": "Neurological complications of varicella zoster virus (VZV) reactivation have rarely been described in dialysis patients. We report a case of a continuous ambulatory peritoneal dialysis (CAPD) patient who developed herpes zoster encephalitis. The patient was treated with acyclovir and steroids and had a slow but complete return to her prior cognitive status. The available literature is reviewed and the differential diagnosis with acyclovir toxicity is discussed.",
"affiliations": "Department of Internal Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands. sigaloff@yahoo.com",
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"abstract": "•Checkpoint inhibitor therapy affecting PD-L1 as treatment for advanced solid tumors.•Success in trial pembrolizumab therapy in multiresistant metastatic choriocarcinoma.•Long-term remission after pembrolizumab therapy in multiresistant choriocarcinoma.•Only six reported cases, one with comparable follow-up and outcome.",
"affiliations": "Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Gynecologic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Austria.;Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Gynecologic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Austria.;Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Austria.;Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Gynecologic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Austria.;Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Gynecologic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Austria.;Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Gynecologic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Austria.",
"authors": "Paspalj|V|V|;Polterauer|S|S|;Poetsch|N|N|;Reinthaller|A|A|;Grimm|C|C|;Bartl|T|T|",
"chemical_list": null,
"country": "Netherlands",
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"doi": "10.1016/j.gore.2021.100817",
"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789\nElsevier\n\nS2352-5789(21)00121-1\n10.1016/j.gore.2021.100817\n100817\nCase Reports and Case Series\nLong-term survival in multiresistant metastatic choriocarcinoma after pembrolizumab treatment: A case report\nPaspalj V. a\nPolterauer S. stephan.polterauer@meduniwien.ac.at\nab⁎\nPoetsch N. c\nReinthaller A. ab\nGrimm C. ab\nBartl T. a\na Division of General Gynecology and Gynecologic Oncology, Department of Obstetrics and Gynecology, Gynecologic Cancer Unit, Comprehensive Cancer Center, Medical University of Vienna, Austria\nb Karl Landsteiner Institute for General Gynecology and Experimental Gynecologic Oncology, Vienna, Austria\nc Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Austria\n⁎ Corresponding author at: Department of Obstetrics and Gynecology, Division of General Gynecology and Gynecologic Oncology, Medical University of Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria. stephan.polterauer@meduniwien.ac.at\n24 6 2021\n8 2021\n24 6 2021\n37 10081718 4 2021\n18 6 2021\n20 6 2021\n© 2021 The Authors. Published by Elsevier Inc.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nHighlights\n\n• Checkpoint inhibitor therapy affecting PD-L1 as treatment for advanced solid tumors.\n\n• Success in trial pembrolizumab therapy in multiresistant metastatic choriocarcinoma.\n\n• Long-term remission after pembrolizumab therapy in multiresistant choriocarcinoma.\n\n• Only six reported cases, one with comparable follow-up and outcome.\n\nKeywords\n\nChoriocarcinoma\nPembrolizumab\nGTN\nβ-HCG\nAbbreviations\n\nβ-HCG, beta-human chorionic gonadotropin\nCPI, checkpoint inhibitor\nCT, computed tomography\ncMRI, cerebral magnetic resonance imaging\nWHO, Worl Health Organization\nECOG, Eastern Cooperative Oncology Group\nETT, epithelioid trophoblastic tumor\nGTD, gestational trophoblastic disease\nGTN, gestational trophoblastic neoplasia\nPD-1/PDL-1, programmed cell death-1/ programmed cell death ligand-1\nPSTT, placental site trophoblastic tumor\n==== Body\n1 Introduction\n\nChoriocarcinoma is considered the most malignant subtype of gestational trophoblastic disease (GTD) with a high invasive and metastatic potential (Seckl et al., 2000). Incidence is reported to be approximately 1 in 40 000 pregnancies in North America and Europe (Lurain, 2010).\n\nBased on the FIGO-staging for gestational trophoblastic neoplasia, patients with choriocarcinoma can be divided into high- and low-risk gestational trophoblastic neoplasia (GTN) groups (FIGO staging for gestational trophoblastic neoplasia, 2000). Whereas the treatment of low-risk GTN is single-agent chemotherapy, high-risk GTN are treated with multiple agent chemotherapy. >95% of patients with high-risk GTN experience complete response after chemotherapy (Ngan et al., 2018). However, 0.5–5.0% succumb to the disease, mainly due to late diagnosis or multidrug resistance (Powles et al., 2007).\n\nAs the recent introduction of checkpoint inhibitor (CPI) therapy targeting programmed cell death ligand 1 (PD-L1) provided a new therapeutic strategy for several advanced solid tumors (Herbst et al., 2016), the anti-PD-inhibitor pembrolizumab appears to be a promising therapeutic option for the subset of patients with choriocarcinoma experiencing chemotherapy resistance (Huang et al., 2017, Ghorani et al., 2017, Goldfarb et al., 2020, Clair et al., 2020).\n\n2 Case presentation\n\nIn August 2018, a thirty-one-year-old woman presented at our clinic after being diagnosed with choriocarcinoma at a secondary care center. Six months before, she had delivered at term by cesarean section after uneventful pregnancy. Due to postpartal vaginal bleeding and alleged placenta residuals, the patient was treated with dilation and curettage twice. The Beta-human chorionic gonadotropin (β-HCG) levels were 28872 IU/L (June 2018) and 4323 IU/L (August 2018), post-curettage respectively (Fig. 1). The histology of the tissue gained from the second curettage revealed choriocarcinoma and the patient was transferred to our institution.Fig. 1 Beta-human chorionic gonadotropin (β -HCG) trend with presentation of treatment.\n\nHistology was confirmed at our institution: Predominantly solid formations of cytotrophoblasts, intermediate trophoblasts and syncytiotrophoblasts were found. Tumor cells showed a pronounced nuclear polymorphism and focal-microscopically up to 14 partially pluripolar mitoses. On top of hemorrhagic necroses, there was also lymphatic invasion. In the immunohistochemical examination tumor cells diffusely and particularly strongly expressed β-HCG and cytokeratin AE1/3. The proliferation marker MIB-1 amounted up to 90%. The intermediate trophoblast cells stained MUC4 positive. In some cases, focal low-grade expression of alpha inhibin, GATA3 and CK18 as well as SMA in myometrial smooth muscle cells was also observed. Melan A, S100 and HPL were negative.\n\nStaging commenced on 6th August 2018 by computed tomography (CT) and cerebral magnetic resonance imaging (cMRI). CT demonstrated the presence of multiple (n = 14) pulmonary and two (n = 2) vaginal metastases. Considering these findings, the WHO risk score was 10 (Table1).Table 1 WHO prognostic scoring system for GTN with highlighted scoring according to our patient, total score ≤ 6 low-risk, ≥7 high-risk.\n\nModified WHO prognostic scoring system\t\nScores\t0\t1\t2\t4\t\nAge\t<40\t>40\t–\t–\t\nAntecedent pregnancy\tmole\tabortion\tterm\t–\t\nInterval months from index pregnancy\t<4\t4–6\t7–12\t>12\t\nPretreatment serum β -HCG\t<103\t103–104\t104–105\t>105\t\nLargest tumor size (including uterus)\t<3\t3–4 cm\t≥5 cm\t–\t\nSite of metastases\tlung\tspleen, kidney\tgastro-intestinal\tliver, brain\t\nNumber of metastases\t–\t1–4\t5–8\t>8\t\nPrevious failed chemotherapy\t–\t–\tSingle drug\t≥2 drugs\t\n\nAfter the case was taken over by our clinic, a chemotherapy regimen of etoposide, methotrexate, actinomycin- D, cyclophosphamide and vincristine (EMA-CO) was induced. From 14th August to 26th September the patient received four cycles of EMA-CO. After an initial drop from 7584 IU/l to 1234 IU/l β-HCG, levels reached a plateau at 221 IU/l. (Fig. 1). Due to an alleged chemotherapy resistance, treatment was modified to etoposide, methotrexate, actinomycin-D, followed by etoposide and cisplatin (EMA-EP) on 3rd October (Fig. 1).\n\nAs β-HCG levels were observed to rise from 231 IU/l on 3rd October to 776 IU/l on 23rd October, treatment was adapted to paclitaxel/cisplatin followed by paclitaxel/etoposide starting from 9th November.\n\nThe patient, however, experienced disease progression and β-HCG level increased to 2115 IU/L. In the meantime, computed tomography showed progression of disease. The intrauterine mass showed a progression in size from 1,5 × 1,2 × 1,4 cm before to 3,5 × 2,5 × 3,3 cm. Also the size of the vaginal metastases increased from 1,2 × 1,2 × 1,2 cm to 1,8 × 2,4 × 2,3 cm. In an additional immunohistochemical work-up on PDL1, 90% of tumor cells and 5% of immune cells expressed complete membrane positivity.\n\nBased on these findings, an experimental therapy with pembrolizumab 200 mg q3w was induced on 6th December after consulting Michael Seckl for advice (Department of Medical Oncology, Charing Cross Hospital, London, UK). The therapy was well tolerated without relevant side effects. A steady decline of β-HCG-levels and respective radiological response, regarding significant size reduction of the primary, the pulmonal and vaginal metastases was observed (Fig. 1, Fig. 2).Fig. 2 Computed tomography demonstrating a 26,5-mm nodule in right superior lobe before initiation of pembrolizumab (A) and after four cycles (B). Choriocarcinoma and vaginal metastasis with a diameter of 20,2 mm before the first cycle of pembrolizumab (C) and after four cycles (D) demonstrating decrease in size to 15,4 mm.\n\nAfter completion of four cycles of pembrolizumab, a salvage-hysterectomy with partial colpectomy was conducted on 13th February. Final histology reported no vital tumor cells. After surgery, therapy with pembrolizumab was continued for three additional consolidation cycles (total of 7 cycles until 8th April 2019).\n\nThe β-HCG levels dropped below the positivity threshold of 0.1 IU/L on 29th April 2019 and the patient remained in good clinical condition (Eastern Cooperative Oncology Group (ECOG) Score 0). The patient is enrolled in regular follow-up in our institution and latest visit in April 2021 showed complete clinical remission and negative β-HCG levels 24 months after end of treatment and 33 months after initial diagnosis.\n\n3 Discussion\n\nThe expression of PD-L1 in tumor cells, however, can be observed in varying extent and has been associated with CPI therapy response (Keir et al., 2008). In addition to expression in tumor cells, evidence suggests that PD-L1 plays an essential role in fetomaternal tolerance (Guleria et al., 2005). The placental trophoblast is substantial in the suppression of maternal immunological rejection against the fetus and shows in nearly all trophoblastic lineages expression of PD-L1 (Lu et al., 2019). As GTN immunostaining shows intense PD-L1 immunoreactivity, this type of tumors appear to be a promising target for CPI therapy (Veras et al., 2017).\n\nIn line, activity of pembrolizumab in chemotherapy-resistant GTN has been investigated in small cohorts and reported to be very successful in this patient group (Huang et al., 2017, Ghorani et al., 2017, Choi et al., 2019, Goldfarb et al., 2020, Clair et al., 2020). However, only five cases of pembrolizumab treatment for chemotherapy-resistant choriocarcinoma have been reported to date. Few patients with other forms of GTN (ETT, PSTT) have also been treated with pembrolizumab (Table 2). Also, a Chinese preliminary study of PD-1 inhibitor treatment in eight patients with drug-resistant recurrent GTN showed a high effective rate and relatively mild side effects (Cheng et al., 2020).Table 2 Overview of cases to date.\n\nAuthor\tPatient characteristics\tAgent, dosage and number of cycles\tOutcome and previously described PFS\t\nHuang et al. (Huang et al., 2017)\t26-year-old woman with metastasized chemotherapy-resistant choriocarcinoma\tTwo cycles 200 mg q3w followed by two cycles 100 mg q3w pembrolizumab\tFull remission\t\nGhorani et al. (Ghorani et al., 2017)\t39-year-old and a 37-year-old patient with metastasized chemotherapy-resistant choriocarcinoma\tNine and seven cycles of 2 mg/kg q3w pembrolizumab\tFull remission for 24 and five months\t\nMin Chul Choi et al. (Choi et al., 2019)\t39-year-old patient with a PSTT and a 49-year-old patient with an ETT, both metastasized and chemotherapy-resistant\tNine and eleven cycles of 200 mg q3w pembrolizumab\tFull remission\t\nGoldfarb et al. (Goldfarb et al., 2020)\t50-year-old woman with metastasized chemotherapy-resistant choriocarcinoma\tSix cycles of pembrolizumab\tProgression after 22 months, re-induction with pembrolizumab\t\nClair et al. (Clair et al., 2020)\t30-year-old woman with metastasized chemotherapy-resistant choriocarcinoma\tTen cycles of 200 mg q3w pembrolizumab\tFull remission for 31 months\t\n\nThe suggestion that the immune system and thus also immunotherapy plays an essential role in GTN is collaborated by the only prospective study of immunotherapy in GTN to date (You et al., 2020). The TROPHIMMUN trial assessed avelumab, which is an anti-programmed death ligand-1 (anti-PD-L1) immunoglobulin G1 monoclonal antibody, in woman with chemotherapy-resistant GTN. In this study approximately 50% of patients could be cured with avelumab.\n\nApart from that, side effects observed less frequently and less severely with CPI than with chemotherapies in the TROPHIMMUN trial and other trials from different tumors (André et al., 2020).\n\nFurthermore, an ongoing phase II trial (NCT04303884) investigates – exactly fitting to our patient case - the clinical efficacy of patients with GTN resistant to multi-agents chemotherapy who treat with pembrolizumab.\n\n4 Conclusion\n\nSimilar to a few described cases so far and moving into center of interest, in our case, the patient́s tumor demonstrated strong PD-L1 expression. Despite frustrating response to cytotoxic chemotherapy, she experienced full remission after pembrolizumab and has durable response of currently more than two years after end of treatment. Except for Clair et al. (Clair et al., 2020) no one has yet reported such a long progression-free follow-up. Even though reported observations appear promising for patients with metastasized chemotherapy resistant GTN, sizeable prospective multicenter trials will be necessary to substantiate current evidence on CPI treatment in this particular setting.\n\nPrevious presentations\n\nNone.\n\nDisclaimers\n\nThe Authors have nothing to disclaim.\n\nAuthor contribution\n\nVP and TB performed the literature search, investigation and screened the data. NP extracted the imaging. VP wrote the draft manuscript. TB, AR, CG, SP critically revised the manuscript for important intellectual content. SP supervised the project. All authors gave final approval of the version submitted and any revised version.\n\nDeclaration of Competing Interest\n\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\n\nAndré T. Shiu K.-K. Kim T.W. Jensen B.V. Jensen L.H. Punt C. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer N. Engl. J. Med. [Internet] 383 23 2020 2207 2218 Available from: www.nejm.org/doi/10.1056/NEJMoa2017699, Dec 3 [cited 2021 Jun 15]\nCheng, H.Y., Yang, J.J., Zhao, J., Ren, T., Feng, F.Z., Wan, X.R., et al., 2020. [Preliminary study of PD-1 inhibitor in the treatment of drug-resistant recurrent gestational trophoblastic neoplasia]. Zhonghua Fu Chan Ke Za Zhi [Internet]. Jun 25 [cited 2021 Jun 15];55(6):390–4. Available from: www.ncbi.nlm.nih.gov/pubmed/32842245.\nChoi M.C. Oh J. Lee C. Effective anti-programmed cell death 1 treatment for chemoresistant gestational trophoblastic neoplasia Eur. J. Cancer [Internet] 2019 Nov [cited 2020 Apr 3];121:94–7. Available from: linkinghub.elsevier.com/retrieve/pii/S0959804919304848\nClair K.H. Gallegos N. Bristow R.E. Successful treatment of metastatic refractory gestational choriocarcinoma with pembrolizumab: A case for immune checkpoint salvage therapy in trophoblastic tumors Gynecol. Oncol. Rep. [Internet] 2020 Nov [cited 2021 Mar 24];34:100625. Available from: www.ncbi.nlm.nih.gov/pubmed/32964090\nFIGO staging for gestational trophoblastic neoplasia 2000. Int J Gynecol Obstet [Internet]. 2002 Jun 1 [cited 2020 Apr 5];77(3):285–7. Available from: doi.wiley.com/10.1016/S0020-7292%2802%2900063-2.\nGhorani Ehsan, Kaurb Baljeet, Fisher Rosemary, Short Dee, Joneborg Ulrika, Carlson Joseph W., Akarca Ayse, Marafioti Teresa, Quezada Sergio A., Naveed Sarwar, M.J.S., 2017. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia [Internet]. [cited 2019 Dec 26]. Available from: www.thelancet.com.\nGoldfarb J.A. Dinoi G. Mariani A. Langstraat C.L. A case of multi-agent drug resistant choriocarcinoma treated with Pembrolizumab Gynecol. Oncol. Rep. [Internet] 32 2020 May [cited 2021 Mar 24]. Available from: www.ncbi.nlm.nih.gov/pubmed/32395603\nGuleria I. Khosroshahi A. Ansari M.J. Habicht A. Azuma M. Yagita H. A critical role for the programmed death ligand 1 in fetomaternal tolerance J. Exp. Med. [Internet] 202 2 2005 231 237 Available from: www.ncbi.nlm.nih.gov/pubmed/16027236, Jul 18 [cited 2021 Jun 16]\nHerbst, R.S., Baas, P., Kim, D.-W., Felip, E., Pérez-Gracia, J.L., Han, J.-Y., et al., 2016. Articles Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. www.thelancet.com [Internet]. [cited 2019 Dec 26];387. Available from: dx.doi.org/10.1016/.\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. [Internet] 35 27 2017 3172 3174 Sep 20 [cited 2019 Dec 26]. Available from: ascopubs.org/doi/10.1200/JCO.2017.74.4052\nKeir M.E. Butte M.J. Freeman G.J. Sharpe A.H. PD-1 and its ligands in tolerance and immunity Annu. Rev. Immunol. [Internet] 2008 Apr [cited 2019 Dec 26];26(1):677–704. Available from: www.ncbi.nlm.nih.gov/pubmed/18173375\nLu B. Teng X. Fu G. Bao L. Tang J. Shi H. Analysis of PD-L1 expression in trophoblastic tissues and tumors Hum. Pathol. [Internet] 2019 [cited 2021 Jun 15];84:202–12. Available from: www.ncbi.nlm.nih.gov/pubmed/30339966\nLurain J.R. Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole AJOG [Internet] 2010 [cited 2019 Dec 26]; Available from: www.AJOG.org\nNgan H.Y.S. Seckl M.J. Berkowitz R.S. Xiang Y. Golfier F. Sekharan P.K. Update on the diagnosis and management of gestational trophoblastic disease Int. J. Gynecol. Obstet. [Internet] 2018 10.1002/ijgo.12615 Oct [cited 2019 Dec 26];143:79–85. Available from:\nPowles T. Savage P.M. Stebbing J. Short D. Young A. Bower M. A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia Br. J. Cancer [Internet] 96 5 2007 732 737 Mar 13 [cited 2019 Dec 26], Available from: www.nature.com/articles/6603608\nSeckl M.J. Fisher R.A. Salerno G. Rees H. Paradinas F.J. Foskett M. Choriocarcinoma and partial hydatidiform moles Lancet 356 9223 2000 36 39 [Internet]. Jul 1 [cited 2019 Dec 26]. Available from: www.sciencedirect.com/science/article/pii/S0140673600024326?via%3Dihub 10892763\nVeras E. Kurman R.J. Wang T.-L. Shih I.-M. PD-L1 expression in human placentas and gestational trophoblastic diseases Int. J. Gynecol. Pathol. [Internet] 36 2 2017 146 153 Mar [cited 2021 Mar 24], Available from: www.ncbi.nlm.nih.gov/pubmed/27362903\nYou B. Bolze P.-A. Lotz J.-P. Massardier J. Gladieff L. Joly F. Avelumab in patients with gestational trophoblastic tumors with resistance to single-agent chemotherapy: Cohort A of the TROPHIMMUN phase II trial J. Clin. Oncol. [Internet] 38 27 2020 3129 3137 Available from: www.ncbi.nlm.nih.gov/pubmed/32716740. [cited 2021 Jun 16]\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "37()",
"journal": "Gynecologic oncology reports",
"keywords": "CPI, checkpoint inhibitor; CT, computed tomography; Choriocarcinoma; ECOG, Eastern Cooperative Oncology Group; ETT, epithelioid trophoblastic tumor; GTD, gestational trophoblastic disease; GTN; GTN, gestational trophoblastic neoplasia; PD-1/PDL-1, programmed cell death-1/ programmed cell death ligand-1; PSTT, placental site trophoblastic tumor; Pembrolizumab; WHO, Worl Health Organization; cMRI, cerebral magnetic resonance imaging; β-HCG; β-HCG, beta-human chorionic gonadotropin",
"medline_ta": "Gynecol Oncol Rep",
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"pages": "100817",
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"pmid": "34258357",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
"references": "26712084;32964090;27362903;30306586;20728069;30339966;29185430;32842245;31569067;16027236;33264544;18173375;32395603;32716740;17299394;28742453;10892763",
"title": "Long-term survival in multiresistant metastatic choriocarcinoma after pembrolizumab treatment: A case report.",
"title_normalized": "long term survival in multiresistant metastatic choriocarcinoma after pembrolizumab treatment a case report"
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"abstract": "We report a case of a 60-year-old man who underwent orthotopic heart transplantation after short-term receipt of low-dose oral amiodarone for the management of ventricular tachycardia. Prior to transplant surgery, he had a normal chest radiograph and was free of supplemental oxygen. His initial postoperative chest radiograph showed subtle infiltrates, and thereafter his chest imaging continued to worsen. Although he was eventually able to wean off mechanical ventilation via a tracheostomy, he remained dyspneic and oxygen-dependent with persistently abnormal chest imaging as his post-transplant corticosteroid regimen was being tapered. In light of progressively worsening diffuse lung disease, he underwent bronchoscopy with transbronchial biopsies. Histology revealed foamy macrophages in association with foci of organizing pneumonia, a picture consistent with amiodarone pulmonary toxicity. Given these findings, corticosteroid dosing was increased for the clinical diagnosis of acute amiodarone pulmonary toxicity with subsequent normalization of oxygen saturation and chest radiography. Our case is the first to identify orthotopic heart transplantation as a potential trigger for acute amiodarone pulmonary toxicity. It is also only the second documented example of organizing pneumonia as the histological substrate of amiodarone pulmonary toxicity, which is an association that has therapeutic implications.",
"affiliations": "Division of Pulmonary, Critical Care, and Sleep Medicine, Westchester Medical Center, Valhalla, NY, USA.;Division of Transplant Cardiology, Westchester Medical Center, Valhalla, NY, USA.;Department of Pathology, Westchester Medical Center, Valhalla, NY, USA.;Division of Pulmonary, Critical Care, and Sleep Medicine, Westchester Medical Center, Valhalla, NY, USA.",
"authors": "Kozlova|Natalya|N|;Lanier|Gregg M|GM|;Kleinman|George|G|;Epelbaum|Oleg|O|",
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"doi": "10.1016/j.rmcr.2021.101532",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00194-5\n10.1016/j.rmcr.2021.101532\n101532\nCase Report\nAcute amiodarone pulmonary toxicity in the form of organizing pneumonia triggered by orthotopic heart transplantation\nKozlova Natalya a\nLanier Gregg b\nKleinman George c\nEpelbaum Oleg oleg.epelbaum@wmchealth.org\na∗\na Division of Pulmonary, Critical Care, and Sleep Medicine, Westchester Medical Center, Valhalla, NY, USA\nb Division of Transplant Cardiology, Westchester Medical Center, Valhalla, NY, USA\nc Department of Pathology, Westchester Medical Center, Valhalla, NY, USA\n∗ Corresponding author. Westchester Medical Center Division of Pulmonary, Critical Care, and Sleep Medicine, 100 Woods Road, Macy Pavilion—Pulmonary Lab, Valhalla, NY, 10595, USA. oleg.epelbaum@wmchealth.org\n22 10 2021\n2021\n22 10 2021\n34 10153216 8 2021\n19 10 2021\n© 2021 Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe report a case of a 60-year-old man who underwent orthotopic heart transplantation after short-term receipt of low-dose oral amiodarone for the management of ventricular tachycardia. Prior to transplant surgery, he had a normal chest radiograph and was free of supplemental oxygen. His initial postoperative chest radiograph showed subtle infiltrates, and thereafter his chest imaging continued to worsen. Although he was eventually able to wean off mechanical ventilation via a tracheostomy, he remained dyspneic and oxygen-dependent with persistently abnormal chest imaging as his post-transplant corticosteroid regimen was being tapered. In light of progressively worsening diffuse lung disease, he underwent bronchoscopy with transbronchial biopsies. Histology revealed foamy macrophages in association with foci of organizing pneumonia, a picture consistent with amiodarone pulmonary toxicity. Given these findings, corticosteroid dosing was increased for the clinical diagnosis of acute amiodarone pulmonary toxicity with subsequent normalization of oxygen saturation and chest radiography. Our case is the first to identify orthotopic heart transplantation as a potential trigger for acute amiodarone pulmonary toxicity. It is also only the second documented example of organizing pneumonia as the histological substrate of amiodarone pulmonary toxicity, which is an association that has therapeutic implications.\n\nHighlights\n\n• Amiodarone pulmonary toxicity can present acutely, often precipitated by cardiothoracic interventions.\n\n• Organizing pneumonia has only rarely been shown to underlie acute amiodarone pulmonary toxicity.\n\n• Orthotopic heart transplantation surgery was the putative trigger in the present case, making this the first such description.\n\nKeywords\n\nAmiodarone\nPulmonary toxicity\nOrganizing pneumonia\nHeart transplantation\n==== Body\npmcAbbreviations\n\nAPT Amiodarone pulmonary toxicity\n\nAAPT Acute/Accelerated amiodarone pulmonary toxicity\n\nCOPD Chronic obstructive pulmonary disease\n\nCT Computed tomography\n\nCXR Chest radiograph\n\nGGO Ground glass opacity\n\nIABP Intra-aortic balloon pump\n\nNICM Non-ischemic cardiomyopathy\n\nOHT Orthotopic heart transplantation\n\nOP Organizing pneumonia\n\nPOD post-operative day\n\n1 Introduction\n\nAmiodarone is a heavily iodinated compound that was first introduced into clinical practice as an antianginal agent in the 1960s [1]. Given its multifaceted antiarrhythmic properties and favorable cardiovascular side effect profile, amiodarone has become a widely prescribed pharmaceutical for atrial fibrillation and ventricular tachycardia. At the same time, the prescribing community has encountered amiodarone's myriad adverse reactions with amiodarone pulmonary toxicity (APT) being perhaps the most familiar. Typically presenting subacutely and afflicting those with large cumulative drug dosing, APT also has an acute variant in which antecedent cardiothoracic interventions are implicated as inciting events in an apparent “two-hit” phenomenon. Almost every type of cardiothoracic procedure and operation has been linked to acute APT with the notable exception of orthotopic heart transplantation (OHT). We describe a case of acute APT that complicated the immediate postoperative course of an OHT recipient with relatively brief pre-transplant amiodarone exposure. Our patient's lung biopsy revealed organizing pneumonia, a pattern heretofore associated more closely with subacute than acute APT and important to recognize because of its exquisite corticosteroid sensitivity.\n\n2 Case report\n\n2.1 Clinical history\n\nA 60-year-old man was transferred to our institution from an outlying hospital for OHT evaluation. He had a history of non-ischemic cardiomyopathy (NICM) with a left ventricular ejection fraction by echocardiography of 25%. His NICM was complicated by multiple episodes of ventricular tachycardia, which was the reason for his admission to the outlying hospital. He had been taking amiodarone for approximately 3 months prior to presentation to that hospital. There he was continued on amiodarone and was transferred to our institution with a dose of 200mg orally twice daily, which was later reduced to 200mg once daily. He had known chronic kidney disease. He was a former smoker with a history of chronic obstructive pulmonary disease (COPD) and was receiving combination inhaled therapy with fluticasone-salmeterol at time of transfer.\n\nUpon transfer, he was hemodynamically stable while receiving a dobutamine infusion and was breathing comfortably on room air with an oxygen saturation of 97%. Physical examination was remarkable for the absence of jugular venous distention and lower extremity edema. Lungs were clear to auscultation, and he had warm extremities. Laboratory evaluation was significant for elevated serum creatinine of 2.61mg/dL (normal range 0.72–1.25mg/dL). Liver function testing was normal. His initial chest radiograph (CXR) demonstrated clear lung fields.\n\nHis hospital course was characterized by persistent requirement for inotropic and vasodilator therapy as well as support with an intra-aortic balloon pump (IABP). He remained with oxygen saturations of >90% on room air throughout. On hospital day 78, he underwent OHT with a graft ischemic time of 191 minutes. The donor was seropositive for cytomegalovirus; the patient was seronegative. Amiodarone had been continued up until the day of surgery. His immediate post-transplant course was complicated by biventricular acute graft dysfunction, so IABP support was maintained, and he received milrinone, dopamine, and epinephrine infusions. Inhaled nitric oxide was initiated at 40 parts per million. His initial immunosuppressive regimen consisted of methylprednisolone and mycophenolate mofetil, in addition to which he received three doses of antithymocyte globulin, and then tacrolimus was added. CXR performed on postoperative day (POD) 0 showed subtle bilateral infiltrates interpreted as mild postoperative pulmonary edema (Fig. 1A). A pre-operative CXR had been obtained 12 days prior to transplant, and at that time the lung fields were clear, as they had been when he first arrived to our institution (Fig. 1B). Despite normalization of left ventricular function and a course of diuresis, by POD 5 the patient remained mechanically ventilated and exhibited progressively worsening chest radiography (Fig. 1C). Chest computed tomography (CT) performed on that day showed diffuse ground glass opacities (GGO) bilaterally, most prominently affecting the upper lobes (Fig. 2A). Over the ensuing weeks, the patient underwent tracheostomy and was weaned off mechanical ventilation. His corticosteroid regimen was gradually reduced to 20mg daily. Off the ventilator, he remained dependent on supplemental oxygen and dyspneic with persistently abnormal chest radiography. On POD 35, chest CT was repeated, now showing a mixture of GGO and consolidation as well as subpleural reticulation, the latter consistent with evolving fibrotic changes (Fig. 2B). At that point, his corticosteroid regimen was changed to prednisone 60mg daily, and bronchoscopy with transbronchial biopsies of the right upper, middle, and lower lobes was performed a week later.Fig. 1 Portable chest radiographs. (A) The patient's chest radiograph upon emerging from the operating room after his orthotopic heart transplantation showed subtle reticular infiltrates interpreted at the time as mild postoperative pulmonary edema. (B) The patient's chest radiograph obtained upon arrival to our institution had shown clear lung fields as had his last preoperative chest radiograph taken 12 days prior to transplantation (not provided). (C) The patient's chest radiograph from the fifth postoperative day demonstrated progression of diffuse bilateral opacities in comparison to the initial postoperative film in panel (A). (D) The patient's chest radiograph obtained following completion of corticosteroid therapy for organizing pneumonia revealed marked improvement in the appearance of lung fields compared to panel (C).\n\nFig. 1\n\nFig. 2 Chest computed tomography (CT). (A) Axial chest CT section set to lung window from the scan obtained on the fifth postoperative day showing confluent bilateral ground glass opacities heavily affecting the upper lobes. (B) Axial CT section set to lung window from the scan repeated on postoperative day 35 showing residual ground glass opacities along with a subpleural focus of consolidation in the right upper lobe (arrows). The same pattern was observed in other lung zones, and areas of subpleural reticulation were noted elsewhere, concerning for evolving fibrosis (not shown).\n\nFig. 2\n\n2.2 Histopathological findings\n\nMicroscopic sections revealed lung parenchyma with thickened alveolar septa and mild chronic inflammation. Vaguely nodular and relatively demarcated areas of loose fibrosis were evident (Fig. 3A). Characteristic of the organizing pneumonia (OP) pattern, fibrocollagenous polypoid plugs were present within the alveolar spaces and partially obstructed and obliterated bronchiolar lumina. Alveolar spaces were focally collapsed and filled by loose collections of histiocytes, many of which exhibited cytoplasmic vacuolization (so-called “foamy” appearance), indicative of amiodarone exposure. Yellow-brown pigment within the alveolar lumina was also seen, suggesting antecedent mild focal alveolar hemorrhage (Fig. 3B). Additionally, diffuse type II pneumocyte hyperplasia and focal squamous metaplasia were identified (Fig. 3C). No histological evidence of viral cytopathic changes, intracellular organisms, or granulomata were identified. The constellation of histopathological findings detailed above is consistent with the OP pattern.Fig. 3 (A) Lung histology from transbronchial biopsy. (A) Low power magnification showing lung parenchyma with thickened alveolar septa and mild chronic inflammation. Vaguely nodular and relatively demarcated areas of loose fibrosis, as well as numerous desquamated pneumocytes, are seen (H&E 100X). (B) High power magnification showing fibrocollagenous polypoid plugs (asterisks) within the alveolar spaces that also partially obstruct the bronchiolar lumina. Alveolar spaces are filled by loose collections of histiocytes, many of which reveal cytoplasmic vacuolization, indicative of amiodarone exposure. Yellow-brown pigment (arrow) is evident, suggestive of prior alveolar hemorrhage or exudation (H&E 400X). (C) Intermediate power magnification showing alveolar wall thickening with diffuse type II pneumocyte hyperplasia and focal squamous metaplasia (H&E 200X). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\n2.3 Follow up\n\nThe patient completed a prolonged course of prednisone for the clinical diagnosis of OP as a manifestation of acute APT. After two months of therapy, his CXR markedly improved (Fig. 1D), and he was free of supplemental oxygen. Chest CT did, however, continue to show residual subpleural fibrosis. His subsequent post-transplant course was complicated by Pneumocystis jirovecii pneumonia and invasive pulmonary aspergillosis. The patient ultimately passed away at his local hospital from mounting complications of OHT.\n\n3 Discussion\n\nAmiodarone is a class III antiarrhythmic drug with a broad range of applications that have been reviewed elsewhere [2]. The use of this versatile agent is limited by a correspondingly broad range of extra-cardiac toxicities; lung involvement, although not the most frequent, tends to be the most feared. Classically, APT is an indolent process in which patients present with subacute symptoms such as cough and dyspnea after accumulation of a threshold amiodarone exposure in a dose-dependent fashion. The histological signature of the exposure of lung to amiodarone is the presence of so-called “foamy” macrophages that acquire this appearance due to phospholipid inclusions resulting from amiodarone's interference with intracellular phospholipid processing. Although these complexes of amiodarone bound to phospholipids are one of the factors implicated in APT pathogenesis, their presence in isolation is not a marker of lung toxicity. Histopathological patterns associated with typical subacute APT are numerous and include cellular nonspecific interstitial pneumonia, lymphoid interstitial pneumonia, eosinophilic pneumonia, and OP [3]. All of these substrates share sensitivity to corticosteroids, explaining the robust response of subacute APT to this form of therapy. Although rarely fatal, APT may leave behind a fibrotic diffuse parenchymal lung disease that can be difficult to differentiate from idiopathic fibrotic lung diseases such as idiopathic pulmonary fibrosis and idiopathic fibrosing nonspecific interstitial pneumonia [4]. It should be noted that lung histology in patients with APT who are selected for biopsy or autopsy may be characterized predominantly by diffuse alveolar damage (DAD), a lung injury pattern that correlates with acute respiratory distress syndrome (ARDS), at time of sampling [5].\n\nIt has been recognized since at least the 1980s that APT can also develop very rapidly, leading to acute or accelerated APT (AAPT) that in its most sudden and catastrophic form fulfills criteria for ARDS [6]. Occurrence of this type of APT tends to follow cardiothoracic procedures and surgeries, an observation that suggests triggering by the interventions themselves or the associated mechanical ventilation, including high inspired oxygen fractions, among other potential culprits [7]. Most descriptions of AAPT involve amiodarone use over months to years, but cases limited to perioperative exposure measured in days to weeks have also been reported [8,9]. To our knowledge, OHT has not been previously implicated as the catalyst for onset of AAPT. Although amiodarone is recognized as a valuable antiarrhythmic option in pre-OHT patients, it has been previously linked to increased post-transplant mortality and primary graft dysfunction, which was present in this case [10]. However, both a recent study [11] as well as an updated meta-analysis [12] found no association between amiodarone use of any duration and reduced post-OHT survival. It is unknown whether APT has been a contributing factor to the turbulent history between amiodarone and OHT.\n\nOP is a lung histology pattern that can occur in response to an insult of any form, including drug toxicity. Predictably, it has been described as both the predominant and accompanying finding on lung biopsy of patients with APT. The vast majority of reported APT cases characterized by histologically confirmed OP in lung samples have been classic ones with subacute evolution and prolonged exposure to amiodarone (Table 1). Of note, they include an OHT candidate diagnosed with APT prior to transplant who improved with drug discontinuation and eventually underwent successful transplantation [13]. They also include a case of AAPT following thoracic surgery in a patient treated with amiodarone only in the immediate postoperative period [8]. In this specific group of cases with OP histology, ours stands out as only the second with AAPT and the first linked to OHT. As mentioned, we are not aware of another published case wherein OHT served as the trigger for amiodarone pulmonary toxicity irrespective of lung histology, disease tempo, and duration of exposure. OHT is unique among cardiac surgeries in that it is followed by initiation of potent immunosuppressive therapy, including calcineurin inhibitors such as tacrolimus. Because immunosuppression is likewise the treatment for OP, it could be reasonably hypothesized that OHT surgery would be a rare inciting event for AAPT. On the other hand, there does exist a case report of APT following lung transplantation [21]. This raises the possibility that certain post-transplant medications like tacrolimus, which is metabolized by the liver, could potentiate toxicity from amiodarone. Our patient's lung disease persisted while post-transplant corticosteroid therapy was tapered, and it remitted only after the dose was increased to an effective level for OP.Table 1 Tabulation of published cases of amiodarone pulmonary toxicity, including the present case, with organizing pneumonia as the underlying lung histology.\n\nTable 1Source/Year\tAge/Gender\tAmiodarone exposure\tAPT or AAPT\tDiagnostic modality\tTherapy\tOutcome\t\nValle 1995 [14]\t61/F\t8 years\tAPT\tTBB\tCS\tRecovered\t\nConte 1997 [15]\t69/M\t4 years\tAPT\tOLB\tCS\tRecovered\t\nAranda 1998 [16]\t77/M\t1.5 years\tAPT\tTBB\tCS\tRecovered\t\nMalhotra 2003 [17]\t82/M\t1 year\tAPT\tOLB\tCS\tRecovered\t\nOtt 2003 [18]\t82/M\t2 years\tAPT\tOLB\tCS\tDied\t\nOmeroglu 2006 [13]\t67/M\tNR\tAPT\tOLB\tAW\tRecovered\t\nBoriani 2012 [8]\t77/M\t4 daysa\tAAPT\tOLB\tCS\tDied\t\nChatterjee 2017 [19]\t58/M\t7 months\tAPT\tOLB\tCS\tRecovered\t\nCoulier 2020 [20]\t78/M\t10 years\tAPT\tNR\tAW\tRecovered\t\nPresent Case\t60/M\t6 monthsb,c\tAAPT\tTBB\tCS\tRecovered\t\nAPT= (subacute) amiodarone pulmonary toxicity; AAPT = acute amiodarone pulmonary toxicity; AW = amiodarone withdrawal; CS = corticosteroids; OLB = open lung biopsy; TBB = transbronchial lung biopsy.\n\na Postoperative administration.\n\nb Approximate duration.\n\nc Preoperative administration.\n\n4 Conclusion\n\nAAPT is a characteristic form of lung injury that could develop in a patient with primary cardiovascular disease, typically following an invasive procedure or surgery. Our case is a reminder that the exposure to amiodarone need not be extensive for this type of APT to occur in the early postoperative period. This case also adds OHT to the list of interventions that can be viewed as potential triggers for the development of AAPT. As post-transplant immunosuppression is tapered, corticosteroid-sensitive AAPT substrates such as OP may persist or even progress.\n\nFunding\n\nNone.\n\nAuthor contributions\n\nNK: Conceived and designed the manuscript; labeled histopathology images and provided legends.\n\nGL: Wrote the paper.\n\nGK: Obtained and selected the histopathology images.\n\nOE: Conceived and designed the manuscript; wrote the paper.\n\nDeclaration of competing interest\n\nNone of the authors has any conflicts of interest to declare.\n\nAcknowledgements\n\nNone.\n==== Refs\nReferences\n\n1 Papiris S.A. Triantafillidou C. Kolilekas L. Markoulaki D. Manali E.D. Amiodarone: review of pulmonary effects and toxicity Drug Saf. 33 7 2010 Jul 1 539 558 10.2165/11532320-000000000-00000 20553056\n2 Vassallo P. Trohman R.G. Prescribing amiodarone: an evidence-based review of clinical indications J. Am. Med. Assoc. 298 11 2007 Sep 19 1312 1322 10.1001/jama.298.11.1312\n3 Larsen B.T. Vaszar L.T. Colby T.V. Tazelaar H.D. Lymphoid hyperplasia and eosinophilic pneumonia as histologic manifestations of amiodarone-induced lung toxicity Am. J. Surg. Pathol. 36 4 2012 Apr 509 516 10.1097/PAS.0b013e318243fd9a 22314187\n4 Bedrossian C.W. Warren C.J. Ohar J. Bhan R. Amiodarone pulmonary toxicity: cytopathology, ultrastructure, and immunocytochemistry Ann. Diagn. Pathol. 1 1 1997 Oct 47 56 10.1016/s1092-9134(97)80008-1 9869825\n5 Dean P.J. Groshart K.D. Porterfield J.G. Iansmith D.H. Golden E.B. Jr. Amiodarone-associated pulmonary toxicity. A clinical and pathologic study of eleven cases Am. J. Clin. Pathol. 87 1 1987 Jan 7 13 10.1093/ajcp/87.1.7 3799544\n6 Wood D.L. Osborn M.J. Rooke J. Holmes D.R. Jr. Amiodarone pulmonary toxicity: report of two cases associated with rapidly progressive fatal adult respiratory distress syndrome after pulmonary angiography Mayo Clin. Proc. 60 9 1985 Sep 601 603 10.1016/s0025-6196(12)60983-5 4021550\n7 Teerakanok J. Tantrachoti P. Chariyawong P. Nugent K. Acute amiodarone pulmonary toxicity after surgical procedures Am. J. Med. Sci. 352 6 2016 Dec 646 651 10.1016/j.amjms.2016.08.013 27916222\n8 Boriani G. Ferruzzi L. Corti B. Ruffato A. Gavelli G. Mattioli S. Short-term onset of fatal pulmonary toxicity in a patient treated with intravenous amiodarone for post-operative atrial fibrillation Int. J. Cardiol. 159 1 2012 Aug 9 e1 4 10.1016/j.ijcard.2011.10.134 22130226\n9 Baumann H. Fichtenkamm P. Schneider T. Biscoping J. Henrich M. Rapid onset of amiodarone induced pulmonary toxicity after lung lobe resection - a case report and review of recent literature Ann Med Surg (Lond). 21 2017 Jul 19 53 57 10.1016/j.amsu.2017.07.034 28794867\n10 Cooper L.B. Mentz R.J. Edwards L.B. Wilk A.R. Rogers J.G. Patel C.B. Amiodarone use in patients listed for heart transplant is associated with increased 1-year post-transplant mortality J. Heart Lung Transplant. 36 2 2017 Feb 202 210 10.1016/j.healun.2016.07.009 27520780\n11 Rivinius R. Helmschrott M. Ruhparwar A. Darche F.F. Thomas D. Bruckner T. Comparison of posttransplant outcomes in patients with no, acute, or chronic amiodarone use before heart transplantation Drug Des. Dev. Ther. 11 2017 Jun 19 1827 1837 10.2147/DDDT.S136948\n12 Jennings D.L. Baker W.L. Pre-cardiac transplant amiodarone use is not associated with postoperative mortality: an updated meta-analysis Int. J. Cardiol. 236 2017 Jun 1 345 347 10.1016/j.ijcard.2017.02.045 28238350\n13 Omeroglu G. Kalugina Y. Ersahin C. Wojcik E.M. Amiodarone lung toxicity in a cardiac transplant candidate initially diagnosed by fine-needle aspiration: cytologic, histologic, and electronmicroscopic findings Diagn. Cytopathol. 34 5 2006 May 351 354 10.1002/dc.20313 16604561\n14 Valle J.M. Alvarez D. Antúnez J. Valdés L. Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: a rare aetiology Eur. Respir. J. 8 3 1995 Mar 470 471 10.1183/09031936.95.08030470 7789497\n15 Conte S.C. Pagan V. Murer B. Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: clinical, radiological and histological pattern Monaldi Arch. Chest Dis. 52 1 1997 Feb 24 26 9151516\n16 Antón Aranda E. Alkiza Basañez R. Laplaza Jiménez Y. Bronchiolitis obliterans organising pneumonia secondary to amiodarone treatment Neth. J. Med. 53 3 1998 Sep 109 112 10.1016/s0300-2977(98)00060-6 9803141\n17 Malhotra A. Muse V.V. Mark E.J. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 12-2003. An 82-year-old man with dyspnea and pulmonary abnormalities N. Engl. J. Med. 348 16 2003 Apr 17 1574 1585 10.1056/NEJMcpc030005 12700378\n18 Ott M.C. Khoor A. Leventhal J.P. Paterick T.E. Burger C.D. Pulmonary toxicity in patients receiving low-dose amiodarone Chest 123 2 2003 Feb 646 651 10.1378/chest.123.2.646 12576397\n19 Chatterjee K. Rochlani Y.M. Kuriakose K. AndrewDunn Khasawneh K. Paydak H. Amiodarone induced interstitial and organizing pneumonia reversed with steroids J. Ark. Med. Soc. 113 12 2017 Jun 294 296 29649357\n20 Coulier B. Colin G.C. Beniuga G. Amiodarone-induced cryptogenic organizing pneumonia (COP) Diagn Interv Imaging 101 9 2020 Sep 623 625 10.1016/j.diii.2020.01.004 31983617\n21 Diaz-Guzman E. Mireles-Cabodevila E. Arrossi A. Kanne J.P. Budev M. Amiodarone pulmonary toxicity after lung transplantation J. Heart Lung Transplant. 27 9 2008 1059 1063 10.1016/j.healun.2008.05.023 18765204\n\n",
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"journal": "Respiratory medicine case reports",
"keywords": "Amiodarone; Heart transplantation; Organizing pneumonia; Pulmonary toxicity",
"medline_ta": "Respir Med Case Rep",
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"title": "Acute amiodarone pulmonary toxicity in the form of organizing pneumonia triggered by orthotopic heart transplantation.",
"title_normalized": "acute amiodarone pulmonary toxicity in the form of organizing pneumonia triggered by orthotopic heart transplantation"
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"abstract": "Paraneoplastic cerebellar degeneration is rare and noteworthy in children. In this 7-year-old, it was documented to have occurred within a year of ataxia presentation. The instigating cancer was stage III adrenal adenocarcinoma, remitted after surgical resection at age 2. When her severe ataxia progressed, neuroinflammation was characterized by high cerebrospinal fluid Purkinje cell cytoplasmic antibody type 1 titers, oligoclonal bands, and neurofilament light chain. The immunotherapy strategy was to replace IV methylprednisolone, which lowered Purkinje cell cytoplasmic antibody type 1 titers without clinical improvement, with induction of adrenocorticotropic hormone/intravenous immunoglobulin/rituximab (ACTH/IVIG/rituximab) combination immunotherapy, ACTH/dexamethasone transition, and intravenous immunoglobulin maintenance. She became self-ambulatory and cerebrospinal fluid inflammatory markers regressed. Down syndrome predisposed her to a second cancer, pre-B acute lymphoblastic leukemia, 4 years later. Despite reversible cytosine arabinoside-provoked cerebellar toxicity, the ataxia is stable on monthly intravenous immunoglobulin without relapse, now 5 years after initial diagnosis. This report illustrates the use of cerebrospinal fluid biomarkers to detect, target, and monitor neuroinflammation, and successful combinations of immunotherapy to better the quality of life.",
"affiliations": "Department of Pediatric Neurology, Golisano Children's Hospital of Southwest FL, Fort Myers, FL, USA.;National Pediatric Myoclonus Center and National Pediatric Neuroinflammation Organization, Inc., Orlando, FL, USA.;National Pediatric Myoclonus Center and National Pediatric Neuroinflammation Organization, Inc., Orlando, FL, USA.",
"authors": "Philipps|Guillermo|G|;Tate|Elizabeth D|ED|;Pranzatelli|Michael R|MR|",
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"doi": "10.1177/2329048X18795546",
"fulltext": "\n==== Front\nChild Neurol OpenChild Neurol OpenCNOspcnoChild Neurology Open2329-048XSAGE Publications Sage CA: Los Angeles, CA 10.1177/2329048X1879554610.1177_2329048X18795546Case ReportIntensive Combination Immunotherapy and Neuroinflammation Resolution in a\nChild With Anti-PCA-1 (Yo) Paraneoplastic Syndrome and 2 Malignancies Philipps Guillermo MD12Tate Elizabeth D. MN, ARNP2Pranzatelli Michael R. MD2\n1 Department of Pediatric Neurology, Golisano Children’s Hospital of Southwest\nFL, Fort Myers, FL, USA\n2 National Pediatric Myoclonus Center and National Pediatric Neuroinflammation\nOrganization, Inc., Orlando, FL, USAMichael R. Pranzatelli, MD, National Pediatric\nNeuroinflammation Organization, Inc., 12001 Research Parkway, Suite 236, Orlando, FL\n32826, USA. Email: mpranzatelli@omsusa.org01 10 2018 2018 5 2329048X1879554603 5 2018 28 6 2018 12 7 2018 © The Author(s) 20182018SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution\n4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any use,\nreproduction and distribution of the work without further permission provided the\noriginal work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Paraneoplastic cerebellar degeneration is rare and noteworthy in children. In this\n7-year-old, it was documented to have occurred within a year of ataxia presentation. The\ninstigating cancer was stage III adrenal adenocarcinoma, remitted after surgical resection\nat age 2. When her severe ataxia progressed, neuroinflammation was characterized by high\ncerebrospinal fluid Purkinje cell cytoplasmic antibody type 1 titers, oligoclonal bands,\nand neurofilament light chain. The immunotherapy strategy was to replace IV\nmethylprednisolone, which lowered Purkinje cell cytoplasmic antibody type 1 titers without\nclinical improvement, with induction of adrenocorticotropic hormone/intravenous\nimmunoglobulin/rituximab (ACTH/IVIG/rituximab) combination immunotherapy,\nACTH/dexamethasone transition, and intravenous immunoglobulin maintenance. She became\nself-ambulatory and cerebrospinal fluid inflammatory markers regressed. Down syndrome\npredisposed her to a second cancer, pre-B acute lymphoblastic leukemia, 4 years later.\nDespite reversible cytosine arabinoside-provoked cerebellar toxicity, the ataxia is stable\non monthly intravenous immunoglobulin without relapse, now 5 years after initial\ndiagnosis. This report illustrates the use of cerebrospinal fluid biomarkers to detect,\ntarget, and monitor neuroinflammation, and successful combinations of immunotherapy to\nbetter the quality of life.\n\nPCA-1 syndromepediatric neuroinflammatory disordersadrenocortical carcinomaDown syndromeOMSpediatric paraneoplastic cerebellar degenerationacute lymphoblastic leukemiacytosine arabinoside-induced ataxiaANNA-1 (Hu) syndromeedited-statecorrected-proof\n==== Body\nPurkinje cell autoimmunity is now known to comprise a variety of demonstrable autoantibody\ndisorders. The Purkinje cell cytoplasmic antibody type 1 (PCA-1 or anti-Yo) is an\nanti-onconeural autoantibody, giving rise to an ataxia-predominant paraneoplastic syndrome in\nwomen with breast or gynecologic cancers.1 Purkinje cell cytoplasmic antibody type 1 is prone to development of paraneoplastic\ncerebellar degeneration, which can be the presenting sign of cancer, or a delayed phenomenon\nin 30%.2,3 Studies of the adaptive and innate immune response are few. Immunotherapies, such as\nsteroids, intravenous immunoglobulin (IVIG), and plasma exchange are used with limited success.1 With some exceptions,3 the prognosis is poor; most adults become bedridden.1 We now present observations on the neuroimmunologic profile, and clinical and\nimmunologic responses to a novel treatment approach in a child with Purkinje cell cytoplasmic\nantibody type 1-induced paraneoplastic cerebellar degeneration.4\n\n\nCase Overview\nPrior to any concerns about neuroinflammatory disorders, the patient carried diagnoses of\nDown syndrome; stage III adrenocortical carcinoma, which was resected at the age of 2 (along\nwith her left kidney); static mild congenital hydrocephalus (not shunted, stable); reactive\nairway disease (prn albuterol); and developmental delay (speaking in sentences at 5, toilet\ntrained at 6). The family history was pertinent for multiple sclerosis in the maternal great\naunt and gene-loaded for cancer on the paternal side (leukemia)—father deceased from grade\nIV glioblastoma multiforme—and maternal side (breast cancer). At the age 7 years, she\npresented with progressive ataxia, which was not recognized as being paraneoplastic until 3\nmonths later. Four years afterward, she developed acute lymphoblastic leukemia, as\npredisposed by trisomy 21. A p53 mutation, causing risk of recurrent malignancies in keeping\nwith Li Fraumeni syndrome, was discovered. It is noteworthy that the appearance of the\nparaneoplastic syndrome was delayed 5 years, and the interval between the 2 malignancies\nspanned 9 years. Additional clinical description and a detailed clinical course summary are\nprovided in Table 1.\n\nTable 1. Clinical Course by Clinic Visit.a\n\n\nClinic Visit\tTime After Ataxia (Months)\tDrug/Biological Treatments\tHistory and Neurological Examination\t\n1\t1\tNone\tNew-onset ataxia, progressing. Intermittent horizontal nystagmus, low tone. Not\ncooperative for proprioception testing. Gait wide based and unsteady. Falls over\neasily with changes in position. One month prior MRI brain report: enlarged\nlateral ventricles, unchanged from prior studies. Dx: ataxia of unknown\netiology\t\n2\t2\tIVIG 1 g/kg/d × 2 days\tWorsening ataxia needs to hold onto walls. CSF: normal protein/WBC. Normal MRI\nc/t/l-spine. EMG/NCV normal. Horizontal nystagmus, DTR reduced. Very unsteady\ngait\t\n3\t4\tIVIG 1 g/kg/d × 2 days, IV MPRED 30 mg/kg/d × 3 days, PRED taper (1mg/kg/d × 3\ndays, 0.75 mg/kg/d × 3 days, 0.5 mg/kg/d × 3 days and stopped)\tAtaxia persists. Using a walker. No significant improvement. Exam unchanged.\nParaneoplastic panel positive for anti-yo (PCA-1) antibodies: serum 1:15360, CSF\n1:256. Repeat CSF 1WBC, protein 38.6\t\n4\t5\tIVIG 1 g/kg/day × 1 day (repeated monthly), IV MPRED 30 mg/kg/d × 1 day\n(repeated monthly)\tAtaxia not clearly progressing anymore. Can walk with hand held. Difficulty\nusing a walker. Repeat PCA-1 titers: Serum 1:1920, CSF 1:128. P53 mutation\ndetected—missense mutation in exon 8\t\n5\t6\tMonthly IVIG 1 g/kg/d × 1 day, and IV MPRED 30 mg/kg/d × 1 day\tAtaxia again progressing. CSF with oligoclonal bands. Exam: highly unsteady with\nstanding. Severe ataxia\t\n6\t8\tMonthly IVIG 1g/kg/d × 1 day, PO DEX 7 mg/m2/d × 3 days, RTX 300\nmg/m2 × 4 weekly\tAtaxia stabilized and improved. Falling less often. Can now throw a ball from\nstanding. On exam, gait wide based, but can bend over, but falls\t\n7\t10\tMonthly IVIG 1g/kg/d × 1 day. ACTH: 75 IU/m2 BID × 1 week, 75\nIU/m2 daily × 4 weeks, 75 IU/m2 QOD × 3 weeks, 65\nIU/m2 QOD × 1 week, 55 IU/m2 QOD × 1 week\tAtaxia worsened again 2 months after rituximab completed. Initiated ACTH 4 mo\ntreatment course with improvements. Minor side effects of increased BP. Exam:\nsways with standing position. Base in gait narrower. Turns and bends over without\nfalling. Repeat MRI brain—cerebellar atrophy\t\n8\t12\tMonthly IVIG 1 g/kg/d × 1 day, ACTH: 45 IU/m2 QOD × 1 week, 35\nIU/m2 QOD × 1 week, 25 IU/m2 QOD × 1 week, 15\nIU/m2 QOD × 1 week, 10 IU/m2 QOD × 1 week, 5\nIU/m2 QOD × 1 week\tSeizure and altered mental status secondary to elevated BP. Started on\nlevetiracetam. BP managed with enalapril. Balance improving. Can pick up things\nwithout falling. Climbing up and down stairs. Falls with quick turns, but less\noften. On exam, cushingoid with weight gain. Mild irritability\t\n9\t15\tMonthly IVIG 1 g/kg/d × 1 day, PO DEX 7 mg/m2/d × 3 days/months\tCSF PCA-1 titer: 1:8. Off ACTH for past month. Balance continued to improve. Can\nrun. Intermittent worsening of balance when ill. Off levetiracetam. BP\nnormalized\t\n10\t22\tMonthly IVIG 1 g/kg/d × 1 day, PO DEX 7 mg/m2/d × 3 days/months\tBalance stable. Does not sleep well despite melatonin. Per PT report: Can walk\n200 to 300 feet without falling (compared to 10 feet, 12 months prior).\nMild–moderate unsteadiness with standing on 2 feet. Can stand on one leg with\nminimal assistance. Stance 10 to 15 inches (was >18)\t\n11\t37\tMonthly IVIG 1 g/kg/day × 1 day, PO DEX 7 mg/m2/d × 2\ndays/months\tGait stable to improved. Still with intermittent worsening of ataxia when ill.\nContinued sleeping problems, failed clonidine due to low BP. Exam, stands steadily\nwith minimally wide based stance. Minimal unsteadiness\t\n12\t48\tMonthly IVIG 1 g/kg/d × 1 day; PO; DEX 7 mg/m2/d × 2 days/months. IV\nMPRED 2 mg/kg/d × 2 days; IV DEX 7 mg/m2 × 1 day\tAtaxia stable. However, ambulation limited by left hip/knee pain for past 3\nmonths. Left hip effusion found. Suspicion for autoimmune process. Improved with\nIV steroids\t\n13\t51\tMonthly IVIG 1 g/kg/d × 1 day, COG AALL 11311\tNew onset thrombocytopenia during steroid wean. Elevated inflammatory markers.\nBone marrow positive for Pre-B ALL. CSF negative for malignancy. ALL in Remission\nat day 15. Cytogenetics showed near tetraploidy. Heterozygous for TPMT. Repeat\nPCA-1: serum undetectable, CSF 1:32\t\n14\t57\tMonthly IVIG 1 g/kg/d × 1 day, chemotherapy\tAt home, ataxia stable. Developed Altered mental status and worsened ataxia\nsecondary to Ara-c toxicity. ALL in remission. MRI brain unchanged from 2013 study\nwith cerebellar atrophy and ventriculomegaly\t\n15\t62\tMonthly IVIG 1 g/kg/d × 1 day, maintenance chemotherapy\tRecovered from Ara-c toxicity. Mental status back to her normal. Cognition also\nimproving. Ataxia stable. Continues to be able to do stairs. ALL in remission.\nExam: child happy and interactive. Fairly steady gait, mild wide base\t\n16\t68\tMonthly IVIG 1 g/kg/d × 1 day, maintenance chemotherapy\tContinues in remission from ALL. Ataxia remains unchanged. Repeat CSF PCA-1\nantibody titer 1:8. Exam unchanged from last visit\t\nAbbreviations: ACTH, adrenocorticotropic hormone; ALL, acute lymphoblastic leukemia;\nAra-c, cytosine arabinoside; BID, twice a day; BP, blood pressure; COG, Children’s\nOncology Group; DEX, dexamethasone; CSF, cerebrospinal fluid; IVIG, intravenous\nimmunoglobulin; MPRED, methylprednisolone; PO, orally; PRED, prednisone; RTX,\nrituximab; TPMT, thiopurine S-methyltransferase gene; QOD, once a day.\n\n\naCOG AALL 1131: Chemotherapy days 1-14: Ara-C IT 70 mg/m2,\nVincristine IV 1.5 mg/m2/dose days 1 and 8, Methotrexate 15 mg IT day 8,\nPrednisone 30 mg/m2/dose BID PO days 1-14, PEG-Asparaginase IV 2500\nunits/m2 day 4. Days 15-29: Vincristine IV 1.5 mg/m2/dose day 15 and day\n22, Prednisone 30 mg/m2/dose BID PO days 15-29, Methotrexate 15 mg IT day\n29.\n\nMethods\nClinical\nThe patient was referred to the National Pediatric Myoclonus Center for second evaluation\nof clinical deterioration. Parents gave written informed consent for their child to\nparticipate in this institutional review board–approved study of immunological\nabnormalities in opsoclonus–myoclonus as a related neuroinflammatory/paraneoplastic\ndisorder (SIU SOM, Springfield, Illinois). Clinical data were collected, and extra\ncerebrospinal fluid and blood for research purposes were obtained from lumbar puncture and\nvenipuncture performed for clinical reasons. Immunotherapy was given in clinical practice,\nnot a drug trial, by the local treating physicians. Given the clinical gravity of\nparaneoplastic cerebellar degeneration and the persistent ataxia, parents were reconsented\nfor a second lumbar puncture to rule out ongoing neuroinflammation.5 Years later, oncologists at the referring hospital performed 2 lumbar punctures to\nrule out central nervous system leukemic infiltration and subsequent laboratory testing.\nWestern institutional review board (Puyallup, Washington) conferred exempt review status\nfor retrospective data analysis. A modified Opsoclonus Myoclonus Evaluation Scale\n(nystagmus substituted for opsoclonus) was used to compute Total Score (0-36) from videotapes.6 Retrospective gait ataxia scoring by the first author was used to summarize ataxia\nevaluations from the clinic. The patient’s mother gave written approval for publication of\nthis report with videotapes, including recognizable facial images necessitated by the\npresence of nystagmus.\n\nLaboratory\nLymphocyte subsets were measured in cerebrospinal fluid and blood by flow cytometry in\nthe clinical laboratory as previously described.6 Lymphocytes gated were 1633 from 14 mL of fresh cerebrospinal fluid from the first\nvisit lumbar puncture and 6838 from 14.5 mL for the second lumbar puncture at the National\nPediatric Myoclonus Center. Cerebrospinal fluid oligoclonal bands not found in serum\n(positive if ≥2) were measured by isoelectric focusing with immunofixation at ARUP Lab\n(Salt Lake City, Utah).\n\nCerebrospinal fluid and serum immunobiomarkers were measured in Dr Pranzatelli’s\nneuroimmunology laboratory by enzyme-linked immunosorbent assay using commercial kits, as\nper the manufacturer’s instructions. The neurofilament light chain kit was purchased from\nUlman Diagnostics (Umeá, Sweden; lot no. 70189); the microglial/macrophage marker soluble\nchitinase 3-like 1 (sCHI3L1) kit, from R&D systems, Inc (Minneapolis, Minnesota; lot\nno. 298223). Both were used as previously described.7,8\n\n\nA commercial paraneoplastic serologic evaluation was performed by Mayo Clinic Lab\n(Rochester, Minnesota) for ANNA Type 1, 2, and 3, anti-glial nuclear antibody type 1,\nPurkinje cell cytoplasmic antibody (Purkinje cell cytoplasmic antibody type 1, 2, and Tr),\namphiphysin antibody, and CRMP-5-immunoglobulin G; antibodies to GAD65 and to\nN-methyl-D-aspartate (NMDA), γ-aminobutyric acid (GABA), or\nα-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors; SRP, striational,\nP/Q-Type calcium channel, N-Type calcium channel, ACh receptor binding, AChR ganglionic\nneuronal, and neuronal (V-G) K+ channel antibodies.\n\nPublished control data from Dr Pranzatelli’s neuroimmunology laboratory were obtained\nfrom children with noninflammatory neurological disorders and non-neurological disorders\nwho underwent lumbar puncture as part of clinical diagnostic testing. Those data provided\nmedians and reference ranges for use in comparison with the index patient.\n\nResults\nClinical and Radiological Response to Immunotherapy\nThe treatment sequence, involving a multiplicity of immunotherapeutic agents, is shown in\nFigure 1A. In brief, the initial\nregimen of methylprednisolone and prednisone after only a single treatment of intravenous\nimmunoglobulin was changed substantially for the lack of clinical effectiveness. An\nongoing regimen of intravenous immunoglobulin was supplemented by a course of rituximab\nfollowed by initiation of adrenocorticotropic hormone (ACTH) after IV dexamethasone, then\nchanged to oral dexamethasone after ACTH weaning and discontinuation. Maintenance\nintravenous immunoglobulin and oral dexamethasone were extended during the cancer\nchemotherapy for acute lymphocytic leukemia.\n\nFigure 1. Time course of clinical and CSF measures and effect of immunotherapy. A, Treatment\nrecord. Zero marks ataxia presentation. Sequence of treatment reads from bottom to top\nof Y axis. The −1, −2, −3 suffixes on treatments refer to treatment periods, not\nindividual doses. Intravenous immunoglobulin (IVIG) was monthly; methylprednisolone\n(MPRED) IV pulse; Adrenocorticotropic hormone (ACTH) twice daily, then daily, then\nonce a day SQ; DEX was 21 mg/m2 ÷ TID × 3 pulses, first intravenous, then\norally. Treatment in the first 12 months was for induction, then maintenance from 12\nto 49 months, then for acute lymphocytic leukemia. More detailed reporting of doses\nand dosing schedule are provided in Table 1. B, Sequence of diagnoses. C, Percent\nCSF B cells. The control mean is < 1%. D, CSF OCB count. Per reference lab ≥ 2\nbands is positive. E, CSF Purkinje cell cytoplasmic antibody type 1 titers. F, Serum\nPurkinje cell cytoplasmic antibody type 1 titers. G, Percent blood cells. H, Thyroid\nperoxidase antibody titers. Normal range is < 9.0 IU/mL. I, Ataxia score. Scale: 0,\nnormal; 1, walks independently, somewhat wide base, steady; 2, walks independently,\nquite wide base, not falling; 3, walks independently, quite wide base, falling; 4,\nrequires walker, doable; 5, requires walker, difficult; 6, needs to hold on walls to\nwalk; 7, not independently walking; 8, nonambulatory. J, Total Score on a modified\nOpsoclonus Myoclonus Evaluation Scale. Clinical interpretation is mild severity if\nscore 0 to 12; moderate, 13 to 24; severe, 25 to 36. Ara-cx Rec. indicates cytosine\narabinoside recovery; Ara-c Atax., cytosine arabinoside-induced cerebellar ataxia;\nCSF, cerebrospinal fluid; DEX, dexamethasone; OCB, oligoclonal bands; PCD,\nparaneoplastic cerebellar degeneration; Regres., regression (mild ataxia 1 week before\nIVIG was due); Vit D Insuf., vitamin D insufficiency.\n\nThe cumulative sequence of diagnoses is depicted in Figure 1B. Besides the initial diagnoses of ataxia,\nparaneoplastic cerebellar degeneration, Purkinje cell cytoplasmic antibody type 1, and\nautoimmune thyroiditis, the patient was subsequently shown to have vitamin D insufficiency\nand received vitamin D supplementation. At 46 to 50 months before the presentation of\nacute lymphocytic leukemia, the patient began to experience mild ataxia regression 1 week\nbefore intravenous immunoglobulin was due (ie, 3 weeks after dose) on several occasions,\nwhich remitted quickly after intravenous immunoglobulin was given. After exposure to\ncytosine arabinoside, the patient’s ataxia worsened—a known cerebellar toxicity of\ncytosine arabinoside—but it recovered. Autoimmune thyroiditis was diagnosed on the basis\nof positive thyroglobulin at 415 IU/mL (normal < 116 IU/mL) and elevated\nthyroperoxidase antibodies at 37.9 IU/mL (normal < 9.0 IU/mL). The thyroperoxidase\nantibodies concentration fell on immunotherapy (Figure 1H). She remains on levothyroxine therapy.\n\nThe ataxia response is depicted in Figure 1I. By the end of multimodal induction, ataxia severity had declined by\n50%, with the functional improvement of beginning to walk independently, though still\nataxic. Further improvement occurred despite switching ACTH to dexamethasone. On long-term\nintravenous immunoglobulin maintenance therapy, ataxia remained at a low level before and\nafter a small rise associated with acute lymphocytic leukemia/cytosine arabinoside.\n\nUsing the modified Opsoclonus Myoclonus Evaluation Scale (Figure 1J), Total Score declined by 24% on\nACTH/intravenous immunoglobulin/rituximab induction therapy (Supplemental materials,\ncompare Video 1 and Video 2), although remaining in same moderate severity category (13-24\npoints). Comparison of the neurologic examinations is shown in Table 2. On long-term maintenance therapy, however,\nTotal Score fell into the upper end of the mild range (0-12 points), a 48% drop from the\ninitial score (Supplemental Material, Video 3). As the Opsoclonus Myoclonus Evaluation\nScale also evaluates development, Total Score might not be expected to drop much further\ndue to Down syndrome.\n\nTable 2. Neurologic Examinations at the NPMC Before and 6 Months After Initiation of Intensive\nImmunotherapy.\n\nFeature\tVisit 1\tVisit 2\t\nCooperative\tMostly\tMostly\t\nFollows commands\tWith coaching\tWith coaching\t\nDysarthria\tModerate\tMild\t\nSentences\tNo\t3 words\t\nCranial nerves\tIntact\tIntact\t\nDTR\tAbsent\tAbsent\t\nAnkle clonus\tNo\tNo\t\nExtensor plantar\tNo\tNo\t\nBlock stacking\t0 of 8 (right hand)\t3 of 8 (right)\t\n\t3 of 8 (left)\t6 of 8 (left)\t\nPaperclip in bottle\tWith anchoring\tWith anchoring\t\nFinger–nose dysmetria\tModerate\tMild\t\nMuscle tone\tDecreased\tDecreased\t\nMuscle strength\tNormal\tNormal\t\nStandinga\n\tWide base, backstepping\tWide base\t\nGait\tWide base, ataxic\tWide base, ataxic\t\nOne-foot balance\tNo\t1 second\t\nHopping\tNo\tNo\t\nFalling\tSeveral times\tA few times\t\nAble to run\tNo\tNo\t\nBall throwing\t0 of 3 tries\t1 of 3 times\t\nBall catching\t0 of 3 tries\t1 of 3 tries\t\nGetting off floor\t4-limb push off\t4-limb push off\t\nAbbreviations: NPMC, National Pediatric Myoclonus Center.\n\n\na One-foot gap between feet while standing on visit 1.\n\nNeuroimaging of the brain (Figure\n2) revealed correlates. The magnetic resonance imaging (MRI) that was obtained 2\nmonths prior to Purkinje cell cytoplasmic antibody type 1 diagnosis (about 2 weeks into\nthe ataxia symptoms) did not show paraneoplastic cerebellar degeneration (Figure 2A and D). Presumably, the\ncerebellum was normal because it was early in the disease course. How fast the\ndegeneration developed thereafter is unknown, except to say that it had occurred by the\nnext MRI 10 months after the initial scan (Figure 2B and E). The radiologic appearance of\nparaneoplastic cerebellar degeneration did not improve on immunotherapy nor did it\nprogress (Figure 2C and F).\n\nFigure 2. MRI axial and sagittal FLAIR imaging. A, Pre-PCD axial T1 image at time of ataxia\nonset, 2 months prior to Purkinje cell cytoplasmic antibody type 1 diagnosis (5.5\nyears ago). Patient had known congenital dilatation of the lateral ventricles,\nparticularly occipital horns. The size of the ventricles remained stable over years\nwith no need for neurosurgical intervention. B, MRI was performed 9 months after onset\nof symptoms at time of most severe ataxia (5 years ago). It was diagnostic for PCD; T2\nimage shows cerebellar atrophy with enlargement of fourth ventricle. C, MRI T2 axial\nimage 8 months after acute lymphocytic leukemia diagnosis at time of cytosine\narabinoside encephalopathy (1 year ago). Cerebellar volume remained stable when\ncompared to MRI 4 years prior. D, Sagittal image from MRI at onset of ataxia\n(corresponding to A). Cerebellar vermian volume appears normal. E, On the sagittal\nimage (corresponding to B), there is notable progression of cerebellar vermian atrophy\nafter progression of PCA-1 disease. F, The sagittal image from MRI 1 year ago\n(corresponding to C) shows no interval change after immunotherapy and systemic\nchemotherapy. Although only a single image can be shown here, when the entire 2 MRI\nstudies (sagittal, axial, coronal images) were compared with our radiologist, they\nlook remarkably similar, including the dimensions of the vermis and fovea. Despite the\nsevere vermian volume loss, the patient has mild ataxia with minimal impact on the\nquality of daily life. MRI indicates magnetic resonance imaging; PCA-1, Purkinje cell\ncytoplasmic antibody type 1; PCD, paraneoplastic cerebellar degeneration.\n\nNeuroimmunologic Studies\nAt the first diagnostic evaluation, the main neuroimmunologic observations were mildly\nincreased the frequency of cerebrospinal fluid B cells (1.6%), positive oligoclonal bands\n(6), and elevated Purkinje cell cytoplasmic antibody type 1 titer (Figure 1 C-E). Cerebrospinal fluid immunoglobulin G\nindex, immunoglobulin G synthesis rate, immunoglobulin G/albumin ratio, protein, and\nglucose were normal. There was no cerebrospinal fluid pleocytosis (WBC 1/cu mm; RBC 0).\nThe cerebrospinal fluid leukocyte differential was 80% lymphocytes and 20% monocytes. The\ncerebrospinal fluid CD4/CD8 T-cell ratio was low at 1.8 (normal 2.5-3). The\nneuronal/axonal marker neurofilament light chain was elevated 10-fold in cerebrospinal\nfluid at 3254 ng/mL (controls, 300 ng/mL) and also in serum at 722 ng/mL (controls, 22\nng/mL), and the neurofilament light chain cerebrospinal fluid: serum ratio was 4.5. The\nserum Purkinje cell cytoplasmic antibody type 1 titer was grossly elevated at 1:15360\n(Figure 1F). The blood B cell\nfrequency of 9.8% was not elevated (Figure 1G).\n\nAt 7 months on intensified combination immunotherapy, there was amelioration of adaptive\nimmunity: undetectable cerebrospinal fluid B cells, and reduction in oligoclonal bands\ncount (3) and Purkinje cell cytoplasmic antibody type 1 titers (1:8). WBC count was 4/cu\nmm (81% lymphocytes/19% monocytes); RBC 0. Cerebrospinal fluid immunoglobulin G index was\nnormal; immunoglobulin G index, slightly elevated at 0.71. The cerebrospinal fluid CD4/CD8\nT-cell ratio normalized. The frequency of γδ T-cells, primarily considered to be innate\nimmune cells, was normal at 2.6% in cerebrospinal fluid and 10.8% in blood. The\nconcentration of the M2 macrophage marker CHI3L1 in serum was 36 ng/mL at the low range of\ncontrols (431 ng/mL). Blood B cell frequency was 0%.\n\nWhen acute lymphocytic leukemia presented (on prednisone 15 mg/d and intravenous\nimmunoglobulin 8 days prior), cerebrospinal fluid oligoclonal bands was 2, immunoglobulin\nG synthesis rate 11.5 mg/d (vs < 8), cerebrospinal fluid immunoglobulin G 8.3 mg/dL (vs\n≤ 6), and albumin index (10.9 vs ≤ 9). These were interpreted as mild elevations.\n\nDiscussion\nThis case introduces several novelties. First, intensified combination immunotherapy\ninduced marked clinical improvement, whereas prior methylprednisolone/intravenous\nimmunoglobulin also reduced Purkinje cell cytoplasmic antibody type 1 titers but with little\nclinical benefit. Second, signs of neuroinflammation steadily declined, all but a few\nnormalizing, corresponding to functional improvement. Third, no major relapses occurred on\ndexamethasone/intravenous immunoglobulin maintenance therapy, despite Down\nsyndrome–associated leukemia and chemotherapy. Fourth, the features are consistent with\nadult-onset Purkinje cell cytoplasmic antibody type 1, but with better outcome. Fifth,\ncerebrospinal fluid neurofilament light chain was elevated, as in opsoclonus–myoclonus\nsyndrome and anti-ANNA-1 (Hu) syndrome, suggesting a shared immunopathologic aspect of\notherwise distinct clinical syndromes. Sixth, the patient had concomitant autoimmune\nthyroiditis, which responded to the same immunotherapy given for the paraneoplastic\nsyndrome. Seventh, the patient was vitamin D insufficient, a common association with\nautoimmune disorders. Eight, there were two malignancies: the first, rare and previously not\nknown to be associated with paraneoplastic cerebellar degeneration, the second, associated\nwith Down syndrome.\n\nThe “Time is Brain” motto has been applied to the cerebellum: “Time is cerebellum.”9 Despite the cerebellum’s capacity for compensating and restoring lost functions, the\ntherapeutic opportunity for intervention occurs early in patients with cerebellar diseases,\nparticularly immune ataxias. Advanced cell loss degrades cerebellar “reserve,” hastening the\ntransition from a restorable or treatable state to an untreatable one.9 Timely immunotherapy is necessary to treat neuroinflammation comprised of the\nadaptive immune response of B cells and T cells, among others, and possible involvement of\nthe innate immune system, which is involved in neurodegeneration. Yo-paraneoplastic\ncerebellar degeneration tumors are infiltrated by large numbers of B and T cells, some\norganized in tertiary lymphoid structures, and Yo-paraneoplastic cerebellar\ndegeneration-manifesting ovarian carcinomas harbor at least 1 genetic alteration of\nYo-antigens thought to trigger the breakdown of immune tolerance.10 There is a differential genetic susceptibility to anti-Yo per cancer with primary\nhuman lymphocyte antigens class II involvement.11\n\n\nThe combination of ACTH, intravenous immunoglobulin, and rituximab, with or without\ntransitioning to dexamethasone for maintenance prior to weaning, has been successful in\nchildren with opsoclonus–myoclonus syndrome, both clinically and against neuroinflammation.6 Rituximab (anti-CD20) targets B cells. In a pilot study of rituximab in 9 adult\npatients (anti-Yo and anti-Hu), 3 patients improved ≥ 1 Rankins Scale point after monthly IV\nrituximab 375 mg/m2.12 Combination immunotherapy with dexamethasone, intravenous immunoglobulin, and\nrituximab (DEXIR-CI) also has similar effects.13 Rituximab influences neuroinflammation whether or not the clinical benefit occurs\nduring the 4-week infusions or thereafter. In the broader view, there are now several\ndifferent treatment protocols for paraneoplastic disorders available to child neurologists13-16 so clinical deterioration, partial response, and relapse can be addressed by\nforward-thinking, biomarker-assisted initial treatment planning or mid-course\ncorrections.\n\nIn comparison of our case with the Purkinje cell cytoplasmic antibody type 1 syndrome in\nadults, early cerebrospinal fluid studies in adults reveal lymphocytic pleocytosis,\noligoclonal bands, and elevated protein,1 but our patient did not have pleocytosis or elevated protein. The B-cell frequency\nwas lower than usually found in OMS. As with our case, anti-Purkinje cell cytoplasmic\nantibody type 1 antibodies may persist for years.2 Serum Purkinje cell cytoplasmic antibody type 1 has recently been reported outside\nthe context of cancer in 77% of children with attention deficit hyperactivity disorder\n(ADHD) and 22% of controls in association with elevated interleukin 6 (IL-6) and IL-10 serum concentrations.17 Pending replication of that finding by other investigators, the clinical\nsignificance, and presence of any such parallels in adults remains uncertain.\n\nThe striking elevation of cerebrospinal fluid neurofilament light chain concentration in\npediatric-onset paraneoplastic neurological disorders is significant. An elevated\ncerebrospinal fluid to serum neurofilament light chain ratio indicates intrathecal\nconcentration. Now described in pediatric-onset ANNA-1 (Hu) paraneoplastic syndrome18 and OMS,7 it is a useful biochemical measure. Well known to have utility in assessing\nneuroinflammation in multiple sclerosis and related disorders in adults, the opportunity to\nutilize it presents itself to child neurologists.\n\nCytarabine-induced ataxia due to toxicity, which degrades cytoskeleton components like neurofilament,19 has been well described.20 The antineoplastic and immunosuppressant drug acts through inhibition of DNA\npolymerase. With intrathecal administration, cerebrospinal fluid cytarabine levels decline\nwith a half-life of 2 hours. The incidence of cerebellar ataxia is up to 14%.21 In a study of 418 patients aged 2 to 74 years with leukemia or lymphoma, 8% developed\nsevere cytarabine-induced cerebellar toxicity, especially if > 50 years old, regardless\nof gender, diagnosis, or regimen.22 Drug dose and schedule, cumulative dose, renal and hepatic dysfunction, and use of\nneurotropic antiemetic drugs can also affect risk.21 In our patient, it is possible that paraneoplastic cerebellar degeneration may have\nmade the patient more vulnerable to the cerebellar toxicity, which was clinically\nreversible; however, the cerebellum, with its extended postnatal development, is\nparticularly sensitive to toxic agents, even in patients without paraneoplastic cerebellar\ndegeneration.\n\nCerebellar abnormalities associated with Down syndrome and a Down syndrome murine model\nincludes reduced cerebellar volume and granule cells.23 Although they may contribute to the hypotonia of Down syndrome, as exhibited by this\npatient, they do not account for her substantial cerebellar/vermian atrophy or the\nrelatively short course of its development. Pre-paraneoplastic cerebellar\ndegeneration/Purkinje cell cytoplasmic antibody type 1 neuroimaging did not display\ncerebellar hypoplasia or appreciable atrophy.\n\nWhereas only 0.2% of all pediatric malignant cancers are adrenocortical tumors,24 children with Down syndrome are well known to have a greatly increased risk of leukemias.25 For acute lymphocytic leukemia, their event-free and overall survival is poorer than\nin non-Down syndrome acute lymphocytic leukemia.25 Although the 5-year event-free survival for adrenocortical tumors is only 54%,24 our patient did well. The outcome is better with localized tumors of small volume.26 The patient thus far is responding well to chemotherapy. Paraneoplastic cerebellar\ndegeneration also occurs rarely with other pediatric-onset cancers, such as Hodgkin disease.27\n\n\nThis patient’s autoimmune thyroiditis, found on screening, presented differently than acute\n“steroid-responsive encephalopathy associated with autoimmune thyroiditis” (alias Hashimoto encephalopathy),28,29 with its requirement for negative brain neuroimaging and exclusion of all other\ncauses. Here, the autoimmune thyroiditis most likely reflects the increased risk of\nHashimoto thyroiditis and Grave disease in Down syndrome,30 and of having subsequent autoimmune disorders in addition to the initial one in\nchildren with perturbed autoimmunity. The thyroiditis was responsive to immunotherapy and\nhas not returned.\n\nVitamin D insufficiency or deficiency is more common in patients with autoimmune disorders\nand has been associated with multiple sclerosis, systemic lupus erythematosus, polymyositis\nand dermatomyositis, rheumatoid arthritis, Behçet disease, type 1 diabetes mellitus, and\nsystemic scleroderma.31 Besides autoimmune disorders, the inestimable consequences of vitamin deficiency,\nwhich is now a pandemic, include cancers, infectious disease, cardiovascular diseases, and\nchildhood dental caries and periodontitis.32 Testing for 25-OH-vitamin D levels and supplementing with vitamin D if low is highly\nrecommended in patients with autoimmune disorders.31\n\n\nConclusion\nThe clinical importance of our observations is that intensive, long-term, biomarker-based,\ncombination immunotherapy made a difference in this rare child with paraneoplastic\ncerebellar degeneration and anti-Purkinje cell cytoplasmic antibody type 1 paraneoplastic\nsyndrome, both in quality of life and amelioration of neuroinflammation. Given the better\noutcome than would be predicted from poor treatment responses in adults, this immunotherapy\napproach should be pursued in others who share the diagnosis. Purkinje cell cytoplasmic\nantibody type 1 antibodies should be measured in children with ataxia or paraneoplastic\ncerebellar degeneration presentation, even if years after cancer treatment. Alertness to the\nincreased risk of a second autoimmune disorder and/or malignancy and testing for vitamin D\ndeficiency/insufficiency should be routine. Such patients need long-term follow-up to stay\nthe course.\n\nSupplementary Material\nSupplementary material\n Supplementary material\n Supplementary material\n Acknowledgments\nThe authors thank Nathan R. McGee, B.S., for performing the neurofilament light chain and\nsCHI3L assays at the National Pediatric Myoclonus Center, the patient, and her family. They\nalso thank the following individuals at Golisano Children’s Hospital of SWF: Michael Weiss,\nMD, Florida Radiology Consultants, and the entire hematology/oncology team: Craig MacArthur\nMD, Cameron Nicholson MD, Emad Salman MD, Kelly Sawczyn MD, Pamela Bolton ARNP, Jennifer\nVega ARNP, the medical assistants, nurses, customer service representatives who made getting\napproval of the patient’s treatment course possible, and former attending Susan Alisanski\nMD.\n\nAuthor Contributions: GP treated the patient, gathered the clinical and laboratory information, wrote the case\ndescription and made the clinical table, and selected the MRI scan images. ET performed\nthe lumbar punctures at the National Pediatric Myoclonus Center, gathered the histories,\nexamined the patient, scored the videotapes, and made the movies from them. MP examined\nthe patient, conceptualized the manuscript, interpreted the data and flow cytometry\nreports, graphed the data, and drafted the manuscript. All authors read, revised, and\napproved the final manuscript.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research,\nauthorship, and/or publication of this article.\n\nFunding: The authors received no financial support for the research, authorship, and/or\npublication of this article.\n\nSupplemental Material: Supplemental material for this article is available online.\n\nEthical Approval: This study was approved by the Institutional Review Board of SIU SOM (Springfield, IL).\nWritten informed consent for the collection of cerebrospinal fluid and peripheral blood\nsamples at the NPMC was obtained from the parent, giving consent for herself and on behalf\nof her cognitively impaired, minor child. Western IRB (Puyallup, WA) granted permission\nfor retrospective analysis of all the data reported.\n==== Refs\nReferences\n1 \nVenktraman A Opal P \nParaneoplastic cerebellar degeneration with anti-Yo\nantibodies – a review . Ann Clin Transl Neurol .\n2016 ;3 (8 ):655 –663 .27606347 \n2 \nFinstere J Unterberger U Grisol W \nAsymptomatic persistence of anti-Yo antibodies for 5 years\nwith relapse of malignancy . Neuropathology .\n2007 ;27 (3 ):300 –304 .17645247 \n3 \nCui D Xu L Li WY Qian WD \nAnti-Yo positive and late-onset paraneoplastic cerebellar\ndegeneration associated with ovarian carcinoma. A case report .\nMedicine .\n2017 ;96 (32 ):e7362 \ndoi: 10.1097/MD.0000000000007362 .28796031 \n4 \nPhilipps G Alisanski SB Pranzatelli M Clardy SL Lennin VA McKeon A \nPurkinje cell cytoplasmic antibody type 1 (anti-Yo)\nautoimmunity in a child with Down Syndrome . JAMA\nNeurology .\n2014 ;71 (3 ):347 –349 .24424854 \n5 \nBielekova B Pranzatelli MR \nPromise, progress, and pitfalls in the search for CNS\nbiomarkers in neuroimmunological diseases: a role for CSF\nimmunophenotyping . Sem Pediatr Neurol .\n2017 ;24 (3 ):229 –239 .\n6 \nPranzatelli MR Tate ED Travelstead AL Colliver JA \nLong-term cerebrospinal fluid and blood lymphocyte\ndynamics after rituximab for pediatric opsoclonus-myoclonus . J\nClin Immunol .\n2010 ;30 (1 ):106 –113 .19838774 \n7 \nPranzatelli MR Tate ED McGee NR Verhulst SJ \nCSF neurofilament light chain is increased in OMS,\ndecreasing with immunotherapy, and other pediatric neuroinflammatory\ndisorders . J Neuroimmunol .\n2014 :266 (1-2 ):75 –81 .24342231 \n8 \nPranzatelli MR Tate ED McGee NR \nMicroglial/macrophage markers CHI3L1, sCD14, and sCD163 in\nCSF and serum of pediatric inflammatory and non-inflammatory neurological disorders: a\ncase-control study and reference ranges . J Neurol Sci .\n2017 :381 :285 –290 .\ndoi: 10.1016/j.jns.2017.09.006 .28991699 \n9 \nMitoma H Manto M Hampe CS \nTime is cerebellum .\nCerebellum .\n2018 ;17 (4 ):387 –391 .\ndoi: 10.1007/s12311-018-0925-6 .29460203 \n10 \nSmall M Treilleux I Couillault C \nGenetic alterations and tumor immune attack in Yo\nparaneoplastic cerebellar degeneration . Acta\nNeuropathol .\n2018 ;135 (4 ):569 –579 .\ndoi: 10.1007/s00401-017-1802-y .29299667 \n11 \nHilary RP Ollila HM Lin L \nComplex HLA association in paraneoplastic cerebellar\nataxia with anti-Yo antibodies . J Neuroimmunol .\n2018 ;315 :28 –32 .29306402 \n12 \nShams’ili S de Beukelaar J Gratama JW \nAn uncontrolled trial of rituximab for antibody associated\nparaneoplastic neurological syndromes . J Neurol .\n2006 ;253 (1 ):16 –20 .16444604 \n13 \nPranzatelli MR Tate ED \nDexamethasone, intravenous immunoglobulin, and rituximab\ncombination immunotherapy for pediatric opsoclonus-myoclonus syndrome .\nPediatr Neurol .\n2017 ;73 :48 –56 .28651977 \n14 \nPranzatelli MR Tate ED Allison TJ \n6-Mercaptopurine modifies cerebrospinal fluid T-cell\nabnormalities in pediatric opsoclonus-myoclonus as steroid sparer .\nClin Exp Immunol .\n2017 ;190 (2 ):217 –225 .\ndoi: 10.1111/cei.13015 .28710878 \n15 \nPranzatelli MR Tate ED Alber M \nRituximab, IVIG, and tetracosactide (ACTH 1-24)\ncombination immunotherapy (“RITE-CI”) for pediatric opsoclonus-myoclonus syndrome:\nimmunomarkers and clinical observations .\nNeuropediatrics \n2017 \ndoi: 101055/s-0037-1609038 .\n16 \nPranzatelli MR Allison TJ Tate ED \nEffect of low-dose cyclophosphamide, ACTH, and IVIg\ncombination immunotherapy on neuroinflammation in pediatric-onset OMS: a retrospective\npilot study . Eur J Paediatr Neurol .\n2018 ;22 (4 ):586 –594 .\ndoi: 10.1016/j.ejpn.2018.02.009 .29555260 \n17 \nDonfrancesco R Nativio P Di Benedetto A \nAnti-Yo antibodies in children with ADHD: First results\nabout serum cytokines . J Atten Disord .\n2016 : pii: 10870547116643387 .\n18 \nPranzatelli MR McGee NR \nNeuroimmunology of OMS and ANNA-1/anti-Hu paraneoplastic\nsyndromes in a child with neuroblastoma . Neurol Neuroimmunol\nNeuroinflamm .\n2017 ;5 (2 );e433 ; doi\n10.1212/NXI.0000000000000433 \n29318181 \n19 \nKoros C Kitraki E \nNeurofilament isoform alterations in the rat cerebellum\nfollowing cytosine arabinoside administration . Toxicol\nLett .\n2009 ;1898 (3 ):215 –218 .\n20 \nSylvester RK Fisher AJ Lobell M \nCytarabine-induced cerebellar syndrome: case report and\nliterature review . Drug Intell Clin Pharm .\n1987 ;21 (2 ):177 –180 .3470173 \n21 \nBaker WJ Royer GL Weiss RB \nCytarabine and neurologic toxicity .\nJ Clin Oncol .\n1991 ;9 (4 ):679 –693 .1648599 \n22 \nHerzig RH Hines JD Herzig GP \nCerebellar toxicity with high-dose cytosine\narabinoside . J Clin Oncol .\n1987 ;5 (6 ):927 –932 .3585447 \n23 \nMoldrich RX Dauphinot L Laffaire J Rossier J Potier MC \nDown syndrome gene dosage imbalance on cerebellum\ndevelopment . Prog Neurobiol .\n2007 ;82 (2 ):87 –94 .17408845 \n24 \nXu X Sergi C \nPediatric adrenal cortical carcinomas: histopathological\ncriteria and clinical trials. A systematic review . Contemp Clin\nTrials .\n2016 ;50 :37 –44 .27424218 \n25 \nMaloney KW Taub JW Ravindranath Y Roberts I Vyas P \nDown syndrome preleukemia and leukemia .\nPediatr Clin North Am .\n2015 ;62 (1 ):121 –137 .25435116 \n26 \nCecchetto G Ganarin A Bien E \nOutcome and prognostic factors in high-risk childhood\nadrenocortical carcinomas: a report from the European Cooperative Study Group on\nPediatric Rare Tumors (EXPeRT) . Pediatr Blood Cancer .\n2017 ;64 (6 ). doi:\n10.1002/pbc.26368 .\n27 \nHahn A Claviez A Brinkmann G Altermatt HJ Schneppenheim R Stephani U \nParaneoplastic cerebellar degeneration in pediatric\nHodgkin disease . Neuropediatrics .\n2000 ;31 (1 ):42 –44 .10774996 \n28 \nHilberath JM SAchmidt H Wolf GK \nSteroid-responsive encephalopathy associated with\nautoimmune thyroiditis (SREAT): case report of reversible coma and status epilepticus in\nan adolescent patient and review of the literature . Eur J\nPediatr .\n2014 ;173 (10 ):1263 –1273 .25084973 \n29 \nOlmez I Moses H Sriram S Kirschner H Lagrange AH Pawate S \nDiagnostic and therapeutic aspects of Hashimoto’s\nencephalopathy . J Neuro Sci .\n2013 ;331 (1-2 ):67 –71 .\n30 \nAversa T Crisafulli G Zirilli G De Luca F Gallizzi R Valenzise M \nEpidemiological and clinical aspects of autoimmune thyroid\ndiseases in children with Down’s syndrome . Ital J\nPediatr .\n2018 ;44 (1 ):39 \ndoi:\n10.1186/s13052-018-0478-9 .29562915 \n31 \nPelajo CF Lopez-Benitez JM Miller LC \nVitamin D and autoimmune rheumatologic\ndisorders . Autoimmun Rev .\n2010 ;9 (7 ):507 –510 .20146942 \n32 \nHolick MF \nThe vitamin D deficiency pandemic: approaches for\ndiagnosis, treatment and prevention . Rev Endocr Metab\nDisord .\n2017 ;18 (2 ):153 –165 .28516265\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2329-048X",
"issue": "5()",
"journal": "Child neurology open",
"keywords": "ANNA-1 (Hu) syndrome; Down syndrome; OMS; PCA-1 syndrome; acute lymphoblastic leukemia; adrenocortical carcinoma; cytosine arabinoside-induced ataxia; pediatric neuroinflammatory disorders; pediatric paraneoplastic cerebellar degeneration",
"medline_ta": "Child Neurol Open",
"mesh_terms": null,
"nlm_unique_id": "101691975",
"other_id": null,
"pages": "2329048X18795546",
"pmc": null,
"pmid": "30288393",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "29306402;27606347;25435116;19523508;1648599;28516265;27424218;27957799;29103430;23759502;10774996;28710878;3585447;16444604;17408845;25084973;17645247;24342231;28796031;28651977;3470173;24424854;27095560;19838774;29562915;29460203;29258131;28991699;20146942;29299667;29555260;29318181",
"title": "Intensive Combination Immunotherapy and Neuroinflammation Resolution in a Child With Anti-PCA-1 (Yo) Paraneoplastic Syndrome and 2 Malignancies.",
"title_normalized": "intensive combination immunotherapy and neuroinflammation resolution in a child with anti pca 1 yo paraneoplastic syndrome and 2 malignancies"
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"abstract": "Background and Purpose: Fiducial marker placement is required in patients undergoing robotic-based Stereotactic Body Radiotherapy (SBRT) or image-guided radiation therapy (IGRT) for prostate cancer. Many patients take antiplatelet or anticoagulant medication due to other medical comorbidities. They are often required to temporarily discontinue these medications prior to invasive medical procedures as they are prone to bleed. Some patients are unable to discontinue therapy due to an elevated risk of thromboembolic events. The purpose of this study is to report this institution's experience placing fiducial markers in prostate cancer patients who are on chronic antiplatelet or anticoagulant medication. Materials and Methods: From August 2015-March 2019 57 patients on chronic antiplatelet or anticoagulation therapy who were not cleared to stop these medications underwent transrectal ultrasound guided (TRUS) fiducial marker placement for SBRT/IGRT. All patients were monitored by a registered nurse during the procedure for prolonged bleeding that required staff to hold pressure to the area with a 4 × 4 gauze until it resolved. All patients were also called the following day to assess for ongoing bleeding events. Treatment planning CT scan confirmed the ideal geometry of the marker placement. Results: All 57 patients on antiplatelet or anticoagulant medication who underwent fiducial marker placement were discharged home the same day of the procedure. Four patients experienced persistent bleeding that required a nurse to hold prolonged pressure to the area. No patient experienced significant bleeding the following day or any untoward cardiovascular event. Conclusions: This series suggests the use of antiplatelet or anticoagulant medication is not an absolute contraindication to fiducial marker placement in patients undergoing SBRT or IGRT for prostate cancer. These patients should be closely monitored after the procedure for bleeding complications. Practitioners may consider the patient's medical comorbidities, risk factors for thromboembolism, and overall functional status as there is no standardized protocol for discontinuing anticoagulant or antiplatelet therapy for fiducial marker placement.",
"affiliations": "Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States.;Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States.;Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States.;Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States.;Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States.;Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States.;Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States.;Department of Urology, NYU Winthrop Hospital, Mineola, NY, United States.;Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States.",
"authors": "Iocolano|Michelle|M|;Blacksburg|Seth|S|;Carpenter|Todd|T|;Repka|Michael|M|;Carbone|Susan|S|;Demircioglu|Gizem|G|;Miccio|Maryann|M|;Katz|Aaron|A|;Haas|Jonathan|J|",
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"doi": "10.3389/fonc.2020.00203",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.00203\nOncology\nOriginal Research\nProstate Fiducial Marker Placement in Patients on Anticoagulation: Feasibility Prior to Prostate SBRT\nIocolano Michelle 12 Blacksburg Seth 1 Carpenter Todd 1 Repka Michael 1 Carbone Susan 1 Demircioglu Gizem 1 Miccio Maryann 1 Katz Aaron 3 Haas Jonathan 1* 1Department of Radiation Oncology, NYU Winthrop Hospital, Mineola, NY, United States\n2Stony Brook University School of Medicine, Stony Brook, NY, United States\n3Department of Urology, NYU Winthrop Hospital, Mineola, NY, United States\nEdited by: Johnny Kao, Good Samaritan Hospital Medical Center, United States\n\nReviewed by: Amar Kishan, University of California, Los Angeles, United States; Angela G. M. O'Neill, Belfast Health and Social Care Trust, United Kingdom\n\n*Correspondence: Jonathan Haas jonathan.haas@nyulangone.orgThis article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology\n\n\n27 2 2020 \n2020 \n10 20312 10 2019 06 2 2020 Copyright © 2020 Iocolano, Blacksburg, Carpenter, Repka, Carbone, Demircioglu, Miccio, Katz and Haas.2020Iocolano, Blacksburg, Carpenter, Repka, Carbone, Demircioglu, Miccio, Katz and HaasThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background and Purpose: Fiducial marker placement is required in patients undergoing robotic-based Stereotactic Body Radiotherapy (SBRT) or image-guided radiation therapy (IGRT) for prostate cancer. Many patients take antiplatelet or anticoagulant medication due to other medical comorbidities. They are often required to temporarily discontinue these medications prior to invasive medical procedures as they are prone to bleed. Some patients are unable to discontinue therapy due to an elevated risk of thromboembolic events. The purpose of this study is to report this institution's experience placing fiducial markers in prostate cancer patients who are on chronic antiplatelet or anticoagulant medication.\n\nMaterials and Methods: From August 2015–March 2019 57 patients on chronic antiplatelet or anticoagulation therapy who were not cleared to stop these medications underwent transrectal ultrasound guided (TRUS) fiducial marker placement for SBRT/IGRT. All patients were monitored by a registered nurse during the procedure for prolonged bleeding that required staff to hold pressure to the area with a 4 × 4 gauze until it resolved. All patients were also called the following day to assess for ongoing bleeding events. Treatment planning CT scan confirmed the ideal geometry of the marker placement.\n\nResults: All 57 patients on antiplatelet or anticoagulant medication who underwent fiducial marker placement were discharged home the same day of the procedure. Four patients experienced persistent bleeding that required a nurse to hold prolonged pressure to the area. No patient experienced significant bleeding the following day or any untoward cardiovascular event.\n\nConclusions: This series suggests the use of antiplatelet or anticoagulant medication is not an absolute contraindication to fiducial marker placement in patients undergoing SBRT or IGRT for prostate cancer. These patients should be closely monitored after the procedure for bleeding complications. Practitioners may consider the patient's medical comorbidities, risk factors for thromboembolism, and overall functional status as there is no standardized protocol for discontinuing anticoagulant or antiplatelet therapy for fiducial marker placement.\n\nfiducial markersradiotherapyimage-guidedanticoagulantsprostate cancerSBRT\n==== Body\nIntroduction\nIn 2019, it is anticipated that prostate cancer will account for almost 20 percent of new cancer diagnoses in men (1). There are many options for treating localized prostate cancer. Stereotactic body radiation therapy (SBRT) allows precise delivery of a large dose of radiation to the prostate in one to five fractions with toxicity rates comparable to conventionally fractionated radiation (2–5). Placement of fiducial markers prior to radiotherapy is necessary for robotic-based SBRT to account for the six degrees of prostate motion during treatment and to prevent over- irradiation of normal surrounding tissue (6, 7). Fiducials are utilized in the majority of those treated with SBRT delivered with gantry-mounted linear accelerators although their role in platforms equipped with cone beam CT imaging is actively being debated (8).\n\nMany patients with prostate cancer eligible for SBRT are on chronic antiplatelet or anticoagulant medication for other medical comorbidities. Fiducial marker placement is an invasive procedure that confers an elevated risk for bleeding complications in these patients and several institutions require the temporary discontinuation of their medication prior to the procedure (6, 7, 9). For many patients, however, this is not feasible due an elevated risk of thromboembolic events. One potential alternative for patients who require active anticoagulation being treated on a unit with cone beam CT are prostatic calculi as they are prevalent in 85% of patients (10). To our knowledge, no study has assessed the feasibility of maintaining antiplatelet or anticoagulant medication prior to fiducial marker placement. The purpose of this study is to report a high-volume academic institution's experience placing fiducial markers for prostate SBRT in this patient population.\n\nMaterials and Methods\nPatient Population\nThis study was approved by the institutional review board at NYU Winthrop Hospital. From August 2015-March 2019, 57 patients with prostate cancer scheduled for fiducial marker placement and subsequent SBRT or image guided radiation therapy (IGRT) at NYU Winthrop Hospital were identified and consented to the study. Eligible patients included those on chronic antiplatelet or anticoagulant medication who were not cleared to stop their medication prior to fiducial marker placement. Antiplatelet medications included aspirin and clopidogrel. Anticoagulants included warfarin, heparin, apixaban, rivaroxaban, and dabigatran. There was no exclusion criteria and no patients declined to undergo fiducial marker placement. Fiducials were placed by three radiation oncologists. Nursing staff monitored all patients during the procedure to assess for prolonged bleeding from the perineum which required the use of sustained pressure to the area with a 4 × 4 gauze until it resolved. All patients were also called 1 day after the procedure to assess for persistent bleeding events.\n\nTreatment Technique\nStudy participants had four gold fiducial markers placed in the prostate transperineally with transrectal ultrasound guidance prior to SBRT/IGRT. Prior to marker placement, lidocaine gel, and EMLA cream were used to numb the perineum and rectum. Two needles were double loaded with two gold fiducial markers each with a spacer in between. The needles were inserted transperineally into the prostate. Two fiducial seeds were placed at the right and left base and two seeds were placed in the right and left apex. Following withdrawal of the ultrasound transducer and needle, nursing staff provided gentle pressure to the area and monitored patients for persistent bleeding. A treatment planning CT scan was used to confirm the ideal geometry of the marker placement. Patients were planned and treated as previously described (11).\n\nResults\nThe average age of the study population was 70.3 with a range of 54–83. All 57 patients who underwent fiducial marker placement were on antiplatelets or anticoagulation and discharged home on the same day of the procedure. Baseline patient characteristics are found in Table 1. As seen in Table 2, most patients were on a single antiplatelet agent (63.2%), followed by a single anticoagulant (17.5%), dual antiplatelet agents (17.5%), and triple anticoagulant/antiplatelet agents (1.8%) at the time of procedure. Medical comorbidities requiring the use of anticoagulation or antiplatelet medication are listed in Table 3. Coronary artery disease (56.1%) and primary prevention (17.5%) were most commonly reported.\n\nTable 1 Baseline patient characteristics.\n\n\tn =\t(%)\t\nClinical stage\t\n Tx\t3\t5.3\t\n T1c\t43\t75.4\t\n T2a\t2\t3.5\t\n T2b\t5\t8.8\t\n T2c\t1\t1.8\t\n T3a\t3\t5.3\t\n T3b\t0\t0\t\nPSA\tMean 9.08 ng/ml (3.0–48.0)\t\t\n <10 ng/ml\t39\t68.4\t\n 10–20 ng/ml\t16\t28.1\t\n >20 ng/ml\t2\t3.5\t\nGleason score\t\t\t\n 6 (3+3)\t10\t17.5\t\n 7 (3+4)\t21\t36.8\t\n 7 (4+3)\t14\t24.6\t\n 8–10\t12\t21.1\t\nNCCN risk stratification\t\t\t\n Low\t7\t12.3\t\n Intermediate\t36\t63.2\t\n High\t14\t24.6\t\nTable 2 Antiplatelet and anticoagulant medication.\n\n\tn =\t(%)\t\nSingle agent\t\nAntiplatelet\t\n Aspirin\t28\t49.1\t\n Clopidogrel\t8\t14.0\t\n Total\t36\t63.2\t\nAnticoagulant\t\n Warfarin\t3\t5.3\t\n Heparin\t3\t5.3\t\n Apixaban\t1\t1.8\t\n Rivaroxaban\t2\t13.5\t\n Dabigatran\t1\t1.8\t\n Total\t10\t17.5\t\nDual agent\t\t\t\n Aspirin + Plavix\t6\t1.5\t\n Apixaban + Plavix\t4\t7.0\t\n Total\t10\t17.5\t\nThree agents\t\t\t\n Aspirin + Apixaban + Clopidogrel\t1\t1.8\t\n Total\t1\t1.8\t\nTable 3 Patient comorbidities requiring use of anticoagulant or antiplatelets.\n\n\tn =\t(%)\t\nPulmonary embolism\t2\t3.5\t\nCoronary artery disease\t32\t56.1\t\nAtrial Fibrillation\t3\t5.3\t\nCerebral vascular accident\t2\t3.5\t\nPrimary prevention\t10\t17.5\t\nOther\t3\t8.8\t\nUnknown\t5\t5.3\t\nFour patients experienced transient CTCAE grade 1 bleeding at the time of fiducial placement requiring a registered nurse to provide sustained pressure on the perineum with a 4 × 4 gauze. Two of these patients took Aspirin 81 mg daily; one took Aspirin 162 mg daily; and one patient took Aspirin 81 mg, Eliquis 5 mg, and Plavix 75 mg daily. The following day, these patients reported via telephone they did not experience further bleeding events. No other significant bleeding or cardiovascular events in the peri-procedural window were reported. There were no cases of fiducial remediation in this cohort and all patients subsequently received definitive SBRT for their prostate malignancy without untoward medical event precluding completion of their prostate cancer treatment. No patient had signs or symptoms to indicate further bleeding on initiation of radiation treatment.\n\nDiscussion\nSBRT offers patients with low- to intermediate risk prostate cancer the convenience of a shortened treatment course with excellent local control rates and treatment toxicities comparable to other definitive radiation modalities. Patients who opt for fiducial marker placement and subsequent SBRT may also be on antiplatelet or anticoagulant regimens for other medical conditions. A review of the literature suggests patients may be required to temporarily discontinue their medication prior to fiducial placement (6, 7, 9, 12). For some patients this is not possible due to an elevated risk of thromboembolism. There is limited evidence to guide management in these patients with a theoretically increased risk of bleeding following fiducial marker placement.\n\nAt our institution, 57 patients on chronic antiplatelet or anticoagulant medication were not found to have significant bleeding events following the placement of fiducial markers for prostate SBRT. While four patients experienced bleeding at the time of procedure, it had resolved with no further complications as per patient report the following day. Similarly, Ihezue et al. suggest that patients on warfarin did not experience clinically significant hematuria, hematospermia or rectal bleeding within 10 days following transrectal ultrasound guided prostate biopsy when compared to those not on anticoagulants (13). While Saito et al. analogously found comparable bleeding risk in patients on anticoagulant or antiplatelet therapy and those who were not, patients on these medications were more likely to have clot retention and minor bleeding following biopsy. Notably, there was no report of significant bleeding events in any patient undergoing transrectal ultrasound guided biopsy (13, 14).\n\nWhile this is the first study to suggest that chronic antiplatelet or anticoagulant medication is not an absolute contraindication for seed placement, further research is required. The small sample size in this study may be insufficient to detect bleeding complications in the larger patient population eligible for this procedure and a prospective, randomized study with greater patient numbers could provide greater clarity on this topic. While there is no standardized protocol for discontinuing these medications in preparation for fiducial marker placement, practitioners must consider many clinical factors including overall risk of thromboembolism, functional status, other comorbidities prior to making a treatment decision.\n\nData Availability Statement\nAll datasets generated for this study are included in the article/supplementary material.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by NYU Winthrop Hospital IRB. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nMI and JH were responsible for the conception of this study. All authors contributed to the writing of this review, editing, and final approval prior to submission.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. JH and SB have received honoraria from Accuray.\n==== Refs\nReferences\n1. Siegel RL Miller KD Jemal A \nCancer statistics, 2019\n. CA Cancer J Clin . (2019 ) 69 :7 –34\n. 10.3322/caac.21551 30620402 \n2. Boyer MJ Papagikos MA Kiteley R Vujaskovic Z Wu J Robert Lee W . Toxicity and quality of life report of a phase II study of stereotactic body radiotherapy (SBRT) for low and intermediate risk prostate cancer\n. Radiat Oncol . (2017 ) 12 :14 . 10.1186/s13014-016-0758-8 28086825 \n3. Widmark A Gunnlaugsson A Beckman L Thellenberg-Karlsson C Hoyer M Lagerlund M . Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial\n. Lancet . (2019 ) 394 :385 –95\n. 10.1016/S0140-6736(19)31131-6 31227373 \n4. Kishan AU Dang A Katz AJ Mantz CA Collins SP Aghdam N . Long-term outcomes of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer\n. JAMA Netw Open . (2019 ) 2 :e188006 . 10.1001/jamanetworkopen.2018.8006 30735235 \n5. Brand DH Tree AC Ostler P van der Voet H Loblaw A Chu W . Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B):acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial\n. Lancet Oncol . (2019 ) 20 :1531 –43\n. 10.1016/S1470-2045(19)30569-8 31540791 \n6. Saad A Goldstein J Lawrence YR Weiss I Saad R Spieler B . Transperineal implantation of gold fiducial markers (gold seeds) for prostate image-guided radiation therapy: a feasible technique associated with a low risk of complications\n. J Med Radiat Sci . (2015 ) 62 :261 –6\n. 10.1002/jmrs.122 27512572 \n7. Gill S Li J Thomas J Bressel M Thursky K Styles C . Patient-reported complications from fiducial marker implantation for prostate image-guided radiotherapy\n. Br J Radiol . (2012 ). 85 :1011 –7\n. 10.1259/bjr/68127917 22253345 \n8. Njeh CF Parker BC Orton CG . Implanted fiducial markers are no longer needed for prostate cancer radiotherapy\n. Med Phys . (2017 ) 44 :6113 –6\n. 10.1002/mp.12633 29072317 \n9. Fawaz ZS Yassa M Nguyen DH Vavassis P . Fiducial marker implantation in prostate radiation therapy: complication rates and technique\n. Cancer Radiother . (2014 ). 18 :736 –9\n. 10.1016/j.canrad.2014.07.160 25451675 \n10. O'Neill AGM Osman SO Jain S Hounsell AR O'Sullivan JM \nObserved high incidence of prostatic calculi with the potential to act as natural fiducials for prostate image guided radiotherapy\n. Tech Innov Patient Suport Radiat Oncol . (2019 ) 9 :35 –40\n. 10.1016/j.tipsro.2019.01.004 \n11. Vu CC Haas JA Katz AE Witten MR . Prostate-specific antigen bounce following stereotactic body radiation therapy for prostate cancer\n. Front Oncol . (2014 ). 4 :8 . 10.3389/fonc.2014.00008 24478988 \n12. Kably I Bordegaray M Shah K Salsamendi J Narayanan G . Single-center experience in prostate fiducial marker placement: technique and midterm follow-up\n. J Vasc Interv Radiol . (2014 ). 25 :1125 –32\n. 10.1016/j.jvir.2014.03.017 24788207 \n13. Ihezue CU Smart J Dewbury KC Mehta R Burgess L . Biopsy of the prostate guided by transrectal ultrasound: relation between warfarin use and incidence of bleeding complications\n. Clin Radiol. (2005 ). 60 :459 –63\n; discussion: 457–8. 10.1016/j.crad.2004.10.014 15767103 \n14. Saito K Washino S Nakamura Y Konishi T Ohshima M Arai Y \nTransperineal ultrasound-guided prostate biopsy is safe even when patients are on combination antiplatelet and/or anticoagulation therapy\n. BMC Urol . (2017 ). 17 :53 \n10.1186/s12894-017-0245-z 28679384\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "10()",
"journal": "Frontiers in oncology",
"keywords": "SBRT; anticoagulants; fiducial markers; image-guided; prostate cancer; radiotherapy",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "203",
"pmc": null,
"pmid": "32175274",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "31227373;15767103;28679384;25451675;32095594;24478988;24788207;29072317;22253345;30620402;31540791;27512572;30735235;28086825",
"title": "Prostate Fiducial Marker Placement in Patients on Anticoagulation: Feasibility Prior to Prostate SBRT.",
"title_normalized": "prostate fiducial marker placement in patients on anticoagulation feasibility prior to prostate sbrt"
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