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"abstract": "OBJECTIVE\nAcne vulgaris is a chronic inflammatory disease affecting the pilosebaceous unit in the skin. Isotretinoin is a synthetic vitamin A derivative regarded as the most effective agent in the treatment of acne. There have recently been increasing reports of adverse effects of isotretinoin on the skeletal system. Our aim in this study was to evaluate the rheumatic side-effects triggered by this drug, and particularly the prevalence of sacroiliitis.\n\n\nMETHODS\nA total of 73 patients receiving isotretinoin due to moderate or severe acne vulgaris were included. All patients were questioned about inflammatory low back pain and musculoskeletal pains during the treatment process. Inflammatory low back pain was evaluated using Assessment of Spondyloarthritis International Society (ASAS) criteria. Patients meeting ASAS criteria were evaluated with radiography and when necessary with sacroiliac magnetic resonance.\n\n\nRESULTS\nThe dose range for isotretinoin was between 0.4 and 0.8 mg/kg/day (mean 0.53 mg/kg/day). Treatment lasted for 6-8 months (mean 6.8 months). Lethargy was determined in 37 (50.7%) patients, myalgia in 31 (42.5%) and low back pain in 36 (49.3%). Mechanical low back pain symptoms were present in 20 of the patients describing low back pain and inflammatory low back pain in 16. Acute sacroiliitis was determined in six patients (8.2%) following a sacroiliac magnetic resonance imaging (MRI). Five (83.3%) of the patients with sacroiliitis were female and one (16.7%) was male. No statistically significant difference was determined between male and female patients in terms of prevalence of sacroiliitis (p = 0.392).\n\n\nCONCLUSIONS\nThe incidence of sacroiliitis in patients using isotretinoin is quite high. Patients using isotretinoin must be questioned about sacroiliitis findings and must be subjected to advanced assessment when necessary. Further studies regarding the development of sacroiliitis under isotretinoin therapy are now needed.",
"affiliations": "a Dermatology Department, School of Medicine, Karadeniz Technical University , Trabzon , Turkey and.;a Dermatology Department, School of Medicine, Karadeniz Technical University , Trabzon , Turkey and.;b Physical Therapy and Rehabilitation Department, Maçka Ömer Burhanoğlu Physical Therapy and Rehabilitation Hospital , Trabzon , Turkey.;a Dermatology Department, School of Medicine, Karadeniz Technical University , Trabzon , Turkey and.;a Dermatology Department, School of Medicine, Karadeniz Technical University , Trabzon , Turkey and.",
"authors": "Baykal Selçuk|Leyla|L|;Aksu Arıca|Deniz|D|;Baykal Şahin|Hanife|H|;Yaylı|Savas|S|;Bahadır|Sevgi|S|",
"chemical_list": "D003879:Dermatologic Agents; D015474:Isotretinoin",
"country": "England",
"delete": false,
"doi": "10.1080/15569527.2016.1237521",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "36(2)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Acne vulgaris; isotretinoin; low back; pain; sacroiliitis",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000152:Acne Vulgaris; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D003879:Dermatologic Agents; D005260:Female; D006801:Humans; D015994:Incidence; D015474:Isotretinoin; D017116:Low Back Pain; D008279:Magnetic Resonance Imaging; D008297:Male; D010147:Pain Measurement; D015995:Prevalence; D011446:Prospective Studies; D011859:Radiography; D058566:Sacroiliitis; D012720:Severity of Illness Index; D055815:Young Adult",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "176-179",
"pmc": null,
"pmid": "27764978",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The prevalence of sacroiliitis in patients with acne vulgaris using isotretinoin.",
"title_normalized": "the prevalence of sacroiliitis in patients with acne vulgaris using isotretinoin"
} | [
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"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-143879",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
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"abstract": "I am a 24-year-old male who was diagnosed with chronic Lyme disease after 4 years of multiple, non-specific symptoms. I have written this case as first author with my faculty mentor listed as the coauthor. The objective of this report is to highlight the experience with doxycycline treatment. In 2007, at around age 19 years, I had an acute onset of sore throat, tonsillitis, low-grade fever, stiff upper back and neck muscles, migraines and severely stiff, cracking jaw joints. This led to >24 medical visits, multitudes of tests and examinations, and exploratory surgery over the next 3 years. In 2011, a Lyme-literate medical doctor (LLMD) diagnosed me with chronic Lyme disease. I started taking doxycycline 100 mg by mouth every 12 hours, leading to atypical sequences of events deemed a Jarisch-Herxheimer reaction by a LLMD. This case highlights the unique clinical expression of chronic Lyme disease and the Jarisch-Herxheimer response to doxycycline.",
"affiliations": "Ohio State University, Columbus, Ohio, USA.;College of Pharmacy, Ohio State University, Columbus, Ohio, USA.",
"authors": "Haney|Chad|C|;Nahata|Milap C|MC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004318:Doxycycline",
"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": "D000328:Adult; D000900:Anti-Bacterial Agents; D002908:Chronic Disease; D003866:Depressive Disorder; D003967:Diarrhea; D004318:Doxycycline; D005207:Fasciculation; D005334:Fever; D006261:Headache; D006801:Humans; D008193:Lyme Disease; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27440843",
"pubdate": "2016-07-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8006888;21648354;15581390;15928636;17412541;20012878;8248757;12715663;7793869;3056201;17113969;9610974;659915;15730009;3581911;8085687",
"title": "Unique expression of chronic Lyme disease and Jarisch-Herxheimer reaction to doxycycline therapy in a young adult.",
"title_normalized": "unique expression of chronic lyme disease and jarisch herxheimer reaction to doxycycline therapy in a young adult"
} | [
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"companynumb": "US-PFIZER INC-2016383354",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "BIFIDOBACTERIUM ANIMALIS SUBSP. LACTIS"
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"abstract": "Primary angiosarcoma of the breast is a highly aggressive but rare malignant neoplasm. Palliative chemotherapy with different agents and combinations has been tried in the metastatic setting with poor results. We present the case of a young woman with this disease describing her aggressive course. We used a metronomic combination of oral drugs due to her poor general condition and achieved disease stabilization although not durable.",
"affiliations": "Department of Medical Oncology, BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India.;Department of Medical Oncology, BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India.;Department of Medical Oncology, BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India.;Department of Medical Oncology, BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Pramanik|Raja|R|;Gogia|Ajay|A|;Malik|Prabhat Singh|PS|;Gogi|Ramana|R|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.4103/ijmpo.ijmpo_156_16",
"fulltext": "\n==== Front\nIndian J Med Paediatr OncolIndian J Med Paediatr OncolIJMPOIndian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology0971-58510975-2129Medknow Publications & Media Pvt Ltd India IJMPO-38-22810.4103/ijmpo.ijmpo_156_16Case ReportMetastatic Primary Angiosarcoma of the Breast: Can We Tame It the Metronomic Way Pramanik Raja Gogia Ajay Malik Prabhat Singh Gogi Ramana Department of Medical Oncology, BRA-IRCH, All India Institute of Medical Sciences, New Delhi, IndiaAddress for correspondence: Dr. Ajay Gogia, Department of Medical Oncology, BRA-IRCH, All India Institute of Medical Sciences, New Delhi, India. E-mail: ajaygogia@gmail.comApr-Jun 2017 38 2 228 231 Copyright: © 2017 Indian Journal of Medical and Paediatric Oncology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Primary angiosarcoma of the breast is a highly aggressive but rare malignant neoplasm. Palliative chemotherapy with different agents and combinations has been tried in the metastatic setting with poor results. We present the case of a young woman with this disease describing her aggressive course. We used a metronomic combination of oral drugs due to her poor general condition and achieved disease stabilization although not durable.\n\nAngiosarcomametronomicpropranolol\n==== Body\nIntroduction\nAngiosarcoma of the breast may be primary or secondary to lymphedema or radiation. Pregnancy-related angiosarcoma is rarer. This disease follows an aggressive malignant course, and the relapsing metastatic disease is a nightmare for a medical oncologist. We present here the case of a young female with pregnancy-associated angiosarcoma who progressed while on adjuvant treatment and could be stabilized on oral metronomic chemotherapy in combination with a nonspecific beta-adrenergic blocker propranolol although the response did not remain durable.\n\nCase Report\nA 36-year-old female presented during the third trimester of her pregnancy with a progressive lump in her left breast. A trucut biopsy showed features of angiosarcoma of the breast. She delivered a healthy baby and underwent a modified radical mastectomy. It was a 10 cm mass with 1/15 LN+. Adjuvant postoperative radiotherapy was given 60 Gy/30#/6 weeks. In view of its high-risk behavior, adjuvant paclitaxel was planned in weekly fashion.\n\nDuring her adjuvant chemotherapy, on d15, she presented with progressive abdominal distension, bipedal edema, jaundice, and dyspnea on exertion.\n\nClinically, she was pale, icteric, had bilateral pedal edema and dullness on percussion at the left base. Her Eastern Cooperative Oncology Group performance status (PS) was 3. She had a hemoglobin of 4.3 g/dl, total leukocyte count 14,100/mm3, platelet 135,000/mm3. Serum creatinine was 0.5 mg/dl. Serum bilirubin was 4.46 mg/dl (conjugated = 2.49 mg/dl). Serum albumin = 2.54 g/dl, aspartate aminotransferase/alanine aminotransferase = 128/82 U/L, serum alkaline phosphatase = 759 U/L. On evaluation, her positron emission tomography computed tomography (CT) scan showed left-sided pleural effusion with passive collapse of left lower lobe, no ascites, but multiple hypodense nodules (largest 10 cm) in an enlarged liver [Figure 1]. There were no significant uptake on FDG -PET Scan or DOTANOC -PET Scan. There were no intrahepatic biliary radicle dilatation. There were ill-defined lytic lesions in multiple visualized bones.\n\nFigure 1 Computed tomography scan of abdomen of the patient in June 2015, showing multiple large hypodense nodules of metastatic angiosarcoma in both lobes of liver\n\nBiopsy from the liver nodules showed features of angiosarcoma. However, pleural fluid cytology was negative for malignancy.\n\nOn evaluating the cause of her anemia, her iron profile was normal (serum transferrin = 283, total iron-binding capacity = 333, transferrin saturation = 18.62%, serum ferritin = 1636.57). Peripheral smear showed a leukoerythroblastic picture with myelocytes, nucleated red blood cell (RBC), and tear drop RBCs (N75 L9M5Myelo5 nRBC7). The bone marrow biopsy showed infiltration with tumor cells, CD31+ve.\n\nHence, the final diagnosis made was metastatic angiosarcoma of the breast (liver, bone marrow, pleural fluid) with anemia, conjugated hyperbilirubinemia, and hypoalbuminemia.\n\nIn view of her poor PS and disseminated disease, and progression on paclitaxel chemotherapy, her family was counseled and after discussing the benefits and risks, a decision of palliative oral metronomic chemotherapy was taken along with supportive care.\n\nShe was started on oral thalidomide 200 mg daily, capsule celecoxib 400 mg twice a day, and alternating cycles of oral etoposide (50 mg daily 3 weeks on 3 weeks off) and oral cyclophosphamide (100 mg daily 3 weeks on 3 weeks off). Added to this regimen was oral propranolol sustained release tablet 40 mg BD. She also received zoledronic acid 4 mg intravenous monthly.\n\nWe thought of the above regimen as a rational one because this regimen has been used as an antiangiogenic metronomic regimen in different studies as well as in our institution. Raina et al. had reported the successful use of thalidomide in the treatment of radiation-induced angiosarcoma.[1] Oral propranolol was recently reported by Banavali et al. to be an effective agent along with metronomic chemotherapy for advanced stage angiosarcoma.[2]\n\nAfter 1 month of therapy, a contrast-enhanced CT (CECT) chest, abdomen, and pelvis was done for response assessment, which showed a stable disease as compared to the baseline CT.\n\nHer transfusion requirement decreased significantly over the next 2 months. Her PS improved from 3 to 1, dyspnea resolved, and she was now ambulatory.\n\nShe developed Grade II neutropenia at the 4th week for which she received two injections of granulocyte-colony stimulating factor, and her dose of etoposide and cyclophosphamide was reduced by 50%.\n\nShe was on close follow-up in the outpatient department. At 2-month follow-up, she complained of some puffiness over her face and fatigue. Her hemoglobin was 8.9 g/dl, and she had not required transfusion for a month. A CECT was repeated which now showed extensive hepatic and skeletal metastases with the appearance of three new pulmonary nodular metastases and new hepatic nodules and ascites. There was a new metastatic lesion involving bilateral sphenoid sinuses with extradural component in the middle cranial fossa. This suggested a progressive disease on the metronomic oral chemotherapy.\n\nWe planned a palliative radiotherapy to the sphenoid lesion and changed her therapy to doxorubicin 30 mg/m2 q3 weekly and continued thalidomide and propranolol. However, her condition deteriorated with progressive disease, and she succumbed to her illness on September 29, 2015.\n\nDiscussion\nThis patient with pregnancy-associated angiosarcoma of the breast had a rapid progression while on adjuvant therapy. Her disease was extensive involving liver, bones, and bone marrow. She derived some significant clinical improvement from the oral metronomic regimen but progressed after 2 months with new sites of disease.\n\nThis case report captures the aggressive course of this rare malignancy. Metronomic chemotherapy can significantly improve these patients’ clinical status and quality of life without much toxicity, but responses are not as durable.\n\nBreast angiosarcoma can be observed as a primary neoplasm or, more commonly, is described in upper limb lymphedema as a result of mastectomy and radiotherapy for breast carcinoma.[3] Primary angiosarcoma of the breast constitutes 0.04% of all malignant breast neoplasms. Both primary and secondary breast angiosarcomas have a prognosis inferior to mammary carcinoma.[4] The first documented case of breast angiosarcoma was presented by Borrman in 1907.[5]\n\nDifferent from breast carcinomas, primary angiosarcoma of the breast occurs sporadically in young women, usually during the third and fourth decades of life. Between 6% and 12% of primary breast, angiosarcomas are diagnosed during pregnancy or shortly after, suggesting hormones involvement, but hormone receptor positivity is rare making it impossible to assign a link between estrogen dependency and angiosarcoma. In most published cases, breast angiosarcoma is presented as a palpable mass, without pain and with a fast growing rate.[67] Bluish skin discoloration occurs in up to a third of patients and is thought to be attributable to the vascular nature of the tumor. Radiographically, breast angiosarcomas exhibit no pathognomonic features. Tumors smaller than 5 cm are usually associated to a better prognosis, even in the presence of worsening factors. Pathologically, these tumors are subdivided into three grades according to the classification proposed by Donnell et al.[8] The degree of differentiation has a significant prognostic value, with regard to both local failure and metastases. The endothelial cells show reactivity for several markers, including CD31, CD34, and von Willebrand factor (factor VIII). Among them, CD31 is considered the most sensitive and most specific endothelial cell marker.[9] Differential diagnosis of this rare tumor include benign hemangioma, phyllodes sarcoma, stromal sarcoma, metaplastic carcinoma, fibrosarcoma, liposarcoma, squamous cell carcinoma with sarcomatoid features, myoepithelioma, fibromatosis, reactive spindle cell proliferative lesion, and high-grade mammary carcinoma, especially in small biopsy specimens containing only solid areas.\n\nSurgery is the principal mode of treatment for primary angiosarcoma of the breast and generally consists of a total mastectomy.[10] Hematogenous dissemination is the rule, making axillary lymph node dissection unnecessary. Adjuvant radiation therapy should be administered especially when the margins of resection are microscopically involved after definitive surgical treatment. There was no statistical correlation of adjuvant radiation therapy with survival in the study, due to the small number of patients and the retrospective nature of the study. However, patients at high risk of recurrence (with large, high-grade tumors) may benefit from adjuvant treatment with improved local control and disease-free survival.[10] Studies examining the efficacy of adjuvant chemotherapy are lacking, due in part to the low incidence of breast angiosarcomas. One retrospective study revealed that 36% of patients with primary angiosarcoma received chemotherapy in an adjuvant or neoadjuvant setting.[11]\n\nSher et al. reported that adjuvant chemotherapy using an anthracycline and ifosfamide or gemcitabine and a taxane did not significantly improve recurrence-free survival compared with patients who did not receive chemotherapy (38 vs. 31 patients; hazard ratio, 0.47; P = 0.11). However, administration of chemotherapy at the time of recurrence resulted in a 48% response rate.[12] In the case of secondary angiosarcomas induced by radiation treatment, docetaxel showed promise in patients that were refractory to anthracycline-based chemotherapy.[13] Bevacizumab, the anti-vascular endothelial growth factor antibody, has been used as treatment for angiosarcomas, but the results have been variable.\n\nRelapsed metastatic angiosarcoma is a challenge for medical oncologists. Neither standard maximum tolerated dose chemotherapy nor targeted agents has yielded good and durable responses. Options for chemotherapy in metastatic angiosarcoma include doxorubicin, liposomal doxorubicin, paclitaxel, docetaxel, and bevacizumab.\n\nSeveral case reports[1415] and small case series[1617] have documented durable benefits of metronomic chemotherapy in relapsing angiosarcoma. Vogt et al. in their pilot study reported the use of a combination of trophosphamide, pioglitazone, and rofecoxib in advanced vascular malignancies. They reported two complete responses, one partial response, and three stable diseases with a median progression-free survival of 7.7 months.\n\nRecently, beta-blockers have been reported to have anticancer effects in many tumors.[18] The anticancer effects of beta-blockers on angiosarcoma in vivo and in vitro have also been published.[19] Significant expression of beta-adrenergic receptors have also been reported in several types of vascular tumors.[20] Pasquier et al.[2122] have reported synergy between chemotherapy and beta-blockers in breast cancer and neuroblastoma. Recently, Banavali et al. have reported a durable complete remission of a relapsing metastatic angiosarcoma with a three-drug metronomic regimen and propranolol.[2] All these evidence suggest that propranolol may also have contributed to the response we observed in this patient.\n\nConclusion\nPregnancy-associated primary angiosarcoma of the breast is an extremely rare and aggressive soft-tissue malignant tumor. The findings of this case report are of extreme significance. With this case, the combination of metronomic chemotherapy and propranolol in angiosarcoma warrants additional studies.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Raina V Sengar M Shukla NK Deo SS Mohanty BK Sharma D Complete response from thalidomide in angiosarcoma after treatment of breast cancer J Clin Oncol 2007 25 900 1 17327613 \n2 Banavali S Pasquier E Andre N Targeted therapy with propranolol and metronomic chemotherapy combination: Sustained complete response of a relapsing metastatic angiosarcoma Ecancermedicalscience 2015 9 499 25624880 \n3 Armah HB Rao UN Parwani AV Primary angiosarcoma of the testis: Report of a rare entity and review of the literature Diagn Pathol 2007 2 23 17601346 \n4 Babarovic E Zamolo G Mustac E Strcic M High grade angiosarcoma arising in fibroadenoma Diagn Pathol 2011 6 125 22185665 \n5 Borrman R Metastasis in histologic benign tumors: Case of metastasizing angioma Beitr Pathol Anat 1907 40 372 93 \n6 Johnson CM Garguilo GA Angiosarcoma of the breast: A case report and literature review Curr Surg 2002 59 490 4 15727796 \n7 Georgiannos SN Sheaff M Angiosarcoma of the breast: A 30 year perspective with an optimistic outlook Br J Plast Surg 2003 56 129 34 12791356 \n8 Donnell RM Rosen PP Lieberman PH Kaufman RJ Kay S Braun DW Jr Angiosarcoma and other vascular tumors of the breast Am J Surg Pathol 1981 5 629 42 7199829 \n9 Bennani A Chbani L Lamchahab M Wahbi M Alaoui FF Badioui I Primary angiosarcoma of the breast: A case report Diagn Pathol 2013 8 66 23607567 \n10 Kaklamanos IG Birbas K Syrigos KN Vlachodimitropoulos D Goutas N Bonatsos G Breast angiosarcoma that is not related to radiation exposure: A comprehensive review of the literature Surg Today 2011 41 163 8 21264749 \n11 Rosen PP Kimmel M Ernsberger D Mammary angiosarcoma. The prognostic significance of tumor differentiation Cancer 1988 62 2145 51 3179927 \n12 Sher T Hennessy BT Valero V Broglio K Woodward WA Trent J Primary angiosarcomas of the breast Cancer 2007 110 173 8 17541936 \n13 Mano MS Fraser G Kerr J Gray M Evans V Kazmi A Radiation-induced angiosarcoma of the breast shows major response to docetaxel after failure of anthracycline-based chemotherapy Breast 2006 15 117 8 16473744 \n14 Sumikawa Y Inui S Nishimura Y Morita E Kurachi K Long-term metronomic docetaxel chemotherapy for inoperative angiosarcoma of the scalp J Dermatol 2011 38 393 5 21352341 \n15 Kopp HG Kanz L Hartmann JT Complete remission of relapsing high-grade angiosarcoma with single-agent metronomic trofosfamide Anticancer Drugs 2006 17 997 8 16940811 \n16 Vogt T Hafner C Bross K Bataille F Jauch KW Berand A Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors Cancer 2003 98 2251 6 14601096 \n17 Mir O Domont J Cioffi A Bonvalot S Boulet B Le Pechoux C Feasibility of metronomic oral cyclophosphamide plus prednisolone in elderly patients with inoperable or metastatic soft tissue sarcoma Eur J Cancer 2011 47 515 9 21251814 \n18 Tang J Li Z Lu L Cho CH β-Adrenergic system, a backstage manipulator regulating tumour progression and drug target in cancer therapy Semin Cancer Biol 2013 23 6 Pt B 533 42 24012659 \n19 Stiles JM Amaya C Rains S Diaz D Pham R Battiste J Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angiosarcoma PLoS One 2013 8 e60021 23555867 \n20 Chisholm KM Chang KW Truong MT Kwok S West RB Heerema-McKenney AE β-Adrenergic receptor expression in vascular tumors Mod Pathol 2012 25 1446 51 22743651 \n21 Pasquier E Street J Pouchy C Carre M Gifford AJ Murray J β-blockers increase response to chemotherapy via direct antitumour and anti-angiogenic mechanisms in neuroblastoma Br J Cancer 2013 108 2485 94 23695022 \n22 Pasquier E Ciccolini J Carre M Giacometti S Fanciullino R Pouchy C Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: Implication in breast cancer treatment Oncotarget 2011 2 797 809 22006582\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-5851",
"issue": "38(2)",
"journal": "Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology",
"keywords": "Angiosarcoma; metronomic; propranolol",
"medline_ta": "Indian J Med Paediatr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9604571",
"other_id": null,
"pages": "228-231",
"pmc": null,
"pmid": "28900339",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "16940811;23555867;17541936;21251814;22743651;21264749;16473744;23695022;12791356;23607567;21352341;7199829;22185665;25624880;3179927;24012659;17601346;22006582;17327613;14601096;15727796",
"title": "Metastatic Primary Angiosarcoma of the Breast: Can We Tame It the Metronomic Way.",
"title_normalized": "metastatic primary angiosarcoma of the breast can we tame it the metronomic way"
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"abstract": "Some patients with severe mental disorders are refractory to psychotherapeutic or psychopharmacological interventions. We describe a patient with severe symptoms from the age of 16 to 44. Her illness is best described as a schizo-affective disorder. Several series of electroconvulsive therapy (ECT) followed by maintenance once a week for more than six years has kept her out of hospital beds for three years. The patient demonstrates the feasibility of long term ECT and the absence of disturbing cognitive reductions.",
"affiliations": "Oslo and Akershus University College, Faculty of Health Sciences, Oslo, Norway.",
"authors": "Berg|John E|JE|",
"chemical_list": null,
"country": "England",
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"doi": "10.4081/mi.2012.e20",
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"issue": "4(2)",
"journal": "Mental illness",
"keywords": "cognition; electroconvulsive treatment; schizoaffective disorder.; side effects",
"medline_ta": "Ment Illn",
"mesh_terms": null,
"nlm_unique_id": "101634942",
"other_id": null,
"pages": "e20",
"pmc": null,
"pmid": "25478121",
"pubdate": "2012-07-26",
"publication_types": "D016428:Journal Article; D016454:Review",
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"title": "Intractable schizo-affective disorder successfully treated with electroconvulsive treatment over six years.",
"title_normalized": "intractable schizo affective disorder successfully treated with electroconvulsive treatment over six years"
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{
"abstract": "Although the risk of bleeding after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is low, the safety of EUS-FNA in patients prescribed antithrombotic agents is unclear. Therefore, this study evaluated the incidence of bleeding after EUS-FNA in those patients.\nBetween September 2012 and September 2015, patients who were prescribed antithrombotic agents underwent EUS-FNA at 13 institutions in Japan were prospectively enrolled in the study. The antithrombotic agents were managed according to the guidelines of the Japanese Gastrointestinal Endoscopy Society. The rate of bleeding events, thromboembolic events and other complications within 2 weeks after EUS-FNA were analyzed.\nOf the 2,629 patients who underwent EUS-FNA during the study period, 85 (62 males; median age, 74 years) patients were included in this stduy. Two patients (2.4%; 95% confidence interval [CI], 0.6% to 8.3%) experienced bleeding events. One patient required surgical intervention for hemothorax 5 hours after EUS-FNA, and the other experienced melena 8 days after EUS-FNA and required red blood cell transfusions. No thromboembolic events occurred (0%; 95% CI, 0.0% to 4.4%). Three patients (3.5%; 95% CI, 1.2% to 10.0%) experienced peri-puncture abscess formation.\nThe rate of bleeding after EUS-FNA in patients prescribed antithrombotic agents might be considerable.",
"affiliations": "Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.;Department of Gastroenterology, Tomakomai City Hospital, Tomakomai, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Japanese Red Cross Kitami Hospital, Kitami, Japan.;Department of Gastroenterology, NTT East Sapporo Hospital, Sapporo, Japan.;Department of Gastroenterology, Obihiro Kosei Hospital, Obihiro, Japan.;Department of Gastroenterology, Keiwakai Ebetsu Hospital, Ebetsu, Japan.;Department of Gastroenterology and Hepatology, Hakodate City Hospital, Hakodate, Japan.;Department of Gastroenterology, Kushiro Rosai Hospital, Kushiro, Japan.;Department of Gastroenterology, NTT East Sapporo Hospital, Sapporo, Japan.;Department of Gastroenterology, Oji General Hospital, Tomakomai, Japan.;Department of Gastroenterology, National Hospital Organization Hokkaido Medical Center, Sapporo, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.;Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University, Sapporo, Japan.;Department of Medical Oncology and Hematology, Sapporo Medical University, Sapporo, Japan.;Department of Gastroenterology, Japanese Red Cross Kitami Hospital, Kitami, Japan.;Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.",
"authors": "Kawakubo|Kazumichi|K|;Yane|Kei|K|;Eto|Kazunori|K|;Ishiwatari|Hirotoshi|H|;Ehira|Nobuyuki|N|;Haba|Shin|S|;Matsumoto|Ryusuke|R|;Shinada|Keisuke|K|;Yamato|Hiroaki|H|;Kudo|Taiki|T|;Onodera|Manabu|M|;Okuda|Toshinori|T|;Taya-Abe|Yoko|Y|;Kawahata|Shuhei|S|;Kubo|Kimitoshi|K|;Kubota|Yoshimasa|Y|;Kuwatani|Masaki|M|;Kawakami|Hiroshi|H|;Katanuma|Akio|A|;Ono|Michihiro|M|;Hayashi|Tsuyoshi|T|;Uebayashi|Minoru|M|;Sakamoto|Naoya|N|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Korea (South)",
"delete": false,
"doi": "10.5009/gnl17293",
"fulltext": "\n==== Front\nGut LiverGut LiverGut and Liver1976-22832005-1212Editorial Office of Gut and Liver 2940930810.5009/gnl17293gnl-12-353Original ArticleA Prospective Multicenter Study Evaluating Bleeding Risk after Endoscopic Ultrasound-Guided Fine Needle Aspiration in Patients Prescribed Antithrombotic Agents Kawakubo Kazumichi 1Yane Kei 2Eto Kazunori 3Ishiwatari Hirotoshi 4Ehira Nobuyuki 5Haba Shin 67Matsumoto Ryusuke 8Shinada Keisuke 9Yamato Hiroaki 10Kudo Taiki 710Onodera Manabu 611Okuda Toshinori 12Taya-Abe Yoko 13Kawahata Shuhei 1Kubo Kimitoshi 1Kubota Yoshimasa 1Kuwatani Masaki 1Kawakami Hiroshi 1Katanuma Akio 2Ono Michihiro 4Hayashi Tsuyoshi 4Uebayashi Minoru 5Sakamoto Naoya 1\n1 Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, \nJapan\n2 Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, \nJapan\n3 Department of Gastroenterology, Tomakomai City Hospital, Tomakomai, \nJapan\n4 Department of Medical Oncology and Hematology, Sapporo Medical University, Sapporo, \nJapan\n5 Department of Gastroenterology, Japanese Red Cross Kitami Hospital, Kitami, \nJapan\n6 Department of Gastroenterology, NTT East Sapporo Hospital, Sapporo, \nJapan\n7 Department of Gastroenterology, Kushiro Rosai Hospital, Kushiro, \nJapan\n8 Department of Gastroenterology, Obihiro Kosei Hospital, Obihiro, \nJapan\n9 Department of Gastroenterology, Keiwakai Ebetsu Hospital, Ebetsu, \nJapan\n10 Department of Gastroenterology and Hepatology, Hakodate City Hospital, Hakodate, \nJapan\n11 Department of Gastroenterology, Abashiri Kosei Hospital, Abashiri, \nJapan\n12 Department of Gastroenterology, Oji General Hospital, Tomakomai, \nJapan\n13 Department of Gastroenterology, National Hospital Organization Hokkaido Medical Center, Sapporo, \nJapanCorrespondence to: Kazumichi Kawakubo, Department of Gastroenterology and Hepatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15 Nishi 7, Kita-ku, Sapporo 060-8638, Japan, Tel: +81-117161161, Fax: +81-117067867, E-mail: kkawakubo-gi@umin.ac.jp5 2018 08 2 2018 12 3 353 359 05 7 2017 08 9 2017 20 9 2017 Copyright © 2018 by The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background/Aims\nAlthough the risk of bleeding after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is low, the safety of EUS-FNA in patients prescribed antithrom-botic agents is unclear. Therefore, this study evaluated the incidence of bleeding after EUS-FNA in those patients.\n\nMethods\nBetween September 2012 and September 2015, patients who were prescribed antithrombotic agents underwent EUS-FNA at 13 institutions in Japan were prospectively enrolled in the study. The antithrombotic agents were managed according to the guidelines of the Japanese Gastrointestinal Endoscopy Society. The rate of bleeding events, thromboembolic events and other complications within 2 weeks after EUS-FNA were analyzed.\n\nResults\nOf the 2,629 patients who underwent EUS-FNA during the study period, 85 (62 males; median age, 74 years) patients were included in this stduy. Two patients (2.4%; 95% confidence interval [CI], 0.6% to 8.3%) experienced bleeding events. One patient required surgical intervention for hemothorax 5 hours after EUS-FNA, and the other experienced melena 8 days after EUS-FNA and required red blood cell transfusions. No thromboembolic events occurred (0%; 95% CI, 0.0% to 4.4%). Three patients (3.5%; 95% CI, 1.2% to 10.0%) experienced peri-puncture abscess formation.\n\nConclusions\nThe rate of bleeding after EUS-FNA in patients prescribed antithrombotic agents might be considerable.\n\nEndoscopic ultrasound-guided fine needle aspirationHemorrhageFibrinolytic agents\n==== Body\nINTRODUCTION\nEndoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is the most reliable method for the histological diagnosis of pancreatic and gastrointestinal submucosal tumors, as well as mediastinal and abdominal lymphadenopathies.1–3 The rate of overall EUS-FNA specific morbidity has been reported to be 0.98%.4 Major adverse events after EUS-FNA include postprocedure pain, pancreatitis, bleeding and fever.\n\nThe number of patients taking antithrombotic agents to prevent thromboembolic events is increasing.5,6 For example, 10.5% of patients in Japan undergoing endoscopic mucosal biopsy were taking antithrombotic agents.7 Guidelines have recommended that antithrombotic agents be managed in patients undergoing endoscopic procedures, based on a balance between the risk of bleeding associated with the procedure and the risk of thrombotic events associated with the underlying condition. Guidelines of the American Society of Gastrointestinal Endoscopy and the Japanese Society of Gastrointestinal Endoscopy (JSGE) have regarded EUS-FNA as having a high risk of bleeding, whereas the guidelines of the European Society of Gastrointestinal Endoscopy regard this procedure as having a low risk of bleeding.8–10 Only one study to date has evaluated the safety of EUS-FNA in patients taking aspirin, but that was a single-center study performed in a relatively small number of patients.11 We hypothesized that bleeding risk after EUS-FNA would be low among patients taking antithrombotic agents, but there have been no reports about the safety of EUS-FNA in patients taking other antiplatelet agents and/or anticoagulants. This study therefore analyzed the safety of EUS-FNA among patients taking antithrombotic agents, including antiplatelet and anticoagulant agents.\n\nMATERIALS AND METHODS\n1. Study design\nThis prospective, multicenter study enrolled patients taking antithrombotic agents who underwent EUS-FNA in accordance with Japanese guidelines between September 2012 and September 2015 at 13 institutions in Japan. Indications for EUS-FNA were basically determined by European Society of Gastrointestinal Endoscopy guidelines.12 This study was approved by the Institutional Review Board of each hospital and registered at www.ClinicalTrials.gov (NCT01798654). All authors had access to the study data and reviewed and approved the final manuscript.\n\n2. Patients\nPatients were included if they were older than 20 years, were at high risk of thrombotic events according to the guidelines of the JGES,8 and provided written informed consent to be enrolled in this study. Patients were excluded if they had pancreatic cystic lesions, a platelet count <50,000/m3, an American Society of Anesthesiologists Physical Status Classification System score >3 or an Eastern Cooperative Oncology Group performance status of 4. Written informed consent was obtained from each patient prior to EUS-FNA.\n\n3. Management of antithrombotic agents\nBefore EUS-FNA, antithrombotic agents were managed according to modified JSGE guidelines.8 Aspirin was continued throughout the procedure. Thienopyridines were discontinued for 5 days and replaced with aspirin. Antiplatelet agents other than thienopyridines were discontinued for 1 day. Warfarin was discontinued for 3 days and non-vitamin K antagonist oral anticoagulants (NOAC) were discontinued for 2 days, with both replaced by intravenous heparin (10,000 to 20,000 units/day). Intravenous heparin was stopped 3 hours before EUS-FNA, restarted 1 day later and maintained until the international normalized ratio (INR) reached its therapeutic range (1.5 to 2.5). All antithrombotics were resumed 1 day after EUS-FNA. In patients taking NOACs, however, heparin was not re-administered after EUS-FNA.\n\n4. EUS-FNA procedure and follow-up\nEUS-FNA was performed in a standard manner, using a standard EUS-FNA needle and negative pressure suction, in an inpatient setting by endoscopists with experience performing more than 50 EUS-FNAs. The selection of needle size and the number of punctures was at the discretion of each endoscopist. After EUS-FNA, the patient was discharged and followed-up for 2 weeks.\n\n5. Outcome measurements\nThe primary outcome measure was the rate of bleeding complication within 2 weeks. Patients with melena or other symptoms suggesting bleeding events underwent upper gastrointestinal endoscopy or other imaging examinations to confirm the bleeding site. Otherwise, patients were interviewed at the outpatient clinic or by telephone about the presence of melena or other symptoms 2 weeks after EUS-FNA, thus eliminating attrition bias. The grading and severity of bleeding complications were defined by the American Society of Gastrointestinal Endoscopy guidelines.13 Secondary outcome measures included the rates of thromboembolic and other adverse events and the histopathological diagnosis of EUS-FNA.\n\n6. Sample size calculation\nThe incidence of bleeding after EUS-FNA was estimated at 1.0%.4 Calculations showed that a sample size of 300 patients was required to detect a bleeding rate of 1%, in accordance with the rule of three.\n\n7. Statistical analysis\nCategorical variables were described as proportions and continuous variables as medians and ranges. The rates of bleeding complications, thromboembolic events and other complications were calculated, along with their 95% confidence intervals (CIs). All statistical analyses were performed using JMP version 11 (SAS Institute Inc., Cary, NC, USA).\n\nRESULTS\n1. Patient characteristics\nDuring the study period, 2,629 patients underwent EUS-FNA for solid lesions; among these, 120 patients (4.6%) were taking antithrombotic agents (Fig. 1). Eighty-seven patients were deemed at high risk for thrombotic events according to JSGE guidelines and included in this study. After excluding two patients, one with a high American Society of Anesthesiologists score and the other who refused consent, 85 patients were included in this study (Table 1). Their median age was 74 years (range, 40 to 85 years) and 62 patients (72.9%) were male. Median platelet count was 195×103/mm3 (range, 57 to 370×103/ mm3), and median INR before EUS-FNA was 1.09 (range, 0.90 to 1.66). Numbers of antithrombotic agents taken by patients are shown in Table 1 and the reasons for antithrombotic agents in Table 2. Fifty-one patients (60.0%) were each taking a single antithrombotic agent, whereas 28 (32.9%) and six (7.1%) patients were taking two and three antithrombotic agents, respectively.\n\n2. EUS-FNA procedures\nThe target lesions in the 85 patients included pancreatic tumors in 54 (63.5%), lymph nodes in 11 (12.9%), gastrointestinal submucosal tumors in 10 (11.8%), bile ducts in five (5.9%) and others in five (5.9%). The median target lesion diameter was 24.2 mm (range, 6.0 to 130.0 mm). Gastrointestinal puncture sites included the stomach in 43 patients (50.6%), the duodenum in 38 (44.7%), the esophagus in three (3.5%) and the small intestine in one (1.2%). Needle size was 19 gauge in 11 patients (12.9%), 22 gauge in 65 (76.5%) and 25 gauge in nine (10.6%). The median number of punctures was 3 (range, 1 to 7). Rapid on-site evaluation was performed in 68 patients (80.0%). Based on the results of EUS-FNA, 66 patients (77.6%) were histologically diagnosed with neoplastic diseases (Table 3).\n\n3. Bleeding complications\nTwo patients (2.4%; 95% CI, 0.6% to 8.3%) experienced bleeding complications. The first patient was a 72-year old male who was taking aspirin and thienopyridine because of a recent ischemic stroke. He discontinued thienopyridine for 5 days and underwent EUS-FNA of a submucosal tumor at the gastric fornix using a 19-gauge needle with two needle passes and was histologically diagnosed with a gastrointestinal stromal tumor. Five hours after EUS-FNA, he developed dyspnea and hypoxia. Chest-computed tomography showed left hemothorax, and he underwent emergency video-assisted thoracoscopic surgery for the confirmation of hemostasis. He was discharged 2 weeks after surgery. The second patient was a 62-year-old male, who was taking warfarin because of a mechanical valve replacement. Three days before EUS-FNA, warfarin was discontinued and replaced by intravenous heparin. He underwent EUS-FNA of a swollen para-aortic lymph node using a 25-gauge needle. Although discharged without complications, he presented with melena 8 days after EUS-FNA. Upper gastrointestinal endoscopy showed a duodenal ulcer, but no bleeding at the EUS-FNA puncture site in the stomach. He was transfused with two units of red blood cells. The rates of bleeding complications according to needle size were 9.1% (1/11), 0% (0/65), and 11.1% (1/9) for 19-, 22-, and 25-gauge needles, respectively. There were no bleeding events in the 17 patients who required only a single dose of aspirin or cilostazol.\n\n4. Other complications\nNo patient experienced thromboembolic events and there were no procedure related deaths (0%; 95% CI, 0.0% to 4.4%). Three patients (3.5%; 95% CI, 1.2% to 10.0%) experienced other complications, with all showing abscess formation around the puncture site. One patient required endoscopic ultrasound-guided abscess drainage, whereas the other two were managed conservatively.\n\nDISCUSSION\nOur study demonstrated, for the first time, that the rate of bleeding complications after EUS-FNA for patients taking anti-thrombotic agents was 2.4%. In the rule of three, the upper limit of the 95% CI of the probability of an event is calculated as 3 divided by the number of procedures if no event occurred in a finite number of procedures.14 The rate of bleeding in this study exceeded the estimated upper limit of the 95% CI (1%). From this point of view, the rate of bleeding events in patients with antithrombotic agents was not as low as 1%, and the relatively high rate of bleeding complications in our study should not be generalized.\n\nA previous meta-analysis showed that the rate of bleeding complications after EUS-FNA was 0.13%,4 and assessments of the Japanese national database reported that the rates of severe bleeding after EUS-FNA in patients with gastrointestinal submucosal tumors and pancreatic tumors were 0.44% and 0.23%, respectively.15,16 A recent retrospective study reported that EUS-FNA-related bleeding was as low in patients with antithrombotic agents as in those without them.17 The retrospective nature of the present study, however, did not allow estimation of postoperative bleeding complications. In agreement with an earlier study, we found that 4.6% of patients undergoing EUS-FNA were taking antithrombotic agents.7 The higher rate of bleeding complications in our study of patients taking antithrombotic agents was likely due to their higher risk for bleeding complications after invasive endoscopic procedures and the patients’ comorbidities that required antithrombotic agents.18,19\n\nThe efficacy of perioperative heparin bridging in preventing thromboembolic events is unclear.20 One of the patients in our study who was taking warfarin experienced a bleeding complication, but this was considered related to a comorbidity rather than the EUS-FNA procedure itself. A recent large, randomized controlled trial reported that heparin bridging increased the risk of major bleeding without reducing the risk of thromboembolism.21 The incidence of bleeding complications following endoscopic mucosal biopsy in patients treated with antithrombotic agents was reported to be low, even without discontinuation of these agents.22 The lack of thromboembolic events in our study suggested that warfarin discontinuation with heparin bridging would not be necessary prior to EUS-FNA in patients taking warfarin. Furthermore, NOACs have been shown more effective and safe than warfarin in preventing thromboembolic events.23,24 Because few patients in our study were taking NOACs, the safety of EUS-FNA for those patients remains to be determined.\n\nWe also found that one patient taking both aspirin and thienopyridine, discontinuing the latter before EUS-FNA, experienced a severe bleeding complication. This was consistent with findings showing that dual antiplatelet treatment was a risk factor for bleeding complications after gastric endoscopy.25 Because stent thrombosis is a life-threatening event, dual antiplatelet therapy for at least 1 year has been recommended after drug-eluting stent placement.26,27 However, novel drug-eluting stents have a low risk of restenosis following a short duration of dual antiplatelet treatment, suggesting that the number of patients will likely decrease in the near future.28,29 Nevertheless, caution before EUS-FNA is necessary for those patients.\n\nIn our study, there were no bleeding events in any of the patients who took aspirin or cilostazol without interruption. This finding was consistent with that of a previous study by Inoue et al.17 Therefore, use of EUS-FNA may be feasible with continued aspirin or cilostazol.\n\nAnother concern in the management of antithrombotic agents for endoscopic procedures is that a thromboembolic event may occur after the discontinuation of antithrombotic agents.30 Thromboembolic events may be more harmful than bleeding events and may even be fatal.31 None of the patients in our study, however, experienced a thromboembolic event. Because bleeding events could be successfully managed without any sequelae or mortality, EUS-FNA may be feasible without discontinuing antithrombotic agents.\n\nWe observed three patients with abscess formation around the puncture site. The reason for relatively high incidence of this complication was not clear, but it might be possible that the enrolled patients had comorbid diseases requiring antithrombotic agents, so the healing process may have been compromised.\n\nThis study had several limitations, including the relatively small number of patients, making its statistical power low. In addition, this was not a comparative study because the huge number of patients is mandatory to evaluate the rate of rare events. Instead, we calculated the sample size in accordance with the rule of three. EUS-FNA procedures may have differed among the participating institutions; therefore performance bias could not be excluded. Furthermore, patients in this study were taking various antithrombotic agents, making comparisons difficult; and only Japanese patients were included, making it difficult to generalize these results among different ethnic groups. We excluded patients with cystic lesions (who were more likely to develop bleeding complications) than those with solid lesions, so we might have underestimated the overall rate of bleeding complications. Finally, we could not determine whether bleeding was due to the antithrombotic agents themselves or the comorbidity requiring those agents.\n\nThe rate of bleeding complications after EUS-FNA for patients taking antithrombotic agents might be considerable, regardless of whether the bleeding was attributed to EUS-FNA itself. Endoscopists should evaluate the risks of both thromboembolic events and bleeding complications before performing EUS-FNA on patients being treated with antithrombotic agents. A large prospective study is necessary to develop new guidelines for the management of patients with antithrombotic agents who undergo EUS-FNA.\n\nACKNOWLEDGEMENTS\nThis study was supported by a grant from the Japanese Foundation for Research and Promotion of Endoscopy. The founder had no role in the study design, nor collection, analysis, or interpretation of the data.\n\nWe express our greatest appreciation to Dr. Hiroaki Iijima for statistical support.\n\nAuthor contributions: Kazumichi Kawakubo contributed to study design; acquisition, analysis and interpretation of data; and drafting of the manuscript. K.Y., K.E., H.I., N.E., S.H. R.M., K.S., H.Y., T.K., M.O., T.O., Y.T.A., S.K., Kimitoshi Kubo, Y.K., M.O., and M.U. contributed to study design; and acquisition, analysis and interpretation of data. M.K., H.K., T.H., A.K., and N.S. contributed to study design; acquisition, analysis and interpretation of the data; and critical revision of the manuscript.\n\nSee editorial on page 225.\n\nThe manuscript was presented as part at Digestive Disease Week 2016, at San Diego, USA (http://www.giejournal.org/article/S0016-5107(16)00510-1/abstract).\n\nCONFLICTS OF INTEREST\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Flow chart of this study.\n\nEUS-FNA, endoscopic ultrasound-guided fine needle aspiration; ASA, American Society of Anesthesiologists.\n\nTable 1 Patient Characteristics and Antithrombotic Agents Administered to Patients Prior to EUS-FNA\n\nVariable\tValue\t\nAge, yr\t74 (40–85)\t\nMale sex\t62 (72.9)\t\nPlatelets, ×104/mm3\t19.5 (5.7–37.0)\t\nPT-INR\t1.09 (0.90–1.66)\t\nAntithrombotic agents\t\n Antiplatelets\t\n Aspirin\t43\t\n Thienopyridine\t30\t\n Cilostazol\t8\t\n Others\t4\t\n Anticoagulants\t\n Warfarin\t25\t\n NOAC\t14\t\nNo. of antithrombotic agents\t\n 1/2/3\t51/28/6\t\nData are presented as median (range) or number (%).\n\nEUS-FNA, endoscopic ultrasound-guided fine needle aspiration; PT-INR, prothrombin time-international normalized ratio; NOAC, non-vitamin K antagonist oral anticoagulants.\n\nTable 2 Reasons for Antithrombotic Agent Prescriptions\n\nTwo months after insertion of a bare metal stent into the coronary artery\t5\t\nTwelve months after insertion of a drug-eluting stent into the coronary artery\t8\t\nIschemic stroke or transient ischemic attack with >50% stenosis of major intracranial arteries\t12\t\nRecent ischemic stroke or transient ischemic attack\t8\t\nObstructive peripheral artery disease ≥Fontaine grade 3 (rest pain)\t9\t\nUltrasonic examination of carotid arteries and magnetic resonance angiography of the head and neck region where withdrawal is considered high risk of thromboembolism\t5\t\nHistory of cardiogenic brain embolism\t13\t\nAtrial fibrillation accompanying valvular heart disease\t6\t\nAtrial fibrillation without valvular heart disease but with high risk of stroke\t19\t\nFollowing mechanical mitral valve replacement\t2\t\nHistory of thromboembolism following mechanical valve replacement\t3\t\nDeep vein thrombosis/pulmonary thromboembolism\t1\t\nTable 3 Histological Diagnosis of Endoscopic Ultrasound-Guided Fine Needle Aspiration\n\nAdenocarcinoma\t44\t\nAdenosquamous carcinoma\t1\t\nSquamous cell carcinoma\t3\t\nClear cell carcinoma\t2\t\nNeuroendocrine tumor\t4\t\nUndifferentiated carcinoma\t1\t\nSmall cell carcinoma\t1\t\nGastrointestinal stromal tumor\t5\t\nLeiomyoma\t1\t\nLymphoma\t2\t\nParaganglioma\t1\t\nSolid pseudopapillary neoplasm\t1\t\nAtypical epithelial cells\t4\t\nNonneoplastic tissue\t13\t\nInsufficient materials\t1\t\nNot analyzed\t1\n==== Refs\nREFERENCES\n1 Hewitt MJ McPhail MJ Possamai L Dhar A Vlavianos P Monahan KJ EUS-guided FNA for diagnosis of solid pancreatic neoplasms: a meta-analysis Gastrointest Endosc 2012 75 319 331 10.1016/j.gie.2011.08.049 22248600 \n2 Polkowski M Larghi A Weynand B Learning, techniques, and complications of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) technical guideline Endoscopy 2012 44 190 206 10.1055/s-0031-1291543 22180307 \n3 Yasuda I Goto N Tsurumi H Endoscopic ultrasound-guided fine needle aspiration biopsy for diagnosis of lymphoproliferative disorders: feasibility of immunohistological, flow cytometric, and cytogenetic assessments Am J Gastroenterol 2012 107 397 404 10.1038/ajg.2011.350 21989147 \n4 Wang KX Ben QW Jin ZD Assessment of morbidity and mortality associated with EUS-guided FNA: a systematic review Gastrointest Endosc 2011 73 283 290 10.1016/j.gie.2010.10.045 21295642 \n5 Furie KL Goldstein LB Albers GW Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association Stroke 2012 43 3442 3453 10.1161/STR.0b013e318266722a 22858728 \n6 Grines CL Bonow RO Casey DE Jr Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians Circulation 2007 115 813 818 10.1161/CIRCULATIONAHA.106.180944 17224480 \n7 Ara N Iijima K Maejima R Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of antithrombotics in Japan Dig Endosc 2015 27 458 464 10.1111/den.12407 25425518 \n8 Fujimoto K Fujishiro M Kato M Guidelines for gastro-enterological endoscopy in patients undergoing antithrombotic treatment Dig Endosc 2014 26 1 14 10.1111/den.12183 \n9 ASGE Standards of Practice Committee Anderson MA Ben-Menachem T Management of antithrombotic agents for endoscopic procedures Gastrointest Endosc 2009 70 1060 1070 10.1016/j.gie.2009.09.040 19889407 \n10 Boustière C Veitch A Vanbiervliet G Endoscopy and anti-platelet agents. European Society of Gastrointestinal Endoscopy (ESGE) Guideline Endoscopy 2011 43 445 461 10.1055/s-0030-1256317 21547880 \n11 Kien-Fong Vu C Chang F Doig L Meenan J A prospective control study of the safety and cellular yield of EUS-guided FNA or Trucut biopsy in patients taking aspirin, nonsteroidal anti-inflammatory drugs, or prophylactic low molecular weight heparin Gastrointest Endosc 2006 63 808 813 10.1016/j.gie.2005.09.033 16650543 \n12 Dumonceau JM Polkowski M Larghi A Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline Endoscopy 2011 43 897 912 10.1055/s-0030-1256754 21842456 \n13 Cotton PB Eisen GM Aabakken L A lexicon for endoscopic adverse events: report of an ASGE workshop Gastrointest Endosc 2010 71 446 454 10.1016/j.gie.2009.10.027 20189503 \n14 Eypasch E Lefering R Kum CK Troidl H Probability of adverse events that have not yet occurred: a statistical reminder BMJ 1995 311 619 620 10.1136/bmj.311.7005.619 7663258 \n15 Hamada T Yasunaga H Nakai Y Rarity of severe bleeding and perforation in endoscopic ultrasound-guided fine needle aspiration for submucosal tumors Dig Dis Sci 2013 58 2634 2638 10.1007/s10620-013-2717-7 23695878 \n16 Hamada T Yasunaga H Nakai Y Severe bleeding and perforation are rare complications of endoscopic ultrasound-guided fine needle aspiration for pancreatic masses: an analysis of 3,090 patients from 212 hospitals Gut Liver 2014 8 215 218 10.5009/gnl.2014.8.2.215 24672664 \n17 Inoue T Okumura F Sano H Bleeding risk of endoscopic ultrasound-guided fine-needle aspiration in patients undergoing antithrombotic therapy Dig Endosc 2017 29 91 96 10.1111/den.12687 27305322 \n18 Koh R Hirasawa K Yahara S Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms Gastrointest Endosc 2013 78 476 483 10.1016/j.gie.2013.03.008 23622974 \n19 Hamada T Yasunaga H Nakai Y Bleeding after endoscopic sphincterotomy or papillary balloon dilation among users of anti-thrombotic agents Endoscopy 2015 47 997 1004 10.1055/s-0034-1392408 26126160 \n20 Matsumoto M Mabe K Tsuda M Multicenter study on hemorrhagic risk of heparin bridging therapy for periendoscopic thromboprophylaxis BMC Gastroenterol 2015 15 89 10.1186/s12876-015-0315-1 26215103 \n21 Douketis JD Spyropoulos AC Kaatz S Perioperative bridging anticoagulation in patients with atrial fibrillation N Engl J Med 2015 373 823 833 10.1056/NEJMoa1501035 26095867 \n22 Ono S Fujishiro M Kodashima S Evaluation of safety of endoscopic biopsy without cessation of antithrombotic agents in Japan J Gastroenterol 2012 47 770 774 10.1007/s00535-012-0538-7 22350697 \n23 Granger CB Alexander JH McMurray JJ Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med 2011 365 981 992 10.1056/NEJMoa1107039 21870978 \n24 Schulman S Kearon C Kakkar AK Dabigatran versus warfarin in the treatment of acute venous thromboembolism N Engl J Med 2009 361 2342 2352 10.1056/NEJMoa0906598 19966341 \n25 Ono S Fujishiro M Yoshida N Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study Endoscopy 2015 47 632 637 10.1055/s-0034-1391354 25590184 \n26 Windecker S Kolh P Alfonso F 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Eur Heart J 2014 35 2541 2619 10.1093/eurheartj/ehu278 25173339 \n27 Levine GN Bates ER Blankenship JC 2011 ACCF/AHA/ SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines and the Society for Cardiovascular Angiography and Interventions Circulation 2011 124 e574 e651 10.1161/CIR.0b013e31823ba622 22064601 \n28 Colombo A Chieffo A Frasheri A Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial J Am Coll Cardiol 2014 64 2086 2097 10.1016/j.jacc.2014.09.008 25236346 \n29 Gilard M Barragan P Noryani AA 6- versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial J Am Coll Cardiol 2015 65 777 786 10.1016/j.jacc.2014.11.008 25461690 \n30 Fujishiro M Oda I Yamamoto Y Multi-center survey regarding the management of anticoagulation and antiplatelet therapy for endoscopic procedures in Japan J Gastroenterol Hepatol 2009 24 214 218 10.1111/j.1440-1746.2008.05604.x 18823431 \n31 Claessen BE Henriques JP Jaffer FA Mehran R Piek JJ Dangas GD Stent thrombosis: a clinical perspective JACC Cardiovasc Interv 2014 7 1081 1092 10.1016/j.jcin.2014.05.016 25341705\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1976-2283",
"issue": "12(3)",
"journal": "Gut and liver",
"keywords": "Endoscopic ultrasound-guided fine needle aspiration; Fibrinolytic agents; Hemorrhage",
"medline_ta": "Gut Liver",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D005260:Female; D005343:Fibrinolytic Agents; D006471:Gastrointestinal Hemorrhage; D006491:Hemothorax; D006801:Humans; D008297:Male; D008551:Melena; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors",
"nlm_unique_id": "101316452",
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"pages": "353-359",
"pmc": null,
"pmid": "29409308",
"pubdate": "2018-05-15",
"publication_types": "D000068397:Clinical Study; D016428:Journal Article; D016448:Multicenter Study",
"references": "7663258;23695878;25341705;21989147;21295642;19889407;24215155;27305322;19966341;20189503;26126160;26095867;18823431;25425518;16650543;22064601;25236346;23622974;21547880;25590184;21842456;25461690;22350697;21870978;22180307;25173339;24672664;26215103;22858728;17224480;22248600",
"title": "A Prospective Multicenter Study Evaluating Bleeding Risk after Endoscopic Ultrasound-Guided Fine Needle Aspiration in Patients Prescribed Antithrombotic Agents.",
"title_normalized": "a prospective multicenter study evaluating bleeding risk after endoscopic ultrasound guided fine needle aspiration in patients prescribed antithrombotic agents"
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"abstract": "BACKGROUND\nGefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer.\n\n\nMETHODS\nThis phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status.\n\n\nRESULTS\nDue to a low accrual rate in this study, the sample size (n = 50) was not reached. Sixteen patients were included in four centers, 50% had adenocarcinoma and 75% were male. Genomic alterations (7 patients studied) retrieved TP53 mutation in 2 patients and no EGFR mutation. Four weeks after radiotherapy, 3 patients (19%) had a partial response, 6 (38%) had a stable disease, and 7 had a progression (44%). Median overall survival was 11 months and median progression-free survival was 5 months. At the time of the last contact, 5 patients (31%) were still alive. Main toxicities were gastrointestinal (81%), cutaneous (81%), general (56%), and respiratory (50%). There were 12>G3 adverse events in 7 (47%) patients, and there was one toxic-death during the concomitant period due to an interstitial pneumonitis. There were two possible adverse events-related deaths during the chemotherapy period (pulmonary embolism (n = 1) and sudden death after the administration of the 3rd course of chemotherapy (n = 1)).\n\n\nCONCLUSIONS\nThe benefit of Gefitinib-RT could not be confirmed due to premature trial discontinuation. Further evaluation is required, especially in patients with EGFR mutated NSCLC.",
"affiliations": "Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, Institut Thoracique d'Oncologie (IOT), Villejuif, France.;Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes, France.;Gustave Roussy, Université Paris-Saclay, Department of Biostatistics and Epidemiology, Villejuif, France.;Gustave Roussy, Université Paris-Saclay, Department of Biostatistics and Epidemiology, Villejuif, France.;Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank (UMS3655 CNRS / US23 INSERM), INSERM Unit U981, Villejuif, France.;Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank (UMS3655 CNRS / US23 INSERM), INSERM Unit U981, Villejuif, France.;Department of Radiation Oncology, University Hospital Grenoble, Grenoble, France.;Department of Radiation Oncology, Centre Jean Perrin, Clermont-Ferrand, France.;Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, Institut Thoracique d'Oncologie (IOT), Villejuif, France.",
"authors": "Levy|Antonin|A|;Bardet|Etienne|E|;Lacas|Benjamin|B|;Pignon|Jean-Pierre|JP|;Adam|Julien|J|;Lacroix|Ludovic|L|;Artignan|Xavier|X|;Verrelle|Pierre|P|;Le Péchoux|Cécile|C|",
"chemical_list": "D011799:Quinazolines; D000077156:Gefitinib",
"country": "United States",
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"doi": "10.18632/oncotarget.12741",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 1274110.18632/oncotarget.12741Clinical Research PaperA phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer Levy Antonin 123Bardet Etienne 4Lacas Benjamin 56Pignon Jean-Pierre 56Adam Julien 7Lacroix Ludovic 7Artignan Xavier 810Verrelle Pierre 9Le Péoux Cécile 11 Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, Institut Thoracique dOncologie (IOT), Villejuif, France2 INSERM U1030, Molecular Radiotherapy, Gustave Roussy, Université Paris-Saclay, Villejuif, France3 Univ Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France4 Department of Medical Oncology, Institut de Cancérologie de lOuest, Nantes, France5 Gustave Roussy, Université Paris-Saclay, Department of Biostatistics and Epidemiology, Villejuif, France6 INSERM U1018, CESP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France7 Department of Medical Biology and Pathology, Translational Research Laboratory and Biobank (UMS3655 CNRS / US23 INSERM), INSERM Unit U981, Villejuif, France8 Department of Radiation Oncology, University Hospital Grenoble, Grenoble, France9 Department of Radiation Oncology, Centre Jean Perrin, Clermont-Ferrand, France10 Department of Radiation Oncology, St Grégoire Hospital, St Grégoire, FranceCorrespondence to:Cécile Le Péoux,cecile.lepechoux@gustaveroussy.fr28 2 2017 18 10 2016 8 9 15924 15933 6 7 2016 12 10 2016 Copyright: © 2017 Levy 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.Background\nGefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer.\n\nPatients and Methods\nThis phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status.\n\nResults\nDue to a low accrual rate in this study, the sample size (n = 50) was not reached. Sixteen patients were included in four centers, 50% had adenocarcinoma and 75% were male. Genomic alterations (7 patients studied) retrieved TP53 mutation in 2 patients and no EGFR mutation. Four weeks after radiotherapy, 3 patients (19%) had a partial response, 6 (38%) had a stable disease, and 7 had a progression (44%). Median overall survival was 11 months and median progression-free survival was 5 months. At the time of the last contact, 5 patients (31%) were still alive. Main toxicities were gastrointestinal (81%), cutaneous (81%), general (56%), and respiratory (50%). There were 12>G3 adverse events in 7 (47%) patients, and there was one toxic-death during the concomitant period due to an interstitial pneumonitis. There were two possible adverse events-related deaths during the chemotherapy period (pulmonary embolism (n = 1) and sudden death after the administration of the 3rd course of chemotherapy (n = 1)).\n\nConclusion\nThe benefit of Gefitinib-RT could not be confirmed due to premature trial discontinuation. Further evaluation is required, especially in patients with EGFR mutated NSCLC.\n\niressathoracic radiotherapylung cancerphase II trial\n==== Body\nINTRODUCTION\nThe standard treatment for locally advanced unresectable non-small cell lung cancer (NSCLC) is the association of conventional chemotherapy (platinum based doublets) and radiotherapy [1–3]. Outcomes of locally advanced NSCLC however remain poor and new efficient, safe, and more specific treatments are needed. In the last decades, an enhanced understanding of the NSCLC oncogenic molecular pathways has led to the expansion of individualized targeted therapies. Molecular anomalies include KRAS mutation and / or mutation and overexpression of epidermal growth factor receptor (EGFR). Mutations in the EGFR tyrosine kinase are observed in approximately in 15% to 62% of patients and are predictors of responsiveness to EGFR tyrosine kinase inhibitors (TKIs) [4–7]. In the metastatic setting, several EGFR TKIs (erlotinib, gefitinib, afatinib) prolong progression-free survival as compared with platinum based chemotherapy doublets in patients with EGFR mutated lung cancer [5].\n\nGefitinib (iressa™, ZD1839) is an oral EGFR TKI indicated for the treatment of adult patients with locally advanced/metastatic NSCLC with activating mutations of EGFR [6,7]. Preclinical evidence suggests that gefitinib enhanced the radioresponse of NSCLC cells by suppressing cellular DNA repair [8]. Concomitant use of EGFR inhibitor and radiotherapy has also demonstrated a significantly increased overall survival (OS) as compared with radiotherapy alone in one randomized controlled trial in head and neck cancer [9]. In light of these data, we conducted a phase II trial that aimed to evaluate the efficacy of gefitinib associated with irradiation, followed by chemotherapy in patients with inoperable stage III NSCLC.\n\nPATIENTS AND METHODS\nEligibility criteria\nPatients (≥18 years) were eligible for inclusion if they had histologically confirmed unresectable non-pretreated stage III NSCLC. Additional inclusion criteria were: at least one measurable lesion according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.0); World Health Organisation (WHO) performance status (PS) of 0 to 2 at inclusion; adequate pulmonary function (forced expiratory volume in 1 second [FEV1] is greater than or equal to 1 L, oxygen diffusion capacity of greater than or equal to 40%); pulmonary dose volume histogram V20Gy inferior or equal to 40%; life expectancy of at least 6 months; Female patients could be included if use of secure contraceptive precautions, or post-menopausal. Exclusion criteria were: prior anticancer treatment (including thoracic radiotherapy or anti-EGFR therapy); known hypersensitivity to gefitinib, cisplatin or vinorelbine, or any of the excipients of these product; interstitial lung disease; malignancies diagnosed within the last 5 years; severe coexisting, psychological, or uncontrolled condition; documented or symptomatic metastases, including positive cytology in the case of pleural effusion; pregnancy or breast feeding; concomitant use of inhibitors of CYP3A4; and weight loss of over 15% in the 3 months before the start of the study. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and brain magnetic resonance imaging (MRI) were not mandatory for patient inclusion.\n\nStudy design and treatments\nThis was a phase II, multicenter, open-label, one-arm study in patients with inoperable histologically confirmed stage III NSCLC to explore the efficacy of 250 mg gefitinib administered concurrently with thoracic radiotherapy followed by chemotherapy.\n\nGefitinib 250 mg was administered orally once daily beginning 7 days before the onset of radiotherapy, until the end of radiotherapy, disease progression, unacceptable toxicity or withdrawal of consent. Conformal thoracic radiotherapy was delivered at the total dose of 66 Gy in 33 daily fractions of 2 Gy, over a 45-day period. There were no time constraints between staging procedures and start of treatment. Four weeks after completion of gefitinib and radiotherapy, patients received 3 cycles of chemotherapy combining intravenous cisplatin (100 mg/m2 once every 28 days) and vinorelbine (25 mg/m2 once per week for 3 weeks out of 4). We chose cisplatin-vinorelbine doublet for its good efficacy/toxicity profile when delivered sequentially to thoracic radiotherapy [10, 11]. Patients were assessed one month after the completion of the experimental combination and one month after the last chemotherapy cycle with physical examination and imaging studies. The study was approved by the relevant ethics committee/institutional review board and was conducted in compliance with the Declaration of Helsinki as well as good clinical practice guidelines. Written informed consent was obtained from all patients before trial initiation. This study is registered with ClinicalTrials.gov, number NCT00333294.\n\nMolecular analysis\nAs planned in the study, formalin-fixed, paraffin-embedded material from baseline biopsy was evaluated for Ki67, phospho(p)ERK, pAKT, EGFR, and pEGFR expression using immunohistochemistry (IHC).\n\nGenomic analysis was performed in the accessible samples. The mutational status of specific cancer genes was determined using next generation sequencing based onIon Torrent approach with Ampliseq Cancer Hotspot panelV2 (Lifetechnologie, Darmstadt, Germany) library preparation as previously described [12].\n\nMolecular analysis was an exploratory objective of this study, and it was not mandatory to have enough tissue available for translational research.\n\nEndpoints and statistical considerations\nThe primary endpoint was objective response rate (complete response [CR] and partial response [PR]) 4 weeks after completion of gefitinib and irradiation (immediately prior to chemotherapy), based on the RECIST criteria on computed tomography. Secondary endpoints included: objective response rate at study closure, incidence of controlled disease (CR, PR and stable disease [SD]) at study closure, progression-free survival (PFS), duration of response, overall survival (OS), and safety variables (acute and late toxicity graded according to Common Terminology Criteria for Adverse Events v3.0 [CTCAE], adverse events [AEs], drug interruptions, and study drug exposure).\n\nFleming's method was used to calculate the number of patients required. A sample size of 50 patients was sufficient to have a power of 80% to detect an objective response rate of 60% and 78% as null and alternative hypothesis respectively, with an alpha of 5% (one-sided). If 37 or more responses were observed out of the 50 patients, it would be possible to conclude in favour of the efficacy of the treatment. All patients that were enrolled and received trial drug were considered the intention-to-treat (ITT) population.\n\nOS and PFS were estimated using the Kaplan-Meier method and defined as the time between inclusion and death from any cause for OS, death or tumor progression for PFS, or last follow-up for surviving patients, whichever came first. Median follow-up was calculated according to Schemper's method [13]. Statistical analyses were performed using SAS (version 9.3). All reported p-values are two-sided, and p-values lower than 0.05 were considered significant.\n\nRESULTS\nTrial conduct\nA total of 16 (/22 screened) patients with stage IIIB NSCLC were enrolled in 4 French centers between 09/2004 and 01/2006. Due to a low accrual rate in this study, the sample size was not reached and the study was prematurely closed.\n\nTable 1 lists the main characteristics of the study population. Most patients were males (75%) and the median age was 56 years old (range, 43-70 years). Immunohistochemistry analysis of the tumor was performed for 10 patients (Ki67, pERK, pAKT, EGFR and pEGFR). Two, 2, and 4 patients had positive biopsies for pERK, pAKT, and EGFR, respectively. All patients had low Hirsch scores for pEGFR and median Ki67 proliferation index was 40% (range, 5-90%). Since response to EGFR TKIs relies on mutational status, a genomic analysis was performed on accessible samples. Genomic alterations (n = 7 analyzed, others biopsies not available/assessable) retrieved TP53 mutation in 2 patients and no EGFR mutation. There were 3 patients without retrieved alteration, and 2 without detectable DNA. Other samples were not accessible or not assessable.\n\nTable 1 Patients’ baseline characteristics at inclusion\nCharacteristics\tN=16 (%)\t\nAge (years)*\t55.5 (43-70)\t\nGender\t\t\nMale\t12 (75)\t\nFemale\t4 (25)\t\nWHO PS score\t\t\n0\t8 (50)\t\n1\t7 (44)\t\n2\t1 (6)\t\nTobacco\t\t\nYes\t11 (69)\t\nNo\t5 (31)\t\nHistology of primary tumor\t\t\nSquamous\t6 (37)\t\nAdenocarcinoma\t8 (50)\t\nOthers\t2 (13)\t\nTNM classification (Stage IIIB: n=16)\t\t\nT2N3M0\t3 (19)\t\nT3N2M0\t1 (6)\t\nT4N0M0\t3 (19)\t\nT4N2M0\t5 (31)\t\nT4N3M0\t4 (25)\t\nPulmonary Function Testing*\t\t\nFEV1(liter)\t2.3 (1.3-3.4)\t\nDLCO (% theo.)\t70 (47-103)\t\n* Median (range)\n\nWHO PS: World Health Organisation performance status; N: number of patients; FEV1: Forced Expiratory Volume in one second; DLCO: diffusing capacity for carbon monoxide ; % theo: % of the theoretical value.\n\nTreatment delivery\nCompliance with gefitinib was good: all patients received the entire planned treatment except six interruptions (corresponding to more than 85% of the initial planned dose): four temporary and two patients did not resume the treatment (disease progression: n = 1; asthenia: n = 1). No dose reduction of gefitinib was allowed. The median duration of gefitinib exposure was 55 days (range, 32-65 days).\n\nAll patients but two received the entire planned radiotherapy. The median dose delivered was 60 Gy (range, 40-66 Gy) in 30 fractions (range, 20-33) with a median duration of 48.5 days (range, 30-57 days) with 3D-conformal radiotherapy (n = 16; no used intensity modulated radiation therapy [IMRT] or respiratory gating).\n\nConsolidation chemotherapy was delivered 10 patients and 7/10 patients received the three initially planned cycles of cisplatin and vinorelbine. Five/7 patients had a dose reduction (8% of the initially planned dose) from the second cycle.\n\nThe median duration of the overall treatment was 132 days (range, 38-165 days). However, even if compliance was good, 10 out of 16 patients (63%) withdrew prematurely from study: one due to an adverse event (G3 hemoglobin decrease during the 2nd cycle of chemotherapy), and others due to cancer related-disease progression or death (two during radiotherapy, four after radiotherapy and before chemotherapy, and three during the chemotherapy period [including one that received the 3 planned cycles]).\n\nResponse and survival\nFour weeks after radiotherapy, 3 patients (19%) had a PR, 6 (38%) had a SD and 7 patients (43.8%) had progressive disease (PD). No patients presented with CR. The proportion of patients with objective tumor response was therefore 19%. At study closure, on 14 evaluated patients, there were 4 (29%) PR, one SD (7%; resulting in a disease control rate of 36%), and 9 PD (64%). The median TTP was 148 days (95% confidence interval [CI]: 85-not reached) and recurrence rate was 56% (n = 9). No information on patterns of relapse was available.\n\nAt the time of the last contact (median follow-up of 2.1 years [range, 1.0-2.4 years]), 5 patients (31%, including three that survived more than two years) were still alive resulting in a median OS of 11 months (95% CI: 5.9-27.7). In this study, 4 patients died during the study and 7 patients died after study withdrawal. Causes of death during the protocol were disease progression (n = 1) or adverse events (n = 3, cf. below). One-year PFS and OS rates were 31% (95% CI: 14-56%) and 44% (95% CI: 23-67%), respectively (Figure 1). Smoking status did not correlate with survival outcomes.\n\nFigure 1 Overall (OS) and progression-free survivals (PFS) among the 16 patients\nTable 2 Most common AEs (>10 % of patients overall) observed in 16 patients during the combination of gefitinib and radiotherapy (weeks 1-11)\nToxicity\tNumber of patients N (%)\tAEs N\t\nGastrointestinal disorders\t13 (81.3%)\t34\t\nNausea\t7 (43.8%)\t9\t\nDiarrhea\t6 (37.5%)\t7\t\nEsophagitis\t4 (25.0%)\t4\t\nVomiting\t4 (25.0%)\t6\t\nDysphagia\t2 (12.5%)\t2\t\nStomatitis\t2 (12.5%)\t2\t\nSkin disorders\t13 (81.3%)\t16\t\nDermatitis\t5 (31.3%)\t5\t\nRash\t4 (25.0%)\t4\t\nErythema\t3 (18.8%)\t3\t\nGeneral disorders\t9 (56.3%)\t21\t\nChest pain\t4 (25.0%)\t4\t\nFatigue\t3 (18.8%)\t5\t\nAsthenia\t2 (12.5%)\t3\t\nMucosal inflammation\t2 (12.5%)\t2\t\nPyrexia\t2 (12.5%)\t4\t\nRespiratory disorders\t8 (50.0%)\t12\t\nCough\t4 (25.0%)\t4\t\nInvestigations\t7 (43.8%)\t12\t\nALT increased\t3 (18.8%)\t3\t\nAST increased\t3 (18.8%)\t3\t\nWeight decreased\t2 (12.5%)\t2\t\nMetabolism and nutrition disorders\t6 (37.5%)\t8\t\nAnorexia\t4 (25.0%)\t4\t\nDehydration\t2 (12.5%)\t2\t\nNervous system disorders\t5 (31.3%)\t7\t\nHeadache\t2 (12.5%)\t4\t\nVascular disorders\t5 (31.3%)\t6\t\nHypotension\t3 (18.8%)\t3\t\nProcedural complications\t4 (25.0%)\t4\t\nRadiodermitis\t2 (12.5%)\t2\t\nCardiac disorders\t3 (18.8%)\t5\t\nEye disorders\t3 (18.8%)\t3\t\nInfections\t3 (18.8%)\t3\t\nPsychiatric disorders\t2 (12.5%)\t2\t\nAEs: adverse events, N: number of, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase.\n\nToxicity\nDuring the experimental combination period, a total of 135 adverse events (AEs) were observed in the 16 patients evaluable, and 12 were > grade (G) 3 (9 G3, two G4, and one G5; cf. Tables 3 & 4). Most frequent AEs (all grades) were: gastrointestinal (81%), cutaneous (81%), general (56%), and respiratory (50%) (Table 2). The most common G3-4 AEs were: gastrointestinal (n = 2), general (n = 2), hematologic (n = 2) and respiratory (n = 2) (Table 3). Six patients had at least one serious adverse event (SAE); 2 of these patients had four SAEs. There were three possible adverse events-related deaths: one during the gefitinib-radiotherapy period (interstitial pneumonitis: n = 1), and two after (pulmonary embolism at week 18, n = 1; sudden death within the hour after the administration of the 3rd course of chemotherapy, n = 1).\n\nTable 3 Grade 3 or 4 AEs during the combination of gefitinib and radiotherapy (weeks 1 to 11)\nToxicity\tNumber of patients N (%)\tAEs N\tRelated to gefitinib-RT Number of patients\t\nGastrointestinal disorders\t2 (12.5%)\t2\t2\t\nEsophagitis\t2 (12.5%)\t2\t2\t\nGeneral disorders\t2 (12.5%)\t2\t2\t\nFatigue\t2 (12.5%)\t2\t2\t\nGeneral physical deterioration\t1 (6.3%)\t1\t1\t\nInvestigations\t2 (12.5%)\t2\t1\t\nALT increased\t1 (6.3%)\t1\t1\t\nAST increased\t1 (6.3%)\t1\t1\t\nHemoglobin decreased\t1 (6.3%)\t1\t0\t\nRespiratory disorders\t2 (12.5%)\t2\t0\t\nCough\t1 (6.3%)\t1\t0\t\nDyspnea exacerbated\t1 (6.3%)\t1\t0\t\nPneumonia\t1 (6.3%)\t1\t0\t\nCardiac disorders\t1 (6.3%)\t1\t1\t\nAtrioventricular block\t1 (6.3%)\t1\t1\t\nProcedural complications\t1 (6.3%)\t1\t1\t\nInterstitial pneumonitis*\t1 (6.3%)\t1\t1\t\nMetabolism and nutrition disorders\t1 (6.3%)\t1\t0\t\nDehydration\t1 (6.3%)\t1\t0\t\nVascular disorders\t1 (6.3%)\t1\t0\t\nDeep vein thrombosis\t1 (6.3%)\t1\t0\t\nAEs: adverse events, N: number of, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, RT: radiotherapy.\n\n*Grade 5\n\nTable 4 Literature overview of concurrent anti-EGFR agents and radiotherapy\nStudy\tPhase\tPatients N\tEGFR+ N (%)*\tRT (Gy)\tChemotherapy\tPFS (med. m)\tOS (med. m)\tToxicity >G4b\n(%)\t\n\t\t\t\t\tGefitinib\t\t\t\t\n\t\t\t\t\tErlotinib\t\t\t\t\n\t\t\t\t\tCetuximab\t\t\t\t\nReady\tII\tPR:29 GR:21\t13 (26)\t66\tPR: none GR: Conc Ca Txl\tPR: 13.4 GR:9.2\tPR: 19 GR: 13\tPR:0 GR: G5 pneumonitis (8) G4 neutrop (36)\t\nNiho\tII\t38\tNS\t60\tInd CDDP Vin\t11.2\t28.5\tG4 HLE increase (6)\t\nStinchcombe\tII\t23\tNS\t74\tInd Ca Txl Iri\nConc Ca Txl\t9\t16\tG4 embolism (4.8)\nG4 thrombopenia (4.8)\t\nOkamoto\tII\t9\t2 (29)\t60\tNone\tNS\tNS\tNone\t\nCenter\tI\t16\tNS\t70\tConc+Cons Txt\t7.1\t21\tG5 pneumonitis (13)\t\nRothschild\tI\tStep 1: 9\nStep 2: 5\tNS\t63\tStep 1 : none\nStep 2 : CDDP\t6m: 42.9%\t6m: 85.7%\tG4 dyspnea (7)\t\nCurrent\tII\t16\t0\t66\tCons CDDP Vin\t5\t11\tG5 pneumonitis (6.3)\nG4 pneumonia (6.3)\nG4 dehydration (6.3)\t\nLilenbaum\tII\t75\t0\t66\tInd Ca nab-Txl\t11\t17\tG4 blood (8)\nG4 fatigue (1)\t\nKomaki\tII\t48\t4 (8)\t63\tConc+Cons Ca Txl\t14\t36.5\tG4 pneumonitis (2)\t\nSocinski\tI/II\t45\tNS\t74\tInd+Conc Ca Txl Bev+Cons Bev\t10.2\t18.4\tG4 neutrop (18)\nG4 esophagitis (2)\t\nBradley\tIII\t147\n110\tNS\t60\n74\tConc+Cons Ca Txl\nidem\t10.8\t25\tG4 blood (46)\nG4/5 dyspnea (2)\nG4 pneumonitis (1)\nG4 dehydration (2)\nG4 dysphagia (1)\t\nBlumenscheina\tII\t93\tNS\t63\tConc+Cons Ca Txl\t2y FR : 44.8%\t22.7\tG5 pneumonitis (2)\nG5 ARDS (1)\t\nHallqvist\tII\t75\tNS\t68\tInd CDDP Txt\tNS\t17\tG5 pneumonitis (1.4)\nG4 hypersens (2.8)\t\nRamalingam\tII\t40\tNS\t73.5\tCons Ca Txl\t9.3\t19.4\tG4 infection\nG4 infusion reaction\nG4 embolism\nG4 feb neutrop (9.8)\t\nGovidan\tII\t53\tNS\t70\tConc Ca Pem\t12.3\t25.2\tG5 pneumonitis (4)\nG5 embolism (2)\t\nN: number of; EGFR+ : epidermal growth factor receptor mutation; RT: radiotherapy; Conc: concurrent; Cons: Consolidation (post-RT); med. m: median months; PR: poor risk: GR: good risk; Ca: carboplatin: Txl: paclitaxel; Txt: docetaxel; Vin: vinorelbine; Bev: bevacizumab; Pem: pemetrexed; 6m: 6 month; neutrop: neutropenia; hypersens: hypersensitivity; HLE: hepatic liver enzymes; feb: febrile; ARDS: Acute respiratory distress syndrome; FR: failure rate; y: year; NS: not stated.\n\n*Only genomic analyses are reported\n\na Only G5 are reported here for this study\n\nb Only the concurrent period is generally reported\n\nDISCUSSION\nThis trial was interrupted because of low accrual. The impact of Gefitinib (250 mg daily) in combination with RT on outcomes in patients with locally advanced NSCLC then remains to be determined, especially in EGFR mutated patients (no EGFR mutated patients in our series). Previous clinical trials assessing gefitinib with irradiation did not include selected patients for EGFR mutations (Table 4) [14–19]. In the largest experience reported by Ready et al, stage III NSCLC patients received gefitinib in combination with radiotherapy alone (“poor risk group”: n = 21), or with weekly paclitaxel and carboplatin (“good-risk group”: n = 39). Poor-risk group outcomes were promising with a median PFS and OS of 13.4 and 19.0 months, respectively (vs. 5 and 11 months in our study). The poorer outcomes reported in our study might be due to the different chemotherapy administration schedule or imaging modality used. Given the time-period of the study, 18FDG-PET and brain MRI were not mandatory for inclusion and may indeed have caused inadequate staging. It may likewise be difficult to differentiate local relapse and computed tomography changes correlating with radiation fibrosis after thoracic irradiation. Modern protocols generally integrate as 18F-FDG PET/CT, and a biopsy confirmation if a relapse is suspected. There are also data that EGFR wild-type patients could have a superior local control in comparison with mutated patients, however more distant metastases (no information on pattern of relapse in this study) [20, 21]. In Ready et al's experience, there was no apparent survival difference with EGFR-activating mutations (13/45 available tumors, including 2 who had also T790M mutations) vs. wild type or KRAS mutation [17]. On the other hand, we recently reported in 78 stage IIIA/IIIB NSCLC patients who received irradiation, that selected gene alterations could be associated with a poorer PFS. The EGFR/ALK (EML4-anaplastic lymphoma kinase) group and patients with any other mutations (n = 28) had a poorer PFS (median 9.6 and 6.0 months; p = 0.005) compared to the wild-type group (median = 12.0 months) [22]. Anyway, the question of whether certain gene alterations could be predictive of radio-sensitivity or radio-resistance remains debated.\n\nThe combination of gefitinib and radiotherapy was mild. The most common G3-4 AEs were: gastrointestinal (n = 2), general (n = 2), hematologic (n = 2) and respiratory (n = 2). In our trial, chemotherapy was delivered sequentially because concomitant administration of chemoradiotherapy and gefitinib could have been much more toxic. The triple combination of bioradiotherapy and chemotherapy may lead to unexpected toxicities [23]. The authors were quite cautious since pulmonary toxicity (interstitial pneumonia or interstitial lung disease) had been reported in stage IV NSCLC, and this may occur more frequently in the Asian population [24, 25]. In other studies, concurrent weekly cisplatin likely enhanced toxicity [12] but weekly paclitaxel-carboplatin did not [17]. Rotschild et al, observed 2 dose-limiting toxicities (DLT) in 9 patients (22.2%) receiving concurrent weekly cisplatin, whereas no DLT occurred in the 5 patients without concomitant chemotherapy. DLT consisted of a G3 pulmonary infection (and thus related to a G4 infection dyspnea), and of a G2 increase in hepatic enzymes.\n\nIn our trial, one patient died from an acute interstitial pneumonitis. Others have reported severe interstitial pneumonitis with concurrent irradiation-gefitinib (or other anti-EGFR, Table 4). New available radiotherapy techniques such as IMRT or respiratory gating could help delivering smaller irradiated volumes / sparing organ at risk from higher radiation doses [26, 27]. Though IMRT may be damaging to lung because of low-dose bath. Constraints of normal irradiated lung were, in this study, less tight than recommended nowadays (volume of normal lung minus the planned target volume [PTV] receiving at least 20 Gy (V20) < 40%). This must be emphasized for the conception of new trials, since any loosening in radiotherapy constraints, especially to the lung but also to the heat, may alter the safety of the combination as shown in the recently published RTOG (Radiation Therapy Oncology Group) trial [28].\n\nOf note, concurrent erlotinib and whole brain radiotherapy (WBRT) have also been prospectively studied in brain metastatic NSCLC patients with a good overall response rate (86%) and no increased neurotoxicity [29]. A randomized study still did not show survival advantage for concurrent erlotinib and WBRT followed by maintenance erlotinib in patients with predominantly EGFR wild-type NSCLC as compared to placebo [30].\n\nAdditional anti-EGFR treatments [14–19, 28, 31–37] and other newer molecular compounds [38] are tested with concomitant radiation in this setting (Table 4). In the only phase III trial [28], the anti-EGFR cetuximab associated to chemoradiotherapy lead to higher toxic effects but did not increase OS in unselected NSCLC stage III patients. Further experiences evaluating concomitant erlotinib with chemoradiation were also disappointing [31–33]. The RTOG 1306 II trial is currently recruiting patients with mutations in EGFR and/or ALK fusion arrangement who receive induction erlotinib or crizotinib before thoracic chemoradiotherapy. Finally, as some of the effects of ionizing radiation are now recognized as contributing to antitumor immunity [39, 40], targeting molecules that downregulate the T cell immune response with immunotherapy such as anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4) or anti-PD-1/PD-L1 (programmed death-1 and it ligands) are also currently assessed in patients with locally advanced NSCLC receiving definitive radiotherapy (NCT02125461, NCT02434081, NCT02400814).\n\nCONCLUSION\nIn this phase II trial, gefitinib (250mg once daily) in combination with thoracic radiotherapy administered with conventional fractionation at the dose of 66 Gy followed by chemotherapy in previously untreated stage III NSCLC was feasible but lead to substantial toxicities (one toxic death during the concomitant period and two possible adverse events-related deaths during the chemotherapy period). Due to premature trial discontinuation and the absence of patients with EGFR mutated NSCLC, our results should be cautiously interpreted. Further investigation is needed to better assess the therapeutic ratio of this combination in trials that take into account modern radiation-delivery techniques and incorporate the biological abnormalities of tumors (EGFR mutated NSCLC).\n\nThis work was presented at the 16th World Conference on Lung Cancer (WCLC 2015)\n\nConflicts of interest\n\nAuthors have no conflict of interest to declare.\n\nFunding\n\nThis trial has been sponsored by AstraZeneca. The funders of the study had no role in the writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.\n\nAuthor contributions\n\nAL, BL, JPP, JA, LL, and CLP analyzed the data\n\nAL, BL, JPP, and CLP wrote the manuscript\n\nAll authors reviewed and approved the paper\n\nClinicalTrials.gov identifier: NCT00333294\n==== Refs\nREFERENCES\n1 Aupérin A Le Péchoux C Pignon JP Koning C Jeremic B Clamon G Einhorn L Ball D Trovo MG Groen HJ Bonner JA Le Chevalier T R; Arriagada Meta-Analysis of Cisplatin/carboplatin based Concomitant Chemotherapy in non-small cell Lung Cancer (MAC3-LC) Group. 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Eur J Cancer 2016 62 36 45\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(9)",
"journal": "Oncotarget",
"keywords": "iressa; lung cancer; phase II trial; thoracic radiotherapy",
"medline_ta": "Oncotarget",
"mesh_terms": "D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011799:Quinazolines",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "15924-15933",
"pmc": null,
"pmid": "27764781",
"pubdate": "2017-02-28",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": "20035186;20556756;25384173;25031274;21555682;20541833;25968826;21747084;20573926;23979958;20828860;23341526;8889347;25701455;21903745;23045594;20686428;23849982;27200491;18281562;22079735;12531582;26743855;16500915;16087956;22052228;23036459;19897418;18317067;25601342;24419411;24026540;25442336;19692680;20646869;18337594;23594426;22357446",
"title": "A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer.",
"title_normalized": "a phase ii open label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage iii non small cell lung cancer"
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"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VINORELBINE\\VINORELBINE TARTRATE"
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{
"abstract": "High doses of opioids are often needed in the management of cancer-related pain. A discussion of a patient's perioperative opioid management and mechanisms contributing to opioid-induced hyperalgesia (OIH) are presented. In the present case report, a patient on high doses of opioids, including morphine and methadone, with severe worsening back pain and a history of increasing opioid requirements for the last 2 months due to metastatic leiomyosarcoma to the femur, spine, and neck is described. Use of high dose opioids is associated with numerous challenges, including tolerance. The successful management of this patient was multimodal and included the use of potent analgesics, N-methyl-D-aspartatereceptor antagonists, and the α-2 agonist clonidine.",
"affiliations": "Department of Anesthesiology, Louisiana State University Health Science Center, New Orleans, Louisiana; Professor, Department of Pharmacology, Louisiana State University Health Science Center, New Orleans, Louisiana.;Department of Anesthesia, Yale University School of Medicine, New Haven, Connecticut.;Department of Anesthesia, Yale University School of Medicine, New Haven, Connecticut.;Department of Anesthesia, Yale University School of Medicine, New Haven, Connecticut.",
"authors": "Kaye|Alan David|AD|;Alian|Aymen A|AA|;Vadivelu|Nalini|N|;Chung|Keun Sam|KS|",
"chemical_list": "D016202:N-Methylaspartate; D009020:Morphine; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1551-7489",
"issue": "10(1)",
"journal": "Journal of opioid management",
"keywords": null,
"medline_ta": "J Opioid Manag",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008691:Methadone; D009020:Morphine; D016202:N-Methylaspartate; D009369:Neoplasms; D010148:Pain, Intractable; D010149:Pain, Postoperative",
"nlm_unique_id": "101234523",
"other_id": null,
"pages": "69-72",
"pmc": null,
"pmid": "24604572",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Perioperative dilemma: challenges of the management of a patient on mega doses of morphine and methadone.",
"title_normalized": "perioperative dilemma challenges of the management of a patient on mega doses of morphine and methadone"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2014-RO-01157RO",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
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"abstract": "Nephritis has been rarely associated with methimazole, primarily in the development of nephrotic syndrome. We describe a case of acute kidney injury without evidence of nephrotic syndrome following methimazole initiation.\nWe present the relevant history, laboratory data, and nuclear medicine data and review relevant documentation from the literature.\nA 72-year-old male recently diagnosed with new-onset atrial fibrillation was found to have suppressed thyroid-stimulating hormone (TSH) levels; elevated free T3, T4, and thyroid-stimulating immunoglobulin (TSI) levels; and a nonnodular thyroid gland with normal iodine uptake. He was diagnosed with Graves' disease and treated with propylthiouracil (PTU) for 5 years. When his poor compliance with PTU was impeding his antithyroid treatment, he was converted to methimazole. Within 1 month following methimazole initiation, his serum creatinine (SCr) had risen to 1.6× baseline in the absence of other contributing nephrotoxins. SCr returned to baseline within 2 weeks of methimazole discontinuation, and the patient was subsequently managed on PTU.\nAcute kidney injury with or without the presence of nephrotic syndrome may occur during treatment with methimazole. Renal function should be closely monitored after the initiation of methimazole to prevent progressive renal dysfunction.",
"affiliations": "Department of Pharmacy, Memphis VA Medical Center, Memphis, TN, USA.;Department of Pharmacy, Memphis VA Medical Center, Memphis, TN, USA.",
"authors": "Shell|Abigail|A|;Sullivan|Joshua W|JW|",
"chemical_list": "D013956:Antithyroid Agents; D008713:Methimazole; D011441:Propylthiouracil",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190018789277",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "33(1)",
"journal": "Journal of pharmacy practice",
"keywords": "Graves' disease; acute kidney injury; hyperthyroidism; methimazole; nephrotoxicity",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D013956:Antithyroid Agents; D006111:Graves Disease; D006801:Humans; D008297:Male; D008713:Methimazole; D009404:Nephrotic Syndrome; D011441:Propylthiouracil",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "99-101",
"pmc": null,
"pmid": "30111225",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Kidney Injury Following Methimazole Initiation: A Case Report.",
"title_normalized": "acute kidney injury following methimazole initiation a case report"
} | [
{
"companynumb": "US-PFIZER INC-2018368835",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"abstract": "Immune reconstitution inflammatory syndrome is a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of highly active antiretroviral therapy (HAART) in individuals infected with human immunodeficiency virus (HIV). It involves a wide range of pathogens, neoplasms such as Kaposi's sarcoma (KS) and some autoimmune diseases. We describe an autopsy report of a 40-year-old man infected with HIV. He experienced a rapid dissemination of KS resulting in death within 6 months after starting HAART. His serum viral load had significantly decreased 4 log10 within 32 days and his CD4+ T-cell count increased 4-fold. He presented with multiple skin lesions over the chin and anterior neck, which rapidly spread over the trunk, 4 extremities, perianal region, and penis. Finally, he developed acute dyspnea and a plain chest radiograph showed bilateral pulmonary infiltrations. Despite treatment, he died of acute respiratory failure. At autopsy, multiple KS lesions were noted in the bilateral lungs, liver, kidneys, and gastrointestinal tract. Increased inflammatory cytokines during immune reconstruction from HAART-reactive human herpes virus type-8 infection, linked to the tumorigenesis of KS, finally led to rapid dissemination and death.",
"affiliations": "Department of Pathology, Buddhist Tzu Chi General Hospital and University, Taiwan.;Department of Pathology, Buddhist Tzu Chi General Hospital and University, Taiwan.",
"authors": "Cheng|Chiu-Hsuan|CH|;Hsu|Yung-Hsiang|YH|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.4103/tcmj.tcmj_9_17",
"fulltext": "\n==== Front\nTzu Chi Med J\nCi Ji Yi Xue Za Zhi\nTCMJ\nTzu-Chi Medical Journal\n1016-3190 2223-8956 Medknow Publications & Media Pvt Ltd India \n\nTCMJ-29-41\n10.4103/tcmj.tcmj_9_17\nCase Report\nImmune reconstitution inflammatory syndrome-associated disseminated Kaposi's sarcoma in a patient infected with human immunodeficiency virus: Report of an autopsy case\nCheng Chiu-Hsuan a Hsu Yung-Hsiang ab* a Department of Pathology, Buddhist Tzu Chi General Hospital and University, Taiwan\nb School of Medicine, Tzu Chi University, Hualien, Taiwan\n* Address for correspondence: Dr. Yung-Hsiang Hsu, Department of Pathology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien, Taiwan. E-mail: yhhsu@mail.tcu.edu.tw\nJan-Mar 2017 \n29 1 41 45\n02 6 2016 09 8 2016 11 8 2016 Copyright: © 2017 Tzu Chi Medical Journal2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Immune reconstitution inflammatory syndrome is a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of highly active antiretroviral therapy (HAART) in individuals infected with human immunodeficiency virus (HIV). It involves a wide range of pathogens, neoplasms such as Kaposi's sarcoma (KS) and some autoimmune diseases. We describe an autopsy report of a 40-year-old man infected with HIV. He experienced a rapid dissemination of KS resulting in death within 6 months after starting HAART. His serum viral load had significantly decreased 4 log10 within 32 days and his CD4+ T-cell count increased 4-fold. He presented with multiple skin lesions over the chin and anterior neck, which rapidly spread over the trunk, 4 extremities, perianal region, and penis. Finally, he developed acute dyspnea and a plain chest radiograph showed bilateral pulmonary infiltrations. Despite treatment, he died of acute respiratory failure. At autopsy, multiple KS lesions were noted in the bilateral lungs, liver, kidneys, and gastrointestinal tract. Increased inflammatory cytokines during immune reconstruction from HAART-reactive human herpes virus type-8 infection, linked to the tumorigenesis of KS, finally led to rapid dissemination and death.\n\nKeywords\nAcquired immune deficiency syndromeHuman immunodeficiency virusImmune reconstitution inflammatory syndromeKaposi's sarcoma\n==== Body\nIntroduction\nThe use of highly active antiretroviral therapy (HAART) has resulted in a dramatic reduction in the incidence of opportunistic infections, acquired immune deficiency syndrome (AIDS)-defining illnesses, and mortality in patients infected with human immunodeficiency virus (HIV) [1]. However, a small proportion of patients with HIV infection exhibit deterioration in their clinical status following HAART initiation despite control of virologic and immunologic parameters. This clinical condition is called immune reconstitution inflammatory syndrome (IRIS) [1]. Kaposi's sarcoma (KS), one of the most common AIDS-related neoplasms associated with human herpesvirus type-8 (HHV-8), can also be reactivated in an IRIS-related process. We report an autopsy case of a 40-year-old man infected with HIV who experienced rapid dissemination of KS resulting in death after HAART. The rapid progression in this patient could be explained by an IRIS-related process.\n\nCase report\nA 40-year-old man who had been generally healthy came to our hospital in June 1996, with chief complaints of fever with chills and malaise for 2 months. He also had a weight loss of 8 kg within 1 month. Physical examination showed right cervical lymphadenopathy and a posterior pharyngeal tumor. The cervical lymph node proved to be tuberculosis on biopsy and acid-fast stain and the posterior pharyngeal tumor showed KS on histology. An abdomen to pelvic computed tomography (CT) scan did not show any abnormal lesion in the liver, spleen, and bilateral kidneys. Both HIV enzyme-linked immunosorbent assay and western blot were positive for HIV-1. The serologic test for syphilis was positive. He was treated with a combination of three antituberculosis drugs (ethanbuthol, pyrazinamide, isoniazid), acyclovir for herpes simplex virus infection, ceftriaxone, amikacin, and trimethoprim-sulfamethoxazole. He began receiving zidovudine in October in 1996. This was replaced by didanosine (ddI) 1 month later because of refractory bone marrow suppression.\n\nAt his second admission to our hospital in December 1996, multiple skin lesions were found over his chin and anterior neck. Excisional biopsies of those lesions revealed cutaneous KS. The CD4+ T-cell absolute count was only 18 cells/μL. Tuberculosis, syphilis, candidiasis, and cytomegalovirus retinitis were diagnosed and treated. The antiretroviral drug ddI was discontinued in January 1997. Bilateral pulmonary infiltrations were observed in chest radiographs. Pneumocystic pneumonia was impressed and treated with trimethoprim-sulfamethoxazole. The symptoms had improved at the time of hospital discharge.\n\nThe patient was admitted again 1 month later for dyspnea and cough with sputum production for 2 weeks. More immunosuppression was noted with a CD4+ T-cell absolute count of 10 cells/μL. HAART was initiated in April 1997 with zalcitabine, lamivudine, and saquinavir. The pre-HAART serum HIV RNA level was 313.1 × 103 copies/mL.\n\nThe HIV viral load decreased to 20.93 copies/mL (4 log10 drop) at 32 days after initiation of HAART. Meanwhile, the CD4+ T-cell count increased to 41 cells/μL (4-fold rise). However, the patient's skin lesions progressed to involve the trunk, all extremities, the perianal region, and foreskin of the penis. He received amputation of the right big toe because of KS following a biopsy.\n\nAfter 5 months, the patient developed fever with dyspnea. Bilateral diffuse pulmonary infiltrations were observed again in plain chest radiographs. Despite treatment with antituberculosis drugs, HAART, trimethoprim-sulfamethoxazole, cephapirin, and gentamycin, he died approximately 6 months after starting HAART.\n\nAt autopsy, multiple KS lesions were seen over the chin, neck, left flank, four extremities, perianal area, and prepuce of the penis, mostly presenting as nodular or ulcerative lesions. Two tumor masses were seen between the tonsils and between the tongue base and oropharynx. No pleural effusion was seen in the thoracic cavity. The right and left lungs weighed 750 and 780 g, respectively, and had thickened pleurae and foci of adhesions. Some hemorrhagic nodules were seen on the pleural surfaces. On cutting, hemorrhagic, yellowish nodules involving all segments of all lobes were found [Figure 1a]. The hilar nodes and paratracheal nodes were also involved by tumors. Serous ascitic fluid 300 mL was obtained from the abdominal cavity. Some foci of KS lesions were observed in the liver appearing as small nodules [Figure 1b]. The kidneys weighed 120 g each and were also involved by KS, especially in the cortical areas [Figure 1c]. In the gastrointestinal (GI) tract, many KS nodules were observed in the mucosa of the stomach (especially at the lesser curvature), duodenum, jejunum, ileum, colon, and anal canal. Those tumors presented with polypoid, nodular, and/or ulcerative patterns [Figure 1d–g].\n\nFigure 1 Gross appearance of Kaposi's sarcoma in various organs. (a) Multiple yellowish nodules surrounding the bronchovascular structures of the left lung. (b) A well-circumscribed lesion (arrow) 0.5 cm in diameter in the liver. (c) One nodular tumor (arrow) in the left kidney. (d) Two solid nodules at the lesser curvature surrounded by smaller lesions over the gastric mucosa. (e-g) Multiple polypoid or nodular lesions found throughout the entire alimentary tract\n\nMicroscopically, all representative tumor nodules were composed of spindle cells in fascicles or bundles or storiform, vascular channels filled with erythrocytes lined by flat endothelial cells and extravasated erythrocytes [Figure 2a], with HHV-8 antigen positivity [Figure 2b], diagnostic of KS. Multiple disseminated KS nodules involving the lungs surrounded the bronchioles and vessels (bronchocentric and angiocentric patterns), which were the cause of death in this patient [Figure 2c].\n\nFigure 2 Histological findings of Kaposi's sarcoma. (a) Skin: proliferating spindle cells and split-like vessels in the dermis (H and E, ×200). (b) Skin: human herpes virus type-8 positive (arrows) spindle cells (IHC, ×400). (c) Lung: Bronchocentric and angiocentric patterns (H and E, ×40)\n\nThe patient had no lesions in the liver, kidneys, or GI tract in the abdomen to pelvic CT scans taken in June 1996. Multiple disseminated KS was observed in several visceral organs at autopsy. Skin KS progression was noted 1 month after HAART in spite of a rise in the CD4+ T-cell count and a significant reduction in the viral load. Thus, his rapid progression before death could be explained as a consequence of IRIS.\n\nDiscussion\nKS was first described by Hungarian dermatologist, Moritz Kaposi, in 1872. It is the most common neoplasm in patients with AIDS. There are four epidermiological-clinical types of KS. The classic type occurs in the lower legs of elderly men of Mediterranean and East European descent and has a good prognosis. The endemic type, seen in Equatorial Africa, is aggressive in children, with frequent lymph node involvement. Posttransplant immunosuppressed patients may experience iatrogenic KS. AIDS-related KS is the most aggressive type and affects young homo- or bi-sexual men with frequent visceral organ involvement [2].\n\nTypically, KS involves the skin of the trunk, penis, legs, and feet and mucosa of the mouth and nose and less frequently affects visceral organs. Common extracutaneous sites of involvement are the GI tract, lung, liver, and lymph nodes. The incidence of pulmonary KS is approximately 10% in patients with AIDS and 6%–32% in patients with cutaneous KS. Pulmonary disease is seldom found without a concomitant extrapulmonary presentation [3]. The clinical presentation of pulmonary KS is nonspecific. The most common symptoms are cough, shortness of breath, and fever. The radiographic findings typically show reticulonodular infiltrations or diffuse interstitial infiltrations [4]. Pathologic findings consist of loosely aggregated spindle cells with atypical nuclei and occasional mitotic figures, often displaying angiocentric and lymphangitic distribution as in our case. Pulmonary lesions are typically less cellular than cutaneous lesions. Split-like spaces filled with erythrocytes are lined by flat endothelial cells. Extravasated erythrocytes and hemosiderin between the spindle cells are present [2].\n\nWidespread use of combined antiretroviral therapy and HAART has dramatically reduced the incidence and improved the prognosis of AIDS-associated KS. However, a small proportion of patients with HIV infection experience deterioration in their clinical status following initiation of HAART despite control of virologic and immunologic parameters. This clinical response, known as IRIS, has been related to a growing number of infectious, autoimmune, and neoplastic manifestations, including tuberculosis, nontuberculous mycobacteria, cryptococcus, herpesviruses, and KS [5].\n\nThe criteria proposed by French et al. define IRIS-associated KS as an abrupt clinical worsening of a previously existing KS (paradoxical IRIS-KS) or a new presentation of a previously unknown KS (unmasking IRIS-KS) in temporal association with initiation or reinitiation of HAART or change to a more active regimen, either with a concomitant reduction of at least 1 log10 in the HIV-1 RNA levels at the time of the IRIS event or with 2 of the following 3 minor criteria: (a) a 2-fold increase in the CD4+ T-cell count after HAART, (b) an increase in the immune response (HHV-8 antibodies), and (c) a spontaneous resolution of disease without specific chemotherapy with continuation of HAART [5].\n\nIRIS results from the rapid expansion of antigen-specific CD4+ and CD8+ lymphocytes following initiation of HAART [6] Recovery of the CD4 T lymphocyte count following HAART is normally biphasic. The first phase is associated with an increase in the numbers of CD45RO+ memory T-cells redistributed from lymphoid tissue to the peripheral circulation. Thereafter, a slower secondary increase of predominately naive CD4+ T-cells (CD45RA+, CD62 L+) occurs [7]. Interferon gamma (IFN-γ)-secreting CD4+ cells and an excess of T-helper 1 cytokines with a concomitant suppression of interleukin-10, a physiological suppressor of IFN-γ production, lead to an imbalance between pro- and anti-inflammatory immune responses during the immune reconstitution phase characterized by IRIS [6]. HAART can increase the absolute number of lymphocytes secreting tumor necrosis factor alpha, IFN-γ, and interleukin-1-beta, which are linked to the tumorogenesis of KS. These inflammatory cytokines both reactivate latent HHV-8 infection, and upregulate the expression of integrins, matrix metalloproteinases, and vascular endothelial growth factor receptors by endothelial cells [6]. In addition, most HIV-infected patients with KS have low or undetectable HHV-8-specific cytotoxic T lymphocytes. After the initiation of HAART, CD8+ T-cells specific for HHV-8 antigens are detectable. Thus, the recovery of this cell population is also thought to be partly responsible for IRIS [6].\n\nA prospective study in Mozambique identified 4 independent predictors of IRIS-KS, including clinical pretreatment of KS, detectable plasma HHV-8 DNA, hematocrit <30%, and a high plasma HIV viral load (≥50 copies/mL) [8]. Another study performed with the Chelsea and Westminster HIV cohort showed that IRIS-KS occurred in patients with higher CD4+ cell counts at the time of KS diagnosis, KS-associated edema, and whose receiving therapy with both protease inhibitors and nonnucleosides together [1].\n\nPulmonary KS is often fatal and almost always requires chemotherapy. Adding HAART to chemotherapy in patients with pulmonary KS significantly improved the median survival in a study conducted by Holkova et al. [9] However, HAART may rarely induce an immune system reconstitution and finally lead to death. Nonetheless, IRIS does not indicate failure of HAART or a need for changes in the antiretroviral regimen. Instead, chemotherapy in conjunction with HAART can effectively control the symptoms of IRIS and resolve KS [10].\n\nConclusion\nIn this case study and autopsy report, we present an unusually rapid dissemination of KS to various internal organs including pulmonary involvement, which was the cause of death, despite viral control and immunologic improvement by HAART. The pathogenesis was explained by an excess of inflammatory cytokines including KS tumorogenic ones during the IRIS-related process induced by treatment.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nDeclaration of patient's consent\nThe authors certify that the patient have obtained appropriate patient consent form. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initial will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n==== Refs\nReferences\n1 Bower M Nelson M Young AM Thirlwell C Newsom-Davis T Mandalia S Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma J Clin Oncol 2005 23 5224 8 16051964 \n2 Fletcher CD Bridge JA Hogendoorn PC Mertens F WHO Classification of Tumours of Soft Tissue and Bone 2013 4th ed Lyon IRAS Press 151 3 \n3 Wang TH Hsu YH Hsu WL Pulmonary Kaposi's sarcoma in patient with HIV infection: A case report Ther Radiol Oncol 2010 17 153 9 \n4 Garay SM Belenko M Fazzini E Schinella R Pulmonary manifestations of Kaposi's sarcoma Chest 1987 91 39 43 3792084 \n5 French MA Price P Stone SF Immune restoration disease after antiretroviral therapy AIDS 2004 18 1615 27 15280772 \n6 Stover KR Molitorisz S Swiatlo E Muzny CA A fatal case of Kaposi sarcoma due to immune reconstitution inflammatory syndrome Am J Med Sci 2012 343 421 5 22227511 \n7 Pakker NG Notermans DW de Boer RJ Roos MT de Wolf F Hill A Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: A composite of redistribution and proliferation Nat Med 1998 4 208 14 9461195 \n8 Letang E Almeida JM Miró JM Ayala E White IE Carrilho C Predictors of immune reconstitution inflammatory syndrome-associated with Kaposi sarcoma in mozambique: A prospective study J Acquir Immune Defic Syndr 2010 53 589 97 19801945 \n9 Holkova B Takeshita K Cheng DM Volm M Wasserheit C Demopoulos R Effect of highly active antiretroviral therapy on survival in patients with AIDS-associated pulmonary Kaposi's sarcoma treated with chemotherapy J Clin Oncol 2001 19 3848 51 11559722 \n10 Odongo FC Fatal disseminated Kaposi's sarcoma due to immune reconstitution inflammatory syndrome following HAART initiation Case Rep Infect Dis 2013 2013 546578\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": null,
"issue": "29(1)",
"journal": "Ci ji yi xue za zhi = Tzu-chi medical journal",
"keywords": "Acquired immune deficiency syndrome; Human immunodeficiency virus; Immune reconstitution inflammatory syndrome; Kaposi's sarcoma",
"medline_ta": "Ci Ji Yi Xue Za Zhi",
"mesh_terms": null,
"nlm_unique_id": "9514171",
"other_id": null,
"pages": "41-45",
"pmc": null,
"pmid": "28757763",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "9461195;19801945;23936695;15280772;11559722;3792084;16051964;22227511",
"title": "Immune reconstitution inflammatory syndrome-associated disseminated Kaposi's sarcoma in a patient infected with human immunodeficiency virus: Report of an autopsy case.",
"title_normalized": "immune reconstitution inflammatory syndrome associated disseminated kaposi s sarcoma in a patient infected with human immunodeficiency virus report of an autopsy case"
} | [
{
"companynumb": "TW-PFIZER INC-2017360097",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "A 65-year-old man with treatment-resistant psoriatic arthritis, hypertension, dyslipidaemia and benign prostatic hyperplasia (BPH) presented with herpes simplex virus (HSV) oral ulcers and a recent 15 lb weight loss due to reduced consumption. Five weeks previously, his methotrexate was tapered and he had begun taking azathioprine. The patient's thiopurine S-methyltransferase (TPMT) activity level was normal prior to starting azathioprine. He was found to have pancytopenia with normal folate levels and azathioprine was discontinued. His pancytopenia worsened, with a nadir 8 days after stopping azathioprine, before returning to normal levels. His oral ulcers improved and he was able to tolerate solid food. This case illustrates that decreased TPMT activity is not the only risk factor for pancytopenia as an adverse reaction to azathioprine. Furthermore, HSV stomatitis may be the presenting symptom of pancytopenia. The timeline of improvement in cell counts illustrated in this patient has implications for the management of suspected azathioprine-induced pancytopenia.",
"affiliations": "School of Medicine and Health Sciences, George Washington University, Washington, District of Columbia, USA.;Department of Medicine, George Washington University, Washington, District of Columbia, USA.;Department of Medicine, George Washington University, Washington, District of Columbia, USA.",
"authors": "Jensen|Caroline H|CH|;Tiu|John|J|;Catalanotti|Jillian S|JS|",
"chemical_list": "D007166:Immunosuppressive Agents; D008780:Methyltransferases; C000628225:TPMT protein, human; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "contraindications and precautions; haematology (drugs and medicines); malignant disease and immunosuppression; safety; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D001379:Azathioprine; D006561:Herpes Simplex; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008780:Methyltransferases; D019226:Oral Ulcer; D010198:Pancytopenia; D018139:Simplexvirus",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30002211",
"pubdate": "2018-07-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23270895;7249508;20970225;2299301;15705694;3467886;21270794;18250137;5059641;14566029;2341582;19550063;1115745;24029750;4185320;1494166;7458518;21712851;9336428",
"title": "Azathioprine-induced pancytopenia with normal TPMT activity presenting with HSV oral ulcers.",
"title_normalized": "azathioprine induced pancytopenia with normal tpmt activity presenting with hsv oral ulcers"
} | [
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"companynumb": "US-CELGENEUS-USA-20180710563",
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"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ADALIMUMAB"
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... |
{
"abstract": "We conducted a randomized controlled trial to investigate whether an additional platelet inhibition with tirofiban would reduce the extent of myocardial damage and prevent periprocedural myonecrosis in patients with Non-ST-elevation acute coronary syndrome (NSTE-ACS) with a high residual platelet activity (HPR).\n\n\n\nPatients with an HPR, defined as P2Y12 reaction unit (PRU) > 230, were randomly assigned to group A (tirofiban treatment, n = 30) or C1 (n = 30) and patients without an HPR to C2 (n = 78). Periprocedural myocardial damage was assessed using the area under the curve (AUC) of serial cardiac enzyme levels from the time of the procedure to post-36 h. Periprocedural myonecrosis incidence was evaluated.\n\n\n\nThe troponin I AUC was not different between the groups (197.2 [41.5395.7], 37.9 [8.9313.9], 121.3 [43.7481.8] h∙ng/mL; p = 0.088). The results did not change when the baseline levels were adjusted (365.3 [279.5, 451.1], 293.0 [207.1, 379.0], and 298.0 [244.7, 351.3] h∙ng/mL; p = 0.487). The rate of periprocedural myonecrosis was also not different between the groups (53.0% vs. 50.0% vs. 33.3%, p = 0.092). The CK-MB isoenzyme analysis showed similar results. No difference in complications was noted.\n\n\n\nAdditional tirofiban administration was not beneficial to patients with NSTE-ACS even with an HPR.\n\n\n\nClinical trial no. NCT03114995 , registered 11 April, 2017, retrospectively.",
"affiliations": "Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seongnam-si, Gyeonggi-do, Korea.;Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seongnam-si, Gyeonggi-do, Korea.;Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seongnam-si, Gyeonggi-do, Korea.;Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seongnam-si, Gyeonggi-do, Korea.;Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seongnam-si, Gyeonggi-do, Korea.;Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seongnam-si, Gyeonggi-do, Korea. ytjmd@snubh.org.;Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seongnam-si, Gyeonggi-do, Korea.",
"authors": "Lee|Wonjae|W|;Suh|Jung-Won|JW|;Park|Jin Joo|JJ|;Yoon|Chang-Hwan|CH|;Cho|Young-Seok|YS|;Youn|Tae-Jin|TJ|0000-0001-9957-4204;Chae|In-Ho|IH|",
"chemical_list": "D015415:Biomarkers; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D019210:Troponin I; D000077144:Clopidogrel; D052279:Creatine Kinase, MB Form; D000077466:Tirofiban; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1186/s12872-018-0938-6",
"fulltext": "\n==== Front\nBMC Cardiovasc DisordBMC Cardiovasc DisordBMC Cardiovascular Disorders1471-2261BioMed Central London 93810.1186/s12872-018-0938-6Research ArticleEffect of tailored use of tirofiban in patients with Non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: a randomized controlled trial Lee Wonjae wpiglet7@gmail.com 12Suh Jung-Won suhjw1@gmail.com 12Park Jin Joo jinjooparkmd@gmail.com 12Yoon Chang-Hwan kunson2@snu.ac.kr 12Cho Young-Seok flammeus1@gmail.com 12http://orcid.org/0000-0001-9957-4204Youn Tae-Jin +82-31-787-7031ytjmd@snubh.org 12Chae In-Ho ihchae@snubh.org 121 0000 0004 0470 5905grid.31501.36Division of Cardiology, Department of Internal Medicine, College of Medicine, Seoul National University, Seongnam-si, Gyeonggi-do Korea 2 0000 0004 0647 3378grid.412480.bCardiovascular Center, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do Korea 22 10 2018 22 10 2018 2018 18 2018 5 2018 10 10 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\nWe conducted a randomized controlled trial to investigate whether an additional platelet inhibition with tirofiban would reduce the extent of myocardial damage and prevent periprocedural myonecrosis in patients with Non-ST-elevation acute coronary syndrome (NSTE-ACS) with a high residual platelet activity (HPR).\n\nMethods\nPatients with an HPR, defined as P2Y12 reaction unit (PRU) > 230, were randomly assigned to group A (tirofiban treatment, n = 30) or C1 (n = 30) and patients without an HPR to C2 (n = 78). Periprocedural myocardial damage was assessed using the area under the curve (AUC) of serial cardiac enzyme levels from the time of the procedure to post-36 h. Periprocedural myonecrosis incidence was evaluated.\n\nResults\nThe troponin I AUC was not different between the groups (197.2 [41.5395.7], 37.9 [8.9313.9], 121.3 [43.7481.8] h∙ng/mL; p = 0.088). The results did not change when the baseline levels were adjusted (365.3 [279.5, 451.1], 293.0 [207.1, 379.0], and 298.0 [244.7, 351.3] h∙ng/mL; p = 0.487). The rate of periprocedural myonecrosis was also not different between the groups (53.0% vs. 50.0% vs. 33.3%, p = 0.092). The CK-MB isoenzyme analysis showed similar results. No difference in complications was noted.\n\nConclusion\nAdditional tirofiban administration was not beneficial to patients with NSTE-ACS even with an HPR.\n\nTrial registration\nClinical trial no. NCT03114995, registered 11 April, 2017, retrospectively.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12872-018-0938-6) contains supplementary material, which is available to authorized users.\n\nKeywords\nGlycoprotein IIb/IIIa inhibitorTailored antiplatelet treatmentPeriprocedural myonecrosisHigh residual platelet activityhttp://dx.doi.org/10.13039/100008378Handok Pharmaceuticalsissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nDual antiplatelet therapy (DAPT) plays a fundamental role in patients undergoing percutaneous coronary intervention (PCI). A decreased response to clopidogrel is related to higher myocardial damage, thus leading to a worse outcome after PCI [1, 2]. Numerous studies have been conducted to improve the outcomes by intensifying the antiplatelet therapy with intravenous glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors and newer-generation P2Y12 inhibitors [3–6]. However, using these drugs in all patients undergoing PCI does not seem cost-effective and increases unwanted bleeding events [7, 8]. Therefore, identifying patients who have a poor response to their current DAPT and require an additional antiplatelet treatment is critical. Ultegra Rapid Platelet Function Analyzer (VerifyNow®) is a point-of-care assay tool that can easily assess platelet reactivity after the administration of clopidogrel and aspirin. Studies showed that platelet reactivity inhibition measured by this device can predict the prognosis of patients who undergo PCI [9]. Tirofiban, a GP IIb/IIIa inhibitor, was known to be beneficial for broader sets of patients with acute coronary syndrome (ACS); however, recent studies have shown a limited role of tirofiban except for high-risk patients with Non-ST-elevation ACS (NSTE-ACS) undergoing an early invasive strategy [10–12].\n\nWe hypothesized that patients with NSTE-ACS stabilized with standard medical treatment can benefit from adding tirofiban to DAPT when they undergo PCI if they have a high platelet reactivity (HPR) identified using VerifyNow®.\n\nMethods\nStudy design\nThis was a prospective randomized clinical study conducted at Seoul National University Bundang Hospital from February 2012 to October 2015.\n\nWe consecutively enrolled patients who are already stabilized with standard medical treatment and diagnosed with NSTE-ACS. Patients had been loaded with aspirin and clopidogrel at least 6 h before the procedure. Patients were excluded if they were < 18 or ≥ 85 years old and had a contraindication for antiplatelet treatment, thrombocytopenia (platelet count < 100,000/μL), history of hemorrhagic stroke, history of ischemic stroke in the recent 2 years, or history of major surgery 6 months prior. All patients provided written informed consents, and the study was authorized by the local institutional review board. The full protocol of the present study has been registered at http://www.clinicaltrials.gov (clinical trial no. NCT03114995).\n\nFigure 1 summarizes the flow of this study. The standard loading doses were 300 mg of aspirin and 600 mg of clopidogrel. We administered a maintenance dose of aspirin 100 mg/d and clopidogrel 75 mg/d to all patients. The VerifyNow P2Y12 assay was used right before PCI at the catheterization laboratory. Based on previous study in our center, the sample size and cutoff value were determined [13].Fig. 1 Study flow of the randomized controlled trial\n\n\n\nWhen the P2Y12 reaction units (PRU) were reported, we designated patients with a cutoff value of ≥252 as the HPR group and randomized them into group A or control group C1. Computerized-random number table was used to generate the sequence, and patients were allocated to each group following simple randomization procedure. Randomization process were conducted by the research nurses right after PRU value were obtained. Patients without an HPR were allocated to control group C2. However, we adjusted the cutoff value of PRU to 230 after enrolling 42 patients (30 patients to control group C2), since there were fewer patients with HPR than the estimated number in the initial enrollment phase. Group A was treated with tirofiban (0.4 μg/kg/min continuous infusion for 30 min and then 0.10 μg/kg/min continuous infusion for 12 h) in addition to heparin (70 U/kg intravenous bolus infusion), while the control groups were administered only with heparin (140 U/kg intravenous bolus infusion). The level of cardiac biomarkers was measured right before the procedure and serially after the procedure at post-6, 12, 18, 24, 30, and 36 h. The cardiac biomarkers used in this study were cardiac troponin I (TnI: VITROS 5600 System, Ortho Clinical Diagnostics, Raritan, New Jersey, USA) and creatine kinase-MB isoenzyme (CK-MB, Dimension Vista 1500 system, Siemens Healthcare Diagnostics, Munich, Germany). All patients were followed up after 1 month to evaluate the clinical outcomes.\n\nPrimary, secondary objectives, and safety results\nThe primary objective of this study was to compare the myocardial damage primarily related to the procedure between the groups. The damage was assessed using the area under the curve (AUC) of the serial cardiac biomarker levels from the time of the procedure to post-36 h. AUC was calculated using the trapezoidal method. The adjusted AUC was calculated to exclude the differences in the cardiac biomarker level owing to the index MI event between the groups. The secondary objective was to evaluate the prevalence of periprocedural myonecrosis. We referenced the 2012 Third Universal Definition of Myocardial Infarction to determine the events of periprocedural myonecrosis with TnI and CK-MB. When the cardiac biomarkers before the procedure were within the 99th percentile upper reference limit (URL), more than a 5-fold elevation in the URL within 12 h after PCI was defined as periprocedural myonecrosis. If the cardiac biomarker level was already above the 99th percentile URL before the procedure and the trend was stationary or decreasing, a ≥ 20% increase compared to the previous level was considered periprocedural myonecrosis. If the trend was still increasing, the levels at the post-6 h and 12-h were compared to determine periprocedural myonecrosis. The PCI-related findings, including the involved vessels, the number of stents used, and immediate post-PCI complications were analyzed. Major adverse cardiac events, including the composite of cardiac death, nonfatal spontaneous myocardial infarction, and urgent target vessel revascularization, were evaluated at 1-month follow-up visit. Other adverse events, including bleeding, were also assessed. The TIMI criteria were used to classify bleeding complications into minimal, minor, and major.\n\nStatistical analysis\nWe planned to recruit 140 patients, expecting 80 patients to have a PRU ≥252 with the assumption of a 4:3 ratio in the general population. The assumption including cutoff value of PRU was derived from previous studies conducted in our center with Korean population [13]. We used the SPSS, version 17.0 (IBM, New York, New York, USA) to perform the statistical analyses. Continuous variables were presented as means±SD or medians [interquartile ranges (IQR)], and categorical variables as crude numbers and percentages. The student’s t-test was used to compare continuous variables and the chi-square or Fisher’s exact test to compare the frequency with categorical variables for the baseline characteristics. To compare the AUCs between the groups, the Kruskal-Wallis test and the Mann-Whitney U test with Bonferroni method for post hoc comparison were conducted. The adjusted AUC was compared while controlling for the initial cardiac enzymes using the one-way analysis of covariance. The results were shown in mean and 95% confidence interval. The chi-square test was used to analyze the periprocedural myonecrosis. Two-sided p values < 0.05 were considered significant.\n\nResults\nStudy population\nIn this study, 140 patients with NSTE-ACS undergoing PCI were enrolled during 44 months as planned. One patient in group A and 1 patient in control group C1 were dropped. Figure 2 shows the number of patients allocated to each group. Since there was a change in the cutoff value of PRU, 6 patients in the initial enrollment phase who had a PRU value between 230 and 252 were assigned to control group C2. In total, around half (48.6%) of the patients had a PRU value ≥230 as shown in Fig. 2.Fig. 2 Histogram showing the distribution of P2Y12 reaction units of all patients. The cut-off values of 230 and 252 are indicated to show the proportion of patients within the ranges\n\n\n\nBaseline characteristics and angiographic and PCI findings\nTables 1 and 2 show the baseline characteristics and PCI and angiographic findings. There was no difference between group A and control group C1 in the baseline characteristics, except for the number of men in control group C1 (control group C1 had a higher number of men [83.3% vs 56.7%, p = 0.048]). In the angiographic findings, group A tended to have more patients with multi-vessel PCI that was not statistically significant (group A: 43.3%, control group C1: 30.0%, p = 0.421). Otherwise, no differences were observed. Between control groups C1 and C2, the hematocrit level was significantly lower in control group C1 than in control group C2 (41.3 ± 4.3% vs 43.5 ± 4.4%, p = 0.022). The low-density lipoprotein cholesterol level was also lower in control group C1. There was no difference in the angiographic findings. Group A and control group C2 had a difference in the baseline characteristics, such as in sex, age, and diabetes. Group A had more stents per target lesion than control group C2 (1.20 ± 0.41 vs 1.05 ± 0.23, p = 0.009).Table 1 Baseline characteristics, laboratory findings, and P2Y12 reaction units\n\nVariables\tGroup A\tControl C1\tp Value\tControl C2\tp Value\tp Value\t\n\t\t\t(A vs C1)\t\t(C1vs C2)\t(A vs C2)\t\nDemographic characteristics\t\n Men (%)\t17 (56.7%)\t25 (83.3%)\t0.048\t67 (85.9%)\t0.973\t0.002\t\n Age (years)\t70.0 ± 12.8\t64.5 ± 12.0\t0.091\t62.9 ± 10.1\t0.486\t0.003\t\n Body mass index (kg/m2)\t25.1 ± 3.0\t24.6 ± 2.0\t0.474\t25.2 ± 3.1\t0.852\t0.320\t\n Diabetes\t14 (46.7%)\t8 (26.7%)\t0.180\t17 (21.8%)\t0.777\t0.020\t\n Hypertension\t19 (63.3%)\t17 (56.7%)\t0.792\t35 (44.9%)\t0.376\t0.132\t\nMedication at ER\t\n Aspirin loading\t27 (90.0%)\t22 (73.3%)\t0.182\t70 (89.7%)\t0.064\t1.000\t\n Clopidogrel loading\t27 (90.0%)\t27 (90.0%)\t1.000\t76 (97.4%)\t0.256\t0.256\t\n Beta blocker\t26 (89.7%)\t23 (76.7%)\t0.326\t71 (91.0%)\t0.095\t1.000\t\n ACEI/ARB\t23 (79.3%)\t25 (83.3%)\t0.950\t63 (80.8%)\t0.975\t1.000\t\n CCB\t1 (3.4%)\t1 (3.3%)\t1.000\t13 (16.7%)\t0.126\t0.139\t\n Statin\t28 (96.6%)\t30 (100.0%)\t0.986\t77 (98.7%)\t1.000\t1.000\t\nMajor laboratory findings\t\n Hematocrit (%)\t39.7 ± 5.8\t41.3 ± 4.3\t0.107\t43.5 ± 4.4\t0.022\t0.000\t\n Platelet (×103/μl)\t213.6 ± 49.0\t226.1 ± 63.2\t0.396\t220.9 ± 47.0\t0.639\t0.483\t\n Total cholesterol (mg/dl)\t162.9 ± 35.6\t176.1 ± 51.1\t0.261\t189.9 ± 38.5\t0.132\t0.002\t\n Triglyceride (mg/dl)\t129.6 ± 85.7\t133.5 ± 92.6\t0.867\t133.1 ± 81.1\t0.982\t0.848\t\n LDL cholesterol (mg/dl)\t98.4 ± 40.3\t100.2 ± 36.5\t0.861\t116.9 ± 33.5\t0.029\t0.022\t\n Serum creatinine (mg/dl)\t0.9 ± 0.6\t0.9 ± 0.2\t0.819\t0.8 ± 0.2\t0.262\t0.331\t\n Ejection fraction (%)\t57.1 ± 9.1\t59.8 ± 6.2\t0.201\t59.6 ± 6.5\t0.852\t0.134\t\n P2Y12 reaction units\t277.2 ± 39.2\t281.4 ± 38.4\t0.672\t171.1 ± 51.6\t0.000\t0.000\t\nER emergency room, ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin-receptor blocker, CCB calcium channel blocker, LDL low-density lipoprotein\n\nTable 2 Percutaneous coronary intervention procedure and angiographic findings\n\nVariables\tGroup A\tControl C1\tp Value\tControl C2\tp Value\tp Value\t\n\t\t(A vs C1)\t\t(C1vs C2)\t(A vs C2)\t\nLesion characteristics\t\n Multivessel PCI\t13 (43.3%)\t9 (30.0%)\t0.421\t25 (32.1%)\t1.000\t0.381\t\n Target vessel\t\n Left main disease\t0 (0.0%)\t1 (3.3%)\t1.000\t5 (6.4%)\t0.875\t0.378\t\n Left anterior descending artery\t18 (60.0%)\t19 (63.3%)\t1.000\t47 (60.3%)\t0.941\t1.000\t\n Left circumflex artery\t11 (36.7%)\t11 (36.7%)\t1.000\t31 (49.7%)\t0.941\t0.941\t\n Right coronary artery\t11 (36.7%)\t11 (36.7%)\t1.000\t20 (25.6%)\t0.370\t0.370\t\n IVUS guidance\t9 (31.0%)\t4 (13.3%)\t0.184\t21 (26.9%)\t0.213\t0.858\t\n Type B2/C lesion\t36 (73.5%)\t35 (79.5%)\t0.657\t90 (81.8%)\t0.922\t0.323\t\n Restenotic lesion\t2 (2.3%)\t1 (4.3%)\t1.000\t0 (0.0%)\t0.634\t0.161\t\n Angiographic thrombus\t13 (43.3%)\t11 (36.7%)\t0.792\t30 (38.5%)\t1.000\t0.807\t\nProcedure characteristics\t\n Stents per target lesion (n)\t1.20 ± 0.41\t1.09 ± 0.29\t0.124\t1.05 ± 0.23\t0.460\t0.009\t\n Stent type\t\n Drug eluting balloon\t1\t0\t\t0\t\t\t\n Bare metal stent\t0\t1\t\t0\t\t\t\n Drug-eluting stent\t53\t47\t\t117\t\t\t\n Stent size\t2.70 ± 0.47\t2.79 ± 0.46\t0.651\t2.84 ± 0.45\t0.409\t0.737\t\n Stent length\t23.7 ± 8.7\t21.8 ± 5.5\t0.548\t23.0 ± 8.7\t0.613\t0.838\t\n Duration of loading time to the procedure\t34.0 ± 18.6\t29.9 ± 18.3\t0.480\t29.4 ± 16.1\t0.917\t0.270\t\n Emergency PCI\t1\t1\t\t0\t\t\t\nPCI percutaneous coronary intervention, IVUS intravascular ultrasound\n\n\n\nComparison of the primary and secondary outcomes\nThe primary endpoint, AUCs of TnI and CK-MB, which represent the extent of periprocedural myocardial damage, was not different among the three groups (TnI, h∙ng/mL: 197.2 [41.5395.7] vs 37.9 [8.9313,9] vs 121.3 [43.7481.8], p = 0.088; CK-MB, h∙ng/mL: 252.5 [48.0,470.1] vs 92.7 [39.1402.1] vs 185.6 [79.7425.3], p = 0.258; Fig. 3). The post-hoc comparison between group A and control group C1 showed no difference (TnI: p = 0.147; CK-MB: p = 0.230). The AUCs were not different group A and C2 (TnI: p = 0.834; CK-MB: p = 0.781). The AUCs of TnI and CK-MB adjusted by the initial level of biomarkers are shown in Fig. 3. The adjusted AUCs (h∙ng/mL) of TnI were 365.3 [279.5, 451.1], 293.0 [207.1, 379.0], and 298.0 [244.7, 351.3]. The adjusted AUCs (h∙ng/mL) of CK-MB were 505.9 [373.7, 638.2], 336.2 [204.1, 468.3], and 333.2 [251.2, 415.2]. The adjusted AUCs confirmed that no difference exists in periprocedural myocardial damage between the groups (TnI: group A vs control group C1, p = 0.465; group A vs control group C2, p = 0.385; CK-MB: group A vs control group C1, p = 0.172; group A vs control group C2, p = 0.074) in the post-hoc comparison.Fig. 3 Comparison of area under curves of serial troponin I and creatine kinase-MB measurements between groups\n\n\n\nThe rates of periprocedural myonecrosis, the secondary endpoint, are shown in Fig. 4. The rates of periprocedural myonecrosis by TnI were 53.3% in group A, 50.0% in control group C1, and 33.3% in control group C2 (p = 0.092). The rates between the groups were not different (group A vs control group C1, p = 0.796; group A vs control group C2, p = 0.091). The rates of periprocedural myonecrosis by CK-MB in group A, control group C1, and control group C2 were 36.7%, 33.3%, and 32.1%, respectively (p = 0.901). The comparison between each group also showed no intergroup difference in the incidence of periprocedural myonecrosis (group A vs control group C1, p = 0.786; group A vs control group C2, p = 0.648).Fig. 4 Incidence of PMI by Troponin I and creatinine kinase-MB\n\n\n\nAnalysis of adverse outcomes\nThere were 2 major adverse cardiac events at 1-month follow-up only in group A. One patient had a massive hematochezia two week after the PCI due to early rectal cancer and died. The other patient died 3 days after the PCI, presumably due to a subacute stent thrombosis. Although the difference in the event rate was not statistically significant between the 3 groups, the mortality cases in group A should be noted. Except for the abovementioned case of hematochezia, no major bleeding was observed in all groups. The event rate of minor to minimal bleeding, such as small hematomas, in group A was the highest with 13.3% among the groups (control group C1: 3.3%; control group C2: 10.3%); however, the differences were not statistically significant.\n\nSubgroup analysis with PRU ≥ 252\nSince the PRU cutoff value 230 could not show any difference in the primary endpoints, we did a subgroup analysis using a PRU 252, a cutoff value initially proposed. Twenty-four patients in group A (group A’) and 21 patients in control group C1 (control C1’) were analyzed. The subgroup analysis did not show any difference between the 2 groups (Fig. 5); the AUCs by TnI were 197.2 [43.2, 383.3] and 17.6 [8.9, 566.5] h∙ng/mL (p = 0.220), and that by CK-MB were 278.5 [86.6, 477.1] and [53.6 [38.7, 464.2] h∙ng/mL (p = 0.104), respectively. The adjusted AUCs were also similar between group A’ and control C1’ (TnI, h∙ng/mL: 373.1 [279.7, 466.4] vs. 298.5 [198.8, 398.3], p = 0.277; CK-MB, h∙ng/mL: 550.1 [304.0, 796.2] vs. 320.4 [57.3, 583.5], p = 0.206).Fig. 5 Subgroup analysis in patients with platelet reactivity unit≥252 comparing area under curves of serial troponin I and creatine kinase-MB measurements between groups\n\n\n\nDiscussion\nWe assessed the benefit of the tailored antiplatelet therapy with GP IIb/IIIa inhibitor tirofiban in patients with NSTE-ACS undergoing PCI who were stabilized with standard medical treatment. Tirofiban did not either reduce the extent of myocardial damage or the incidence of periprocedural myonecrosis in patients who had an HPR defined by a PRU ≥ 230. Although tirofiban tended to increase bleeding events, they were mostly minor, which were not significant and similar to the control groups. A noteworthy finding was that approximately half of the patients enrolled did not achieve an adequate response to clopidogrel before PCI even though clopidogrel was loaded 30.4 ± 17.1 h before PCI on average.\n\nConflicting results of tailored antiplatelet therapies\nA meta-analysis by Daniel et al. showed that a high clopidogrel platelet reactivity measured by an ADP-specific platelet function assay is a strong predictor of major adverse cardiac events in patients after PCI [1]. It was reported that platelet reactivity assessed using the point-of-care assay VerifyNow had a prognostic significance on thrombotic events after drug-eluting stent implantation [9]. Boosted by these findings, series of studies have been conducted to assess the efficacy of a tailored antiplatelet treatment in patients undergoing PCI. A landmark study conducted by Bonello et al. demonstrated that the rate of stent thrombosis and major adverse cardiac events was significantly lower in patients undergoing PCI when a tailored clopidogrel loading dose was given [14]. Patients were administered up to 3 additional loading doses of clopidogrel to achieve an adequate inhibition assessed by the vasodilator-stimulated phosphoprotein index. Valgimigli et al. reported that tirofiban lowered the incidence of MI after elective coronary intervention when administered to low-risk patients who had a poor responsiveness to standard oral platelet inhibitors [15]. A recent observational study conducted by Dridi et al. also showed that patients exhibiting an HPR benefited from the tailored antiplatelet therapy with either a double-dose clopidogrel or the newer P2Y12-inhibitors [16]. However, large clinical trials reported different results on tailored antiplatelet therapies. The GRAVITAS randomized trial, which enrolled 2214 patients with stable angina and NSTE-ACS, concluded that the use of a high-dose clopidogrel in non-responders did not reduce the incidence of ischemic events [17]. In the ARCTIC trial that studied 2440 patients scheduled for an elective PCI, the investigators administered an additional dose of clopidogrel, prasugrel, or aspirin with GP IIb/IIIa inhibitors to the monitored group if the patients had an HPR. The study did not show significant improvements in the clinical outcomes in the monitored group compared to the conventional treatment group without monitoring [18]. In line with these trials, we previously reported in the DM-Verify Now trial that a tailored antiplatelet therapy could not reduce periprocedural myonecrosis in patients with diabetes mellitus [19]. Our study results are consistent with those of previous large clinical trials, which could not demonstrate an improvement in the clinical outcomes of guided antiplatelet therapies with platelet function tests. To date, the current guidelines do not support the routine use of platelet function tests [20]. There were few studies conducted with newer P2Y12 agent for tailored antiplatelet treatment. Aradi et al. evaluated the impact of prasugrel and high-dose clopidogrel for HPR patient with ACS [21]. Switching to prasugrel resulted in better clinical outcome. ANTARCTIC trial is a large scale randomized controlled trial which compared conventional treatment and tailored antiplatelet treatment using prasugrel [22]. In the monitoring group, patient Patients in monitoring groups were tested with VerifyNow assay 14 days after initiation of prasugrel, and the dose of prasugrel of patients with platelet reactivity below 208 were increased to 10 mg. However, tailored antiplatelet treatment did not provide improved clinical outcomes.\n\nIt is possible that conflicting results may have resulted from different study protocols such as modality for measuring antiplatelet reactivity, cutoff values, and timing of measurement. A meta-analysis by Aradi et al. revealed that there were large inter-study and intra-assay heterogeneity in the prevalence of HPR that resulted in a range of 6% to 80%, driven by the differences in the test methods and cutoff values [1]. In fact, several representative trials such as GRAVITAS, TRIGGER-PCI, and ARTIC which used VerifyNow all failed to show improvement in clinical outcomes, whereas other studies which used VASP assay, LTA, or MEA demonstrated the benefit of tailored antiplatelet therapy [23]. Cutoff values for HPR of VerifyNow were mostly between 230 and 240, but recent studies such as ANTARTIC trial used PRU of 208 to define HPR [2, 18, 22]. Timing of measurement also varied. Many studies tested platelet reactivity at least 12 h after loading of clopidogrel, but some studies were as early as 6 h [14, 17, 24]. In GRAVITAS trial, on-treatment reactivity decreased significantly over the first 30 days, and the extent was different between standard dose and high dose clopidogrel while PRU in 48 h were similar [17]. Given that platelet reactivity is enhanced in patients with ACS at early phase, single measurement may not be sufficient to reflect patient’s risk especially in ACS [25, 26].\n\nPotential role of tirofiban in patients with an HPR\nEarlier studies demonstrated that GP IIb/IIIa inhibitors reduce the mortality and other major adverse cardiac events in patients with ACS or undergoing PCI [27, 28]. Desai et al. pointed out that numerous early studies on GP IIb/IIIa inhibitors were conducted without a concomitant antiplatelet therapy with a thienopyridine, a prior standard treatment [12]. This implies that there may be an additional role of GP IIb/IIIa inhibitors for patients when the pretreatment with clopidogrel does not achieve an adequate platelet inhibition. Moreover, benefits could be more evident for patients with higher risks, such as elevated cardiac biomarker levels. However, our findings suggest that the GP IIb/IIIa inhibitor tirofiban does not provide an additional protection to the myocardium regardless of the platelet reactivity after the treatment with aspirin and clopidogrel. It is noteworthy that the subgroup analysis of the patients who had an elevated TnI before PCI showed no tirofiban benefits. One explanation is that our patients were already stabilized with conventional or low-molecular-weight heparin before PCI, thus reducing the thrombotic complications during PCI. In the ISAR-REACT 2 trial that showed the efficacy of abciximab in patients with NSTE-ACS, especially when the TnI level was elevated, clopidogrel loading was performed at least 2 h with an average of 6 h before PCI; in our trial, it was performed 31.5 h on average, which may have given enough time to stabilize patients with the full effects of heparinization.\n\nLimitations\nThe limitation of our study is that we adjusted the cutoff value early in the trial. As planned, 140 patients in total were enrolled in this study. However, we could not gather enough number of patients who have an HPR to clopidogrel for the study groups, since the distribution of the PRU value among the patients was not similar to a previous study conducted in our center. Park et al. suggested that platelet reactivity < 275 PRU is sufficient to achieve lower risks of cardiac death, MI, and stent thrombosis in Koreans. However, they also validated that platelet reactivity between PRU 230 to 240 is an important risk factor for primary outcome in multivariate analysis similar to previous studies with Caucasians [9, 24, 29]. Thus, we also applied a cutoff value of PRU 230, but the low cutoff value may have limited the power to discern the high-risk group that has resistance to clopidogrel, masking the additive effect of tirofiban. To mitigate the issue, we conducted subgroup analysis using cutoff value of 252 for comparison of group A and C1, and the results was not different. In addition, since 6 patients with 230 ≤ PRU < 252 who might have been randomized into Group A or C1 were included in group C2, we performed same analysis after excluding them to confirm there is no difference in result due to change of the cutoff value (Additional file 1: Figure S1 and Additional file 2: Figure S2). There were some differences in baseline characteristics that may have limited the positive results in the tirofiban group though statistically insignificant. The patients in the tirofiban group tended to have more multivessel PCIs and the higher initial value of TnI and CK-MB. This may have resulted from the relatively small number of patients in the study group which could lead to an unsatisfactory randomization. However, we conducted an adjusted AUC analysis that can partly mitigate these issues, and the results were not different. Finally, recent guidelines suggest that prasugrel or ticagrelor should be used in high-risk patients undergoing PCI to overcome antiplatelet resistance [11]. Thus, it may be simpler to use prasugrel or ticagrelor instead of clopidogrel with PRU guidance. However, experts’ consensus is that Asian population has different risk profile on thrombophilia and bleeding compared to Caucasian [30]. The PRASFIT-ACS showed the lower dose of Prasugrel has similar efficacy with lower risk of bleeding in Japanese patients with ACS [31]. Above all, newer-generation P2Y12 inhibitors were not available in Korea when the study was designed. Finally, long recruitment period is another limitation of this study.\n\nConclusion\nWe showed that tirofiban infusion in patients with NSTE-ACS who are poor responders to clopidogrel could not decrease the extent of periprocedural myocardial damage and the rate of periprocedural myonecrosis. Our study suggests that further trials are needed to clarify further the benefit of tailored antiplatelet therapies in patients undergoing PCI.\n\nAdditional files\n\nAdditional file 1: Figure S1. Comparison of area under curves of serial troponin I and creatine kinase-MB measurements between groups (6 patients with PRU higher than 252 in control C2 excluded). (PDF 123 kb)\n\n \nAdditional file 2: Figure S2. Incidence of PMI by Troponin I and creatinine kinase-MB (6 patients with PRU higher than 252 in control C2 excluded). (PDF 76 kb)\n\n \nAdditional file 3: Raw data. (XLSX 343 kb)\n\n \n\n\nAbbreviations\nACSAcute coronary syndrome\n\nAUCArea under curve\n\nCK-MBCreatine kinase-MB isoenzyme\n\nDAPTDual antiplatelet therapy\n\nGP IIb/IIIaGlycoprotein IIb/IIIa\n\nHPRHigh platelet reactivity\n\nIQRInterquartile ranges\n\nNSTE-ACSNon-ST-elevation ACS\n\nPCIPercutaneous coronary intervention\n\nPRUP2Y12 reaction units\n\nTnITroponin I\n\nURLUpper reference limit\n\nThe work was conducted at Seoul National University Bundang Hospital.\n\nWonjae Lee and Jung-Won Suh contributed equally to this work.\n\nAcknowledgements\nNone\n\nFunding\nThis clinical trial was supported by Handok Phamaceutical Ltd. The role of funding was primarily in the collection of the data and not in writing the manuscript.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article and its Additional file 3.\n\nAuthors’ contributions\nResearch idea and study design: IHC, TJY; patients enrollment: IHC, TJY, YSC, JWS, CHY, JWS, data extraction and quality assessment: TJY, YSC, JWS; literature search: JWS, WJL; data analysis and interpretation: TJY, JWS, CHY, JJP, WJL; statistical analysis: JWS, WJL; supervision and mentorship: IHC, YSC; writing manuscript: JWS, WJL. Each author contributed important intellectual content during the writing of the manuscript and each accepts accountability for the overall work by confirming that questions pertaining to the accuracy or integrity of any portion of the work have been appropriately investigated and resolved. All authors read and approved the final version of the manuscript. TJY confirms that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.\n\nEthics approval and consent to participate\nAll informed written consents were obtained when enrolling the patients. and the study was authorized by Seoul National University Bundang Hospital Institutional Review Board.\n\nConsent for publication\nNot applicable\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. Aradi D Komocsi A Vorobcsuk A Rideg O Tokes-Fuzesi M Magyarlaki T Horvath IG Serebruany VL Prognostic significance of high on-clopidogrel platelet reactivity after percutaneous coronary intervention: systematic review and meta-analysis Am Heart J 2010 160 3 543 551 10.1016/j.ahj.2010.06.004 20826265 \n2. Mangiacapra F Barbato E Patti G Gatto L Vizzi V Ricottini E D'Ambrosio A Wijns W Di Sciascio G Point-of-care assessment of platelet reactivity after clopidogrel to predict myonecrosis in patients undergoing percutaneous coronary intervention JACC Cardiovasc Interv 2010 3 3 318 323 10.1016/j.jcin.2009.12.012 20298992 \n3. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med. 1997;336(24):1689–96.\n4. Lindholm D, Varenhorst C, Cannon CP, Harrington RA, Himmelmann A, Maya J, Husted S, Steg PG, Cornel JH, Storey RF, et al. Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial. Eur Heart J. 2014.\n5. Giugliano RP White JA Bode C Armstrong PW Montalescot G Lewis BS van’t Hof A Berdan LG Lee KL Strony JT Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes N Engl J Med 2009 360 21 2176 2190 10.1056/NEJMoa0901316 19332455 \n6. Trenk D Stone GW Gawaz M Kastrati A Angiolillo DJ Muller U Richardt G Jakubowski JA Neumann FJ A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (testing platelet reactivity in patients undergoing elective stent placement on Clopidogrel to guide alternative therapy with Prasugrel) study J Am Coll Cardiol 2012 59 24 2159 2164 10.1016/j.jacc.2012.02.026 22520250 \n7. Mehilli J Kastrati A Schühlen H Dibra A Dotzer F von Beckerath N Bollwein H Pache J Dirschinger J Berger PP Randomized clinical trial of Abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of Clopidogrel Circulation 2004 110 24 3627 3635 10.1161/01.CIR.0000148956.93631.4D 15531766 \n8. Kastrati A Mehilli J Schühlen H Dirschinger J Dotzer F ten Berg JM Neumann F-J Bollwein H Volmer C Gawaz M A clinical trial of Abciximab in elective percutaneous coronary intervention after pretreatment with Clopidogrel N Engl J Med 2004 350 3 232 238 10.1056/NEJMoa031859 14724302 \n9. Price MJ Endemann S Gollapudi RR Valencia R Stinis CT Levisay JP Ernst A Sawhney NS Schatz RA Teirstein PS Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation Eur Heart J 2008 29 8 992 1000 10.1093/eurheartj/ehn046 18263931 \n10. Kastrati A Mehilli J Neumann FJ Dotzer F ten Berg J Bollwein H Graf I Ibrahim M Pache J Seyfarth M Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial Jama 2006 295 13 1531 1538 10.1001/jama.295.13.joc60034 16533938 \n11. Amsterdam EA Wenger NK Brindis RG Casey JDE Ganiats TG Holmes JDR Jaffe AS Jneid H Kelly RF Kontos MC 2014 AHA/ACC guideline for the Management of Patients with non–ST-elevation acute coronary SyndromesA report of the American College of Cardiology/American Heart Association task force on practice guidelines J Am Coll Cardiol 2014 64 24 e139 e228 10.1016/j.jacc.2014.09.017 25260718 \n12. Desai NR Bhatt DL The state of periprocedural antiplatelet therapy after recent trials JACC Cardiovasc Interv 2010 3 6 571 583 10.1016/j.jcin.2010.04.008 20630450 \n13. Suh JW Lee SP Park KW Lee HY Kang HJ Koo BK Cho YS Youn TJ Chae IH Choi DJ Multicenter randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: results of the CILON-T (influence of CILostazol-based triple antiplatelet therapy ON ischemic complication after drug-eluting stenT implantation) trial J Am Coll Cardiol 2011 57 3 280 289 10.1016/j.jacc.2010.08.631 21232664 \n14. Bonello L Camoin-Jau L Armero S Com O Arques S Burignat-Bonello C Giacomoni MP Bonello R Collet F Rossi P Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis Am J Cardiol 2009 103 1 5 10 10.1016/j.amjcard.2008.08.048 19101221 \n15. Valgimigli M Campo G de Cesare N Meliga E Vranckx P Furgieri A Angiolillo DJ Sabate M Hamon M Repetto A Intensifying platelet inhibition with tirofiban in poor responders to aspirin, clopidogrel, or both agents undergoing elective coronary intervention: results from the double-blind, prospective, randomized tailoring treatment with Tirofiban in patients showing resistance to aspirin and/or resistance to Clopidogrel study Circulation 2009 119 25 3215 3222 10.1161/CIRCULATIONAHA.108.833236 19528337 \n16. Paarup Dridi N Johansson PI Lonborg JT Clemmensen P Radu MD Qayyum A Pedersen F Kollslid R Helqvist S Saunamaki K Tailored antiplatelet therapy to improve prognosis in patients exhibiting clopidogrel low-response prior to percutaneous coronary intervention for stable angina or non-ST elevation acute coronary syndrome Platelets 2015 26 6 521 529 10.3109/09537104.2014.948837 25166751 \n17. Price MJ Berger PB Teirstein PS Tanguay JF Angiolillo DJ Spriggs D Puri S Robbins M Garratt KN Bertrand OF Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial Jama 2011 305 11 1097 1105 10.1001/jama.2011.290 21406646 \n18. Collet JP Cuisset T Range G Cayla G Elhadad S Pouillot C Henry P Motreff P Carrie D Boueri Z Bedside monitoring to adjust antiplatelet therapy for coronary stenting N Engl J Med 2012 367 22 2100 2109 10.1056/NEJMoa1209979 23121439 \n19. Suh JW Kim CH Oh IY Yoon CH Kim KI Cho YS Youn TJ Chae IH Choi DJ Effect of tailored antiplatelet therapy on periprocedural myonecrosis in patients with diabetes mellitus (from the DM-Verify now trial) Am J Cardiol 2012 110 12 1749 1755 10.1016/j.amjcard.2012.08.009 22999073 \n20. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery DiseaseA Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68(10):1082–15.\n21. Aradi D Tornyos A Pinter T Vorobcsuk A Konyi A Falukozy J Veress G Magyari B Horvath IG Komocsi A Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel J Am Coll Cardiol 2014 63 11 1061 1070 10.1016/j.jacc.2013.12.023 24486281 \n22. Cayla G Cuisset T Silvain J Leclercq F Manzo-Silberman S Saint-Etienne C Delarche N Bellemain-Appaix A Range G El Mahmoud R Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial Lancet 2016 388 10055 2015 2022 10.1016/S0140-6736(16)31323-X 27581531 \n23. Siller-Matula JM Jilma B Why have studies of tailored anti-platelet therapy failed so far? Thromb Haemost 2013 110 4 628 631 23884166 \n24. Patti G Nusca A Mangiacapra F Gatto L D'Ambrosio A Di Sciascio G Point-of-care measurement of clopidogrel responsiveness predicts clinical outcome in patients undergoing percutaneous coronary intervention results of the ARMYDA-PRO (antiplatelet therapy for reduction of MYocardial damage during angioplasty-platelet reactivity predicts outcome) study J Am Coll Cardiol 2008 52 14 1128 1133 10.1016/j.jacc.2008.06.038 18804738 \n25. Althoff TF Fischer M Langer E Ziemer S Baumann G Sustained enhancement of residual platelet reactivity after coronary stenting in patients with myocardial infarction compared to elective patients Thromb Res 2010 125 5 e190 e196 10.1016/j.thromres.2010.01.003 20116087 \n26. Geisler T Kapp M Göhring-Frischholz K Daub K Dösch C Bigalke B Langer H Herdeg C Gawaz M Residual platelet activity is increased in clopidogrel- and ASA-treated patients with coronary stenting for acute coronary syndromes compared with stable coronary artery disease Heart 2008 94 6 743 747 10.1136/hrt.2006.100891 17567647 \n27. Kong DF Califf RM Miller DP Moliterno DJ White HD Harrington RA Tcheng JE Lincoff AM Hasselblad V Topol EJ Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease Circulation 1998 98 25 2829 2835 10.1161/01.CIR.98.25.2829 9860783 \n28. Karvouni E Katritsis DG Ioannidis JPA Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions J Am Coll Cardiol 2003 41 1 26 32 10.1016/S0735-1097(02)02666-9 12570940 \n29. Park KW Jeon KH Kang SH Oh IY Cho HJ Lee HY Kang HJ Park SK Koo BK Oh BH Clinical outcomes of high on-treatment platelet reactivity in Koreans receiving elective percutaneous coronary intervention (from results of the CROSS VERIFY study) Am J Cardiol 2011 108 11 1556 1563 10.1016/j.amjcard.2011.07.012 21880289 \n30. Levine GN Jeong YH Goto S Anderson JL Huo Y Mega JL Taubert K Smith SC Jr Expert consensus document: world heart federation expert consensus statement on antiplatelet therapy in east Asian patients with ACS or undergoing PCI Nat Rev Cardiol 2014 11 10 597 606 10.1038/nrcardio.2014.104 25154978 \n31. Saito S Isshiki T Kimura T Ogawa H Yokoi H Nanto S Takayama M Kitagawa K Nishikawa M Miyazaki S Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome: the PRASFIT-ACS study Circ J 2014 78 7 1684 1692 10.1253/circj.CJ-13-1482 24759796\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2261",
"issue": "18(1)",
"journal": "BMC cardiovascular disorders",
"keywords": "Glycoprotein IIb/IIIa inhibitor; High residual platelet activity; Periprocedural myonecrosis; Tailored antiplatelet treatment",
"medline_ta": "BMC Cardiovasc Disord",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin; D015415:Biomarkers; D000077144:Clopidogrel; D017023:Coronary Angiography; D052279:Creatine Kinase, MB Form; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D009336:Necrosis; D000072658:Non-ST Elevated Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors; D010979:Platelet Function Tests; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists; D066106:Seoul; D013997:Time Factors; D000077466:Tirofiban; D016896:Treatment Outcome; D019210:Troponin I",
"nlm_unique_id": "100968539",
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"title": "Effect of tailored use of tirofiban in patients with Non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: a randomized controlled trial.",
"title_normalized": "effect of tailored use of tirofiban in patients with non st elevation acute coronary syndrome undergoing percutaneous coronary intervention a randomized controlled trial"
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"abstract": "The present retrospective study analyzed the tolerance of orthotopic ileal neobladders to radiotherapy by reviewing the acute and late toxicity in patients who underwent postoperative radiotherapy after radical cystectomy/cystoprostatectomy.\n\n\n\nA multi-institutional database was created for patients who had undergone radical cystectomy/cystoprostatectomy and neobladder reconstruction, followed by adjuvant radiotherapy (RT). The patient and tumor characteristics were recorded. The RT data were reviewed to determine the treatment technique used, the radiation dose received by the neobladder, and acute and late toxicity evaluated using the Common Terminology Criteria for Adverse Events, version 4.0, scale.\n\n\n\nA total of 25 patients were included, with a median age of 64 years. Of the 25 patients, 18 received a dose of 45 to 50.4 Gy. The most common reasons for postoperative radiotherapy were close or positive surgical margins and pT3-pT4 or N+ disease. Ten patients underwent intensity modulated RT. All but 1 patient completed the RT course. Of the patients who completed their RT schedule, none had grade ≥ 3 acute gastrointestinal toxicity. One patient who received concurrent chemotherapy developed grade 3 acute genitourinary toxicity. Three patients reported late grade 1 genitourinary toxicity (frequency of urination, mild leakage at night), with no reports of chronic gastrointestinal toxicity. None of the patients experienced neobladder perforation, leak, or fistula.\n\n\n\nThe use of moderate doses of pelvic RT (range, 45-50.4 Gy) was well tolerated among the 25 patients who underwent RT after cystoprostatectomy with orthotopic neobladder creation. This finding supports the use of postoperative RT to moderate doses in this patient population when clinically indicated.",
"affiliations": "Department of Radiation Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA. Electronic address: lballas@med.usc.edu.;Département de Radiothérapie, Institut Bergonie, Bordeaux, France.;Département de Radiothérapie, Institut Bergonie, Bordeaux, France.;Department of Radiation Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.;Institute of Urology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.;Department of Radiation Oncology, The Ottawa Hospital Cancer Centre, Ottowa, ON, Canada.",
"authors": "Ballas|Leslie|L|;Sargos|Paul|P|;Orré|Mathieu|M|;Bian|Shelly X|SX|;Daneshmand|Siamak|S|;Eapen|Libni J|LJ|",
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"mesh_terms": "D000368:Aged; D015653:Cystectomy; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms; D016476:Urinary Reservoirs, Continent",
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"references": null,
"title": "Tolerance of Orthotopic Ileal Neobladders to Radiotherapy: A Multi-institutional Retrospective Study.",
"title_normalized": "tolerance of orthotopic ileal neobladders to radiotherapy a multi institutional retrospective study"
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"abstract": "Anaphylactic reactions to protamine are quite rare and almost exclusively reported during cardiac surgery. In this report, we illustrate a rare case of protamine reaction after peripheral vascular surgery a couple of months after cardiac surgery and how the patient survived this critical complication.",
"affiliations": "Department of Vascular Surgery, Jessa Hospital, Hasselt, Belgium. Electronic address: maxim.peeters@jessazh.be.;Department of Cardiothoracic Surgery, Jessa Hospital, Hasselt, Belgium.;Department of Vascular Surgery, Jessa Hospital, Hasselt, Belgium.;Department of Cardiothoracic Surgery, Jessa Hospital, Hasselt, Belgium.",
"authors": "Peeters|Maxim|M|;Yilmaz|Alaaddin|A|;Vandekerkhof|Jos|J|;Kaya|Abdullah|A|",
"chemical_list": "D006494:Heparin Antagonists; D011479:Protamines",
"country": "Netherlands",
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"doi": "10.1016/j.avsg.2020.06.016",
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"issn_linking": "0890-5096",
"issue": "69()",
"journal": "Annals of vascular surgery",
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"medline_ta": "Ann Vasc Surg",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D016887:Cardiopulmonary Resuscitation; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease; D004342:Drug Hypersensitivity; D015199:Extracorporeal Membrane Oxygenation; D006494:Heparin Antagonists; D006801:Humans; D008297:Male; D058729:Peripheral Arterial Disease; D011479:Protamines; D016896:Treatment Outcome; D058017:Vascular Grafting",
"nlm_unique_id": "8703941",
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"pages": "450.e13-450.e15",
"pmc": null,
"pmid": "32554194",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Protamine Induced Anaphylactic Shock after Peripheral Vascular Surgery.",
"title_normalized": "protamine induced anaphylactic shock after peripheral vascular surgery"
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{
"abstract": "Mefenamic acid is a fenamate nonsteroidal anti-inflammatory (NSAI) drug, which is used for several years for pain management. However, it has been rarely reported that, mefenamic acid can induce central nervous system toxicity both in toxic doses and therapeutic usage. We report a case of a 27-year-old female who presented to the emergency department (ED) with altered mental status and vomiting. On admission to the ED, she was lethargic and disoriented. Her vital signs were normal and her physical examination was completely normal except dysarthric speech. The etiology of altered mental status was investigated with electrolyte levels, cranial computed tomography, cranial magnetic resonance imaging and EEG, however the results were normal. Her blood gas analysis revealed a deep metabolic acidosis with a pH of 7.14. Neither etiologic agent nor drug use history was provided at the presentation; she had only osteogenesis imperfecta since several years and she had been using various NSAI drugs. However, her relatives later stated that, she took mefenamic acid for her pains since two weeks. After her admission to intensive care unit, her neurologic state was improved gradually after plasmapheresis and she was discharged healthy. Although mefenamic acid has been considered as one of the safe NSAI drugs, its effects due to central nervous system toxicity should be cautiously handled.",
"affiliations": "Department of Emergency Medicine, Kocaeli University, Faculty of Medicine, Kocaeli, Turkey. Electronic address: nurettinozgurdogan@gmail.com.;Department of Emergency Medicine, Kocaeli University, Faculty of Medicine, Kocaeli, Turkey.;Department of Emergency Medicine, Kocaeli University, Faculty of Medicine, Kocaeli, Turkey.",
"authors": "Doğan|Nurettin Özgür|NÖ|;Çaylak|Sevinç Taş|ST|;Yılmaz|Serkan|S|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D008528:Mefenamic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2018.11.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "37(3)",
"journal": "The American journal of emergency medicine",
"keywords": "Emergency department (MeSH database); Mefenamic acid; Toxicity",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D008528:Mefenamic Acid; D059352:Musculoskeletal Pain; D020258:Neurotoxicity Syndromes; D010013:Osteogenesis Imperfecta; D010956:Plasmapheresis; D011697:Purpura, Thrombotic Thrombocytopenic",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "561.e1-561.e2",
"pmc": null,
"pmid": "30470601",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Central nervous system toxicity due to mefenamic acid.",
"title_normalized": "central nervous system toxicity due to mefenamic acid"
} | [
{
"companynumb": "TR-MICRO LABS LIMITED-ML2019-00848",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MEFENAMIC ACID"
},
"drugadditional":... |
{
"abstract": "Neurologic complications are not uncommon following bariatric surgery. Hyperammonemic encephalopathy (HAE) due to an acquired or unmasked urea cycle deficit is among the rarest of these. Pediatric nutrition support specialists are familiar with recognizing urea cycle deficits, but adult specialists may not be. Here we present a case of a patient initially misdiagnosed with cirrhosis who presented with recurrent HAE 4 years after Roux-en-Y gastric bypass. She was diagnosed with a proximal urea cycle deficit and severe protein calorie malnutrition. The patient recovered with specialized nutrition and medical support targeting this condition. A literature review indicates multiple fatalities from this condition, indicating the importance of early diagnosis and appropriate nutrition support.",
"affiliations": "Department of General Internal Medicine, Palliative Medicine and Medical Education, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.;Department of General Internal Medicine, Palliative Medicine and Medical Education, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky Department Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky.;Department of General Internal Medicine, Palliative Medicine and Medical Education, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.;Department of General Internal Medicine, Palliative Medicine and Medical Education, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky Department of Pharmacology & Toxicology, University of Louisville, Louisville, Kentucky Robley Rex Louisville VAMC, Louisville, Kentucky matt.cave@louisville.edu.",
"authors": "Singh|Sanjeev|S|;Suresh|Swetha|S|;McClave|Stephen A|SA|;Cave|Matt|M|",
"chemical_list": "D000641:Ammonia; D014508:Urea",
"country": "United States",
"delete": false,
"doi": "10.1177/0148607114546900",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-6071",
"issue": "39(8)",
"journal": "JPEN. Journal of parenteral and enteral nutrition",
"keywords": "OTC deficiency; bariatric surgery complications; hyperammonemic; noncirrhotic encephalopathy",
"medline_ta": "JPEN J Parenter Enteral Nutr",
"mesh_terms": "D000328:Adult; D000641:Ammonia; D001928:Brain Diseases, Metabolic; D003951:Diagnostic Errors; D005260:Female; D005355:Fibrosis; D015390:Gastric Bypass; D006801:Humans; D008875:Middle Aged; D011502:Protein-Energy Malnutrition; D014508:Urea",
"nlm_unique_id": "7804134",
"other_id": null,
"pages": "977-85",
"pmc": null,
"pmid": "25185153",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": null,
"title": "Treating Every Needle in the Haystack: Hyperammonemic Encephalopathy and Severe Malnutrition After Bariatric Surgery-A Case Report and Review of the Literature.",
"title_normalized": "treating every needle in the haystack hyperammonemic encephalopathy and severe malnutrition after bariatric surgery a case report and review of the literature"
} | [
{
"companynumb": "US-ABBVIE-16P-163-1547371-00",
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LACTULOSE"
},
"drugadditional": null,
... |
{
"abstract": "An unusual case of nitroglycerin-induced Paracentral Acute Middle Maculopathy (PAMM) is presented. A 50-year-old patient with sudden vision loss and scotoma was followed up with swept-source optical coherence tomography (SS-OCT), optical coherence tomography-angiography (OCT-A), and fluorescein angiography (FA). An anal fissure treated with glyceryl trinitrate (GTN) 0.2% ointment with headache and dizziness after application was reported. Fundoscopy OS revealed mild retinal venous dilatation and tortuosity with scattered blot hemorrhages and subtle, parafoveal, whitish lesions in the outer retina. SS-OCT revealed diffuse, hyperreflective lesions in the inner plexiform (IPL), inner nuclear (INL), and outer plexiform layers (OPL). OCT-A revealed focal dropout in the deep capillary plexus. FA showed masking due to blot hemorrhages and early punctuate leakage in the inner retina. This entity was identified as nitroglycerin-induced PAMM. Over the following 8 months, after discontinuation of the ointment application, the patient was symptom-free with stable visual acuity. OCT revealed INL/OPL thinning and confirmed complete lesion resolution. This first report of retinal vascular abnormalities due to nitrite ointment provides an insight into an unknown side effect of nitroglycerin ointment use. A dose-dependent correlation between GTN application and retinal vascular abnormalities remains to be confirmed.",
"affiliations": "1st Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece.;1st Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece.;1st Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece.;2nd Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece.;1st Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece.;1st Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece.",
"authors": "Rotsos|Tryfon|T|https://orcid.org/0000-0001-7152-4571;Giachos|Ioannis|I|https://orcid.org/0000-0002-6913-4539;Tyrlis|Konstantinos|K|https://orcid.org/0000-0002-9676-2629;Symeonidis|Chrysanthos|C|https://orcid.org/0000-0003-4104-3018;Mani|Ekaterini|E|;Georgalas|Ilias|I|https://orcid.org/0000-0002-6171-5865",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/8215706",
"fulltext": "\n==== Front\nCase Rep Ophthalmol Med\nCase Rep Ophthalmol Med\nCRIOPM\nCase Reports in Ophthalmological Medicine\n2090-6722\n2090-6730\nHindawi\n\n10.1155/2021/8215706\nCase Report\nParamacular Acute Middle Maculopathy Associated with Glyceryl Trinitrate\nhttps://orcid.org/0000-0001-7152-4571\nRotsos Tryfon 1\nhttps://orcid.org/0000-0002-6913-4539\nGiachos Ioannis 1\nhttps://orcid.org/0000-0002-9676-2629\nTyrlis Konstantinos 1\nhttps://orcid.org/0000-0003-4104-3018\nSymeonidis Chrysanthos chrys2209@gmail.com\n2\nMani Ekaterini 1\nhttps://orcid.org/0000-0002-6171-5865\nGeorgalas Ilias 1\n11st Department of Ophthalmology, National and Kapodistrian University of Athens, Athens, Greece\n22nd Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece\nAcademic Editor: Cristiano Giusti\n\n2021\n18 9 2021\n2021 821570624 5 2021\n30 7 2021\n8 9 2021\nCopyright © 2021 Tryfon Rotsos et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nAn unusual case of nitroglycerin-induced Paracentral Acute Middle Maculopathy (PAMM) is presented. A 50-year-old patient with sudden vision loss and scotoma was followed up with swept-source optical coherence tomography (SS-OCT), optical coherence tomography-angiography (OCT-A), and fluorescein angiography (FA). An anal fissure treated with glyceryl trinitrate (GTN) 0.2% ointment with headache and dizziness after application was reported. Fundoscopy OS revealed mild retinal venous dilatation and tortuosity with scattered blot hemorrhages and subtle, parafoveal, whitish lesions in the outer retina. SS-OCT revealed diffuse, hyperreflective lesions in the inner plexiform (IPL), inner nuclear (INL), and outer plexiform layers (OPL). OCT-A revealed focal dropout in the deep capillary plexus. FA showed masking due to blot hemorrhages and early punctuate leakage in the inner retina. This entity was identified as nitroglycerin-induced PAMM. Over the following 8 months, after discontinuation of the ointment application, the patient was symptom-free with stable visual acuity. OCT revealed INL/OPL thinning and confirmed complete lesion resolution. This first report of retinal vascular abnormalities due to nitrite ointment provides an insight into an unknown side effect of nitroglycerin ointment use. A dose-dependent correlation between GTN application and retinal vascular abnormalities remains to be confirmed.\n==== Body\npmc1. Introduction\n\nGlyceryl trinitrate (GTN) is a nitric oxide-releasing drug which is mainly used in the management of angina pectoris, acute myocardial infarction, severe hypertension, and acute coronary artery spasms by dilating the venous system and decreasing ventricular preload. GTN is a prodrug which after denitration produces the active metabolite nitric oxide (NO). Organic nitrates that undergo these two steps within the body are called nitrovasodilators. GTN has also applications in the treatment of benign anal diseases such as anal ulcer and hemorrhoids [1]. An abnormal pressure response of the internal anal sphincter (IAS) plays a role in the pain sensation that characterizes these lesions. In the setting of anal fissure, chemical sphincterotomy leads to reduced anal canal pressure, relieves pain, and promotes localized healing. The IAS is innervated by nitric oxide-releasing nerves, and the release of NO triggers IAS to relaxation [2]. Administration of exogenous NO, via glyceryl trinitrate, has a similar effect [3].\n\nThe most common side effect of topical GTN is headache [1]. This is indicative of systemic absorption of the drug and its potential for clinical manifestations in other organs. Specifically, in the eye, nitroglycerin has the ability to cross the blood-ocular barrier and have a vasodilatory effect to the retinal vessels [4]. In contrast to retinal arteries, retinal veins and capillaries lack any elastic or smooth muscle tissue [5]. They are, however, covered with pericytes that express a contractile filamentous component called alpha-smooth muscle actin (αSMA). This component acts as a major indicator of vascular smooth muscle cells and is the reason why retinal capillaries are affected by vasoregulators like GTN [6].\n\nThe case of a patient with possible nitroglycerin-induced Paracentral Acute Middle Maculopathy (PAMM) after treatment with nitroglycerin ointment is presented [7]. To our best knowledge, this is the first report of a patient presenting with retinal and vascular abnormalities due to nitrite ointment.\n\n2. Case Report\n\nA 50-year-old Caucasian male presented to the emergency department, complaining of sudden vision loss and the presence of scotoma in his left eye (OS) with no ocular pain or discomfort. His past ophthalmic history was unremarkable. The patient had a history of painful anal fissure under treatment with GTN 0.2% ointment three times daily for the previous 2 months. After almost every application of the ointment, he was symptomatic with headache and dizziness that were partially relieved by common analgesics. He also reported that during the previous 15 days, pain from the fissure was significantly stronger, especially after bowel movement, which caused him to apply the ointment more often (up to 6 times daily). During the last 3 days, he reported episodes of transient postural hypotension. He was under no other medications and reported only occasional consumption of caffeine. He had no history of smoking, excessive drinking, or substance abuse.\n\nBest-corrected visual acuity (BCVA) was 85 ETDRS letters OD and 75 ETDRS letters OS. Intraocular pressure was within normal limits. RAPD was negative in both eyes, and Ishihara plates showed no apparent dyschromatopsia. Anterior chamber examination of both eyes was unremarkable. There were no significant fundoscopic findings OD. Fundoscopy OS revealed mild retinal venous dilatation and tortuosity with scattered blot hemorrhages (Figures 1(a) and 1(b)). In the outer retina, subtle, parafoveal, whitish lesions were noted. Extensive multimodal imaging which included OCT, fundus autofluorescence (FAF), optical coherence tomography-angiography (OCT-A), and fluorescein angiography (FA) was performed (Figures 1(c)–1(h)).\n\nSwept-source-optical coherence tomography (DRI OCT Triton, SS-OCT) demonstrated diffuse, hyperreflective lesions at the level of the inner plexiform layer (IPL), inner nuclear layer (INL), and outer plexiform layer (OPL) compatible with Paracentral Acute Middle Maculopathy (PAMM, Figures 2(a) and 2(b)). Fundus autofluorescence did not reveal any hyper- or hypofluorescent lesions of the Retinal Pigment Epithelium (RPE). Optical coherence tomography-angiography (DRI OCT Triton, SS-OCT) revealed a focal, small area of capillary dropout in the deep capillary plexus. Superficial capillary plexus, outer retina, and choriocapillaris appeared normal. No other vascular abnormalities were apparent. Fluorescein angiography revealed normal arteriovenous transit time, masking effect due to blot hemorrhages, and early punctuate leakage in the inner retina (Figure 3).\n\nAn extensive haematological workup which included complete blood count, fasting blood sugar and hemoglobin A1c, ESR, CRP, LDL, HDL, plasma homocysteine level, rheumatoid factor, ANA, ANCA, SACE, FTA-ABS, VDRL, antiphospholipid antibodies, protein C and S levels, factor V Leiden, cryoglobulins and a thrombophilia screen was performed. Moreover, plasma protein electrophoresis, chest X-ray (for the exclusion of sarcoidosis, tuberculosis, and left ventricular hypertrophy), and a magnetic resonance angiography (for any vascular stenosis) with contrast dye were also performed. The patient was also referred to cardiology for a full assessment with electrocardiogram, carotid Doppler imaging, cardiac echocardiogram, and rhythm and blood pressure Holter monitoring. There was no cardiological or vascular disease diagnosed. Haematological workup, X-ray, and MRA revealed no pathological findings.\n\nThe patient was advised to immediately discontinue any application of the drug. During the following month, the patient did not experience any of his previous symptoms and his visual acuity OS was 80 ETDRS letters with no RAPD. Fundoscopy revealed partial resolution of blot hemorrhages. The macula appeared normal. OCT revealed retinal disruption and thinning at the level of INL and OPL and partial resolution of the hyperreflective lesions (Figure 2(c)). OCT-A remained unaltered (Figure 1(i)).\n\nSix months later, the patient was free of symptoms. Visual acuity OS was 80 ETDRS letters. Fundoscopy revealed complete resolution of the hemorrhages and the whitish lesions (Figure 1(j)). OCT showed INL and OPL thinning and complete resolution of the hyperreflective lesions (Figure 2(d)).\n\nThe patient mentioned that 8 months after the initial diagnosis, he had an exacerbation of symptoms regarding his anal fissure. He applied the ointment twice during a day for 4 days, which led to the remission of headaches and transient reduction of his visual acuity. He discontinued the drug application.\n\n3. Discussion\n\nBased on the clinical findings, multimodal imaging approach, laboratory results, and medical history of the patient, this disorder was identified as nitroglycerin-induced PAMM. Differential diagnosis included central retinal vein occlusion, branch retinal vein occlusion, ocular ischemic syndrome, retinal angiitis, diabetic retinopathy, and hypertensive retinopathy. Diabetic retinopathy and hypertensive retinopathy were excluded on the basis that the patient did not suffer from diabetes mellitus or hypertension and on the fact that the right eye remained asymptomatic and with no clinical signs. Central or branch retinal vein occlusion was excluded because of the atypical fundoscopic and fluorescein angiography findings, the presence of PAMM on presentation, the correlation of visual symptoms with the application of the ointment and improvement of symptoms, and findings after discontinuation of the drug. Ocular ischemic syndrome was excluded since the carotid Doppler ultrasound imaging and MRA were normal. A wide array of imaging and laboratory examinations were performed which failed to identify any obvious ocular disease. Valsalva retinopathy was excluded on the basis that the patient reported no episodes of constipation, only pain during defecation.\n\nTo our knowledge, this is the first reported case of nitroglycerin-related PAMM. It is conceivable that the disorder is a result of two possible mechanisms of action, a direct and an indirect one.\n\nThe direct mechanism of action involves the nitrate effect on the retinal vessels. As previously stated, nitroglycerin has the ability to cross the blood-ocular barrier and have a vasodilatory effect to the retinal vessels [4], affecting retinal capillaries and veins despite the lack of any elastic or smooth muscle tissue [6]. This effect can explain the retinal vein dilation. It is conceivable that the vasodilatory effect of nitroglycerin in this patient was so potent that it also facilitated dilation of the retinal capillaries of the superior and inferior temporal branches of the central retinal artery to such a degree, causing hypoperfusion. This hypoperfusion led in turn to ischemia at the level of IPL, INL, and OPL, which resulted in PAMM. The fact that the patient had significant symptoms after almost every application of the drug further supports this hypothesis.\n\nThe indirect mechanism involves the nitrate effect on the circulatory system. At high doses, nitrates are commonly used for the treatment of acute heart failure by venous and arterial dilation. Nitrates lower left ventricular filling pressures and reduce systemic resistance. This provides not only preload but also afterload reduction and resolution of symptoms. However, there have been reports of nitroglycerin-induced hypotension and bradycardia [8]. This patient reported episodes of transient postural hypotension. This hypotension may lead to hypoperfusion of the retina at the level of the retinal capillaries leading in turn to macula ischemia and PAMM.\n\nThere has been a report of PAMM induced by a different vasodilating drug (PDE5 inhibitor) which further supports our hypothesis [9].\n\nA reasonable counter argument against our diagnosis would be the unilateral presentation of the disease. One could argue that since there is systemic absorption of the drug, both eyes should be roughly equally affected. We believe that since the patient applied the ointment for a relatively short period of time (i.e., two months) and used it excessively for only 15 days; it is justifiable to assume that there was not enough time for the changes to manifest in both eyes. If this type of usage continued, it is possible that both eyes would have similar manifestations.\n\nThis is the first report of retinal and vascular abnormalities due to nitrite ointment. Since this type of ointment is widely used for the treatment of anal fissures and hemorrhoids, this case report should raise concerns regarding optimal use of this drug. Patients who have underlying cardiovascular risk factors and/or retinal diseases should be more closely monitored and be advised to seek immediate ophthalmic evaluation, should any visual disturbances occur. Patients who are otherwise healthy should also be advised of potential (albeit rare) visual disturbances especially after overuse. This case report may provide a new insight into an unknown side effect of nitroglycerin ointment. Further studies are needed to confirm a potential correlation between GTN application and vascular abnormalities of the retina.\n\nData Availability\n\nRelevant data is available on request. Please contact Dr. Chrysanthos Symeonidis (chrys2209@gmail.com).\n\nConsent\n\nThe patient in the study has given consent for the clinical study to be published.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Fundus photo OD with no evidence of pathology (a). Fundus photo OS with mild retinal venous dilatation and tortuosity with scattered blot hemorrhages (b). Fundus autofluorescence does not reveal hyperfluorescent lesions or RPE changes (c, d) apart from the masking effect from blot hemorrhages OS (d). Optical coherence tomography-angiography demonstrates a focal, small area of capillary dropout in the deep capillary plexus (f). Superficial capillary plexus, outer retina, and choriocapillaris appear normal (e, g, h). Fundus photo OS, 1 month after presentation with fewer blot hemorrhages (i). Fundus photo after 6 months of OS shows complete resolution of the hemorrhages (j).\n\nFigure 2 Swept-source- (SS-) OCT imaging of the left eye. Horizontal scans are presented on the left column and vertical ones on the right one (lines 1 and 6 on DRI OCT Triton, SS-OCT, respectively). OCT scans on presentation demonstrated diffuse, hyperreflective lesions at the level of the inner plexiform layer, inner nuclear layer, and outer plexiform layer (a, b). Partial resolution (one month later) (c, d) and complete resolution (six months later) (e, f) of the lesions are observed along with thinning of the inner retina.\n\nFigure 3 Fluorescein angiography (FA) images OS shows a masking effect due to blot hemorrhages and early punctuate leakage in the upper retina: (b) 1.09 min, (c) 1.19 min, (d) 1.29 min, (e) 1.38 min, and (f) 4.30 min.\n==== Refs\n1 Scholefield J. H. Bock J. U. Marla B. A dose finding study with 0.1%, 0.2%, and 0.4% glyceryl trinitrate ointment in patients with chronic anal fissures Gut 2003 52 2 264 269 10.1136/gut.52.2.264 2-s2.0-0037302568 12524411\n2 Rattan S. Sarkar A. Chakder S. Nitric oxide pathway in rectoanal inhibitory reflex of opossum internal anal sphincter Gastroenterology 1992 103 1 43 50 10.1016/0016-5085(92)91093-J 2-s2.0-0026639057 1612356\n3 Fung H.-L. Clinical pharmacology of organic nitrates American Journal of Cardiology 1993 72 8 C9 C15 10.1016/0002-9149(93)90249-C 2-s2.0-0027179494\n4 Weigert G. Pemp B. Garhofer G. Nitroglycerin-mediated retinal vasodilatation is maintained in patients with diabetes Investigative Ophthalmology and Visual Science 2008 49 p. 2088\n5 Hogan M. Feeney L. The ultrastructure of the retinal blood vessels: I. The large vessels Journal of Ultrastructure Research 1963 39 10 28 10.1016/s0022-5320(63)80033-7 2-s2.0-0002271148 14065353\n6 Kur J. Newman E. A. Chan-Ling T. Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease Progress in Retinal and Eye Research 2012 31 5 377 406 10.1016/j.preteyeres.2012.04.004 2-s2.0-84863852522 22580107\n7 Sarraf D. Rahimy E. Fawzi A. Paracentral acute middle maculopathy: a new variant of acute macular neuroretinopathy associated with retinal capillary ischemia JAMA Ophthalmology 2013 131 10 1275 1287 10.1001/jamaophthalmol.2013.4056 2-s2.0-84885915145 23929382\n8 Come P. C. Pitt B. Nitroglycerin-induced severe hypotension and bradycardia in patients with acute myocardial infarction Circulation 1976 54 4 624 628 10.1161/01.CIR.54.4.624 2-s2.0-0017144928 822962\n9 Moura-Coelho N. Gaspar T. Ferreira J. Dutra-Medeiros M. Cunha J. P. Paracentral acute middle maculopathy—review of the literature Graefe's Archive for Clinical and Experimental Ophthalmology 2020 258 12 2583 2596 10.1007/s00417-020-04826-1 32661700\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2021()",
"journal": "Case reports in ophthalmological medicine",
"keywords": null,
"medline_ta": "Case Rep Ophthalmol Med",
"mesh_terms": null,
"nlm_unique_id": "101581018",
"other_id": null,
"pages": "8215706",
"pmc": null,
"pmid": "34589244",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "1612356;12524411;32661700;22580107;8372805;822962;14065353;23929382",
"title": "Paramacular Acute Middle Maculopathy Associated with Glyceryl Trinitrate.",
"title_normalized": "paramacular acute middle maculopathy associated with glyceryl trinitrate"
} | [
{
"companynumb": "GR-USP-000002",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NITROGLYCERIN"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nTacrolimus is an immunosuppressive drug that is used to lower the activity of the patient's immune system to prevent organ rejection. Unfortunately, there is limited data regarding the therapeutic equivalency of generic tacrolimus formulations especially in children. We report the case of a pediatric patient having an inability to achieve a therapeutic trough level for tacrolimus after conversion from brand name to the generic formulation.\n\n\nMETHODS\nA 17-month-old male patient diagnosed with T-cell acute lymphoblastic leukemia underwent allogeneic stem cell transplantation. The patient initially received intravenous (i.v.) tacrolimus for graft-versus-host disease (GVHD) prophylaxis and achieved therapeutic levels. The patient was then switched to an oral brand formulation of tacrolimus, and was able to maintain trough levels within the therapeutic range. After being discharged, the patient received the generic formulation of tacrolimus from an outside pharmacy and the care team was unable to reach therapeutic levels despite multiple dose escalations. Returning to brand name tacrolimus resulted in prompt achievement of therapeutic levels.\n\n\nCONCLUSIONS\nA likely etiology for the inability to achieve therapeutic trough levels in this patient is the change in formulation from brand formulation to generic version. Other factors including drug-drug interaction, preparation of the medication by a different pharmacy, drug-food interaction and genetic factors were also considered. Physicians and pharmacists must be aware of the inability to achieve targeted therapeutic concentrations of tacrolimus resulting from the conversion of brand name to the generic formulation until these generic formulations are tested in clinical trials in a pediatric population.",
"affiliations": "Committee of Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL, USA. npinto1@peds.bsd.uchicago.edu.",
"authors": "Madian|Ashraf G|AG|;Panigrahi|Arun|A|;Perera|Minoli A|MA|;Pinto|Navin|N|",
"chemical_list": "D016568:Drugs, Generic; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1186/2050-6511-15-69",
"fulltext": "\n==== Front\nBMC Pharmacol ToxicolBMC Pharmacol ToxicolBMC Pharmacology & Toxicology2050-6511BioMed Central London 2547255735610.1186/2050-6511-15-69Case ReportCase report: inability to achieve a therapeutic dose of tacrolimus in a pediatric allogeneic stem cell transplant patient after generic substitution Madian Ashraf G ashrafmadian@hotmail.com Panigrahi Arun arpani01@louisville.edu Perera Minoli A mperera@bsd.uchicago.edu Pinto Navin npinto1@peds.bsd.uchicago.edu Committee of Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, IL USA 3 12 2014 3 12 2014 2014 15 6925 4 2014 18 11 2014 © Madian et al.; licensee BioMed Central. 2014This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nTacrolimus is an immunosuppressive drug that is used to lower the activity of the patient’s immune system to prevent organ rejection. Unfortunately, there is limited data regarding the therapeutic equivalency of generic tacrolimus formulations especially in children. We report the case of a pediatric patient having an inability to achieve a therapeutic trough level for tacrolimus after conversion from brand name to the generic formulation.\n\nCase presentation\nA 17-month-old male patient diagnosed with T-cell acute lymphoblastic leukemia underwent allogeneic stem cell transplantation. The patient initially received intravenous (IV) tacrolimus for graft-versus-host disease (GVHD) prophylaxis and achieved therapeutic levels. The patient was then switched to an oral brand formulation of tacrolimus, and was able to maintain trough levels within the therapeutic range. After being discharged, the patient received the generic formulation of tacrolimus from an outside pharmacy and the care team was unable to reach therapeutic levels despite multiple dose escalations. Returning to brand name tacrolimus resulted in prompt achievement of therapeutic levels.\n\nConclusions\nA likely etiology for the inability to achieve therapeutic trough levels in this patient is the change in formulation from brand formulation to generic version. Other factors including drug-drug interaction, preparation of the medication by a different pharmacy, drug-food interaction and genetic factors were also considered. Physicians and pharmacists must be aware of the inability to achieve targeted therapeutic concentrations of tacrolimus resulting from the conversion of brand name to the generic formulation until these generic formulations are tested in clinical trials in a pediatric population.\n\nKeywords\nTacrolimusGenericChildrenissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nTacrolimus is a commonly used calcineurin inhibitor used to induce immunosuppression and prevent graft-versus-host disease as well as rejection in patients receiving both hematopoietic and solid organ transplantation [1–3]. When approved in 1994, it was marketed under the brand name Prograf®. The first generic version was approved by the FDA in 2009 [4]. In practice there is a sentiment among physicians and patients that generic immunosuppressants differ in efficacy from their brand versions [5]. The FDA uses a simplified process for the approval of generic drugs called an abbreviated new drug application (ANDA) [1]. In that process the generic drug is tested only in healthy volunteers with ages between 24–36 years old. The FDA defines bioequivalence as “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” Currently, the FDA does not place immunosuppressants within a special category when evaluating the bioequivalency between generic and brand name drugs [5].\n\nAlthough there are 5 generic formulations of tacrolimus currently available in the U.S. [6], there is limited data to confirm their therapeutic equivalency. In this case report we describe a 17-month-old boy with T-cell acute lymphoblastic leukemia who underwent a matched unrelated allogeneic stem cell transplant approximately two months prior. He was initially started on tacrolimus (i.v.) at the time of transplant for GVHD prophylaxis, and after changing to oral brand formulation in the hospital he was still in the therapeutic range. Once he was discharged, he received generic tacrolimus from an outside pharmacy, and was found to be sub-therapeutic despite escalating doses of medication.\n\nCase presentation\nA 17-month-old male patient was diagnosed with T-cell acute lymphoblastic leukemia at 10 months of life, when he was noted to have a white blood cell count of 950,000 with peripheral leukemic blasts as well as systemic symptoms. Subsequently he received multiple courses of chemotherapy, and then underwent a matched unrelated allogeneic stem cell transplant at the age of 15 months. A combination of Busulfan, Fludarabine and Alemtuzumab were utilized for myeloablation prior to allogeneic stem cell transplantation from a matched unrelated donor. Subsequently he was initially started on IV tacrolimus (0.033 mg/kg) for GVHD prophylaxis, and achieved therapeutic levels (Figure 1). Approximately one month after transplant in anticipation of being discharged, the patient was switched to an oral brand name formulation of tacrolimus (Prograf®), and was able to maintain trough levels in the prescribed therapeutic window (Figure 1). The patient was discharged approximately one week later with generic tacrolimus suspension dosed at 0.15 mg/kg PO twice daily which was compounded at an outside pharmacy. Subsequently, he was unable to reach therapeutic levels despite multiple escalations in dosage to a maximum dosage of 0.31 mg/kg PO twice daily (Figure 1). Also during this time the patient’s dose of Voriconazole was reduced from 16.26 mg/kg (therapeutic dosage) to 8.46 mg/kg PO daily (expected prophylactic dosage). During this period when his doses were escalated due to inadequate trough levels, multiple investigations were made, and the pharmacist compounding the medication was contacted. According to the outside pharmacy, the pharmacist compounded the medication in a similar fashion to the inpatient pharmacy and the solvents used were the same. The compounding in the inpatient and outside pharmacy followed a straightforward procedure involving mixing the contents of 6 tacrolimus capsules (5 mg each) with 30 mls of Syrup and 30 mls of oral suspending vehicle. Trough levels were drawn at appropriate times, and the family was compliant with the medication.Figure 1 \nTacrolimus blood levels compared to its daily dose. (A) Blood levels of tacrolimus when patient administered brand or generic version. Day 0 was when patient received matched unrelated allogeneic stem cell transplant. X represents the patient’s blood tacrolimus levels (ng/ml). Red lines represent the upper and lower limits of tacrolimus therapeutic trough level. (GVHD): graft-versus-host disease. (B) Tacrolimus dose per day (mg/kg) and voriconazole dose per day (mg/kg) for the same time interval.\n\n\n\nInitially after transplant the patient manifested evidence of skin GVHD with mild skin erythema; topical steroids were initiated two weeks prior to discharge and were continued as an outpatient. The child’s skin GVHD showed marked improvement with topical steroids yet began to flare a few weeks later when he presented to the clinical pharmacology service for inability to reach a therapeutic level for tacrolimus. Tacrolimus is one of the primary agents used to induce immunosuppression and combat GVHD in bone marrow transplant patients; hence the patient’s resurgence of skin GVHD is likely further manifestation of sub-therapeutic tacrolimus levels.\n\nAt the time of the initial encounter for skin GVHD and subtherapeutic tacrolimus levels the patient was taking the following medications: acetaminophen (15 mg/kg by oral route every 6 hours as needed for pain for 30 doses), diphenhydramine (1 mg/kg by oral route every 6 hours as needed), famotidine (0.53 mg/kg by oral route twice daily), hydrocortisone 0.5% topical ointment (1 application by topical route twice daily), ondansetron (0.15 mg/kg by oral route every 8 hours as needed for nausea/vomiting), sulfamethoxazole-trimethoprim (13.3 mg/kg/2.6 mg/kg) by oral route twice daily on Monday, Tuesday, Wednesday), valacyclovir (29 mg/kg by oral route every 8 hours), voriconazole (oral suspension 10 mg/kg by oral route twice daily), and multivitamins. Patient had an appropriate response to opiates (including codeine) and other medications per the caregivers. Patient did not have any adverse outcomes with surgery and anesthesia.\n\nReview of systems at the initial encounter indicated the patient was irritable due to pruritus. The patient had a generalized rash that caused him to wake at night and necessitated the use of diphenhydramine for symptomatic relief. He also had loose stools yet normal number of bowel movements daily, and was tolerating his diet appropriately. He did not have fever, or a change in appetite or activity. Physical exam showed a fine erythematous rash scattered on face and extremities. Excoriations were present on the lower back and extremities as well. The clinical pharmacology service was consulted at this time to evaluate the etiology of the patient’s inability to reach therapeutic trough levels of tacrolimus.\n\nDiscussion\nIn clinical practice we utilize trough level concentration as a measure of the exposure to tacrolimus. A recent study showed that trough level concentrations can be used as a reliable surrogate measure for area under the curve (AUC) for patients in normal clinical practice receiving generic tacrolimus [7].\n\nSeveral factors, which may have contributed to the subtherapeutic trough levels upon conversion to generic formulation, were considered. For example, although the outside pharmacy claimed that it prepared the medication in a similar way as the hospital pharmacy, it still remains a possibility that this pharmacy had less experience in compounding narrow therapeutic index drugs (NTI) which may have contributed to the difference in drug levels. Additionally, it’s known that voriconazole can inhibit CYP3A4, decreasing the metabolism of tacrolimus and increasing its blood concentration [8]. As shown in Figure 1, the patient’s dose was reduced from 16.26 mg/kg (therapeutic dosage) to 8.46 mg/kg PO daily (expected prophylactic dosage) that may have resulted in increasing the metabolism of tacrolimus and decreasing its concentration in the plasma. The dose of voriconazole was increased back to 19.5 mg/kg/day at the same time of switching back to the brand name tacrolimus and the rise of blood tacrolimus levels. Therefore the change in voriconazole dose could have contributed to the change in blood tacrolimus levels but because the patient maintained therapeutic drug concentrations after discontinuing voriconazole on day +106, the clinical pharmacology consultation team hypothesized that drug-drug interactions did not fully contribute to the observed drop in tacrolimus levels.\n\nAdditionally, it’s unlikely that famotidine administration caused the environment in the stomach to be alkaline and the patient was given it both while in the hospital and after being discharged. Moreover, clinical literature has been inconclusive regarding the impact of antacids on immunosuppresants such as tacrolimus [9]. Moreover, the prevention of tacrolimus absorption due to the concomitant administration of iron or other vitamins is not supported by any clinical literature. In addition to that, the patient received the same iron and vitamins while he was in the hospital. Finally, the other drugs he administered (Acetoaminophen, diphenhydramine, ondansetron, sulfamethoxazole-trimethoprim and valacyclovir) were not reported to interact with tacrolimus. Furthermore, the patient was given these drugs both while he was in the hospital and after being discharged. Finally, he didn’t have any food changes that may have contributed to the changes in bioavailability between the two products when they were given orally.\n\nPharmacogenetic factors were unlikely to have contributed. The CYP 3A5*1 allele has been implicated in lower tacrolimus trough levels than patients with CYP3A5*3 [10]. This allelic variant, though important, is unlikely to play a critical role for our patient, as he was able to maintain therapeutic trough levels with appropriate dosage of tacrolimus.\n\nThe conversion from brand to generic formulation could have contributed to the inability to achieve therapeutic levels of tacrolimus. In general, studying the effect of switching to generic tacrolimus in pediatric patients is not well explored. The only available study that evaluated switching to generic tacrolimus in children was done in renal transplant patients [4]. In that study, both trough and serum creatinine levels were retrospectively analyzed for four patients (with ages range between 8–22 years old). Although trough levels were generally comparable before and after switching from brand name to generic tacrolimus, interindividual differences existed. Serum creatinine levels were identical pre- and post- switch in three of the four patients. The fourth patients suffered from acute rejection immediately after switching to the generic formulation. This was accompanied by a dramatic increase in the patient’s serum creatinine level.\n\nContradictory results exist regarding the clinical equivalency of brand name tacrolimus formulations to their generic versions in the adult population. Despite the aforementioned study that showed that brand name tacrolimus and generic formulations may not be bioequivalent, other studies have showed that they are bioequivalent. For example, one study examined the efficacy and safety of the generic oral capsules of tacrolimus (TacroBell®) in de novo renal transplantation [11]. The study recruited ninety-six renal transplant recipients from 9 transplantation centers in South Korea. In general, the acute rejection and graft survival rates were comparable to brand name treatment. One unresolved issue with this study is that it was carried out in low risk populations with only short term follow up. Another recent study evaluated seventy conversions, of brand name tacrolimus to the generic tacrolimus (Sandoz), from four centers from patients after kidney, liver or multiorgan transplant [12]. This study showed that trough levels and dosage needed are similar between brand name tacrolimus and its generic formulation. Furthermore, a retrospective analysis of the electronic records and clinical databases for 234 clinically stable adult transplant recipients (renal, liver, and heart) whose tacrolimus was converted from brand name to a generic formulation recently occurred [13]. Trough levels were generally comparable between the two formulations. No deaths or acute rejections were reported but thirty-six patients required dose titration. Another open-label, multicenter pilot study in South Korea evaluated 57 patients receiving generic tacrolimus and corticosteroids after liver transplantation [14]. This group of patients was then compared to another retrospectively matched control group consisting of living donor liver transplant recipients at another center who received brand name tacrolimus. Adverse events were generally comparable between the two patient populations and no patients died during this study. In addition to that, a multicenter crossover pharmacokinetic study in which patients would receive both the generic and brand name formulation for 14 days and then crossover revealed that Sandoz generic tacrolimus has a similar pharmacokinetic profile to Prograf® in kidney transplant patients [15]. Finally, a recent prospective study showed that stable kidney transplant recipients can be converted to Sandoz generic tacrolimus by closely monitoring both plasma creatinine levels and trough concentration of tacrolimus [16].\n\nFor our patient, we recommended that the patient return to brand name formulation, after which the patient had therapeutic tacrolimus levels as well as resolution of his GVHD flare.\n\nThere are a number of reasons why the current bioequivalence studies may be inadequate for the approval of generic immunosuppressants [17]. First, studies in healthy subjects may not be extrapolated to transplant recipients. Second, steady state conditions may not be represented by single dose studies. Third, the allowance of the confidence interval to be (80%–125%) may be too variable for drugs with a narrow therapeutic index such as immunosuppressants. Finally, children are excluded from these bioequivalence studies. For this reason the American Society of Transplantation strongly supported studies to demonstrate bioequivalence in potentially at risk patients, especially children [18].\n\nConclusions\nThe fact that previous studies regarding the bioequivalency of generic and brand name tacrolimus were almost exclusively done in adult human highlights the importance of testing them in pediatric patients as well as those who have undergone allogeneic stem cell transplantation. Results from adult case studies cannot be extrapolated for children. Until the use of various generic formulations of tacrolimus can be evaluated in a large randomized clinical trial in children, physician and pharmacists must be aware of possible adverse events following a conversion from brand name to the generic form of tacolimus.\n\nConsent\nWritten informed consent was obtained from the patient’s guardian for publication of this case report.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAGM and AP were directly involved in the patient’s follow up, data acquisition and interpretation. AGM drafted the manuscript. AP assisted in editing the manuscript. MAP and NP who headed the clinical pharmacology consult made significant contribution to the conception, design and revision of the study. All of the authors read and approved the final manuscript.\n\nAcknowledgment\nAGM and AP were supported by funding from NIH/NIGMS Clinical Therapeutics training grant T32GM007019. Additionally AGM was supported by funding from University of Chicago Cancer Research Foundation Women’s Board.\n==== Refs\nReferences\n1. US Department of Health and Human Service FaDA Approved Drug Products With Therapeutic Equivalence Evaluations (Orange Book) 2012 32 \n2. Bora F Aliosmanoglu I Kocak H Dinckan A Uslu HB Gunseren F Suleymanlar G Drug interaction between tacrolimus and ertapenem in renal transplantation recipients Transplant Proc 2012 44 3029 3032 10.1016/j.transproceed.2012.08.003 23195020 \n3. Han N Yun H-Y Hong J-Y Ji E Hong SH Kim YS Ha J Shin WG Oh JM Prediction of the tacrolimus population pharmacokinetic parameters according to CYP3A5 genotype and clinical factors using NONMEM in adult kidney transplant recipients Eur J Clin Pharmacol 2013 69 53 63 10.1007/s00228-012-1296-4 22660440 \n4. Abdulnour HA Araya CE Dharnidharka VR Comparison of generic tacrolimus and Prograf® drug levels in a pediatric kidney transplant program: brief communication Pediatr Transplant 2010 14 1007 1011 10.1111/j.1399-3046.2010.01393.x 20819180 \n5. Christians U Klawitter J Clavijo CF Bioequivalence testing of immunosuppressants: concepts and misconceptions Kidney Int Suppl 2010 S1 S7 \n6. U.S. Food and Drug Administration FDA Approved Drug Products 2013 \n7. Connor A Prowse A Macphee I Rowe PA Generic tacrolimus in renal transplantation: trough blood concentration as a surrogate for drug exposure Transplantation 2012 93 e45 e46 10.1097/TP.0b013e318256dd13 23318306 \n8. Leveque D Nivoix Y Jehl F Herbrecht R Clinical pharmacokinetics of voriconazole Int J Antimicrob Agents 2006 27 274 284 10.1016/j.ijantimicag.2006.01.003 16563707 \n9. Chisholm MA Mulloy LL Jagadeesan M DiPiro JT Coadministration of tacrolimus with anti-acid drugs Transplantation 2003 76 665 666 10.1097/01.TP.0000072339.10649.9C 12973105 \n10. Kim I-W Noh H Ji E Han N Hong SH Ha J Burckart GJ Oh JM Identification of factors affecting tacrolimus level and 5-year clinical outcome in kidney transplant patients Basic Clin Pharmacol Toxicol 2012 111 217 223 10.1111/j.1742-7843.2012.00904.x 22469198 \n11. Kim SJ Huh KH Han DJ Moon IS Kim SJ Kim YL Kim HC Lee S Kang CM Cho BH Kim YS A 6-month, multicenter, single-arm pilot study to evaluate the efficacy and safety of generic tacrolimus (TacroBell) after primary renal transplantation Transplant Proc 2009 41 1671 1674 10.1016/j.transproceed.2009.03.061 19545705 \n12. McDevitt-Potter LM Sadaka B Tichy EM Rogers CC Gabardi S A multicenter experience with generic tacrolimus conversion Transplantation 2011 92 653 657 10.1097/TP.0b013e31822a79ad 21788920 \n13. Spence MM Nguyen LM Hui RL Chan J Evaluation of clinical and safety outcomes associated with conversion from brand-name to generic tacrolimus in transplant recipients enrolled in an integrated health care system Pharmacotherapy 2012 32 981 987 10.1002/phar.1130 23074134 \n14. Yu Y-D Lee S-G Joh J-W Kwon CH Kim DG Suh KS Lee NJ Hwang S Ahn CS Kim KH Moon DB Ha TY Song GW Jung DH Results of a phase 4 trial of Tacrobell® in liver transplantation patients: a multicenter study in South Korea Hepatogastroenterology 2012 59 357 363 10.5754/hge11472 21940371 \n15. Alloway RR Sadaka B Trofe-Clark J Wiland A Bloom RD A randomized pharmacokinetic study of generic tacrolimus versus reference tacrolimus in kidney transplant recipients Am J Transplant 2012 12 2825 2831 10.1111/j.1600-6143.2012.04174.x 22759200 \n16. Rosenborg S Nordström A Almquist T Wennberg L Bárány P Systematic conversion to generic tacrolimus in stable kidney transplant recipients Clin Kidney J 2014 7 151 155 10.1093/ckj/sfu015 24944783 \n17. Ensor CR Trofe-Clark J Gabardi S McDevitt-Potter LM Shullo MA Generic maintenance immunosuppression in solid organ transplant recipients Pharmacotherapy 2011 31 1111 1129 10.1592/phco.31.11.1111 22026398 \n18. Alloway Rita R Isaacs R Lake K Hoyer P First R Helderman H Bunnapradist S Leichtman A Bennett MW Tejani A Takemoto SK Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generic immunosuppressants Am J Transplant 2003 3 1211 1215 10.1046/j.1600-6143.2003.00212.x 14510694\n\n",
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"title": "Case report: Inability to achieve a therapeutic dose of tacrolimus in a pediatric allogeneic stem cell transplant patient after generic substitution.",
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"abstract": "OBJECTIVE\nAbiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy.\n\n\nMETHODS\nThirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing.\n\n\nRESULTS\nAdverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed > or = 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses.\n\n\nCONCLUSIONS\nAbiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.",
"affiliations": "Urologic Oncology Program, University of California, San Francisco, San Francisco, CA 94115, USA. ryanc@medicine.ucsf.edu",
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"title": "Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy.",
"title_normalized": "phase i clinical trial of the cyp17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration resistant prostate cancer who received prior ketoconazole therapy"
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"abstract": "Colchicine is an active alkaloid that is commonly used for treatment of multiple diseases including gout, primary biliary cirrhosis and familial Mediterranean fever. Less commonly, it has been implicated in several fatal overdoses. Deaths from colchicine overdoses are usually due to multi-organ failure, whether directly from colchicine toxicity or due to ensuing sepsis. We report an extreme case of colchicine ingestion (1.38 mg/kg), which is the largest reported non-fatal colchicine overdose. The patient was a 47-year-old First Nations woman with a history of depression and no other comorbidities. Ingestion was intentional and initial presentation was within 2 h of ingestion, at which point she had normal clinical and laboratory parameters. Early implementation of a targeted therapeutic strategy directed at the predicted multi-organ failure which included aggressive use of a GI decontamination protocol, timely supportive measures including ventilator support and renal replacement therapy, as well as the utilization of broad-spectrum antibiotics and G-CSF for sepsis and leucopenia management, resulted in successful support and discharge of this patient off dialysis.",
"affiliations": "Department of Medicine, University of British Columbia, Vancouver, B.C., Canada.",
"authors": "Iosfina|Ioulia|I|;Lan|James|J|;Chin|Carson|C|;Werb|Ronald|R|;Levin|Adeera|A|",
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"fulltext": "\n==== Front\nCase Rep Nephrol UrolCase Rep Nephrol UrolCRUCase Reports in Nephrology and Urology1664-55101664-5510S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000338269cru-0002-0020Published: April, 2012Massive Colchicine Overdose with Recovery Iosfina Ioulia a*Lan James bChin Carson aWerb Ronald bLevin Adeera baDepartment of Medicine, University of British Columbia, Vancouver, B.C., CanadabDepartment of Nephrology, University of British Columbia, Vancouver, B.C., Canada*Dr. Ioulia Iosfina, 2806–833 Homer Street, Vancouver, BC V6B 0H4 (Canada), Tel. +1 778 839 9456, E-Mail jiosfina@gmail.comJan-Jun 2012 11 4 2012 11 4 2012 2 1 20 24 Copyright © 2012 by S. Karger AG, Basel2012This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Colchicine is an active alkaloid that is commonly used for treatment of multiple diseases including gout, primary biliary cirrhosis and familial Mediterranean fever. Less commonly, it has been implicated in several fatal overdoses. Deaths from colchicine overdoses are usually due to multi-organ failure, whether directly from colchicine toxicity or due to ensuing sepsis. We report an extreme case of colchicine ingestion (1.38 mg/kg), which is the largest reported non-fatal colchicine overdose. The patient was a 47-year-old First Nations woman with a history of depression and no other comorbidities. Ingestion was intentional and initial presentation was within 2 h of ingestion, at which point she had normal clinical and laboratory parameters. Early implementation of a targeted therapeutic strategy directed at the predicted multi-organ failure which included aggressive use of a GI decontamination protocol, timely supportive measures including ventilator support and renal replacement therapy, as well as the utilization of broad-spectrum antibiotics and G-CSF for sepsis and leucopenia management, resulted in successful support and discharge of this patient off dialysis.\n\nKey Words\nColchicineOverdoseDialysisSepsis\n==== Body\nIntroduction\nColchicine is used for the treatment of gout, familial Mediterranean fever, primary biliary cirrhosis, amyloidosis and condyloma acuminate. Despite its merits, its narrow therapeutic index has been the source of several incidences of successful suicides by overdose [1]. Deaths from colchicine overdoses are uncommon but well documented, and are associated with a high mortality rate. We present here a case of a profound colchicine overdose, potentially the largest consumption reported in the literature, from which the patient successfully recovered. A multifaceted, aggressive set of interventions, instituted within 24 h of ingestion may well have been the reason for the successful outcome for this patient. Appreciating the mechanism of action by which colchicine causes cell damage and instituting supportive therapies are important learnings from this case.\n\nCase Presentation\nA 47-year-old Aboriginal female was admitted to a hospital in rural British Columbia for attempted suicide. She had ingested 90 mg of her husband's colchicine an hour prior to admission. She was not on regular medications and her past medical history was remarkable only for depression. Coingestions included alcohol, in the form of 6 cans of beer. She presented within one hour of ingestion with mild abdominal pain and normal vital signs. Physical exam was unremarkable. In the emergency room, 250 g of activated charcoal was administered over the course of 12 h. Within the initial presentation, she became febrile, developed diarrhea and severe nausea and vomiting, and developed refractory acidosis requiring urgent transfer to a tertiary hospital for further management 24 h post ingestion (fig. 1).\n\nAt transfer, her vitals were: BP 99/61 mm Hg, HR 106 bpm, RR 26 bpm and T 37.4°C. She had bibasilar inspiratory crackles and chest X-ray showing bilateral infiltrates at the bases. Sodium bicarbonate infusion and fluids were started to treat her acidosis. Over the next 24 h she received 50 g of activated charcoal every 6 h. She was also given N-acetylcysteine (NAC) loading dose of 150 mg/kg IV over 1 h followed by 50 mg/kg IV over 4 h then 100 mg/kg IV over the next 16 h.\n\nDespite the resuscitative and treatment measures described above, she developed multi-organ failure 48 h after ingestion (table 1). She had evidence of cardiovascular collapse with myocardial damage, renal failure and liver failure and altered level of consciousness, with a normal head CT. Hemodialysis was started for acute oliguric renal failure and refractory acidosis. At 72 h post ingestion she became febrile and pancytopenic, and required supportive transfusions. Febrile neutropenia protocol was initiated when WBC fell below 1.0 × 109/l: this included broad spectrum antibiotics and G-CSF. Blood cultures were positive for Moraxella and sputum was positive for Klebsiella. At 5 days post ingestion, she developed septic shock and required intubation. She also developed rhabdomyolysis and was treated supportively with fluids and continued dialysis.\n\nShe was extubated 2 weeks post ingestion after resolution of her sepsis but continued to receive intermittent hemodialysis. Liver function also gradually improved. The patient continued to suffer from alopecia throughout the admission, and complained of hearing loss in her left ear that resolved spontaneously. She also developed gangrene in her toes likely secondary to septic shock and vasopressor use. One month after ingestion, she regained normal urine output and kidney function, and intermittent hemodialysis was discontinued. She was discharged home in stable condition with scheduled follow-up.\n\nDiscussion\nColchicine toxicity occurs through the interruption of mitosis by preventing polymerization of tubulin into microtubules. Therefore, although colchicine is absorbed in all cells of the body, it most adversely affects cells with increased mitotic activity such as those in the GI tract and in the bone marrow [1]. Colchicine poisoning classically presents in three stages. The initial stage at <24 h is characterized by GI symptoms such as abdominal pain, nausea, vomiting and diarrhea. The second phase from day 2 to 7 post ingestion is the most dangerous: it is characterized by multi-organ failure, involving bone marrow suppression, kidney and liver failure, ARDS, arrhythmias and cardiovascular collapse, and neuromuscular involvement. The third stage is only seen in patients who recover from colchicine poisoning. It usually starts after day 7 when there is resolution of organ failure, rebound leukocytosis and alopecia [2].\n\nThe pharmacokinetics of colchicine are complex. It is rapidly absorbed from the GI tract and is metabolized primarily by the liver, which involves de-acetylation following first-order kinetics. Subsequently, there is significant entero-hepatic recirculation with 10–20% renal excretion [2]. The drug's clearance is significantly prolonged in patients with hepatic and renal insufficiency. After absorption, colchicine is rapidly distributed to all tissues where it is heavily protein bound.\n\nFilkenstein et al. [1] have reported high fatalities after ingestion of >0.5 mg/kg of colchicine, with the lowest reported lethal doses ranging from 7–26 mg. In a large French series examining colchicine overdoses, doses of >0.8 mg/kg almost always caused death within 72 h [3]. Our patient ingested approximately 1.38 mg/kg of colchicine, which is the highest non-fatal dose of colchicine that has been reported. Her survival is likely due to a combination of early presentation, timely intervention with activated charcoal, NAC and precise supportive therapy for multi-organ failure.\n\nOur patient was fortunate to present within one hour of ingestion. Activated charcoal was started within 2 h of ingestion and was continued for a total of 36 h. The prolonged use of activated charcoal was aimed to target the extensive entero-hepatic recirculation of colchicine. Due to the high affinity of colchicine to plasma proteins and its large volume of distribution, both hemodialysis and hemoperfusion play a limited role in the acute management of colchicine toxicity. Interestingly, colchicine-specific Fab fragment antibodies have been used successfully in the treatment of severe colchicine intoxication; however, such treatment modality is not commercially available in Canada and precluded its use in our patient [1].\n\nSignificant amounts of NAC were also used in this patient. We utilized the NAC protocol for acetaminophen overdose, as no specific NAC protocol is available for colchicine. NAC has previously been used in the treatment of a variety of conditions including acetaminophen overdose, HIV/AIDS, cystic fibrosis, etc. It exhibits anti-oxidant properties by reducing oxidant-induced cell damage and cell death by apoptosis [4]. We hypothesized that NAC used in this patient may have counteracted the inhibiting effects of colchicine on the endogenous anti-oxidants and may have decreased cell death by apoptosis and contributed to her survival despite the extremely high dose of colchicine ingested.\n\nThe exact mechanism of colchicine toxicity on kidney failure is not known. It may be due to multiple factors such as hypotension, volume depletion, rhabdomyolysis and multi-organ failure. However, it is possible that colchicine may have a direct toxicity on the proximal renal tubules. Cases of severe intoxication invariably demanded renal replacement therapy as a supportive measure for metabolic acidosis, progressive anuria and uremia [5]. Our patient fortunately recovered her kidney function 5 weeks post ingestion, demonstrating the reversibility of acute kidney injury due to colchicine. As a biopsy was not performed, the exact areas of damage cannot be determined.\n\nIn addition to the standard supportive therapies for multi-organ failure, special attention was given to the management of sepsis. Both fever and an elevated WBC may be unreliable indicators of sepsis in the face of colchicine intoxication. Persistent fever is often a feature of colchicine toxicity itself in the absence of sepsis; as for peripheral WBC, it begins with peripheral leukocytosis following acute ingestion, which is then followed by leucopenia in stage 2 of intoxication; finally, one observes rebound leukocytosis in the resolution phase [2]. In our patient, febrile neutropenia protocol proved to be life-saving as she proved to have both bacteremia and pneumonia. However, in the resolution phase her antibiotics were judiciously stopped as her fever and leukocytosis then were more consistent with the rebound effect of colchicine toxicity rather than with sepsis.\n\nBy the end of her hospital stay, our patient's main symptoms were alopecia subtotalis, and gangrene in her toes, which was likely attributed to an aggressive use of inotropes and pressors in the face of cardiovascular collapse.\n\nIn summary, we present a case that demonstrates successful recovery after a massive colchicine overdose, despite complications of multi-organ failure and prolonged dialysis. We demonstrate that understanding the physiologic toxic effects of colchicine and addressing them in a multi-interventional approach may prevent future mortalities from overdose of this drug.\n\nFig. 1 Case timeline and management.\n\nTable 1 Multi-organ failure: lab values for the first week of admission\n\n\t1 h\t12 h\t18 h\t24 h\t48 h\t72 h\t96 h\tDay 5\tDay 6\tDay 7\t\nWBC, 109/l\t5.2\t17.5\t25.9\t23\t8.9\t3\t1\t1.1\t9.1\t29.4\t\nCr, μmol/l\t52\t58\t65\t80\t205\t207\t284\t215\t161\t143\t\nAST, U/l\t29\t96\t218\t364\t12,618\t15,111\t9,830\t3,938\t1,172\t\t\nTroponin, μg/l\t\t\t<0.01\t0.31\t7.99\t4.7\t\t0.79\t\t0.24\t\nCK, U/l\t\t121\t358\t\t3,035\t\t\t28,064\t8,194\t1,862\n==== Refs\nReferences\n1 Filkenstein Y Aks SE Hutson JR Juurlink DN Nguyen P Dubnov-Raz G Pollak U Koren G Bentur Y Colchicine poisoning: the dark side of an ancient drug Clin Toxicol 2010 48 407 414 \n2 Maxwell MJ Muthu P Pritty PE Accidental colchicine overdose: a case report and literature review Emerg Med J 2002 19 265 267 11971849 \n3 Bismuth C Gaultier M Conso F Aplasie médullaire après intoxication aiguë à la colchicine Nouv Presse Med 1977 6 1625 1629 405656 \n4 Atkuri K Mantovani JJ Herzenberg LA Herzenbert LA N-Acetylcysteine – a safe antidode for cysteine/glutathione deficiency Curr Opin Pharmacol 2007 7 355 359 17602868 \n5 Huang WH Hsu CW Yu CC Colchicine overdose-induced renal failure and electrolyte imbalance Ren Fail 2007 29 367 370 17497454\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1664-5510",
"issue": "2(1)",
"journal": "Case reports in nephrology and urology",
"keywords": "Colchicine; Dialysis; Overdose; Sepsis",
"medline_ta": "Case Rep Nephrol Urol",
"mesh_terms": null,
"nlm_unique_id": "101591817",
"other_id": null,
"pages": "20-4",
"pmc": null,
"pmid": "23197951",
"pubdate": "2012-01",
"publication_types": "D002363:Case Reports",
"references": "17497454;17602868;405656;11971849;20586571",
"title": "Massive colchicine overdose with recovery.",
"title_normalized": "massive colchicine overdose with recovery"
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"activesubstancename": "COLCHICINE\\PROBENECID"
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"abstract": "OBJECTIVE\nEhlers-Danlos syndrome (EDS) is a connective tissue disorder resulting in abnormal collagen synthesis leading to skin, joint, ligament, blood vessel, and organ abnormalities. Studies in adult women show an association with heavy menstrual bleeding, dysmenorrhea, and pelvic organ prolapse. We aimed to evaluate gynecologic complaints in pediatric and adolescent patients with EDS and their management by pediatric and adolescent gynecology (PAG) Providers. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Charts of female individuals less than 21 years of age with an International Classification of Diseases (ICD) Ninth or Tenth revision diagnosis of EDS who were evaluated between July 1, 2007, and July 31, 2017, were reviewed for menstrual history, gynecologic complaints, and interventions prescribed.\n\n\nRESULTS\nA total of 156 patients met inclusion criteria, and 26 (16.7%) were seen by PAG providers. The mean age was 14.5 ± 1.9 years. Fifteen (57.7%) reported dysmenorrhea, 13 (50%) complained of heavy menstrual bleeding (HMB), 10 (38.5%) reported irregular menses, and 7 (26.9%) sought contraception. Concurrent medical problems were reviewed, as this affected hormone choice. The cohort was stratified into 2 groups: patients whose menstrual cycles were well controlled on a single method (group A), and patients who tried multiple medications (group B). Progesterone-only pills were most commonly used in froup A. Eleven (73%) patients in group B tried depot medroxyprogesterone acetate (DMPA), but ultimately a levonorgestrel intrauterine device (IUD) was the most popular final choice of treatment and was used by 4 (27%) patients.\n\n\nCONCLUSIONS\nFew adolescents with EDS are referred to PAG providers despite the prevalence of gynecologic complaints and potential for obstetric and gynecologic complications. In this population, early entry to gynecologic care would be beneficial.",
"affiliations": "Department of Obstetrics and Gynecology, University of California San Francisco-Fresno, Fresno, California. Electronic address: angela.marie.hernandez@gmail.com.;Division of Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas; Department of Pediatrics, Baylor College of Medicine, Houston, Texas.",
"authors": "Hernandez|Angela Marie C|AMC|;Dietrich|Jennifer E|JE|",
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"country": "United States",
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"issn_linking": "1083-3188",
"issue": "33(3)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Ehlers-Danlos syndrome; Gynecology; Hypermobility",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000293:Adolescent; D000080066:Contraceptive Agents, Hormonal; D004412:Dysmenorrhea; D004535:Ehlers-Danlos Syndrome; D005260:Female; D006176:Gynecology; D006801:Humans; D016912:Levonorgestrel; D008595:Menorrhagia; D011247:Pregnancy; D012017:Referral and Consultation; D012189:Retrospective Studies",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "291-295",
"pmc": null,
"pmid": "31883462",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Gynecologic Management of Pediatric and Adolescent Patients with Ehlers-Danlos Syndrome.",
"title_normalized": "gynecologic management of pediatric and adolescent patients with ehlers danlos syndrome"
} | [
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"companynumb": "US-BAYER-2020-009489",
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"abstract": "Although acute toxicity of cisplatin-based chemotherapy of germ cell tumors is considerable, major vascular complications have been reported infrequently. This report describes the case of a 36-year-old man developing myocardial infarction after the first cycle of adjuvant cisplatin-based chemotherapy for resected stage II testicular cancer. A close temporal association between the administration of chemotherapy and the vascular event suggests a cause and effect relationship. A drug-induced endothelial cell damage may be an important pathogenetic factor. Although reports on vascular accidents following treatment of testicular cancer raise concern with regard to the safety of chemotherapy, at present the very low incidence of such complications should not enter into therapeutic decisions.",
"affiliations": "KLINIKUM PASSAU,DEPT INTERNAL MED 2,PASSAU,GERMANY. GSF FORSCHUNGSZENTRUM UNWELT & GESUNDHEIT GMBH,MUNICH,GERMANY.",
"authors": "Gerl|A|A|;Weigl|P|P|;Gassel|W|W|;Wilmanns|W|W|",
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"publication_types": "D016428:Journal Article",
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"title": "Myocardial-infarction after adjuvant chemotherapy for resected stage-ii nonseminomatous testicular cancer.",
"title_normalized": "myocardial infarction after adjuvant chemotherapy for resected stage ii nonseminomatous testicular cancer"
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"companynumb": "DE-PFIZER INC-2011315697",
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"abstract": "A 29-year-old man presented with a 5-month history of worsening dry cough, exertional dyspnea, chest tightness, and palpitations. He had been treated by his primary care physician with trials of guaifenesin/codeine, azithromycin, albuterol, and omeprazole without improvement. He denied wheezing, fever, sweats, anorexia, joint pain, swelling, or rash. He had no past medical history. He denied a history of tobacco smoking or IV drug use. He kept no pets, worked as a manager in an office environment, and had no history of occupational inhalational exposure. He reported using aerosolized insect spray to eradicate bed bugs in his house shortly before the cough began but did not report any acute symptoms when using the spray.",
"affiliations": "Department of Thoracic Radiology (Drs Halpenny and Alpert), New York University Langone Medical Center, New York, NY; Department of Pathology, New York University Langone Medical Center, New York, NY; Department of Pulmonology, New York University Langone Medical Center, New York, NY. Electronic address: darraghhalpenny@hotmail.com.;Department of Thoracic Radiology (Drs Halpenny and Alpert), New York University Langone Medical Center, New York, NY; Department of Pathology, New York University Langone Medical Center, New York, NY; Department of Pulmonology, New York University Langone Medical Center, New York, NY.;Department of Thoracic Radiology (Drs Halpenny and Alpert), New York University Langone Medical Center, New York, NY; Department of Pathology, New York University Langone Medical Center, New York, NY; Department of Pulmonology, New York University Langone Medical Center, New York, NY.;Department of Thoracic Radiology (Drs Halpenny and Alpert), New York University Langone Medical Center, New York, NY; Department of Pathology, New York University Langone Medical Center, New York, NY; Department of Pulmonology, New York University Langone Medical Center, New York, NY.",
"authors": "Halpenny|Darragh|D|;Suh|James|J|;Garofano|Suzette|S|;Alpert|Jeffrey|J|",
"chemical_list": "D005938:Glucocorticoids; D007306:Insecticides",
"country": "United States",
"delete": false,
"doi": "10.1378/chest.14-2936",
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"issn_linking": "0012-3692",
"issue": "148(3)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D002637:Chest Pain; D003371:Cough; D003937:Diagnosis, Differential; D004417:Dyspnea; D005938:Glucocorticoids; D006801:Humans; D007306:Insecticides; D017563:Lung Diseases, Interstitial; D008297:Male; D012129:Respiratory Function Tests; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e80-e85",
"pmc": null,
"pmid": "26324141",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 29-Year-Old Man With Nonproductive Cough, Exertional Dyspnea, and Chest Discomfort.",
"title_normalized": "a 29 year old man with nonproductive cough exertional dyspnea and chest discomfort"
} | [
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"companynumb": "US-GLENMARK PHARMACEUTICALS INC, USA.-2015GMK020113",
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"activesubstancename": "CODEINE PHOSPHATE\\GUAIFENESIN"
... |
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"abstract": "Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma with an aggressive clinical course and poor prognosis after conventional chemotherapy, for which there is no current standard of care. We describe here an 87-year-old woman with AITL, whose clinical diagnosis was complicated by the presence of B immunoblasts positive for Epstein-Barr virus in the lymph nodes and monoclonal plasma cells in the bone marrow at initial presentation. Rebiopsy of the lymph node led to the correct diagnosis of AITL with concurrent smoldering plasma cell myeloma. She was treated with several courses of conventional chemotherapy, resulting in progressive disease, and then switched to the immunomodulatory drug lenalidomide, which used in Japan for the treatment of multiple myeloma. Lenalidomide was effective in controlling both AITL and plasma cell myeloma.",
"affiliations": "Department of Hematology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan. wataru.kishimoto@katsura.com.;Department of Hematology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Hematology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Hematology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Hematology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Pathology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.;Department of Pathology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.;Department of Hematology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.;Department of Hematology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan.",
"authors": "Kishimoto|Wataru|W|http://orcid.org/0000-0001-9059-3716;Takiuchi|Yoko|Y|;Nakae|Yoshiki|Y|;Tabata|Sumie|S|;Fukunaga|Akiko|A|;Matsuzaki|Naomi|N|;Yuba|Yoshiaki|Y|;Kitano|Toshiyuki|T|;Arima|Nobuyoshi|N|",
"chemical_list": "D000077269:Lenalidomide",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-018-02587-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "109(4)",
"journal": "International journal of hematology",
"keywords": "Angioimmunoblastic T-cell lymphoma; Lenalidomide; Peripheral T-cell lymphoma; Plasma cell myeloma",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000369:Aged, 80 and over; D049109:Cell Proliferation; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D000077269:Lenalidomide; D016411:Lymphoma, T-Cell, Peripheral; D010950:Plasma Cells",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "499-504",
"pmc": null,
"pmid": "30604313",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11888076;1373088;15613356;17284527;17454592;17721185;18182664;18292286;19961485;21245435;22271479;23213091;23731832;24335103;25355245;25816919;28115369;29502313",
"title": "A case of AITL complicated by EBV-positive B cell and monoclonal plasma cell proliferation and effectively treated with lenalidomide.",
"title_normalized": "a case of aitl complicated by ebv positive b cell and monoclonal plasma cell proliferation and effectively treated with lenalidomide"
} | [
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"companynumb": "PHHY2019JP101450",
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"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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"dr... |
{
"abstract": "Primary penile melanomas are rare tumors that represent less than 0.1% of all melanomas. We report a case of a 60-year-old Japanese male with a mucosal penile melanoma and describe an increased CD8(+) T cell infiltration in brain after dacarbazine (DTIC) administration. After partial penectomy and left inguinal lymphadenectomy, he developed multiple lung, bone, spleen, brain and skin metastases. He was treated with interferon-β, DTIC and nivolumab. However, the metastases were not reduced in size. Immunohistochemistry showed an increase of CD8(+) T cell infiltration and programmed death-ligand 1 (PD-L1) expression after the administration of DTIC, but the expression of programmed cell death protein 1 (PD-1) was negative. We speculate that DTIC exerted immunostimulatory effects, but nivolumab was ineffective due to the negative expression of PD-1 and/or an insufficient infiltration of CD8(+) T cells. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanoma to take advantage of the increased CD8(+) T cell infiltration elicited by chemotherapeutic agents. It would be beneficial to pay more attention to the relationship between DTIC and immune checkpoint modulators.",
"affiliations": "Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Plastic Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.",
"authors": "Funazumi|Masato|M|;Namiki|Takeshi|T|;Arima|Yumi|Y|;Kato|Kohei|K|;Nojima|Kohei|K|;Tanaka|Kentaro|K|;Miura|Keiko|K|;Yokozeki|Hiroo|H|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5021/ad.2016.28.4.486",
"fulltext": "\n==== Front\nAnn DermatolAnn DermatolADAnnals of Dermatology1013-90872005-3894Korean Dermatological Association; The Korean Society for Investigative Dermatology 10.5021/ad.2016.28.4.486Case ReportIncreased Infiltration of CD8+ T Cells by Dacarbazine in a Patient with Mucosal Penile Melanoma Refractory to Nivolumab Funazumi Masato Namiki Takeshi Arima Yumi Kato Kohei Nojima Kohei Tanaka Kentaro 1Miura Keiko 2Yokozeki Hiroo Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.1 Department of Plastic Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.2 Department of Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.Corresponding author: Takeshi Namiki, Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Tel: 81-3-5803-5286, Fax: 81-3-5803-0143, tnamderm@tmd.ac.jp8 2016 26 7 2016 28 4 486 490 14 11 2015 19 2 2016 11 2 2016 Copyright © 2016 The Korean Dermatological Association and The Korean Society for Investigative Dermatology2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary penile melanomas are rare tumors that represent less than 0.1% of all melanomas. We report a case of a 60-year-old Japanese male with a mucosal penile melanoma and describe an increased CD8+ T cell infiltration in brain after dacarbazine (DTIC) administration. After partial penectomy and left inguinal lymphadenectomy, he developed multiple lung, bone, spleen, brain and skin metastases. He was treated with interferon-β, DTIC and nivolumab. However, the metastases were not reduced in size. Immunohistochemistry showed an increase of CD8+ T cell infiltration and programmed death-ligand 1 (PD-L1) expression after the administration of DTIC, but the expression of programmed cell death protein 1 (PD-1) was negative. We speculate that DTIC exerted immunostimulatory effects, but nivolumab was ineffective due to the negative expression of PD-1 and/or an insufficient infiltration of CD8+ T cells. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanoma to take advantage of the increased CD8+ T cell infiltration elicited by chemotherapeutic agents. It would be beneficial to pay more attention to the relationship between DTIC and immune checkpoint modulators.\n\nCD8DacarbazineMelanomaNivolumabT-lymphocytes\n==== Body\nINTRODUCTION\nPrimary penile melanomas are rare tumors that represent less than 0.1% of all melanomas and their prognosis is quite poor1. The development of effective therapeutic modalities against penile melanomas is imperative. Here, we present a 60-year-old Japanese male with a mucosal penile melanoma treated with dacarbazine (DTIC) and nivolumab. Previous studies show that DTIC exerts immunostimulatory effects by inducing the local activation of natural killer (NK) and T cells2. We found an increased CD8+ T cell infiltration after the administration of DTIC. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanomas to take advantage of the increased CD8+ T cell infiltration elicited by chemotherapeutic agents. Our results emphasize the importance of the classification of patients and the discovery of appropriate diagnostic markers for that classification.\n\nCASE REPORT\nA 60-year-old Japanese male presented with a pigmented nodule at his urethral orifice and palpable nodes at his left inguinal lymph node (Fig. 1A). The patient had a history of urination trouble and hematuria a half year before the pigmentation developed. A diagnosis of penile melanoma had been made from a biopsy at the previous hospital and he was referred to Department of Dermatology, Tokyo Medical and Dental University in May 2014. A partial penectomy and left inguinal lymphadenectomy had been performed. Histopathological findings showed melanin deposition and an atypical melanocytic proliferation arranged in sheets and in nests (Fig. 1B). The tumor cells had an eosinophilic cytoplasm and vesicular pleomorphic nuclei with prominent nucleoli and frequent mitoses (Fig. 1C). Immunohistochemical examinations showed positive reactions for Melan-A, HMB-45 and S-100. A histopathological diagnosis of penile melanoma was made. Immunostaining for CD8 revealed that few CD8+ T cells had infiltrated into the primary tumor (4.70±4.75 cells/field) and few CD8+ T cells were observed at the periphery of the tumor (16.15±12.16 cells/field), using a definition of \"peripheral\" as \"both edge and its surrounding of the tumor\" (Fig. 2A). Immunostaining for programmed cell death protein 1 (PD-1) revealed a negative reaction on lymphocytes (Fig. 2B). Immunostaining for programmed death-ligand 1 (PD-L1) revealed a slight positive reaction on tumor cells (Fig. 2C). In October 2014, multiple lung metastases and splenic metastases were suspected by contrast-enhanced computed tomography (CT) (Fig. 3A), and positron emission tomography (PET)-CT revealed multiple lung, bone and splenic metastases. From November 2014, one course of DTIC 1,000 mg/m2 and 4 courses of interferon (IFN)-β 3.0×106 IU local injection had been started. However, a metastatic lesion at the left frontal lobe of his brain was detected by magnetic resonance imaging. Tumorectomy in addition to γ-knife therapy was then performed. Immunostaining revealed an increased peripheral infiltration of CD8+ T cells in the brain metastatic lesion (44.65±24.53 cells/field). This infiltration was significantly increased compared to the primary tumor (p<0.0001) (Fig. 2D, J, K). Immunostaining for PD-1 revealed a negative reaction (Fig. 2E) and immunostaining for PD-L1 revealed a slight positive reaction (Fig. 2F). According to PET-CT and contrast-enhanced CT in December, a local relapse on the remaining penis was found, and multiple lung and bone metastatic lesions and a splenic metastatic lesion had become larger than the last time (Fig. 3B). From January 2015, a first course of nivolumab administration was started. However contrast-enhanced CT after that treatment showed an increased numbers of lung metastatic lesions, a metastasis to the left Gerota fascia and a slight enlargement of the splenic metastatic lesion (Fig. 3C). From February 2015, a second course of nivolumab administration was started. However, we discovered several subcutaneous nodules, which were considered to be new metastases, on his nasolabial sulcus and the right medial surface of his thigh. We performed a biopsy from a nodule (6 mm) at the nasolabial sulcus. Immunostaining revealed a CD8+ T cell infiltration at the peripheral site (18.20±10.16 cells/field) and inner site (6.15±6.54 cells/field) of the tumor. The increase of CD8+ T cell infiltration in the skin metastasis was not significant compared to the primary tumor (Fig. 2G, J, K). Immunostaining for PD-1 revealed a negative reaction (Fig. 2H). Immunostaining for PD-L1 revealed a slight positive reaction (Fig. 2I). We evaluated the effect for a second course of nivolumab administration by CT. The number of lung metastases had increased dramatically and a splenic metastatic lesion had become 33 mm (Fig. 3D). We estimated that the response to nivolumab administration was progressive disease (PD).\n\nThe continuation of a treatment has come to be difficult due to a rapid enlargement and an increased number of metastases in the brain. He was discharged in order to transfer to the previous hospital for the purpose of palliative therapy.\n\nDISCUSSION\nChemotherapeutic agents such as DTIC are capable of inducing tumor cell death and shrinking tumor masses while concurrently facilitating antigen uptake and subsequently activating tumor-resident dendritic cells that prime antigen-specific CD4+ and CD8+ T cells3. Previous studies suggest that DTIC exerts immunostimulatory effects by inducing the local activation of NK and T cells2. DTIC triggers the up-regulation of NKG2D ligands on melanoma cells, leading to NK cell activation and IFN-γ secretion by engagement of NKG2DL and NKG2D on NK cells. The NK cell-derived IFN-γ subsequently favors the up-regulation of major histocompatibility complex class 1 molecules on tumor cells, rendering them sensitive to cytotoxic CD8+ T cells24. In our case, we found an increased peripheral CD8+ T cell infiltration in a brain metastatic lesion after the administration of DTIC (Fig. 2D). Compared with the primary tumor, the infiltration of CD8+ T cells was significantly increased (p<0.0001). This observation may suggest a potentiation of the cancer immune response by a chemotherapeutic agent. One study showed that tumor-associated PD-L1 confers resistance to CD8+ cytotoxic T lymphocyte lysis5. This resistance system could be eliminated by blockade of PD-L1 and/or PD-1; however, other molecules such as PD-L2 also participate in this resistance mechanism. As for PD-1 expression, none of these 3 lesions was PD-1 positive in this patient (Fig. 2B, E, H). We speculate that there are two major reasons why nivolumab was ineffective. One reason is that, since PD-1 was negative, other molecules on CD8+ T cells that participate in immune checkpoint regulation such as LAG-3 or TIM-3 may be key molecules in this patient and the blockade by nivolumab was ineffective. The other reason is the insufficient induction of CD8+ infiltration in order to induce sufficient responses to suppress tumor growth. We also speculate that the decrease of CD8+ T cell infiltration from the brain metastasis to the skin metastasis might be due, at least in part, because the immunostimulatory effect of DTIC couldn't last since the DTIC administration was 5 months before the skin metastasis.\n\nAlthough we cannot deny that the increased infiltration of CD8+ T cells might be due to clonal heterogeneity of melanomas and statistical significances were not exactly rigorous due to a comparison from different metastatic sites including skin and brain, this case is still of great interest because there's few reports67, regarding the increased CD8+ T cells infiltration after an administration of DTIC and a limitation of obtaining biopsy specimens from appropriate metastatic sites of melanoma patients. Recent studies have revealed that immune checkpoint modulators have better effects in cases of high intratumoral CD8+ T cell infiltration8, so the classification of melanoma patients in terms of the effectiveness of nivolumab and its markers to distinguish nivolumab-sensitive patients will be imperative. We also should be cautious about an increased CD8+ T-cell infiltration by nivolumab in analyzing data in order to exclude unnecessary biases. If a strategy targeting PD-1 is ineffective due to the low expression of PD-1 in a melanoma patient, alternative strategies targeting other molecules participating in immune checkpoints should be considered. Although this is only one case, this could be the first step for us to speculate that a novel strategy to control metastatic sites of melanomas in nivolumab-insensitive patients is to take advantage of the enhancing effect on CD8+ T cell infiltration by DTIC. The administration of DTIC prior to nivolumab should have a benefit in a subset of melanoma patients. An appropriate selection of melanoma patients in addition to the development of appropriate markers to identify those patients is important.\n\nIn conclusion, we presented a case with an increased CD8+ T cell infiltration after the administration of DTIC. We speculate that this supports a potentiation of the cancer immune response by chemotherapeutic agents. This analysis based on different metastatic sites including skin and brain, and a bias due to clonal heterogeneity of melanomas is not exactly excluded in this study. An accumulation of such cases is required to substantiate this result by correcting those biases and eventually develop more effective strategies as therapeutics using immune checkpoint modulators such as nivolumab.\n\nACKNOWLEDGMENT\nWe thank C. Miyagishi (Pathology Staff Member) for her technical assistance.\n\nFig. 1 (A) A pigmented nodule on the urethral orifice (indicated by the white arrow). (B) An atypical melanocytic proliferation arranged in sheets and in nests. (H&E, ×40). (C) Eosinophilic cytoplasm and vesicular pleomorphic nuclei with prominent nucleoli and frequent mitoses (H&E, ×200).\nFig. 2 Immunohistochemistry for CD8 in the primary tumor (A), the brain metastatic lesion (D) and a skin metastatic lesion (G). Immunohistochemistry for programmed cell death protein 1 in the primary tumor (B), the brain metastatic lesion (E) and a skin metastatic lesion (H). Immunohistochemistry for programmed death-ligand 1 in the primary tumor (C), the brain metastatic lesion (F) and a skin metastatic lesion (I) (A~I: ×100). Number of cells staining for CD8 expressed as means±standard deviations measured over 10 high-power fields (×400) in the peripheral (J) and inner (K) layer of the tumor. Counting was performed independently by two observers. *p<0.0001.\nFig. 3 Contrast-enhanced computed tomography for a splenic metastatic lesion (A) before dacarbazine administration, after dacarbazine administration (B), after the first course of nivolumab administration (C), and after the second course of nivolumab administration (D). Diameters of the splenic metastatic lesion (indicated by white arrows) are 13 mm (A), 20 mm (B), 21 mm (C) and 32 mm (D), respectively. Arrows indicate splenic metastatic lesions.\n==== Refs\n1 Oliva E Quinn TR Amin MB Eble JN Epstein JI Srigley JR Primary malignant melanoma of the urethra: a clinicopathologic analysis of 15 cases Am J Surg Pathol 2000 24 785 796 10843280 \n2 Ugurel S Paschen A Becker JC Dacarbazine in melanoma: from a chemotherapeutic drug to an immunomodulating agent J Invest Dermatol 2013 133 289 292 23318786 \n3 Müller P Martin K Theurich S von Bergwelt-Baildon M Zippelius A Cancer chemotherapy agents target intratumoral dendritic cells to potentiate antitumor immunity Oncoimmunology 2014 3 e954460 25610745 \n4 Hervieu A Rébé C Végran F Chalmin F Bruchard M Vabres P Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth J Invest Dermatol 2013 133 499 508 22951720 \n5 Hirano F Kaneko K Tamura H Dong H Wang S Ichikawa M Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity Cancer Res 2005 65 1089 1096 15705911 \n6 Ozawa A Nomiyama T Nakai N Hartmann G Takenaka H Kishimoto S Immunohistological analysis of in-transit metastasis in a patient with advanced melanoma treated with combination therapy of cytosine guanine dinucleotide oligodeoxynucleotide, dacarbazine and beta-interferon: a case report J Dermatol 2012 39 1035 1037 22390792 \n7 Nardin A Wong WC Tow C Molina TJ Tissier F Audebourg A Dacarbazine promotes stromal remodeling and lymphocyte infiltration in cutaneous melanoma lesions J Invest Dermatol 2011 131 1896 1905 21654834 \n8 Taube JM Anders RA Young GD Xu H Sharma R McMiller TL Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape Sci Transl Med 2012 4 127ra37\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1013-9087",
"issue": "28(4)",
"journal": "Annals of dermatology",
"keywords": "CD8; Dacarbazine; Melanoma; Nivolumab; T-lymphocytes",
"medline_ta": "Ann Dermatol",
"mesh_terms": null,
"nlm_unique_id": "8916577",
"other_id": null,
"pages": "486-90",
"pmc": null,
"pmid": "27489432",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports",
"references": "22951720;25610745;23318786;21654834;22390792;15705911;10843280;22461641",
"title": "Increased Infiltration of CD8(+) T Cells by Dacarbazine in a Patient with Mucosal Penile Melanoma Refractory to Nivolumab.",
"title_normalized": "increased infiltration of cd8 t cells by dacarbazine in a patient with mucosal penile melanoma refractory to nivolumab"
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"abstract": "BACKGROUND\nAntiretroviral therapy (ART) has decreased AIDS incidence and mortality, rendering comorbidities, such as hepatitis B more relevant for people living with human immunodeficiency virus (HIV). Since antiretroviral drugs may also inhibit hepatitis B virus (HBV) replication, analyzing the impact of ART on management of hepatitis B in this population is important.\n\n\nOBJECTIVE\nTo assess HBV viremia among HIV/HBV coinfected individuals on ART and its associated factors.\n\n\nMETHODS\nFor this cross-sectional study, HIV/HBV-coinfected individuals, aged over 18 years, who were on ART for over six months and receiving care at an outpatient clinic in São Paulo were recruited. Sociodemographic characteristics, information about viral exposure, clinical and laboratory data, including evaluation of liver fibrosis were obtained. Plasma HBV DNA was measured by polymerase chain reaction. Viral genome sequencing was conducted for genotyping and identification of drug resistance-conferring mutations if viral load exceeded 900 IU/mL.\n\n\nRESULTS\nOut of 2,946 patients who attended the clinic in 2015, 83 were eligible and 56 evaluated. Plasma HBV DNA was detected in 16 (28.6%) (95% CI: 18.0-41.3%), all on lamivudine and tenofovir treatment. HBV DNA detection was associated with lower education (p = 0.015), higher international normalized ratios (p = 0.045), history of an AIDS-defining illness [OR: 3.43 (95% CI: 1.10-11.50)], and HBeAg detection [OR: 6.60 (95% CI: 1.84-23.6)]. In contrast, a last CD4+ count above 500 cells/mm3 in the year prior to inclusion [OR: 0.18 (95% CI: 0.04-0.71)] and detection of anti-HBe [OR: 0.21 (95% CI: 0.04-0.99)] were negatively associated. Patients with HBV DNA above 900 IU/mL were infected with subgenotypes A1 (n = 3) and D2 (n = 1), and exhibited viral mutations associated with total resistance to lamivudine and partial resistance to entecavir.\n\n\nCONCLUSIONS\nDespite being on ART, a significant proportion of HIV/HBV-coinfected individuals present HBV viremia. Characterization of factors that are associated with this finding may help professionals provide better management to these patients.",
"affiliations": "Universidade de São Paulo, Faculdade de Medicina, Departamento de Doenças Infecciosas e Parasitárias, São Paulo, SP, Brazil. Electronic address: leo.weissmann@usp.br.;Universidade de São Paulo, Faculdade de Medicina, Departamento de Doenças Infecciosas e Parasitárias, São Paulo, SP, Brazil. Electronic address: camila.picone@hc.fm.usp.br.;Universidade de São Paulo, Faculdade de Medicina, Laboratório de Gastroenterologia e Hepatologia Tropical - LIM-07, São Paulo, SP, Brazil. Electronic address: gomesmic@yahoo.com.br.;Universidade Federal de São Paulo, Departamento de Medicina, São Paulo, SP, Brazil. Electronic address: paulo.abrao.ferreira@gmail.com.;Hospital do Servidor Público Estadual Francisco Morato de Oliveira, Serviço de Gastroclínica e Hepatologia, São Paulo, SP, Brazil. Electronic address: monica.viana@uol.com.br.;Universidade de São Paulo, Faculdade de Medicina, Laboratório de Gastroenterologia e Hepatologia Tropical - LIM-07, São Paulo, SP, Brazil. Electronic address: joao.renato@hc.fm.usp.br.;Universidade de São Paulo, Faculdade de Medicina, Departamento de Doenças Infecciosas e Parasitárias, São Paulo, SP, Brazil. Electronic address: cassenote@usp.br.;Universidade de São Paulo, Faculdade de Medicina, Departamento de Doenças Infecciosas e Parasitárias, São Paulo, SP, Brazil. Electronic address: segurado@usp.br.",
"authors": "Weissmann|Leonardo|L|;Picone|Camila de Melo|CM|;Gouvêa|Michele Soares Gomes|MSG|;Ferreira|Paulo Roberto Abrão|PRA|;Viana|Mônica Salum Valverde Borsoi|MSVB|;Pinho|João Renato Rebello|JRR|;Cassenote|Alex Jones Flores|AJF|;Segurado|Aluísio Cotrim|AC|",
"chemical_list": "D019380:Anti-HIV Agents; D004279:DNA, Viral",
"country": "Brazil",
"delete": false,
"doi": "10.1016/j.bjid.2019.10.002",
"fulltext": "\n==== Front\nBraz J Infect Dis\nBraz J Infect Dis\nThe Brazilian Journal of Infectious Diseases\n1413-8670\n1678-4391\nElsevier\n\nS1413-8670(19)30459-3\n10.1016/j.bjid.2019.10.002\nOriginal Article\nHepatitis B viremia in HIV-coinfected individuals under antiretroviral therapy\nWeissmann Leonardo leo.weissmann@usp.br\na⁎\nPicone Camila de Melo camila.picone@hc.fm.usp.br\na\nGouvêa Michele Soares Gomes gomesmic@yahoo.com.br\nb\nFerreira Paulo Roberto Abrão paulo.abrao.ferreira@gmail.com\nc\nViana Mônica Salum Valverde Borsoi monica.viana@uol.com.br\nd\nPinho João Renato Rebello joao.renato@hc.fm.usp.br\nb\nCassenote Alex Jones Flores cassenote@usp.br\na\nSegurado Aluísio Cotrim segurado@usp.br\na\na Universidade de São Paulo, Faculdade de Medicina, Departamento de Doenças Infecciosas e Parasitárias, São Paulo, SP, Brazil\nb Universidade de São Paulo, Faculdade de Medicina, Laboratório de Gastroenterologia e Hepatologia Tropical - LIM-07, São Paulo, SP, Brazil\nc Universidade Federal de São Paulo, Departamento de Medicina, São Paulo, SP, Brazil\nd Hospital do Servidor Público Estadual Francisco Morato de Oliveira, Serviço de Gastroclínica e Hepatologia, São Paulo, SP, Brazil\n⁎ Corresponding author. leo.weissmann@usp.br\n09 11 2019\nNov-Dec 2019\n09 11 2019\n23 6 441450\n24 7 2019\n6 10 2019\n© 2019 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U.\n2019\nSociedade Brasileira de Infectologia\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/).\nBackground\n\nAntiretroviral therapy (ART) has decreased AIDS incidence and mortality, rendering comorbidities, such as hepatitis B more relevant for people living with human immunodeficiency virus (HIV). Since antiretroviral drugs may also inhibit hepatitis B virus (HBV) replication, analyzing the impact of ART on management of hepatitis B in this population is important.\n\nObjective\n\nTo assess HBV viremia among HIV/HBV coinfected individuals on ART and its associated factors.\n\nMethod\n\nFor this cross-sectional study, HIV/HBV-coinfected individuals, aged over 18 years, who were on ART for over six months and receiving care at an outpatient clinic in São Paulo were recruited. Sociodemographic characteristics, information about viral exposure, clinical and laboratory data, including evaluation of liver fibrosis were obtained. Plasma HBV DNA was measured by polymerase chain reaction. Viral genome sequencing was conducted for genotyping and identification of drug resistance-conferring mutations if viral load exceeded 900 IU/mL.\n\nResults\n\nOut of 2,946 patients who attended the clinic in 2015, 83 were eligible and 56 evaluated. Plasma HBV DNA was detected in 16 (28.6%) (95% CI: 18.0–41.3%), all on lamivudine and tenofovir treatment. HBV DNA detection was associated with lower education (p = 0.015), higher international normalized ratios (p = 0.045), history of an AIDS-defining illness [OR: 3.43 (95% CI: 1.10–11.50)], and HBeAg detection [OR: 6.60 (95% CI: 1.84–23.6)]. In contrast, a last CD4+ count above 500 cells/mm3 in the year prior to inclusion [OR: 0.18 (95% CI: 0.04–0.71)] and detection of anti-HBe [OR: 0.21 (95% CI: 0.04–0.99)] were negatively associated. Patients with HBV DNA above 900 IU/mL were infected with subgenotypes A1 (n = 3) and D2 (n = 1), and exhibited viral mutations associated with total resistance to lamivudine and partial resistance to entecavir.\n\nConclusions\n\nDespite being on ART, a significant proportion of HIV/HBV-coinfected individuals present HBV viremia. Characterization of factors that are associated with this finding may help professionals provide better management to these patients.\n\nKeywords\n\nHIV infections\nHepatitis B\nCoinfection\nAntiretroviral agents\nViremia\nDNA, viral\n==== Body\npmcIntroduction\n\nHepatitis B virus (HBV) infection is the most common chronic viral infection in the world, constituting an important public health problem.1 Globally, it is estimated that 257 million people are living with the infection. However, prevalence rates vary by geographical region. Hepatitis B resulted in 887,000 deaths in 2015 mainly caused by complications such as cirrhosis and hepatocellular carcinoma. Vaccination is an effective way of preventing HBV infection; however, most of the chronic carriers of this infection were born before this immunization became available.2 Since HBV and HIV share common modes of transmission, including unprotected sex and use of injectable drugs, HIV/HBV coinfections are likely to occur.3, 4 In fact, the World Health Organization (WHO) estimated that 36.7 million people were living with HIV worldwide in 2015, of whom 2.7 million were HBV-coinfected.2 Likewise, HIV/HBV coinfection was identified in 5.2% of hepatitis B reported cases in Brazil from 2007 to 2017.5\n\nIn a context in which antiretroviral therapy (ART) has significantly decreased AIDS incidence and mortality, comorbidities such as hepatitis B have become more relevant for the comprehensive care of people living with HIV (PLH).4 Current Brazilian,6 American7, 8 and European9, 10 guidelines recommend initiating ART for all patients with HIV infection, even if they are asymptomatic and regardless of immune status as assessed by CD4+ cell count. For those coinfected with HBV, however, antiretroviral regimens that include tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), TDF/lamivudine (3TC) or TDF/emtricitabine combinations are considered preferable. In Brazil, national guidelines recommend HIV/HBV coinfected patients should be receive with tenofovir as part of their regimen. Despite being regarded as the ideal antiviral to be used in these cases, some patients taking tenofovir may yet exhibit incomplete HBV suppression for unclear reasons, yielding persistent or transient hepatitis B viremia.11\n\nAnalyzing the impact of ART on hepatitis B in this coinfected population during clinical follow-up is thus important to help guide proper clinical management. This study aimed to assess plasma HBV DNA among HIV/HBV coinfected individuals on ART in outpatient care in São Paulo, Brazil, and to identify factors associated with HBV viremia. Furthermore, viral genomic sequencing was used to detect drug resistance-conferring mutations among hepatitis B viremic patients.\n\nMaterials and methods\n\nStudy design and selection of patients\n\nThis cross-sectional was carried out at the HIV/Aids Clinic of the Division of Infectious and Parasitic Diseases of the Hospital das Clínicas, affiliated to the Universidade de São Paulo Medical School (SEAP HIV/AIDS - HCFMUSP), where interdisciplinary and comprehensive care is provided to adults living with HIV.\n\nMedical charts of patients who attended the clinic in 2015 were reviewed in search for eligible subjects: patients aged over 18 years, diagnosed with HIV infection and chronic HBV (HBsAg positivity in serum for six months or more), and using antiretrovirals for at least six months. There was no exclusion criterion.\n\nData collection\n\nPatients who met inclusion criteria were invited to participate in the study. Information regarding variables of interest was collected through individual interviews, chart analysis, evaluation of laboratory tests and transient hepatic elastography, and data recorded in a standardized form, specifically elaborated for the study.\n\nStudy outcomes included:- Presence of HBV viremia, measured by plasma detection of viral deoxyribonucleic acid (DNA);\n\n- HBV genotype (if viremia above 900 IU/mL);\n\n- Presence of drug resistance-conferring mutations identified by sequencing the RT region of the HBV genome (if viremia above 900 IU/mL).\n\nHBV viremia was assessed by testing plasma samples with quantitative real-time polymerase chain reaction (Abbott Real-time HBV®), following manufacturers’ instructions.12 Using a 0.5 mL sample preparation, HBV DNA detection threshold of this test is 6.4 IU/mL (95% CI: 3.97–13.03 IU/mL). However, for viral load quantification a lower limit of 10 IU/mL was used.\n\nSamples that exhibited HBV DNA concentrations above 900 IU/mL were then submitted to sequencing of the RT region of the HBV genome in search of drug resistance-conferring mutations, as previously reported.13 An HBV DNA threshold of 900 IU/mL was used due to the test sensitivity.\n\nIndependent variables included:- Sociodemographic characteristics and anthropometric measures: sex, age, self-reported ethnicity, schooling, and body mass index (BMI);\n\n- Exposure to HBV and/or HIV: time since diagnosis of HBV and HIV infections, exposure categories, history of imprisonment, and other sexually transmitted infections (STI);\n\n- Alcohol consumption (assessed by a modified AUDIT questionnaire14);\n\n- Clinical data: history of AIDS-defining illnesses,15 ART (prescribed antiviral regimens, duration of use, self-reported adherence to ART assessed by a questionnaire modified from the Medication Adherence Self-Report Inventory – MASRI16), and use of other anti-HBV drugs;\n\n- Laboratory data: serum HBeAg and anti-HBe, last CD4+ count in the year before inclusion, nadir CD4+ count, last HIV viral load in the six months prior to inclusion, platelet count, international normalized ratio (INR), serum transaminases, total bilirubin, gamma glutamyl transferase, total protein, albumin, gamma globulin, alpha-fetoprotein, serum anti-HCV antibodies, and plasma HCV RNA;\n\n- Transient liver elastography findings: liver stiffness and controlled attenuation parameter (CAP).\n\nData management and analyses\n\nData were entered into a Microsoft Excel 2010 spreadsheet and analyzed with the aid of the statistical program IBM SPSS Statistics for Windows, Version 23.0, Armonk, NY.\n\nFor descriptive statistics, categorical variables of interest were presented in frequency tables, and quantitative variables with central tendency measures and variability.\n\nFactors associated with HBV viremia were then sought after by correlating HBV DNA detection with patients’ socioeconomic and anthropometric characteristics, and variables related to HIV and HBV exposure, clinical features, as well as with results of laboratory tests and imaging exams. Fisher’s exact test or the chi-square test with calculation of odds ratios (OR) and their respective 95% confidence intervals (95% CI) was used to compare HBV viremic and nonviremic individuals. Quantitative variables were assessed with the nonparametric Mann–Whitney test assessment of variable distribution by the Shapiro–Wilk test. A statistical significance level of 5% was adopted for all analyses.\n\nEthical issues\n\nData collection was initiated only after the study protocol was approved by Institutional Review Boards. Study participation was voluntary and followed informed consent. Confidentiality and anonymity of participants were assured throughout the investigation.\n\nResults\n\nFrom January 1 to December 31, 2015, 2,946 PLH attended medical follow-up consultations at SEAP HIV/AIDS - HCFMUSP. Of these, 83 exhibited serum HBsAg for at least six months, yielding an overall prevalence of 2.8% of PLH, who were chronically coinfected with HBV (95% CI: 2.3–3.4%). They were all receiving ART for six months or longer and were, therefore, eligible for the study. However, 27 of them could not be evaluated due to refusal (n = 11), death (n = 4), loss to follow-up (n = 4), incorrect contact information (n = 5), referral to other HIV clinics (n = 2), or HBsAg seroreversion (n = 1). Therefore, the study cohort consisted of 56 HIV/HBV coinfected adults. These individuals who could not be evaluated were not significantly different in terms of sex [96% male (95% CI: 89–99%) versus 93% (95% CI: 78–98%)] and median age [53 years (95% CI: 51–55) versus 50 (95% CI: 46–54)].\n\nIn the remaining cohort, most participants were male (n = 54, 96%), aged over 50 (n = 37, 66%), white (n = 33, 59%), reported at least eight years of schooling (n = 34, 61%), and presented with normal weight (n = 36, 64%). The median time since HIV diagnosis was 18.1 years (2.0–28.3 years), and the median time since HBV diagnosis was 15.0 years (1.0–29.0 years). Concerning exposure to viral infections, 42 participants reported being men who have sex with men, and three had been in prison (for 15 days, 12 months and 44 months). A total of 41 (73%) individuals had an informed history of at least one episode of STI [syphilis (n = 31), gonorrhea (n = 21), genital warts (n = 10) and herpes (n = 2)]. Seventeen (30%) patients reported more than one STI. History of injectable drug use and of blood transfusion was reported by three patients each.\n\nScreening for hepatitis C disclosed 10 (18%) participants with evidence of previous HCV infection (positive EIA test, but HCV RNA PCR negative) and three (5%) had evidence of HCV viremia before inclusion in the study. All HCV-coinfected patients had been treated with pegylated interferon for six months (n = 1) or 12 months (n = 2), 12, 8 and 11 years, respectively, before inclusion in the study and exhibited sustained virologic responses.\n\nAs for alcohol consumption, 44 (79%) reported none or drinking once a month or less often; in contrast, 13 (28%) informed at least one episode of drinking six or more shots in a single occasion.\n\nIn terms of HIV disease, 23 (41%) reported having experienced an AIDS-defining illness, most often pulmonary tuberculosis (n = 11), Pneumocystis jirovecii pneumonia (n = 5), CMV disease [retinitis or in other organs but the liver, spleen or lymph nodes (n = 4)], or Kaposi’s sarcoma (n = 4). Nine (16%) participants had two or more illnesses.\n\nAs far as anti-HBV medication is concerned, 54 (96%) patients in our cohort were taking lamivudine and tenofovir at the time of inclusion in the study. Two participants, in contrast, were not receiving tenofovir at baseline due to previous renal toxicity, experienced after 104 and 137 months of use of this drug. At inclusion in our study one of these patients was receiving lamivudine plus entecavir, whereas the other was using lamivudine alone. As for other anti-HBV medications, three (5%) individuals reported having used pegylated interferon to treat chronic hepatitis C, as previously mentioned, and two (4%) patients received entecavir before inclusion in the study, while one was using entecavir at the time of inclusion in combination with ART regimens that included lamivudine but not tenofovir.\n\nAdditionally, 31 (55%) patients were on ART regimens that included non-nucleoside reverse transcriptase inhibitor drugs, 24 (43%) were on protease inhibitors, five (9%) were taking integrase inhibitors and one was receiving enfuvirtide. Most patients reported good adherence to ART: 51 (91%) informed having taken more than 85% of prescribed pills in the previous month.\n\nPlasma detection of HBV DNA was achieved in 16 individuals in our cohort (28.6%, 95% CI: 18.0–41.3%), and in 12 (96%) HBV viral load was less than 900 IU/mL.\n\nIn univariate analysis to identify factors associated with HBV viremia, international normalized ratios (INR) was significantly higher (p = 0.045) among viremic patients (Table 1) compared with nonviremic HIV/HBV coinfected individuals. In contrast, no significant difference was shown between the two groups regarding age, BMI, time since HIV and HBV diagnoses, platelet count, serum ALT, AST, bilirubin, gamma glutamyl transferase, total protein, albumin, gamma globulin, and alpha-fetoprotein concentrations.Table 1 Quantitative variables according to HBV viremia.\n\nTable 1\tHBV viremia\t\t\nVariables\tNo\tYes\tp-value\t\n\tMedian\tIQR\tMedian\tIQR\t\t\nSociodemographic characteristics and anthropometric measures\t\t\t\t\t\t\n Age (years)\t52.0\t48.0–57.0\t55.0\t49.0–59.0\t0.643\t\n BMI (kg/m2)\t23.8\t22.0–25.6\t24.8\t20.7–27.0\t0.663\t\nTime since diagnosis (years)\t\t\t\t\t\t\n HIV\t17.9\t15.7–20.9\t19.8\t15.0–22.0\t0.828\t\n HBV\t15.0\t10.5–18.0\t12.5\t3.5–16.5\t0.167\t\nTime using ART (years)\t\t\t\t\t\t\n Lamivudine\t16.0\t13.0–18.0\t18.0\t16.0–20.0\t0.130\t\n Tenofovir\t10.2\t7.5–11.4\t10.3\t5.9–11.2\t0.779\t\nLaboratory data\t\t\t\t\t\t\n Platelet count (x 103/mm3)\t193.5\t163.0–232.5\t181.0\t163.0–232.5\t0.663\t\n ALT (IU/L)\t25.0\t19.0–39.0\t31.0\t20.0–51.0\t0.268\t\n AST (IU/L)\t24.0\t19.0–36.0\t27.0\t22.0–33.0\t0.280\t\n Total bilirubin (mg/dL)\t0.40\t0.29–0.70\t0.60\t0.41–1.02\t0.102\t\n GGT (IU/L)\t34.0\t22.0–79.0\t44.0\t23.0–81.0\t0.580\t\n INR\t1.00\t0.97–1.07\t1.06\t1.03–1.10\t0.045\t\n Total protein (g/dL)\t7.5\t7.2–7.8\t7.6\t7.3–8.3\t0.501\t\n Albumin (g/dL)\t4.1\t3.9–4.3\t4.0\t3.8–4.1\t0.065\t\n Gamma globulin (g/dL)\t1.3\t1.1–1.6\t1.6\t1.3–1.8\t0.147\t\n Alpha-fetoprotein (ng/mL)\t2.5\t2.1–3.3\t2.6\t2.2–3.7\t0.771\t\nHBV, hepatitis B virus; IQR, interquartile range; BMI, body mass index; HIV, human immunodeficiency virus; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase; INR, international normalized ratio.\n\nTime using anti-HBV medication did not differ between HBV viremic and nonviremic patients (Fig. 1A and 1B).Fig. 1 Time using anti-HBV medication (in years) by HBV viremic and nonviremic patients (1A - lamivudine; 1B - tenofovir).\n\nFig. 1\n\nA comparison of categorical variables between HBV viremic and nonviremic patients is shown in Table 2. HBV viremia was positively associated with lower levels of schooling (0% viremic among individuals with university degree versus 50% viremic among those with no education or incomplete basic education (p = 0.015), history of an AIDS-defining illness [OR: 3.43 (95% CI: 1.10–11.50); p = 0.040], and serum HBeAg detection [OR: 6.60 (95% CI: 1.84–23.6); p = 0.003]. In contrast, last CD4+ count over 500 cells/mm3 in the year before inclusion [OR: 0.18 (95% CI: 0.04–0.71); p = 0.016] and serum anti-HBe detection [OR: 0.21 (95% CI: 0.04–0.99); p = 0.043] were negatively associated with HBV viremia.Table 2 Categorical variables according to HBV viremia.\n\nTable 2\tHBV viremia\t\t\t\t\nVariables\tNo (N = 40)\tYes (N = 16)\tOR\t95% CI\tp-value\t\n\tN\t%\tN\t%\t\t\t\t\nSex\t\t\t\t\t\t\t0.506\t\n Male\t38\t70\t16\t30\t1\t–\t\t\n Female\t2\t100\t0\t0\t0\t0\t\t\nEthnicity\t\t\t\t\t\t\t0.123\t\n White\t26\t79\t7\t21\t1\t–\t\t\n Non-White\t14\t61\t9\t39\t2.30\t0.73–7.70\t\t\nSchooling\t\t\t\t\t\t\t0.015a\t\n None or incomplete basic education\t6\t50\t6\t50\t1\t–\t\t\n Basic education\t7\t70\t3\t30\t0.42\t0.07–2.49\t\t\n Medium education\t15\t68\t7\t32\t0.46\t0.10–2.10\t\t\n University degree\t12\t100\t0\t0\t0\t0\t\t\nHIV exposure categories\t\t\t\t\t\t\t0.111\t\n Heterosexual\t10\t91\t1\t9\t1\t–\t–\t\n MSM\t26\t67\t13\t33\t5.00\t0.89–11.90\t\t\n IDU\t1\t33\t2\t67\t20.00\t0.12–68.00\t\t\n Blood transfusion\t3\t100\t0\t0\t0\t0\t\t\nAlcohol consumption\t\t\t\t\t\t\t0.269\t\n Never\t20\t80\t5\t20\t1\t–\t\t\n ≤ Once/month\t12\t63\t7\t37\t2.33\t0.60–9.02\t\t\n ≥Twice/month\t8\t67\t4\t33\t2.00\t0.40–9.40\t\t\nAIDS-defining illness\t\t\t\t\t\t\t0.040\t\n No\t27\t82\t6\t18\t1\t–\t\t\n Yes\t13\t57\t10\t43\t3.43\t1.10–11.50\t\t\nLast CD4+ count (cells/mm3)\t\t\t\t\t\t\t0.016a\t\n ≤500\t5\t42\t7\t58\t1\t–\t\t\n >500\t35\t80\t9\t20\t0.18\t0.04–0.71\t\t\nNadir CD4+ count (cells/mm3)\t\t\t\t\t\t\t0.660a\t\n <100\t14\t64\t8\t36\t1\t–\t\t\n 100–500\t19\t76\t6\t24\t0.55\t0.15–1.55\t\t\n >500\t7\t78\t2\t22\t0.50\t0.08–3.00\t\t\nHIV viral load\t\t\t\t\t\t\t0.135\t\n Undetectable\t38\t75\t13\t25\t1\t–\t\t\n Detectable\t2\t40\t3\t60\t4.38\t0.65–29.20\t\t\nHBeAg\t\t\t\t\t\t\t0.003\t\n Nonreactive\t30\t86\t5\t14\t1\t–\t\t\n Reactive\t10\t48\t11\t52\t6.60\t1.84–23.60\t\t\nAnti-HBe\t\t\t\t\t\t\t0.043\t\n Nonreactive\t24\t63\t14\t37\t1\t–\t\t\n Reactive\t16\t89\t2\t11\t0.21\t0.04–0.99\t\t\nAnti-HCV\t\t\t\t\t\t\t0.301\t\n Nonreactive\t34\t74\t12\t26\t1\t–\t\t\n Reactive\t6\t60\t4\t40\t1.89\t0.45–7.89\t\t\nHCV RNAb\t\t\t\t\t\t\t\t\n Undetectable\t4\t57\t3\t43\t1\t–\t0.666\t\n Detectable\t2\t67\t1\t33\t0.66\t0.03–11.28\t\t\nLiver stiffness (kPa)c\t\t\t\t\t\t\t0.223\t\n <7.2\t19\t76\t6\t24\t1\t–\t\t\n 7.2–11.0\t8\t80\t2\t20\t0.79\t0.13–4.70\t\t\n >11.0\t3\t50\t3\t50\t3.16\t0.50–20.00\t\t\nCAP (dB/m)c\t\t\t\t\t\t\t0.398\t\n <215\t12\t80\t3\t20\t1\t–\t\t\n 215–300\t15\t68\t7\t32\t1.80\t0.39–8.80\t\t\n >300\t3\t75\t1\t25\t1.33\t0.09–17.80\t\t\nHBV, hepatitis B virus; OR, odds ratio; 95% CI, 95% confidence interval; HIV, human immunodeficiency virus; MSM, men who have sex with men; IDU, injection drug use; AIDS, acquired immunodeficiency syndrome; HBeAg, hepatitis B e-antigen; Anti-HBe, hepatitis B e-antibody; Anti-HCV, hepatitis C antibody; HCV RNA, hepatitis C virus RNA; CAP, controlled attenuation parameter.\n\na Chi-square test for linear trend.\n\nb Performed only for 10 anti-HCV-reactive individuals.\n\nc Information available for 41 patients only.\n\nFurthermore, age, ethnicity, HIV exposure category, alcohol consumption, nadir CD4+ count, HIV viral load, anti-HCV, and HCV RNA detection were not associated with HBV viremia. Likewise, transient liver elastography findings (liver stiffness and CAP) did not differ according to HBV viremia.\n\nOut of four patients who exhibited HBV viral loads above 900 IU/mL, three were infected with HBV subgenotype A1 and the fourth with subgenotype D2. In all of them, drug resistance-conferring mutations associated with total resistance to lamivudine and with partial resistance to entecavir (Table 3) were demonstrated.Table 3 HBV viral load, HBV subgenotypes, viral mutations, drug resistance profile, and time using lamivudine and tenofovir in patients who presented HBV viral load greater than 900 IU/mL.\n\nTable 3Patient\tHBV viral load (IU/mL)\tHBV subgenotype\tRT region mutations\tDrug resistance profile\tTime using lamivudine (years)\tTime using tenofovir (years)\t\nLAM\tADV\tETV\tTDF\t\n1\t929\tA1\trtL180 M + rtM204 V + rtL229F\tR\tS\tI\tS\t19.5\t11.1\t\n2\t2,877\tD2\trtV173 L + rtL180 M + rtM204V\tR\tS\tI\tS\t19.2\t11.1\t\n3\t49,425,077\tA1\trtL180 M + rtA200 V + rtM204I\tR\tS\tI\tS\t20.9\t7.1\t\n4\t2,518\tA1\trtL180 M + rtM204 V + rtL229 V + rtV253I\tR\tS\tI\tS\t17.6\t2.1\t\nHBV, hepatitis B virus; LAM, lamivudine; ADV, adefovir; ETV, entecavir; TDF, tenofovir disoproxil fumarate; S, sensitive; I, intermediate susceptibility; R, resistant.\n\nFurthermore, positions rt106, rt126, rt134, and rt269 were also analyzed. In individuals infected with HBV subgenotype A1, the following amino acid patterns were identified at these positions: rtS106, rtY126, rtD134, and rtI269, whereas in the individual infected with subgenotype D2, we found: rtS106, rtR126, rtD134 and rtI269.\n\nDiscussion\n\nIn our cohort, followed up at an University outpatient clinic in São Paulo, 83 (2.8%) of patients were identified as HIV/HBV-coinfected (95% CI: 2.3–3.4%), and among them, 56/83 (28.6%, 95% CI: 18.0–41.3%) presented HBV viremia despite being treated with anti-HBV antivirals.\n\nIt is important to highlight that participants in our cohort were predominantly men who had sex with men, in accordance with findings of previous studies carried out in the same clinic.17, 18 As far as education was concerned, 61% reported at least 11 schooling years, a feature of the clinic clientele, as previously reported.19\n\nNevertheless, the rate of HBV viremic individuals - 28.6% - was high, despite long-term use of antivirals that are active against the virus (median time 10.3 years for tenofovir and 18.0 years for lamivudine). Tenofovir and lamivudine were used by all viremic patients. In addition, patients not taking tenofovir due to past renal toxicity had no HBV viremia.\n\nHBV suppression in HIV/HBV-coinfected individuals on ART has been previously investigated in longitudinal studies in several countries, and usually a more favorable response was seen compared to our findings. de Vries-Sluijs et al.,20 for instance, in a multicenter study with median follow-up of 55 months, showed that among HBeAg-positive individuals, the cumulative probability of achieving virologic response after 1, 2, 3, 4 and 5 years of treatment was 31%, 70%, 83%, 88% and 92%, respectively. Among HBeAg-negative patients, the virologic response in the first four years of therapy was 47%, 85%, 85% and 100%, respectively. Likewise, Price et al.21 reported HBV suppression in more than 85% of cases after three years of tenofovir use. Studying patients from Australia, United States and Thailand, Matthews et al.22 detected HBV viremia in 20.8%, and the outcome was associated with serum HBeAg detection, HIV viral load, CD4+ cell count lower than 200 cells/mm3, use of ART for less than two years, self-reported adherence to therapy below 95%, and HBV monotherapy with lamivudine/emtricitabine or TDF. More recently, Huang et al.23 highlighted that the use of tenofovir-containing regimens as initial antiviral therapy is independently associated with HBV suppression.\n\nLower education was associated with HBV viremia in our cohort. One may hypothesize that this association may be a consequence of lower adherence to therapy, as previously proposed by Carvalho et al.24 In this cohort patients with university degrees were more adherent to therapy compared to those with medium-level education or less (OR: 7.0; p = 0.037). From a broader perspective, Tavares et al.25 pointed out that among Brazilian patients with other chronic diseases, lower education was also associated with poorer adherence to therapy, highlighting the need to take this into consideration in a comprehensive care approach. However, we were not able to show a correlation between education and adherence to therapy in our study. As 95% of cohort participants reported having taken more than 85% of prescribed pills in the 30 days prior to inclusion, adherence to treatment could not be included in the analysis.\n\nAssessing adherence to therapy by means of patients’ self-report should also be put in context since limitations of this technique have been discussed in a previous study conducted at the same clinic. Among those self-reporting good adherence to ART, Gutierrez et al.26 evaluated drug dispensation registries and found that only 39.3%, 54.1%, and 69.3% of patients had in fact collected greater than or equal to 95%, 90% and 80% of prescribed pills in the previous year, respectively. In a systematic review, Lieveld et al.27 reported that mean adherence to hepatitis B therapy ranges from 81 to 99%, and full adherence from 66 to 92% of patients in different studies. Higher adherence rates are found by patients’ self-report, whereas surveys that employed pill counts usually yield poorer rates. However, these investigators emphasize that so far there is no consensus on what adherence rate to HBV therapy should be regarded as optimal. We believe that assessment by patients’ self-report might have overestimated adherence to therapy in our study.\n\nAlthough HIV viral load was not significantly associated with HBV viremia in our cohort, we should highlight that 60% of those with detectable HIV RNA in the last test performed 180 days before inclusion also exhibited HBV viremia. The patient who presented the highest hepatitis B viral load in our cohort (49,425,077 IU/mL) reported having discontinued ART in the month prior to inclusion in the study because of a surgical procedure. As a matter of fact, his HIV viral load was 3,297 RNA copies/mL on the same date. In addition, two other individuals exhibited simultaneous HIV and HBV viremia. Of these, one exhibited an HBV DNA concentration of 929 IU/mL, whereas the other had an HBV load below quantitation threshold (less than 10 IU/mL). The limited number of HIV viremic patients in our cohort may have reduced the statistical power to demonstrate association of HIV viremia with the study outcome.\n\nIn a cohort study of HIV/HBV-coinfected individuals in the United States,28 it has been shown that in patients diagnosed with HBV infection after diagnosis of HIV infection, combined antiretroviral therapy was associated with a reduction in the risk of chronic HBV infection (OR: 0.18; 95% CI: 0.04–0.79). Similarly, in the present study, history of AIDS-defining diseases resulted in an increased risk of HBV DNA detection (OR: 3.43; p = 0.040). Conversely, a CD4+ count above 500 cells/mm3 in the 365 days prior to inclusion was protective of the outcome (OR: 0.18; p = 0.016).\n\nAnother factor directly associated with detection of plasma HBV DNA in our study was the detection of the viral e antigen (HBeAg). In contrast, anti-HBe detection was shown to be protective of the outcome. The association of both variables with the main study outcome was expected, given that HBeAg is a recognized biomarker of HBV replication, whereas anti-HBe seroconversion corresponds to suppression of replication. The same finding had previously been described in coinfected patients from the same clinic, by Mendes-Correa et al.29\n\nA direct association of higher values of INR with the detection of HBV DNA was also verified in this study, suggesting the possibility of a relationship between the outcome and more advanced liver disease. Nonetheless, there was no association of HBV viremia and significant alterations of other biomarkers, such as aminotransferases, total bilirubin, gamma globulins and albumin, has been observed, nor was it related to hepatic rigidity. Although we had no baseline data of the studied individuals, due to the study cross-sectional design, it is well known that nucleos(t)ide analogue therapy can reverse fibrosis, in addition to improving liver function in a substantial number of patients.30, 31\n\nIn patients from whom it was technically feasible to perform HBV DNA sequencing, a predominance of individuals with the A1 subgenotype was detected, followed by the D2 subgenotype, which agrees with other Brazilian studies.32, 33, 34 This observation suggests an effect of “Afrodescendence” in addition to the influence of European colonization in our country. Soriano et al.35 using EuroSIDA study data demonstrated that most patients with genotype A infection on that continent were men who had sex with men, while injecting drug users had genotype D. Moreover, Boyd et al.11 identified genotype A in 63% of patients with transient viremia and in 77% of those with persistent HBV viremia.\n\nMutations in the RT region of the HBV genome were detected in the four individuals assessed by sequencing. Although there were different combinations of mutations, complete resistance to lamivudine and partial resistance to entecavir was observed in all profiles. The most frequently encountered combination was rtL180 M + rtM204 V, which coincides with a previous Brazilian study.36\n\nAs for the amino acid patterns rtY126 and rtI296, which have been recently reported by Park et al.37 as associated with resistance to tenofovir for genotype C, there is so far no evidence that the same phenotype would occur in individuals infected with genotypes A or D. However, these profiles have been previously reported as characteristic of wild-type strains for HBV genotypes A1 and D2.13, 38 We can thus hypothesize that in case these profiles are proven to reduce HBV genotype A and D sensitivity to tenofovir, likewise genotype C, a reduced genetic barrier to this antiretroviral should be considered for Brazilian patients.\n\nSome limitations should be pointed out in our study: the single-center survey design and losses to follow-up or seroreversion. Although it does not present selection bias, as no significant difference was shown between included and eligible but nonincluded patients with respect to sex and age, the reduced sample may have compromised the statistical power of the study besides impairing the possibility to perform multivariate analysis. In addition, the cross-sectional design of our study precludes any conclusion on a causal link between the identified risk/protection factors and HBV viremia.\n\nNevertheless, our findings show the importance of adequate management of HIV/HBV-coinfected patients during long-term use of antiretroviral drugs. The need for strict control and long follow-up is emphasized, since even in the presence of undetected HIV RNA, HBV suppression may occur only after more than four years on proper antiviral chemotherapy. Moreover, in some coinfected individuals, it is possible to find sustained HBV viremia as consequence of poor adherence to therapy or emergence of drug-resistant mutants. Future analyses, preferably in multicenter studies with larger number of participants and longer follow-up, may contribute to better elucidate the virologic response of HIV/HBV-coinfected individuals on HBV therapy and its associated factors.\n\nConflicts of interest\n\nThe authors declare no conflicts of interest.\n==== Refs\nReferences\n\n1 Trépo C. Chan H. Lok A. Hepatitis B virus infection Lancet 384 2014 2053 2063 https://www.ncbi.nlm.nih.gov/pubmed/24954675 24954675\n2 World Health Organization Global hepatitis report 2017 Geneva https://apps.who.int/iris/handle/10665/255016 2017\n3 Sun H.Y. Sheng W.H. Tsai M.S. Lee K.Y. Chang S.Y. Hung C.C. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: a review World J Gastroenterol 20 2014 14598 14614 https://www.ncbi.nlm.nih.gov/pubmed/25356024 25356024\n4 Konopnicki D. Mocroft A. de Wit S. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort AIDS 19 2005 593 601 https://www.ncbi.nlm.nih.gov/pubmed/15802978 15802978\n5 Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância, Prevenção e Controle das IST, do HIV/Aids e das Hepatites Virais (DIAHV). Boletim Epidemiológico 2018 – Hepatites Virais. Ano VI – nº 01. http://portalarquivos2.saude.gov.br/images/pdf/2018/julho/05/Boletim-Hepatites-2018.pdf.\n6 Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Vigilância, Prevenção e Controle das Infecções Sexualmente Transmissíveis, do HIV/Aids e das Hepatites Virais. Protocolo Clínico e Diretrizes Terapêuticas para Manejo da Infecção pelo HIV em Adultos. Brasília: Ministério da Saúde, 2018. http://www.aids.gov.br/pt-br/pub/2013/protocolo-clinico-e-diretrizes-terapeuticas-para-manejo-da-infeccao-pelo-hiv-em-adultos.\n7 Terrault N. Lok A. McMahon B. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance Hepatology 67 2018 1560 1599 https://www.ncbi.nlm.nih.gov/pubmed/29405329 29405329\n8 Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.\n9 Lampertico P. Agarwal K. Berg T. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection J Hepatol 67 2017 370 398 https://www.ncbi.nlm.nih.gov/pubmed/28427875 28427875\n10 European AIDS Clinical Society European guidelines for treatment of HIV-positive adults in Europe Version 9.0. http://www.eacsociety.org/files/guidelines-9.0-portuguese.pdf\n11 Boyd A. Gozlan J. Maylin S. Persistent viremia in human immunodeficiency virus/hepatitis B coinfected patients undergoing long-term tenofovir: Virological and clinical implications Hepatology 60 2014 497 507 https://www.ncbi.nlm.nih.gov/pubmed/24752996 24752996\n12 Abbott RealTime HBV. [Bula]. Wiesbaden, Alemanha: ABBOTT GmbH & Co. KG.\n13 Gomes-Gouvêa M. Ferreira A. Teixeira R. HBV carrying drug-resistance mutations in chronically infected treatment-naive patients Antivir Ther 20 2015 387 395 https://www.ncbi.nlm.nih.gov/pubmed/25624410 25624410\n14 Babor T.F. Higgins-Biddle J.C. Saunders J.B. Monteiro M.G. AUDIT: the alcohol use disorders identification test: guidelines for use in primary care 2nd ed. 2001 World Health Organization Geneva https://apps.who.int/iris/handle/10665/67205\n15 Brasil. Ministério da Saúde. Secretaria de Vigilância em Saúde. Programa Nacional de DST e Aids. Critérios de definição de casos de aids em adultos e crianças. Brasília: Ministério da Saúde 2003 http://bvsms.saude.gov.br/bvs/publicacoes/criterios_definicao_AIDS_adultos_criancas.pdf\n16 Walsh J.C. Mandalia S. Gazzard B.G. Responses to a 1-month self-report on adherence to antiretroviral therapy are consistent with electronic data and virological treatment outcome AIDS 16 2002 269 277 https://www.ncbi.nlm.nih.gov/pubmed/11807312 11807312\n17 Mendes-Corrêa M. Barone A. Cavalheiro N. Tengan F. Guastini C. Prevalence of hepatitis B and C in the sera of patients with HIV infection in São Paulo, Brazil Rev Inst Med Trop Sao Paulo 42 2000 81 85 10810322\n18 Silva A. Spina A. Lemos M. Hepatitis B genotype G and high frequency of lamivudine-resistance mutations among human immunodeficiency virus/hepatitis B virus co-infected patients in Brazil Mem Inst Oswaldo Cruz 105 2010 770 778 20944991\n19 Braga P. Cardoso M. Segurado A. Diferenças de gênero ao acolhimento de pessoas vivendo com HIV em serviço universitário de referência de São Paulo, Brasil Cad Saúde Pública 23 2007 2653 2662 17952258\n20 de Vries-Sluijs T. Reijnders J. Hansen B. Long-term therapy with tenofovir is effective for patients co-infected with human immunodeficiency virus and hepatitis B virus Gastroenterology 139 2010 1934 1941 https://www.ncbi.nlm.nih.gov/pubmed/20801123 20801123\n21 Price H. Dunn D. Pillay D. Suppression of HBV by tenofovir in HBV/HIV coinfected patients: a systematic review and meta-analysis PloS One 8 2013 e68152 https://www.ncbi.nlm.nih.gov/pubmed/23874527\n22 Matthews G. Seaberg E. Avihingsanon A. Patterns and causes of suboptimal response to tenofovir-based therapy in individuals coinfected with HIV and hepatitis B virus Clin Infect Dis 56 2013 e87 94 https://www.ncbi.nlm.nih.gov/pubmed/23315316 23315316\n23 Huang Y.S. Sun H.Y. Chang S.Y. Long-term virological and serologic responses of chronic hepatitis B virus infection to tenofovir disoproxil fumarate-containing regimens in patients with HIV and hepatitis B coinfection Hepatol Int 13 2019 431 439 https://www.ncbi.nlm.nih.gov/pubmed/31177505 31177505\n24 Carvalho C. Merchán-Hamann E. Matsushita R. Determinantes da adesão ao tratamento anti-retroviral em Brasília, DF: um estudo de caso-controle Rev Soc Bras Med Trop 40 2007 555 565 17992413\n25 Tavares N. Bertoldi A. Mengue S. Fatores associados à baixa adesão ao tratamento farmacológico de doenças crônicas no Brasil Rev Saúde Pública 50 2016 10.1590/s1518-8787.2016050006150\n26 Gutierrez E. Sartori A. Schmidt A. Measuring adherence to antiretroviral treatment: the role of pharmacy records of drug withdrawals AIDS Behav 16 2012 1482 1490 https://www.ncbi.nlm.nih.gov/pubmed/22392157 22392157\n27 Lieveld F. van Vlerken L. Siersema P. van Erpecum K. Patient adherence to antiviral treatment for chronic hepatitis B and C: a systematic review Ann Hepatol 12 2013 380 391 https://www.ncbi.nlm.nih.gov/pubmed/23619254 23619254\n28 Landrum M. Fieberg A. Chun H. The effect of human immunodeficiency virus on hepatitis B virus serologic status in co-infected adults PLoS One 5 2010 e8687 https://www.ncbi.nlm.nih.gov/pubmed/20084275 20084275\n29 Mendes-Correa M. Pinho J. Gomes-Gouvea M. Predictors of HBeAg status and hepatitis B viraemia in HIV-infected patients with chronic hepatitis B in the HAART era in Brazil BMC Infect Dis 11 2011 247 https://www.ncbi.nlm.nih.gov/pubmed/21933423 21933423\n30 Marcellin P. Gane E. Buti M. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study Lancet 381 2013 468 475 https://www.ncbi.nlm.nih.gov/pubmed/23234725 23234725\n31 Jang J. Choi J. Kim Y. Long-term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus-related cirrhosis Hepatology 61 2015 1809 1820 https://www.ncbi.nlm.nih.gov/pubmed/25627342 25627342\n32 Mello F. Souto F. Nabuco L. Hepatitis B virus genotypes circulating in Brazil: molecular characterization of genotype F isolates BMC Microbiol 7 2007 103 https://www.ncbi.nlm.nih.gov/pubmed/18036224 18036224\n33 Alvarado-Mora M. Botelho L. Gomes-Gouvêa M. Detection of hepatitis B virus subgenotype A1 in a Quilombo community from Maranhão, Brazil Virol J 8 2011 415 https://www.ncbi.nlm.nih.gov/pubmed/21867526 21867526\n34 Bertolini D. Gomes-Gouvêa M. Carvalho-Mello I. Hepatitis B virus genotypes from European origin explains the high endemicity found in some areas from southern Brazil Infect Genet Evol 12 2012 1296 1304 https://www.ncbi.nlm.nih.gov/pubmed/22538208\n35 Soriano V. Mocroft A. Peters L. Predictors of hepatitis B virus genotype and viraemia in HIV-infected patients with chronic hepatitis B in Europe J Antimicrob Chemother 65 2010 548 555 https://www.ncbi.nlm.nih.gov/pubmed/20051475 20051475\n36 Mendes-Correa M.C. Pinho J. Locarnini S. High frequency of lamivudine resistance mutations in Brazilian patients co-infected with HIV and hepatitis B J Med Virol 82 2010 1481 1488 https://www.ncbi.nlm.nih.gov/pubmed/20648600 20648600\n37 Park E. Lee A. Kim D. Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients J Hepatol 70 2019 1093 1102 https://www.ncbi.nlm.nih.gov/pubmed/30794889 30794889\n38 Rhee S. Margeridon-Thermet S. Nguyen M. Hepatitis B virus reverse transcriptase sequence variant database for sequence analysis and mutation discovery Antiviral Res 88 2010 269 275 https://www.ncbi.nlm.nih.gov/pubmed/20875460 20875460\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1413-8670",
"issue": "23(6)",
"journal": "The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases",
"keywords": "Antiretroviral agents; Coinfection; DNA, viral; HIV infections; Hepatitis B; Viremia",
"medline_ta": "Braz J Infect Dis",
"mesh_terms": "D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D060085:Coinfection; D003430:Cross-Sectional Studies; D004279:DNA, Viral; D004522:Educational Status; D005260:Female; D015658:HIV Infections; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D019562:Viral Load; D014766:Viremia",
"nlm_unique_id": "9812937",
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"pages": "441-450",
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"pmid": "31715124",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hepatitis B viremia in HIV-coinfected individuals under antiretroviral therapy.",
"title_normalized": "hepatitis b viremia in hiv coinfected individuals under antiretroviral therapy"
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"companynumb": "BR-GLAXOSMITHKLINE-BR2019GSK208205",
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"occurcountry": "BR",
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"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
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{
"abstract": "OBJECTIVE\nTo report a farmer's corneal abscess caused by an unusual pathogen: Listeria monocytogenes fluoroquinolone resistant.\n\n\nMETHODS\nA 78-year-old farmer presented a central corneal abscess associated with 1-mm hypopyon and decreased visual acuity evolving since 2 weeks. First an antibiotic therapy associating oral ofloxacin and topical ciprofloxacin, vancomycin and ceftazidime was started. Different samples of the abscess were performed and sent to different microbiological laboratories.\n\n\nRESULTS\nListeria monocytogenes was isolated after 2 days of culture. Antibiotics sensitivity showed resistance to ciprofloxacin, fosfomycin and fusidic acid. Ceftazidime was changed for gentamicin, and after 1 month of treatment the abscess decreased considerably.\n\n\nCONCLUSIONS\nThis case demonstrated that even if Listeria is rarely involved in ocular abscess, it must be evocated for people with risk factors as farmers. This suspicion should lead to an extended incubation to identify the pathogen. The analysis of Listeria resistance is essential to start an efficient therapy.",
"affiliations": "Laboratory of Microbiology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Laboratory of Microbiology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Laboratory of Microbiology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Ophthalmology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.;Research Group on «Bacterial Opportunistic Pathogens and Environment», UMR 5557 Ecologie Microbienne, CNRS, University of Lyon 1, ENVL, Lyon, France.;Laboratory of Microbiology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Laboratory of Microbiology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.;Laboratory of Microbiology, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France. anne.doleans-jordheim@univ-lyon1.fr.",
"authors": "Legendre|Coline|C|;Hannetel|Hélène|H|;Ranc|Anne-Gaëlle|AG|;Bezza|Widad|W|;Pages|Laurence|L|;Vandenesch|François|F|;Tristan|Anne|A|;Doleans-Jordheim|Anne|A|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10792-017-0723-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5701",
"issue": "38(6)",
"journal": "International ophthalmology",
"keywords": "Listeria monocytogenes; Ocular abscess; Resistance; Risk factors",
"medline_ta": "Int Ophthalmol",
"mesh_terms": "D000038:Abscess; D000368:Aged; D000900:Anti-Bacterial Agents; D003316:Corneal Diseases; D006801:Humans; D008089:Listeria monocytogenes; D008088:Listeriosis; D016896:Treatment Outcome",
"nlm_unique_id": "7904294",
"other_id": null,
"pages": "2609-2616",
"pmc": null,
"pmid": "29086326",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25241232;26869751;2118244;2309867;28367407;24493921;24669144;22823015;2328585;3150285;10606462;2028755;21357436;15460335;12163465;3134816;1455294;15599813;15013893;26437938;24822197;27424034;102203;18724160;405962;302649;10230593;15480698;25778543;17332901;17068464;28329887;405090;15297538;11427612",
"title": "Listeria monocytogenes and ocular abscess: an atypical but yet potential association.",
"title_normalized": "listeria monocytogenes and ocular abscess an atypical but yet potential association"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1096590",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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"activesubstance": {
"activesubstancename": "CEFTAZIDIME"
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"drugadditional": "1",
... |
{
"abstract": "Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated antigen-4 and programmed cell death ligand-1) are associated with several immune-related neurological disorders. Cases of meningitis related to ICIs are poorly described in literature and probably underestimated. Several guidelines are available for the acute management of these adverse events, but the safety of resuming ICIs in these patients remains unclear. We conducted a retrospective case series of immune-related meningitis associated with ICIs that occurred between October 1 2015 and October 31 2019 in two centers: Saint-Louis and Cochin hospitals, Paris, France. Diagnosis was defined by a (1) high count of lymphocytes (>8 cells/mm3) and/or high level of proteins (>0.45 g/L) without bacteria/virus or tumor cells detection, in cerebrospinal fluid and (2) normal brain and spine imaging. Patients were followed-up for at least 6 months from the meningitis onset. Seven cases of immune-related meningitis are here reported. Median delay of meningitis occurrence after ICIs onset was 9 days. Steroid treatment was introduced in four patients at a dose of 1 mg/kg (prednisone), allowing a complete recovery within 2 weeks. The other three patients spontaneously improved within 3 weeks. Given the favorable outcome, ICIs were reintroduced in all patients. The rechallenge was well tolerated and no patients experienced meningitis recurrence. In conclusion, in our series, the clinical course was favorable and steroids were not always required. Resuming ICIs in these patients appeared safe and can thus be considered in case of isolated meningitis. However, a careful analysis of the risk/benefit ratio should be done on a case-by-case basis.",
"affiliations": "Université de Paris, Paris, France stefania.cuzzubbo@inserm.fr.;Service de Dermatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Paris, France.;Université de Paris, INSERM U1016, Paris, France.;Service de Neurologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Paris, France.;Service de Neurologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Paris, France.;Université de Paris, Paris, France.;Service de Neurologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Paris, France.;Service de Dermatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude-Bernard, Paris, France.;Service de Dermatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Paris, France.;Service de Dermatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Paris, France.;Université de Paris, Paris, France.",
"authors": "Cuzzubbo|Stefania|S|0000-0003-0288-4607;Tetu|Pauline|P|;Guegan|Sarah|S|;Ursu|Renata|R|;Belin|Catherine|C|;Sirven Villaros|Lila|L|;Mazoyer|Julie|J|;Lheure|Coralie|C|;Lebbe|Celeste|C|;Baroudjian|Barouyr|B|;Carpentier|Antoine F|AF|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2020-001034",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\njitc-2020-001034\n10.1136/jitc-2020-001034\nClinical/Translational Cancer Immunotherapy\n1506\nShort reportReintroduction of immune-checkpoint inhibitors after immune-related meningitis: a case series of melanoma patients\nhttp://orcid.org/0000-0003-0288-4607Cuzzubbo Stefania 12 Tetu Pauline 34 Guegan Sarah 56 Ursu Renata 2 Belin Catherine 2 Sirven Villaros Lila 12 Mazoyer Julie 2 Lheure Coralie 7 Lebbe Celeste 34 Baroudjian Barouyr 3 Carpentier Antoine F 12 \n1 \nUniversité de Paris, Paris, France\n\n\n2 \nService de Neurologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint Louis, Paris, France\n\n\n3 \nService de Dermatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Paris, France\n\n\n4 \nUniversité de Paris, INSERM U976, Paris, France\n\n\n5 \nUniversité de Paris, INSERM U1016, Paris, France\n\n\n6 \nService de Dermatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris, France\n\n\n7 \nService de Dermatologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat-Claude-Bernard, Paris, France\n\nCorrespondence to Dr Stefania Cuzzubbo; stefania.cuzzubbo@inserm.fr\n2020 \n2 8 2020 \n8 2 e00103418 6 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte-associated antigen-4 and programmed cell death ligand-1) are associated with several immune-related neurological disorders. Cases of meningitis related to ICIs are poorly described in literature and probably underestimated. Several guidelines are available for the acute management of these adverse events, but the safety of resuming ICIs in these patients remains unclear. We conducted a retrospective case series of immune-related meningitis associated with ICIs that occurred between October 1 2015 and October 31 2019 in two centers: Saint-Louis and Cochin hospitals, Paris, France. Diagnosis was defined by a (1) high count of lymphocytes (>8 cells/mm3) and/or high level of proteins (>0.45 g/L) without bacteria/virus or tumor cells detection, in cerebrospinal fluid and (2) normal brain and spine imaging. Patients were followed-up for at least 6 months from the meningitis onset. Seven cases of immune-related meningitis are here reported. Median delay of meningitis occurrence after ICIs onset was 9 days. Steroid treatment was introduced in four patients at a dose of 1 mg/kg (prednisone), allowing a complete recovery within 2 weeks. The other three patients spontaneously improved within 3 weeks. Given the favorable outcome, ICIs were reintroduced in all patients. The rechallenge was well tolerated and no patients experienced meningitis recurrence. In conclusion, in our series, the clinical course was favorable and steroids were not always required. Resuming ICIs in these patients appeared safe and can thus be considered in case of isolated meningitis. However, a careful analysis of the risk/benefit ratio should be done on a case-by-case basis.\n\nCTLA-4 antigenimmunotherapymelanomaprogrammed cell death 1 receptorspecial-featureunlocked\n==== Body\nIntroduction\nImmune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death-1 (PD-1) and PD ligand 1 are today a standard of care in the treatment of several cancers. Initially approved for unresectable metastatic melanoma and non-small cell lung cancer, ICIs are now increasingly used to treat a high variety of solid-organ and hematological cancers. They are nevertheless associated with several immune-related (ir) disorders that can potentially involve every organ or system but gastrointestinal, dermatological, hepatic, endocrine and pulmonary toxicities predominate.1 Neurological ir adverse events (irAEs-N) are rare, with an overall incidence of 3.8% for anti-CTLA4 antibodies, 6.1% for anti-PD1 antibodies and 12.0% for the combination of them. However, the incidence of severe irAEs-N is below 1% for all types of treatment. Although rare irAEs-N require prompt recognition and treatment to avoid substantial morbidity.2 3 Several guidelines are available for the acute management of irAEs,4 but their long-term management is less standardized. Specifically, no clear data are available on the safety of resuming ICIs after an irAE. Some studies reported a 40%–60% rate of recurrence of the specific or distinct AE after the reintroduction of ICIs.5–8 As a consequence, only few patients with irAEs-N resume ICI treatment in current practice because of life-threatening risk related to neurological syndromes.\n\nGiven the benefits of ICI therapy in patients with cancer, additional research is necessary to guide clinicians in practical decisions. Considering the heterogeneity of irAEs, even within neurological irAEs, recommendations for resuming ICIs should be specifically defined for each type of them. Herein, we report a retrospective series of seven consecutive patients who developed ir-meningitis with the aim of defining the long-term management and exploring the safety of ICIs reintroduction in these patients.\n\nMethods\nWe collected the cases of ir-meningitis associated with ICIs in adult melanoma patients of Saint-Louis and Cochin hospitals, Paris, between October 1 2015 and October 31 2019. Saint-Louis patients were registered in MelBase, a French clinical database with biobank dedicated to the prospective follow-up of adult patients with advanced melanoma. MelBase protocol was registered in the NIH clinical trials database (NCT02828202). Written informed consent was obtained from all patients.\n\nDiagnosis was defined by the association of (1) a clinical pattern compatible with meningitis; (2) >8 lymphocytes/mm3 and/or protein level >0.45 g/L in cerebrospinal fluid (CSF), without bacteria/virus or tumor cells detection; (3) normal brain/spine imaging. Patients were included in this study if followed by a neurologist for at least 6 months after meningitis occurrence. The decision of ICI reintroduction was made on a case-by-case basis.\n\nWe collected patients demographics and ir-meningitis characteristics. IrAEs were defined using the National Cancer Institute Common Terminology Criteria for Adverse Events, V.4.03.9 Duration of corticosteroids was collected, and patients were considered ‘off steroids’ when hydrocortisone equivalent dose was ≤30 mg/day. We also collected tumor evaluations according to the ir-response criteria10 at 3 months after the ICI readministration and at the latest follow-up.\n\nResults\nWe, here, report seven consecutive cases of ir-meningitis. Table 1 summarizes demographic and clinical characteristics of patients. Median delay of meningitis onset after the first dose of ICI was 9 days (range: 6–95 days). CSF study displayed lymphocytic meningitis in six out of seven patients, and an isolated high protein level in patient 5, but lumbar puncture was realized 45 days after the onset of neurological symptoms in this patient. CSF microbiological studies were negatives in all patients and no evidence of tumor meningitis was found in CFS study or brain and spine MRI. MRI did not find any signs of myelitis nor encephalitis, and therefore, a diagnosis of isolated ir-meningitis was made.\n\nTable 1 Demographic and clinic characteristics of patients\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\tPatient 7\t\nSex, age (years)\tM, 71\tF, 29\tF, 51\tF, 46\tF, 64\tM, 27\tF, 20\t\nStage of melanoma\nBRAF status\tIIIb\nV600E mutant\tIIIc\nWild type\tIV\nV600E mutant\tIV\nWild type\tIIc\nWilde type\tIIIc\nWild type\tIV\nV600E mutant\t\nICI regimen at the irAE-N onset\tNivolumab\n3 mg/kg\tIpilimumab\n1 mg/kg\n+nivolumab\n3 mg/kg\tSpartalizumab\n400 mg/28 days\tIpilimumab\n1 mg/kg\n+nivolumab\n3 mg/kg\tNivolumab\n3 mg/kg\tIpilimumab\n3 mg/kg\n+nivolumab\n1 mg/kg\tIpilimumab\n3 mg/kg+nivolumab\n1 mg/kg\t\nConcomitant cancer treatment\t0\t0\tDabrafenib, Trametinib\t0\t0\t0\t0\t\nNo of ICI doses before irAE-N\t1\t1\t4\t2\t1\t2\t1\t\nDelay of neurological symptoms onset from ICI onset (days)\t6\t6\t95\t50\t6\t9\t17\t\nF, female; ICI, immune-checkpoint inhibitor; irAE-N, neurological immune-related adverse event; M, male.\n\nAfter diagnosis of ir-meningitis, a steroid treatment (prednisone 1 mg/kg) was introduced in patients 1, 2, 4 and 6 (all with irAEs-N ≥grade 2), allowing a complete clinical recovery within 2 weeks. After 1-2 weeks of full dose, corticosteroids were gradually tapered until discontinuation after 6 weeks. The other three patients (all with grade 1 AEs) spontaneously improved within 3 weeks (table 2).\n\nTable 2 Characteristics of ir-meningitis and management with steroids\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\tPatient 7\t\nSeverity grade of meningitis\t3\t2\t1\t2\t1\t2\t1\t\nSymptoms\tFever,\nconfusion,\npartial seizure.\tHeadache,\nnausea,\nphotophobia.\tHeadache,\nfour limbs pain.\tHeadache,\nvomiting.\tHeadache,\nvomiting.\tHeadache,\nfever.\tFever,\nheadache\t\nLumbar puncture\t\ncells/mm3\n\t40 (90% L)\t8 (100% L)\t19 (90% L)\t25 (90% L)\t0\t9 (90% L)\t320 (90% L)\t\nProtein level\t0.99 g/L\t0.30 g/L\t0.39 g/L\t0.43 g/L\t0.59 g/L\t0.54 g/L\t<0.45 g/L\t\nSteroid treatment*\t\nInitial dose\t1 mg/kg/day\t1 mg/kg/day\t0\t1 mg/kg/day\t0\t1 mg/kg\t0\t\nLength at full dose\t7 days\t7 days\t7 days\t14 days\t\nLength of tapering\t42 days\t42 days\t42 days\t42 days\t\nDelay of complete recovery\t\nFrom irAE-N onset\t18 days\t17 days\t10 days\t21 days\t65 days\t49 days\t10 days\t\nFrom steroids onset\t2 days\t14 days\t–\t2 days\t–\t14 days\t–\t\nOther irAEs occurrence\tNone\tNone\tNone\tHypophysitis (gr. 2), diabetes (gr. 2), hepatitis (gr. 1)\tNone\tHypophysitis (gr. 2), hepatitis (gr. 4), colitis (gr. 2) small fibers neuropathy (gr.1)\tNone\t\n*Prednisone equivalent doses.\n\nirAE, immune-related adverse event; irAE-N, neurological immune-related adverse event; L, lymphocytes.\n\nGiven the favorable outcome of ir-meningitis, ICI treatment was reintroduced in four patients (cases 2, 3, 5, 7) after 4–54 days from irAE-N. For the other three patients, despite a quick recovery of meningitis, ICI was not resumed immediately because of the high grade of nAE (grade 3) in patient 1, and of multiple co-occurring non neurological irAEs in patients 4 and 6. These patients were followed by whole body imaging every 3 months and ICIs were reintroduced at time of disease progression.\n\nThe rechallenge was well tolerated in six out of seven cases: no meningitis nor other irAEs occurred. Patient 3 developed a severe interstitial lung disease, without meningitis recurrence, leading to permanent discontinuation of ICI treatment (table 3). Table 3 shows the cancer status at 3 months from the rechallenge of ICIs and at the latest follow-up.\n\nTable 3 Tolerance of ICI reintroduction\n\n\tPatient 1\tPatient 2\tPatient 3\tPatient 4\tPatient 5\tPatient 6\tPatient 7\t\nDelay of resumption of ICI after meningitis\n(days)\t373\t54\t24\t118\t4\n(No ICI discontinuation)\t126\t19\t\nICI regimen at the rechallenge\tIpilimumab\n1 mg/kg\n+nivolumab\n3 mg/kg\tIpilimumab\n1 mg/kg\n+nivolumab\n3 mg/kg\tSpartalizumab\n400 mg\tNivolumab\n3 mg/kg\tNivolumab\n3 mg/kg\tSpartalizumab\n400 mg\n+ribociclib\n600 mg/day\tNivolumab\n3 mg/kg\t\nSteroid treatment at the time of ICI resumption*\t0.5 mg/kg/day\t0\t0\t0\t0\t0\t0\t\nMeningitis recurrence\tNo\tNo\tNo\tNo\tNo\tNo\tNo\t\nOther irAEs occurrence at rechallenge with ICIs\tNo\tNo\tInterstitial lung disease (grade 3)\tNo\tNo\tNo\tNo\t\nCancer status at 3 months from rechallenge with ICIs\tPD\tPR\tPD\tPD\tPR\tPD\tPR\t\nCancer status at latest follow-up\n(months from rechallenge)\tDeath caused by cancer progression\tMaintained CR\n(32 months)\tMaintained PR\n(25 months)\tDeath caused by cancer progression\tMaintained PR\n(6 months)\tDeath caused by cancer progression\tMaintained PR\n(17 months)\t\n*Prednisone equivalent doses.\n\nCR, complete response; ICI, immune-checkpoint inhibitor; irAE, immune-related adverse event; PD, progression disease; PR, partial response.\n\nDiscussion\nA broad spectrum of neurological irAEs has been described in the literature, potentially involving all areas of the central and peripheral nervous system.2 11 Cases of ir-meningitis have been less frequently reported. However, their frequency is likely underestimated because their presentation can be paucisymptomatic. The occurrence of an unusual headache during ICI treatment should raise the suspicion of meningitis and lead to appropriate investigations. Notably, differential diagnosis with bacterial/viral meningitis and meningeal carcinomatosis must be considered in first place, hence lumbar puncture and brain/spine MRI with and without contrast generally lead to the correct diagnosis.\n\nAs reported for other irAEs-N, we did not observe any exclusive association between ir-meningitis and a class of ICIs.2 8 Clinical signs of meningitis occurred early with a median delay of 9 days after the ICI onset and a median number of ICI cycles of 2, compared with 6 weeks and three cycles observed in all kinds of irAEs-N respectively.2 8 Ir-meningitis had a favorable evolution with a fast and full recovery in all patients. According to published recommendations,12 steroid treatment was introduced in more severe cases (grade ≥2) and maintained at full dose (prednisone 1 mg/kg/day) for one or 2 weeks depending on the clinical recovery of meningitis and then tapered over 6 weeks given the half-life of ICI drugs.\n\nThe safety of ICI reintroduction after an irAE is still a matter of debate. Some studies showed a quite poor tolerance of resuming ICI after a severe irAE, reporting an occurrence of the same or a distinct AE in 40%–55% of patients.5–7 The risk of irAEs-N recurrence is likely similar to other ir-AEs, but, very few cases of reintroduction of ICIs after an irAE-N have been reported so far, probably because of concerns on potential severity and life-threatening risk associated to irAEs-N. Dubey et al reported a series of 10 patients retreated with ICIs after a severe irAEs-N. The irAE-N recurrence rate was 60% and the authors suggested a correlation with a short steroid treatment (less than 2 weeks) after the initial AE in these patients.8\n\n\nOnly few cases of ICI rechallenge after an ir-meningitis are reported in literature. Spain et al reported a melanoma patient with meningitis associated with ir-hepatitis. The rechallenge with the same regimen resulted in severe ir-colitis.13 Fellner et al reported another case of reintroduction of ICIs after meningitis related to ipilimumab–nivolumab combination therapy. In this case, only nivolumab was resumed, with a good tolerance.14 In both cases, ICI drugs were reintroduced at the moment of cancer recurrence according to checkmate-067 trial results, in which 68% of patients who discontinued ICI treatment due to toxicity experienced a long response (median time of 13 months).15\n\n\nIn our series of seven consecutive patients, ICI treatment was early reintroduced in four patients (all with irAE-N grade ≤2), as soon as the meningitis symptoms had completely recovered. Tolerance of reintroduction was good in three out of four patients. One patient developed a severe non-neurological irAE (interstitial lung disease) leading to permanent discontinuation of ICI treatment. In the three other cases, ICI reintroduction was differed at the time of disease progression since ir-meningitis was more severe or associated with other irAEs. In cases of multiple irAEs, dual therapy was shifted to anti-PD1 monotherapy regimen. The reintroduction was well tolerated in all cases: no patients experienced a recurrent or new irAE.\n\nConclusions\nCases of meningitis related to ICIs are poorly described in literature. In our cases, the clinical course was favorable and steroids were not always required. In case of isolated ir-meningitis, an early reintroduction of ICI treatment at the same regimen appears to be safe, even in case of combination therapy (anti-CTLA-4/PD-1). On the contrary, a longer discontinuation of ICI drug (until disease progression) and a regimen shift from dual to monotherapy is recommended in case of multiple irAEs. We are aware that our study has some limitations since only one patient experienced a high grade ir-meningitis. A careful analysis of the risk/benefit ratio should be done on a case-by-case basis.\n\nThe authors thank MelBase biobank coordination team for technical support and medical data and PATIO group for the constructive exchanges.\n\nContributors: SC conceptualized the study, collected and analyzed data, and wrote the preliminary version of the paper. AFC conceptualized the study and wrote the preliminary version of the paper. PT, SG, RU, CB, LSV, JM, CLh, CLe and BB contributed to the collection of patient data. All authors participated in critical review and revision of the final manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: BB is a consultor for BMS, MSD and Pierre Fabre; CLh received grants or honoraria from Roche, BMS, MSD, GSK, Novartis and Amgen; AFC is a consultor for BMS.\n\nPatient consent for publication: Not required.\n\nEthics approval: MelBase protocol was approved by the French ethics committee (CPP Ile-de-france XI, no 12027, 2012).\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nData availability statement: All data relevant to the study are included in the article.\n==== Refs\nReferences\n1 \nBaroudjian B , Arangalage D , Cuzzubbo S , et al \nManagement of immune-related adverse events resulting from immune checkpoint blockade\n. Expert Rev Anticancer Ther \n2019 ;19 :209 –22\n. 10.1080/14737140.2019.1562342 \n30572735 \n2 \nCuzzubbo S , Javeri F , Tissier M , et al \nNeurological adverse events associated with immune checkpoint inhibitors: review of the literature\n. Eur J Cancer \n2017 ;73 :1 –8\n. 10.1016/j.ejca.2016.12.001 \n28064139 \n3 \nCuzzubbo S , Belin C , Chouahnia K , et al \nAssessing cognitive function in patients treated with immune checkpoint inhibitors: a feasibility study\n. Psychooncology \n2018 ;27 :1861 –4\n. 10.1002/pon.4725 \n29624771 \n4 \nBrahmer JR , Lacchetti C , Schneider BJ , et al \nManagement of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline\n. JCO \n2018 ;36 :1714 –68\n. 10.1200/JCO.2017.77.6385 \n\n5 \nPollack MH , Betof A , Dearden H , et al \nSafety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma\n. Ann Oncol \n2018 ;29 :250 –5\n. 10.1093/annonc/mdx642 \n29045547 \n6 \nSimonaggio A , Michot JM , Voisin AL , et al \nEvaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer\n. JAMA Oncol \n2019 ;5 :1310 –7\n. 10.1001/jamaoncol.2019.1022 \n\n7 \nSantini FC , Rizvi H , Plodkowski AJ , et al \nSafety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC\n. Cancer Immunol Res \n2018 ;6 :1093 –9\n. 10.1158/2326-6066.CIR-17-0755 \n29991499 \n8 \nDubey D , David WS , Reynolds KL , et al \nSevere neurological toxicity of immune checkpoint inhibitors: growing spectrum\n. Ann Neurol \n2020 ;87 :659 –69\n. 10.1002/ana.25708 \n32086972 \n9 \nPuzanov I , Diab A , Abdallah K , et al \nManaging toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for immunotherapy of cancer (SITC) toxicity management Working group\n. J Immunother Cancer \n2017 ;5 :95 . 10.1186/s40425-017-0300-z \n29162153 \n10 \nWolchok JD , Hoos A , O'Day S , et al \nGuidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria\n. Clin Cancer Res \n2009 ;15 :7412 –20\n. 10.1158/1078-0432.CCR-09-1624 \n19934295 \n11 \nAstaras C , de Micheli R , Moura B , et al \nNeurological adverse events associated with immune checkpoint inhibitors: diagnosis and management\n. Curr Neurol Neurosci Rep \n2018 ;18 :3. 10.1007/s11910-018-0810-1 \n29392441 \n12 \nSpain L , Tippu Z , Larkin JM , et al \nHow we treat neurological toxicity from immune checkpoint inhibitors\n. ESMO Open \n2019 ;4 :e000540. 10.1136/esmoopen-2019-000540 \n31423344 \n13 \nSpain L , Walls G , Messiou C , et al \nEfficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series\n. Cancer Immunol Immunother \n2017 ;66 :113 –7\n. 10.1007/s00262-016-1926-2 \n27838762 \n14 \nFellner A , Makranz C , Lotem M , et al \nNeurologic complications of immune checkpoint inhibitors\n. J Neurooncol \n2018 ;137 :601 –9\n. 10.1007/s11060-018-2752-5 \n29332184 \n15 \nLarkin J , Chiarion-Sileni V , Gonzalez R , et al \nCombined nivolumab and ipilimumab or monotherapy in untreated melanoma\n. N Engl J Med \n2015 ;373 :23 –34\n. 10.1056/NEJMoa1504030 \n26027431\n\n",
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"journal": "Journal for immunotherapy of cancer",
"keywords": "CTLA-4 antigen; immunotherapy; melanoma; programmed cell death 1 receptor",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D008545:Melanoma; D008581:Meningitis; D008875:Middle Aged",
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"title": "Reintroduction of immune-checkpoint inhibitors after immune-related meningitis: a case series of melanoma patients.",
"title_normalized": "reintroduction of immune checkpoint inhibitors after immune related meningitis a case series of melanoma patients"
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"abstract": "The authors describe a case of fatal acetaminophen overdose which occurred in a 16-year-old female. Her serum acetaminophen concentration 11.5 h postingestion was 154 mg/L. Antidotal therapy was unsuccessful, and after 9 days she died. Autopsy findings included centrilobular zonal liver necrosis, acute proximal renal tubular necrosis, and diffuse alveolar pulmonary damage. Her heart was transplanted into a young woman with congenital heart disease. The recipient expired 14 days after the transplant as a result of sepsis complicating bowel ischemia. The transplanted heart showed extensive subendocardial myocyte necrosis related to acetaminophen toxicity and not rejection.",
"affiliations": "Department of Pathology, Medical College of Virginia, Richmond.",
"authors": "Price|L M|LM|;Poklis|A|A|;Johnson|D E|DE|",
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"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D062787:Drug Overdose; D004699:Endocardium; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007668:Kidney; D008099:Liver; D008168:Lung; D009206:Myocardium; D009336:Necrosis; D013405:Suicide",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Fatal acetaminophen poisoning with evidence of subendocardial necrosis of the heart.",
"title_normalized": "fatal acetaminophen poisoning with evidence of subendocardial necrosis of the heart"
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"abstract": "Gene amplification is believed to play an important role in antibiotic resistance but has been rarely documented in clinical settings because of its unstable nature. We report a rise in MICs from 0.5 to 16 μg/ml in successive Acinetobacter baumannii isolated over 4 days from a patient being treated with tobramycin for an infection by multidrug-resistant A. baumannii, resulting in therapeutic failure. Isolates were characterized by whole-genome sequencing, real-time and reverse transcriptase PCR, and growth assays to determine the mechanism of tobramycin resistance and its fitness cost. Tobramycin resistance was associated with two amplification events of different chromosomal fragments containing the aphA1 aminoglycoside resistance gene part of transposon Tn6020. The first amplification event involved low amplification (6 to 10 copies) of a large DNA fragment that was unstable and conferred tobramycin MICs of ≤ 8 μg/ml. The second event involved moderate (10 to 30 copies) or high (40 to 110 copies) amplification of Tn6020. High copy numbers were associated with tobramycin MICs of 16 μg/ml, impaired fitness, and genetic instability, whereas lower copy numbers resulted in tobramycin MICs of ≤8 μg/ml and no fitness cost and were stably maintained in vitro. Exposure in vitro to tobramycin of the initial susceptible isolate and of the A. baumannii AB0057 reference strain led to similar aphA1 amplifications and elevated tobramycin MICs. To the best of our knowledge, this is the first report of in vivo development of antibiotic resistance secondary to gene amplifications resulting in therapy failure. IMPORTANCE A combination of whole-genome sequencing and mapping were used to detect an antibiotic resistance mechanism, gene amplification, which has been presumed for a long time to be of major importance but has rarely been reported in clinical settings because of its unstable nature. Two gene amplification events in a patient with an Acinetobacter baumannii infection treated with tobramycin were identified. One gene amplification event led to high levels of resistance and was rapidly reversible, while the second event led to low and more stable resistance since it incurred low fitness cost on the host. Gene amplification, with an associated rise in tobramycin MICs, could be readily reproduced in vitro from initially susceptible strains exposed to increasing concentrations of tobramycin, suggesting that gene amplification in A. baumannii may be a more common mechanism than currently believed. This report underscores the importance of rapid molecular techniques for surveillance of drug resistance.",
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"authors": "McGann|Patrick|P|;Courvalin|Patrice|P|;Snesrud|Erik|E|;Clifford|Robert J|RJ|;Yoon|Eun-Jeong|EJ|;Onmus-Leone|Fatma|F|;Ong|Ana C|AC|;Kwak|Yoon I|YI|;Grillot-Courvalin|Catherine|C|;Lesho|Emil|E|;Waterman|Paige E|PE|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004251:DNA Transposable Elements; D004269:DNA, Bacterial; D000135:Acid Phosphatase; D014031:Tobramycin",
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"fulltext": "\n==== Front\nmBioMBiombiombiomBiomBio2150-7511American Society of Microbiology 1752 N St., N.W., Washington, DC 24496790mBio00915-1410.1128/mBio.00915-14Research ArticleAmplification of Aminoglycoside Resistance Gene aphA1 in Acinetobacter baumannii Results in Tobramycin Therapy Failure Tobramycin Resistance by Gene AmplificationMcGann Patrick aCourvalin Patrice bSnesrud Erik aClifford Robert J. aYoon Eun-Jeong bOnmus-Leone Fatma aOng Ana C. aKwak Yoon I. aGrillot-Courvalin Catherine bLesho Emil aWaterman Paige E. aa Multidrug-resistant Organism Repository and Surveillance Network, Walter Reed Army Institute of Research, Silver Spring, Maryland, USAb Unité des Agents Antibactériens, Institut Pasteur, Paris, FranceAddress correspondence to Patrick McGann, patrick.t.mcgann4.ctr@mail.mil, or Patrice Courvalin, patrice.courvalin@pasteur.fr.P.M. and P.C. contributed equally to this article.\n\nEditor George A. Jacoby, Lahey Hospital and Medical Center\n\n22 4 2014 Mar-Apr 2014 5 2 e00915-146 2 2014 21 3 2014 Copyright © 2014 McGann et al.2014McGann et al.This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.ABSTRACT\nGene amplification is believed to play an important role in antibiotic resistance but has been rarely documented in clinical settings because of its unstable nature. We report a rise in MICs from 0.5 to 16 μg/ml in successive Acinetobacter baumannii isolated over 4 days from a patient being treated with tobramycin for an infection by multidrug-resistant A. baumannii, resulting in therapeutic failure. Isolates were characterized by whole-genome sequencing, real-time and reverse transcriptase PCR, and growth assays to determine the mechanism of tobramycin resistance and its fitness cost. Tobramycin resistance was associated with two amplification events of different chromosomal fragments containing the aphA1 aminoglycoside resistance gene part of transposon Tn6020. The first amplification event involved low amplification (6 to 10 copies) of a large DNA fragment that was unstable and conferred tobramycin MICs of ≤8 μg/ml. The second event involved moderate (10 to 30 copies) or high (40 to 110 copies) amplification of Tn6020. High copy numbers were associated with tobramycin MICs of 16 μg/ml, impaired fitness, and genetic instability, whereas lower copy numbers resulted in tobramycin MICs of ≤8 μg/ml and no fitness cost and were stably maintained in vitro. Exposure in vitro to tobramycin of the initial susceptible isolate and of the A. baumannii AB0057 reference strain led to similar aphA1 amplifications and elevated tobramycin MICs. To the best of our knowledge, this is the first report of in vivo development of antibiotic resistance secondary to gene amplifications resulting in therapy failure.\n\nIMPORTANCE\nA combination of whole-genome sequencing and mapping were used to detect an antibiotic resistance mechanism, gene amplification, which has been presumed for a long time to be of major importance but has rarely been reported in clinical settings because of its unstable nature. Two gene amplification events in a patient with an Acinetobacter baumannii infection treated with tobramycin were identified. One gene amplification event led to high levels of resistance and was rapidly reversible, while the second event led to low and more stable resistance since it incurred low fitness cost on the host. Gene amplification, with an associated rise in tobramycin MICs, could be readily reproduced in vitro from initially susceptible strains exposed to increasing concentrations of tobramycin, suggesting that gene amplification in A. baumannii may be a more common mechanism than currently believed. This report underscores the importance of rapid molecular techniques for surveillance of drug resistance.\n\n cover-dateMarch/April 2014\n==== Body\nINTRODUCTION\nAcinetobacter baumannii has a remarkable ability to develop resistance to antibiotics by horizontal acquisition of foreign genetic information (1) or by mutation (2). These mechanisms have made A. baumannii a highly successful human nosocomial pathogen (3). In the clinical setting, point mutations in two-component regulatory systems can result in multiple antibiotic resistance in a single step by overexpression of efflux pumps (4) or resistance to colistin, the last resort antibiotic against this species (5).\n\nDespite moderate side effects and increasing resistance, the aminoglycosides continue to be of therapeutic value. Several mechanisms of aminoglycoside resistance have been observed in Acinetobacter spp., the most frequent involving drug inactivation by N-acetylation, O-adenylylation, or O-phosphorylation (6).\n\nResistance genes in A. baumannii are generally part of integrons or resistance islands (AbaR) (7–9). The first island described, AbaR1, includes a large array of laterally transferred antimicrobial resistance genes intermixed with a diverse set of transposons and integrons (10). Since then, truncated derivatives of AbaR3, the ancestral resistance island, all integrated at the same site in the comM ATPase gene, have been reported. They are the result of 5′-ward deletions mediated by IS26 (11, 12).\n\nGene duplication and amplification (GDA) are believed to play an important role in antibiotic resistance (13). However, because of its unstable nature, its relevance in the clinical setting is difficult to assess. Nevertheless, duplication of a 36.4-kb region encompassing blaSHV-11 in a clinical isolate of Klebsiella pneumoniae linked to a 16-fold increase in amoxicillin resistance has been reported (14). Similarly, resistance to sulfonamide and trimethoprim was associated in a clinical isolate of Streptococcus agalactiae with the unstable amplification of a 13.5-kb region carrying five genes involved in dihydrofolate synthesis (15). Duplication of the plasmid-borne blaOXA-58 gene has been shown to be responsible for reduced susceptibility to carbapenems in A. baumannii (16) and Acinetobacter genospecies 3 (17).\n\nWe report the in vivo occurrence of tobramycin resistance in A. baumannii from a patient undergoing tobramycin therapy via gene amplification. Tobramycin resistance emerged by two distinct amplification events. The first event involved low amplification of an approximately 15-kb region containing the aminoglycoside resistance gene aphA1, which is part of transposon Tn6020. The second event was moderate- or high-level amplification of Tn6020. In both cases, tobramycin MICs increased with gene copy number up to a plateau at 16 μg/ml. Very high gene copy numbers (>40) resulted in reduced fitness of the host and were transient in the absence of selection, as opposed to low copy numbers which could be maintained in vitro for at least 1 month.\n\nRESULTS\nSix A. baumannii strains were isolated from the same patient over 10 days and were tested for susceptibility to three clinically important aminoglycosides (Table 1). All were resistant to gentamicin and susceptible to amikacin. Initial isolates (MRSN 3361, MRSN 3363, MRSN 3364, and MRSN 56) were susceptible to tobramycin, but MRSN 57 and MRSN 58 were categorized as intermediate (MIC = 8 μg/ml) and resistant (MIC = 16 μg/ml), respectively. Multilocus sequence typing (MLST) assigned them to sequence type 1 (ST1) (Pasteur scheme) of clonal complex CCI, one of three major A. baumannii clonal groups strongly associated with multidrug resistance and hospital outbreaks in many countries (18).\n\nTABLE 1 Phenotypic characteristics of strains\n\nMRSNa\tIsolation\tTobramycin MIC (μg/ml)c\t\nDayb\tSite\t\n3361\t3\tLeft hip\t0.5\t\n3363\t3\tRight hip\t0.5\t\n3364\t8\tLeft hip\t0.5\t\n56\t11\tLeft hip\t0.5\t\n57\t12\tRight hip\t8\t\n58\t13\tLeft hip\t16\t\na De-identified number used to track isolates throughout the Multidrug-resistant Organism Repository and Surveillance Network (MRSN).\n\nb Day after initial injury.\n\nc MICs were determined in quintuplicate. A. baumannii CLSI breakpoints (μg/ml) for tobramycin are as follows: susceptible, ≤4; intermediate, 8; resistant, ≥16.\n\nDetection of gene amplification by whole-genome mapping.\nWhole-genome mapping showed that all isolates were closely related but that MRSN 57 and MRSN 58 had diverged from the main cluster (Fig. 1). This difference was attributable to a localized and unique restriction pattern that was not present in the other four strains. In MRSN 57, this pattern consisted of six identical and tandem restriction fragments approximately 15 kb in size and in MRSN 58 of a single approximately 270-kb region with no NcoI restriction sites. When these fragments were artificially removed, both isolates shared >99% identity with the remaining strains.\n\nFIG 1 Dendrogram (a) and optical genome map (b) of clinical isolates of A. baumannii and reference strains. Strain relatedness was calculated using the unweighted-pair group method using average linkages (UPGMA) (5). Optical maps were compared with in silico optical maps of A. baumannii reference strains AB0057, AYE, and ACICU generated from GenBank sequences. Blue areas represent regions of alignment compared to isolate MRSN 3361, and white areas represent unaligned regions. Vertical black bars indicate NcoI restriction sites. The areas corresponding to the amplified regions are enclosed in red rectangles.\n\nWhole-genome sequencing of clinical isolates.\nComparative analysis of the genomes of MRSN 56, MRSN 57, and MRSN 58 clinical isolates and reference strain AB0057 identified AbaR28 (Fig. 2a), a novel deletion derivative of AbaR3 (11, 19), in the three clinical isolates. AbaR28 consisted of 20 open reading frames (ORFs) identical to the 3′ end of AbaR3 in A. baumannii AB0057 (19). A truncated comM, a gene encoding an ATPase which is a hot spot for insertion of resistance islands in A. baumannii (9, 11), was present at the 3′ end of the island alongside the characteristic 5-bp duplication (AACGC) generated upon AbaR3 insertion (20). However, unlike other derivatives of AbaR3 (11), AbaR28 was missing the 5′ remnant of comM, most likely following a 5′-ward IS26-mediated deletion that extended 37 bp downstream from dapA, a chromosomal gene for a dihydrodipicolinate synthase (Fig. 2a).\n\nFIG 2 Schematic representation of AbaR28 and amplified units (a) and the genetic environment of Tn6020 (top) and the amplified unit (bottom) in A. baumannii isolate MRSN 58 (b). (a) Resistance island AbaR28 is indicated by a thick black line at the top of the panel. Amplified units are indicated by thin black lines. The sizes of the resistance island or amplified units are in kilobases. The open arrows represent coding sequences (yellow arrows, IS26; red arrows, aminoglycoside resistance genes; blue arrows, genes associated with DNA mobility) and indicate the direction of transcription. The notched arrows represent the truncated comM and sup genes. The chromosomal genes flanking AbaR28 are indicated in black. AbaR28 is a truncated version of AbaR3 generated by a 5′-ward deletion mediated by the IS26 copy located at the left end of Tn6020 which is now the extremity of the island. This element is known to create deletions in adjacent regions (20, 37). The deletion removed the 5′ end of Tn6019 and the 5′ portion of the comM target gene. The right end of AbaR28 corresponds to the 26-bp terminal right inverted repeat (IRR) of Tn6019, known to be associated with AbaRs (arrow) (11), and flanked by a 5-bp (ACCGC) duplication of target DNA (5 bp), the characteristic footprint of AbaR3 insertions (20). (b) The vertical black arrow indicates the insertion site of Tn6020 in isolate MRSN 58. The duplicated target sequence is in blue lettering and the sequence carried over 8 bp is in red. Tn6020 is indicated by a double-head arrow, and its size is shown in kilobases. Gene nomenclature was assigned based on the closest BLAST match from GenBank (http://blast.ncbi.nlm.nih.gov/Blast.cgi, last accessed February 2014) using reference strain AB0057.\n\nAnalysis of average genome read coverage identified one area in isolate MRSN 57 and one in MRSN 58 with significantly higher coverage than in MRSN 56. In MRSN 57, this area consisted of a 15.21-kb region, encompassing 19 of the 20 ORFs of AbaR28 (Fig. 2a), that had a mean depth coverage approximately 6 times higher than that of the corresponding region in MRSN 56 and MRSN 58 (see Fig. S1 in the supplemental material). IS26 formed the 5′ end, and the amplified unit terminated 332 bp into the sulfate permease gene (Fig. 2a). In isolate MRSN 58, amplification occurred in a smaller 3.9-kb region, comprising Tn6020 of AbaR28, with mean depth coverage approximately 65 times higher than that of MRSN 56 and MRSN 57 (Fig. S1). Tn6020 is composed of aphA1 flanked by two directly repeated copies of IS26 (Fig. 2b). In isolate MRSN 58, a single copy of the transposon was found at the original position, but approximately 65 tandem copies of Tn6020 were identified 281 kb downstream, inserted in a gene for a hypothetical protein (Fig. 2b). The presence of the characteristic 8-bp direct repeat of target DNA confirmed that IS26 mediated transposition at this new locus. Surprisingly, rather than direct tandem copies of Tn6020, each copy of the transposon was connected to the next by 8 bp identical to those upstream from Tn6020 at the original location (Fig. 2b). This short sequence (GAATGTTT) was not part of the unit amplified in MRSN 57. The genomes of MRSN 56, MRSN 57, and MRSN 58 were identical outside the amplified regions.\n\nConfirmation of gene amplification and expression by qPCR.\nWhen normalized to the single-copy genes secE and rpiN (21) by quantitative PCR (qPCR), isolate MRSN 57 had an average of 10 (±2) copies of aphA1, aacC1, and uspA (encoding a universal stress protein at the 3′ end of the amplified unit) and MRSN 58 had an average of 75 (±14) copies of aphA1 but a single copy of aacC1 and uspA (see Fig. S3 in the supplemental material). Whole-genome mapping and qPCR demonstrated that aphA1 copy numbers in 3 colonies of MRSN 58 from the same overnight culture were 60, 69, and 71, corresponding to approximate sizes of 259 kb, 278 kb, and 286 kb, respectively (Fig. S2).\n\nStability of gene amplification.\nWhen the bacteria were grown on antibiotic-free solid medium over 30 days, aphA1, aacC1, and uspA copy number (Fig. 3) and expression (see Fig. S3A in the supplemental material) displayed a gradual decrease from 10 copies in isolate MRSN 57. By day 17, a single copy of the genes was present and thereafter oscillated between 1 and 2, indicating that the 15.2-kb sequence was amplified or lost en bloc. When cultured with tobramycin (4 μg/ml), the number of amplification units and gene expression increased rapidly during the first 2 days from approximately 9 to 60, followed by a gradual decrease through day 6 to approximately 15 copies before rising to 30 copies by day 15 and stayed above 20 for the remainder of the exposure (Fig. 3 and Fig. S3A).\n\nFIG 3 Relative gene copy numbers. Number of copies of aphA1 in isolates MRSN 57 (blue line) and MRSN 58 (red line) as determined by qPCR during growth with (solid line) and without (dashed line) tobramycin (4 μg/ml). Data are the averages from three independent experiments; error bars represent 1 standard deviation.\n\nThe aphA1 copy number in strain MRSN 58 declined rapidly from 57 to 17 after the first overnight subculture on antibiotic-free medium and remained moderate with a daily average of 16 (±4) copies over the ensuing 28 days (Fig. 3). When grown in the presence of tobramycin (4 μg/ml), copy number (Fig. 3) and expression (see Fig. S3B in the supplemental material) increased rapidly, reaching 120 (±19) copies on day 10, before gradually declining to 78 (±9) copies by day 20. In all instances, mRNA synthesis was proportional to gene copy number.\n\nGene amplification can be induced in vitro.\nTobramycin-susceptible A. baumannii MRSN 56 and AB0057 were subcultured daily in the presence of increasing concentrations of tobramycin. Isolate MRSN 56 displayed robust growth on 8 μg/ml tobramycin on days 8 and 9 but failed to grow on 16 μg/ml. This evolving phenotype correlated with a change in aphA1, aacC1, and uspA copy number (Fig. 4) and expression (data not shown), which increased moderately from 1 to 10 copies when grown on 4 μg/ml to approximately 70 copies on 8 μg/ml of tobramycin. However, unlike MRSN 57, the fragment downstream from comM was also amplified. Whole-genome sequencing of tobramycin-resistant MRSN 56 on day 8, named MRSN 56T, showed a 19.9-kb region with 30-fold-higher coverage than the remainder of the genome. This DNA portion had the same 5′ end as that in MRSN 57 but extended 4 kb further in the 3′ direction encompassing all of AbaR28, truncated comM, a gene for a conserved hypothetical protein, and terminated 55 bp upstream from glnB encoding the nitrogen regulatory protein P-II (Fig. 2A).\n\nFIG 4 In vitro\n\ninduction of gene amplification. (a and b) Number of copies of aphA1 (blue), aacC1 (red), uspA (green), and comM (purple) genes as determined by qPCR in isolate MRSN 56 (a) and strain AB0057 (b) following growth on increasing concentrations of tobramycin. Data are the averages of three independent experiments; error bars represent 1 standard deviation. No growth was observed for MRSN 56 on 16 μg/ml of tobramycin.\n\nStrain AB0057, which carries AbaR3 including Tn6020, eventually grew on 8 μg/ml after 7 days and moderately on day 9 on 16 μg/ml. Similarly to MRSN 58, increased resistance correlated with changes in aphA1 copy number only, from 1 copy on day 6 to >70 copies on day 9 (Fig. 4). Whole-genome sequencing of the tobramycin-resistant AB0057 derivative on day 9, termed AB0057T, identified a 6.4-kb region with 50-fold-higher coverage than the rest of the genome, ca. twice the size of the unit in MRSN 58. This fragment encompassed Tn6020 but extended 3 kb beyond the 5′ IS26, terminating in the tnpA gene (see Fig. S4 in the supplemental material). This gene is present in AbaR3 but has been deleted in AbaR28. Amplification occurred in situ, but we did not detect repeat sequences at the joint points.\n\nHigh-level aphA1 amplification results in reduced fitness.\nWhether an increase in gene copy number affects fitness can be evaluated by growth rate (GR) determination (22, 23). Initial data indicated that there were no significant differences between the growth rate of tobramycin-susceptible strain MRSN 56 and those of MRSN 57 and MRSN 58 when measured in the absence of antibiotic (the GR of MRSN 57 and MRSN 58 relative to that of MRSN 56 was 1.00 ± 0.02). However, individual colonies from the initial culture of MRSN 58 displayed variable aphA1 amplification: among 18 colonies studied, 12 had an aphA1 copy number between 8 and 13, and five had a copy number between 39 and 72. The GRs of the eighteen colonies were determined, and the same suspension of each colony was used to (i) determine the tobramycin MIC, (ii) prepare DNA to quantify aphA1 copy number by qPCR, and (iii) purify RNA for quantification of aphA1 expression by quantitative reverse transcriptase PCR (qRT-PCR). The level of mRNA production was proportional to gene copy number (see Fig. S3 in the supplemental material).\n\nThe group of 12 colonies with low aphA1 copy numbers (from 8 to 13) had tobramycin MICs of 4 to 8 μg/ml and a relative GR of ≥0.95. The five colonies with high aphA1 copy numbers (39 to 72) had tobramycin MICs of 16 μg/ml and a significantly diminished relative GR of ≤0.92 (P < 0.001). Interestingly, a colony with an intermediate aphA1 copy number (n = 34) presented with an intermediate loss of fitness (relative GR of 0.95) and a tobramycin MIC of 16 μg/ml (Fig. 5).\n\nFIG 5 Biological cost and resistance associated with gene amplification. Tobramycin MICs (filled circles) and relative growth rates (open circles) of individual colonies of isolate MRSN 58 containing various copy numbers of the aphA1 gene. Eighteen individual colonies were grown at 37°C up to an OD600 of 0.9 in BHI broth, and the growth rates and tobramycin MICs by microdilution were determined. The same bacterial suspension was used to purify DNA for aphA1 gene copy number determination by qPCR. Experiments were performed at least three times independently. The logarithmic tendency curves have R2 values of 0.9 (solid line) and 0.8 (dashed line).\n\nAltogether, there was a significant decrease in the growth rate of cells with high copy numbers of aphA1, whereas there was no detectable burden for the cells with an average of 10 copies of the gene, which was the predominant group in strain MRSN 58. The latter genotype was stable over a period of 30 days even in the absence of selection and incurred little or no fitness cost.\n\nDISCUSSION\nCollection of serial A. baumannii isolates from the same patient provided the opportunity to investigate antibiotic resistance by two independent but related events involving amplification of the aminoglycoside phosphotransferase gene aphA1. The first event was moderate amplification of a 15.2-kb region, including transposon Tn6020, composed of aphA1 flanked by two directly repeated copies of IS26, and the second event was replicative transposition and subsequent amplification of Tn6020 (Fig. 2). Tobramycin MICs (Table 1) and gene transcription (see Fig. S3 in the supplemental material) were crudely related to the aphA1 gene copy number but reached a plateau at 16 μg/ml above 30 copies of the gene, and high gene copy number incurred a fitness cost on the host bacterium (Fig. 5).\n\nAll clinical isolates contained antibiotic resistance island AbaR28 (Fig. 2), and the gene amplification events in these strains involved portions of AbaR28.\n\nIn isolate MRSN 57, a 15.2-kb region containing 19 of the 20 ORFs in AbaR28 (Fig. 2) was amplified in situ from 2 to 61 times (Fig. 3). The 5′ end was formed by IS26, and part of the supA gene for a sulfate permease constituted the 3′ end of the amplified fragment. A similar event was observed in MRSN 56T, following in vitro amplification by passage of the initial susceptible isolate MRSN 56 on medium with increasing concentrations of tobramycin. The two events could be accounted for by IS26-mediated amplification via formation of deletion circles and reinsertion (24).\n\nIn strain MRSN 58, a smaller 3.2-kb unit composed of Tn6020 underwent replicative transposition at another site in the chromosome followed by amplification at the new locus through nonequal homologous recombination between directly repeated copies of IS26 (25). We previously reported tandem amplification of aphA1 by similar homologous recombination between two flanking IS15 direct copies in Tn1525 from Salmonella enterica serovar Panama when challenged by kanamycin (26).\n\nIn strain AB0057, which carries AbaR3, a larger 6.4-kb region was amplified in situ after growth in the presence of tobramycin (see Fig. S4 in the supplemental material) by a mechanism likely similar to that in MRSN 57 and MRSN 56T.\n\nMeasurement of the fitness cost associated with gene amplification has shown that the growth rate of the host might be indistinguishable from that of the single-copy counterpart or it may be greatly reduced under nonselective conditions depending on the size and location of the amplification (13). In agreement with these observations, we found no biological cost associated with amplification when the growth rate was measured by the usual method (22). However, when individual colonies from the same plate were examined, we observed a diminished growth rate and higher tobramycin MIC (16 μg/ml) for the rare colonies that harbored high copy numbers (>35) of the aphA1 gene. Hence, greater amplification results in higher levels of resistance to tobramycin but exerts a toll on the host that results in a significant fitness cost.\n\nThe mechanism by which Aph(3′)-I confers tobramycin resistance is of interest, as tobramycin lacks the 3′ hydroxyl group which is the target of this phosphotransferase (27). Tobramycin resistance in Escherichia coli by overproduction of Aph(3′)-I has been reported (28). In that study, high-level expression of aphA1 was due to the presence of a strong promoter upstream of the structural gene for the enzyme, and resistance resulted from the formation of a complex between the protein and tobramycin in a stoichiometric manner (28). Thus, trapping of tobramycin by the enzyme could account for the reproducible correlation between increasing tobramycin MICs and higher aphA1 copy number (Fig. 5). As in E. coli, the resistance achieved, although of clinical relevance, was of intermediate level and reached a plateau at 16 μg/ml (Fig. 5). The saturable intracellular sequestration of the drug suggests that the binding between tobramycin and Aph(3′)-I is not very tight. Our observations are compatible with the notion that a tobramycin concentration of 4 μg/ml represents a crude threshold: at higher concentrations, the aphA1 copy number appeared to coalesce between ca. 30 and 55 in isolate MRSN 57 and between 60 to 120 copies in MRSN 58. At lower drug concentrations, the copy number was maintained at approximately 8 and 15 copies in MRSN 57 and MRSN 58, respectively (Fig. 3).\n\nDetection of gene amplification is difficult due to its transient nature, and thus, its role in antibiotic resistance is thought to be considerably underestimated (13). Typically, amplification is rapidly lost from the bacterial population in the absence of selective pressure (29) primarily by homologous recombination between repeated sequences mediated through recA (30, 31). The decrease in copy number was evident in both isolates MRSN 57 and MRSN 58, eventually leading to a single copy in MRSN 57 (Fig. 3). Consistent with this mechanism, analysis of recA in the clinical isolates did not reveal any mutation in the gene or in its upstream regulatory elements. In MRSN 58, the Tn6020 copy number decreased rapidly from 60 to 17 after a single passage on antibiotic-free medium, but amplification was maintained at an average of 16 (±4) copies over the ensuing 28 days (Fig. 3). As both the size and location play a role in determining the stability and fitness cost of amplification (29), we speculate that these factors may explain the contrasting evolution of aphA1 copy numbers in MRSN 57 and MRSN 58. The growth rate of clones of MRSN 58 carrying less than 30 copies of the transposon was indistinguishable from that of the progenitor, susceptible MRSN 56, confirming that the fitness cost of the additional genes was minimal.\n\nWe provide the first description of in vivo gene amplifications that resulted in the development of antibiotic resistance with subsequent treatment failure. Resistance emerged through two IS26-mediated events involving the amplification of a large or small chromosomal region, both containing the aphA1 resistance gene. As a result of gene dosage effect, production of the aminoglycoside phosphotransferase increased over 50-fold, resulting in the intracellular sequestration of the drug, as demonstrated subsequently for a truncated aminoglycoside acetyltransferase (32). Detection and analysis of gene amplification in clinical isolates were achievable only through a combination of active surveillance with translational research, a strategy that has been alluded to for the detection of these transient events (13). Finally, our data demonstrate that GDA are very dynamic processes that could be readily reproduced in vitro and may play a heretofore underappreciated role in clinical antibiotic resistance.\n\nMATERIALS AND METHODS\nCase report.\nAll isolates (Table 1) were cultured from a 20-year-old male polytrauma victim sustained in combat operations in Afghanistan (day 1). Cultures obtained from day 3 grew A. baumannii (isolates MRSN 3361 and MRSN 3363) susceptible to tobramycin (MIC = 0.5 µg/ml). Tobramycin-susceptible MRSN 3364 was cultured on day 8 from a tissue sample collected from the left hip injury. Upon stabilization of the patient, he was transferred to the United States for definitive care, arriving on day 9, where antibiotics were changed to intravenous tobramycin, meropenem, and vancomycin based on culture results. A. baumannii MRSN 56 was cultured from the left hip wound on day 11 and was susceptible to tobramycin (MIC = 0.5 µg/ml). Throughout this escalation of care, tobramycin was continuously administered. On day 12, MRSN 57 was cultured from a tissue sample collected from the right hip but had an MIC of tobramycin of 8 µg/ml. The following day, MRSN 58 was cultured from a tissue sample collected from the left hip. MRSN 58 had a tobramycin MIC of = 16 µg/ml, which denotes resistance by CLSI guidelines (33). Consequently, tobramycin therapy was discontinued, and the patient was prescribed colistin while continuing meropenem.\n\nWhole-genome mapping.\nWhole-genome mapping (WGM) with NcoI using the Argus system (OpGen Inc., MD, USA) was performed as described previously (5).\n\nDetermination of gene copy number by real-time PCR (qPCR).\nDNA was collected using a modified rapid extraction method (34). Briefly, a 10-µl loopful of bacterial cells was suspended in 300 µl of sterile water, and 20 µl was added to 40 µl of lysis buffer (1% Triton X-100, 0.5% Tween 20, 10 mM Tris-HCl [pH 8.0], and 1 mM EDTA). The resulting solution was heated to 95°C for 12 min, and 2 µl was used for qPCR.\n\nPrimers (see Table S1 in the supplemental material) targeting seven loci within or flanking the amplified unit in A. baumannii MRSN 57 were designed using Primer Express 2.0 (Life Technologies, NY) and tested for sensitivity and specificity using MIQE (minimum information for publication of quantitative real-time PCR experiments) guidelines (35). Standard curves were generated using serial dilutions of DNA from 107 to 101 genome copies of A. baumannii AB0057 as described previously (21). The gene copy number was normalized to the single-copy genes secE and rpiN to calculate relative copy number per genome (21). Experiments were performed from a minimum of three biological replicates with two technical replicates per run.\n\nRNA extraction and qRT-PCR.\nTotal RNA extraction and subsequent quantitative reverse transcriptase PCR (qRT-PCR) were performed as described previously (5).\n\nWhole-genome sequencing.\nWhole-genome sequencing was performed on isolates MRSN 56, MRSN 57, and MRSN 58 using a MiSeq benchtop sequencer (Illumina Inc., CA). Libraries were generated from 550-bp fragments of high-quality DNA using the TruSeq DNA PCR-free LT sample preparation kit (Illumina Inc.). Paired-end sequencing (250 bp) was performed using the MiSeq reagent kit v2 (500-cycle) kit. Newbler version 2.7 (454 Life Sciences, CT) was used to assemble MiSeq sequencing reads into de novo contigs and sequencing reads against reference DNA sequences. A. baumannii AB0057 and AYE were used for comparative genomic analyses. Reference and de novo contigs were combined using Geneious (Biomatters, Auckland, New Zealand) to construct a scaffold genome assembly and verified using a whole-genome map (36).\n\nStability of gene copy number.\nA single colony of isolates MRSN 57 and MRSN 58 was plated in triplicate onto Mueller-Hinton (MH) agar with and without tobramycin (4 µg/ml). After growth overnight at 37°C, half of the cells of two individual colonies was inoculated separately onto fresh MH agar plates and the other half was used to isolate DNA for qPCR as described above. This process was repeated daily for 20 and 30 days in the presence or absence of tobramycin, respectively. MRSN 56, the progenitor susceptible strain, was cultured in parallel on antibiotic-free medium, and 15 colonies were recovered on days 0, 6, 12, and 20 for mRNA extraction and gene expression studies.\n\nIn vitro induction of gene amplification.\nA. baumannii MRSN 56 and AB0057 were cultured on MH agar supplemented with tobramycin (1 µg/ml) in triplicate. Strain AB0057 was selected, as it is of the same sequence type (ST1) as the clinical isolates and carries the AbaR3 resistance island with an intact copy of Tn6020 (19). Single colonies were transferred daily onto plates with increasing concentrations of tobramycin from 1 to 16 µg/ml. Bacteria were harvested for RNA and DNA extraction daily.\n\nGrowth rates.\nGrowth rates were determined in microplates coupled to a Multiskan spectrophotometer (Thermo Fisher Scientific, MA). Strains were grown overnight at 37°C, the cultures were diluted in 5 ml of LB to an optical density at 600 nm (OD600) of 0.15 and grown at 37°C with shaking. At the beginning of the stationary phase, i.e., at an OD600 of 0.9, the cultures were diluted 105-fold to inoculate approximately 1 × 104 bacteria into 200 µl of LB in a 96-well microplate that was incubated at 37°C with shaking. Absorbance was measured at 600 nm every 3 min. Each culture was replicated three times in the same microplate. Growth rates, performed in two independent experiments, were determined at the beginning of the exponential phase, and relative growth rates were calculated as the ratio of the growth rate of the strains versus that of susceptible MRSN 56.\n\nSUPPLEMENTAL MATERIAL\nFigure S1 Average read coverage of aphA1, aacC1, and sul1 in clinical isolates MRSN 56, MRSN 57, and MRSN 58 as determined by whole-genome sequence using the Illumina MiSeq. Read coverage was calculated from raw reads using Geneious (Biomatters, Auckland, New Zealand) software. Download \n\nFigure S1, JPG file, 0.1 MB\n\n Figure S2 Optical genome maps generated from three colonies of isolate MRSN 58 from the same overnight culture plate. The region corresponding to the amplification of Tn6020 is enclosed in red rectangles. The relative aphA1 copy number, as determined by qPCR, is indicated on the right. Download \n\nFigure S2, JPG file, 0.2 MB\n\n Figure S3 Comparison of relative gene copy number (blue) and mRNA transcript levels (red) of usp in isolate MRSN 57 (A) and aphA1 in isolate MRSN 58 (B). Cells were harvested on days 0, 6, 12, and 20 from cultures grown on MH agar with tobramycin at a final concentration of 4 µg/ml (see Materials and Methods for details). Half of the collected cells were used for DNA extraction and qPCR, and the remaining half were used for RNA extraction for qRT-PCR. Data are the averages of three independent experiments. Error bars represent 1 standard deviation. Download \n\nFigure S3, JPG file, 0.2 MB\n\n Figure S4 Schematic representation of the amplified unit in AB0057T. The AbaR3 resistance island is indicated by a thick black line, the amplified unit is indicated by a thin black line, and their sizes are shown in kilobases. The open arrows represent coding sequences (yellow arrows, IS26; red arrows, aminoglycoside resistance genes; blue arrows, genes associated with DNA mobility). The 5′ and 3′ portions of the truncated comM gene flanking AbaR3 are represented by black broken open arrows. The portions of AbaR3 not shown are indicated by the dotted lines. Gene nomenclature was assigned based on the closest BLAST match from GenBank (http://blast.ncbi.nlm.nih.gov/Blast.cgi, last accessed January 2014) using reference strain AB0057. Download \n\nFigure S4, JPG file, 0.1 MB\n\n Table S1 Primers used in this study\n\nTable S1, DOCX file, 0.1 MB.\n\n Citation McGann P, Courvalin P, Snesrud E, Clifford RJ, Yoon E-J, Onmus-Leone F, Ong AC, Kwak YI, Grillot-Courvalin C, Lesho E, Waterman PE. 2014. Amplification of aminoglycoside resistance gene aphA1 in Acinetobacter baumannii results in tobramycin therapy failure. mBio 5(2):e00915-14. doi:10.1128/mBio.00915-14.\n\nACKNOWLEDGMENTS\nThis study was funded by the U.S. Army Medical Command, the Global Emerging Infections Surveillance and Response System, and the Defense Medical Research and Development Program. This work was supported in part by the European Union FP7-PAR grant, which included a fellowship in support of E-J. Yoon.\n\nWe thank all laboratory personnel without whose help we could not have done this study. We thank Jun Hang and the Viral Disease group, WRAIR, for assistance in initial genome sequencing and Matthew Riley for initial assistance with whole-genome mapping. We thank M. Chandler for helpful discussions.\n\nThis material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.\n==== Refs\nREFERENCES\n1. \nGoldstein FW Labigne-Roussel A Gerbaud G Carlier C Collatz E Courvalin P \n1983 \nTransferable plasmid-mediated antibiotic resistance in Acinetobacter . Plasmid \n10 :138 –147 . 10.1016/0147-619X(83)90066-5 6356187 \n2. \nMarchand I Damier-Piolle L Courvalin P Lambert T \n2004 \nExpression of the RND-type efflux pump AdeABC in Acinetobacter baumannii is regulated by the AdeRS two-component system . Antimicrob. Agents Chemother. \n48 :3298 –3304 . 10.1128/AAC.48.9.3298-3304.2004 15328088 \n3. \nPerez F Endimiani A Bonomo RA \n2008 \nWhy are we afraid of Acinetobacter baumannii? \nExpert Rev. Anti Infect. Ther. \n6 :269 –271 . 10.1586/14787210.6.3.269 18588489 \n4. \nYoon EJ Courvalin P Grillot-Courvalin C \n2013 \nRND-type efflux pumps in multidrug-resistant clinical isolates of Acinetobacter baumannii: major role for AdeABC overexpression and AdeRS mutations . Antimicrob. Agents Chemother. \n57 :2989 –2995 . 10.1128/AAC.02556-12 23587960 \n5. \nLesho E Yoon EJ McGann P Snesrud E Kwak Y Milillo M Onmus-Leone F Preston L St. Clair K Nikolich M Viscount H Wortmann G Zapor M Grillot-Courvalin C Courvalin P Clifford R Waterman PE \n2013 \nEmergence of colistin-resistance in extremely drug-resistant Acinetobacter baumannii containing a novel pmrCAB operon during colistin therapy of wound infections . J. Infect. Dis. \n208 :1142 –1151 . 10.1093/infdis/jit293 23812239 \n6. \nRamirez MS Tolmasky ME \n2010 \nAminoglycoside modifying enzymes . Drug Resist. Updat. \n13 :151 –171 20833577 \n7. \nBonomo RA Szabo D \n2006 \nMechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa . Clin. Infect. Dis. \n43 (Suppl 2 ):S49 –S56 . 10.1086/504804 16894515 \n8. \nNemec A Dolzani L Brisse S van den Broek P Dijkshoorn L \n2004 \nDiversity of aminoglycoside-resistance genes and their association with class 1 integrons among strains of pan-European Acinetobacter baumannii clones . J. Med. Microbiol. \n53 :1233 –1240 . 10.1099/jmm.0.45716-0 15585503 \n9. \nPost V Hall RM \n2009 \nAbaR5, a large multiple-antibiotic resistance region found in Acinetobacter baumannii . Antimicrob. Agents Chemother. \n53 :2667 –2671 . 10.1128/AAC.01407-08 19364869 \n10. \nFournier PE Vallenet D Barbe V Audic S Ogata H Poirel L Richet H Robert C Mangenot S Abergel C Nordmann P Weissenbach J Raoult D Claverie JM \n2006 \nComparative genomics of multidrug resistance in Acinetobacter baumannii . PLoS Genet. \n2 :e7 . 10.1371/journal.pgen.0020007 16415984 \n11. \nKrizova L Dijkshoorn L Nemec A \n2011 \nDiversity and evolution of AbaR genomic resistance islands in Acinetobacter baumannii strains of European clone I . Antimicrob. Agents Chemother. \n55 :3201 –3206 . 10.1128/AAC.00221-11 21537009 \n12. \nPost V White PA Hall RM \n2010 \nEvolution of AbaR-type genomic resistance islands in multiply antibiotic-resistant Acinetobacter baumannii . J. Antimicrob. Chemother. \n65 :1162 –1170 . 10.1093/jac/dkq095 20375036 \n13. \nSandegren L Andersson DI \n2009 \nBacterial gene amplification: implications for the evolution of antibiotic resistance . Nat. Rev. Microbiol. \n7 :578 –588 . 10.1038/nrmicro2174 19609259 \n14. \nDuvernay C Coulange L Dutilh B Dubois V Quentin C Arpin C \n2011 \nDuplication of the chromosomal blaSHV-11 gene in a clinical hypermutable strain of Klebsiella pneumoniae . Microbiology \n157 :496 –503 . 10.1099/mic.0.043885-0 20966089 \n15. \nBrochet M Couvé E Zouine M Poyart C Glaser P \n2008 \nA naturally occurring gene amplification leading to sulfonamide and trimethoprim resistance in Streptococcus agalactiae . J. Bacteriol. \n190 :672 –680 . 10.1128/JB.01357-07 18024520 \n16. \nBertini A Poirel L Bernabeu S Fortini D Villa L Nordmann P Carattoli A \n2007 \nMulticopy blaOXA-58 gene as a source of high-level resistance to carbapenems in Acinetobacter baumannii . Antimicrob. Agents Chemother. \n51 :2324 –2328 . 10.1128/AAC.01502-06 17438042 \n17. \nEvans BA Hamouda A Towner KJ Amyes SG \n2010 \nNovel genetic context of multiple blaOXA-58 genes in Acinetobacter genospecies 3 . J. Antimicrob. Chemother. \n65 :1586 –1588 . 10.1093/jac/dkq180 20542900 \n18. \nDiancourt L Passet V Nemec A Dijkshoorn L Brisse S \n2010 \nThe population structure of Acinetobacter baumannii: expanding multiresistant clones from an ancestral susceptible genetic pool . PLoS One \n5 :e10034 . 10.1371/journal.pone.0010034 20383326 \n19. \nAdams MD Goglin K Molyneaux N Hujer KM Lavender H Jamison JJ MacDonald IJ Martin KM Russo T Campagnari AA Hujer AM Bonomo RA Gill SR \n2008 \nComparative genome sequence analysis of multidrug-resistant Acinetobacter baumannii . J. Bacteriol. \n190 :8053 –8064 . 10.1128/JB.00834-08 18931120 \n20. \nMaragakis LL Perl TM \n2008 \nAcinetobacter baumannii: epidemiology, antimicrobial resistance, and treatment options . Clin. Infect. Dis. \n46 :1254 –1263 . 10.1086/529198 18444865 \n21. \nClifford RJ Milillo M Prestwood J Quintero R Zurawski DV Kwak YI Waterman PE Lesho EP McGann P \n2012 \nDetection of bacterial 16S rRNA and identification of four clinically important bacteria by real-time PCR . PLoS One \n7 :e48558 . 10.1371/journal.pone.0048558 23139793 \n22. \nFoucault ML Courvalin P Grillot-Courvalin C \n2009 \nFitness cost of VanA-type vancomycin resistance in methicillin-resistant Staphylococcus aureus . Antimicrob. Agents Chemother. \n53 :2354 –2359 . 10.1128/AAC.01702-08 19332680 \n23. \nFoucault ML Depardieu F Courvalin P Grillot-Courvalin C \n2010 \nInducible expression eliminates the fitness cost of vancomycin resistance in enterococci . Proc. Natl. Acad. Sci. U. S. A. \n107 :16964 –16969 . 10.1073/pnas.1006855107 20833818 \n24. \nWaggoner BT Gonzalez NS Taylor AL \n1974 \nIsolation of heterogeneous circular DNA from induced lysogens of bacteriophage Mu-1 . Proc. Natl. Acad. Sci. U. S. A. \n71 :1255 –1259 4598297 \n25. \nAndersson DI Hughes D \n2009 \nGene amplification and adaptive evolution in bacteria . Annu. Rev. Genet. \n43 :167 –195 . 10.1146/annurev-genet-102108-134805 19686082 \n26. \nLabigne-Roussel A Briaux-Gerbaud S Courvalin P \n1983 \nTn1525, a kanamycin R determinant flanked by two direct copies of IS15 . Mol. Gen. Genet. \n189 :90 –101 . 10.1007/BF00326060 6304464 \n27. \nCourvalin P Carlier C \n1981 \nResistance towards aminoglycoside-aminocyclitol antibiotics in bacteria . J. Antimicrob. Chemother. \n8 (Suppl A ):57 –69 . 10.1093/jac/8.suppl_E.57 7263566 \n28. \nMenard R Molinas C Arthur M Duval J Courvalin P Leclercq R \n1993 \nOverproduction of 3′-aminoglycoside phosphotransferase type I confers resistance to tobramycin in Escherichia coli . Antimicrob. Agents Chemother. \n37 :78 –83 . 10.1128/AAC.37.1.78 8381641 \n29. \nPettersson ME Sun S Andersson DI Berg OG \n2009 \nEvolution of new gene functions: simulation and analysis of the amplification model . Genetica \n135 :309 –324 . 10.1007/s10709-008-9289-z 18568430 \n30. \nAnderson RP Roth JR \n1978 \nTandem chromosomal duplications in Salmonella typhimurium: fusion of histidine genes to novel promoters . J. Mol. Biol. \n119 :147 –166 . 10.1016/0022-2836(78)90274-7 344891 \n31. \nHaack KR Roth JR \n1995 \nRecombination between chromosomal IS200 elements supports frequent duplication formation in Salmonella typhimurium . Genetics \n141 :1245 –1252 8601470 \n32. \nMagnet S Smith TA Zheng R Nordmann P Blanchard JS \n2003 \nAminoglycoside resistance resulting from tight drug binding to an altered aminoglycoside acetyltransferase . Antimicrob. Agents Chemother. \n47 :1577 –1583 . 10.1128/AAC.47.5.1577-1583.2003 12709325 \n33. \nClinical and Laboratory Standards Institute \n2012 \nPerformance standards for antimicrobial susceptibility testing. M100–S22 . Clinical and Laboratory Standards Institute , Wayne, PA \n34. \nReischl U Linde HJ Metz M Leppmeier B Lehn N \n2000 \nRapid identification of methicillin-resistant Staphylococcus aureus and simultaneous species confirmation using real-time fluorescence PCR . J. Clin. Microbiol. \n38 :2429 –2433 10835024 \n35. \nBustin SA Benes V Garson JA Hellemans J Huggett J Kubista M Mueller R Nolan T Pfaffl MW Shipley GL Vandesompele J Wittwer CT \n2009 \nThe MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments . Clin. Chem. \n55 :611 –622 . 10.1373/clinchem.2008.112797 19246619 \n36. \nKearse M Moir R Wilson A Stones-Havas S Cheung M Sturrock S Buxton S Cooper A Markowitz S Duran C Thierer T Ashton B Meintjes P Drummond A \n2012 \nGeneious Basic: an integrated and extendable desktop software platform for the organization and analysis of sequence data . Bioinformatics \n28 :1647 –1649 . 10.1093/bioinformatics/bts199 22543367 \n37. \nDijkshoorn L Nemec A Seifert H \n2007 \nAn increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii . Nat. Rev. Microbiol. \n5 :939 –951 . 10.1038/nrmicro1789 18007677\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "5(2)",
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"keywords": null,
"medline_ta": "mBio",
"mesh_terms": "D000135:Acid Phosphatase; D000151:Acinetobacter Infections; D040981:Acinetobacter baumannii; D000900:Anti-Bacterial Agents; D004251:DNA Transposable Elements; D004269:DNA, Bacterial; D024881:Drug Resistance, Bacterial; D005784:Gene Amplification; D018628:Gene Dosage; D016680:Genome, Bacterial; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014031:Tobramycin; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "101519231",
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"pubdate": "2014-04-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
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"title": "Amplification of aminoglycoside resistance gene aphA1 in Acinetobacter baumannii results in tobramycin therapy failure.",
"title_normalized": "amplification of aminoglycoside resistance gene apha1 in acinetobacter baumannii results in tobramycin therapy failure"
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"abstract": "We describe the case of a patient with malignant vasodepressive cough syncope. We demonstrated a vaso-vagal mechanism related to left vagal neuritis, by means of laryngoscopy and laryngeal electromyography. The condition resolved with steroid therapy.\nLeft vagal neuritis should be considered in the differential diagnosis of recent onset repetitive loss of consciousness, in particular if cough related.Steroids were used to successfully treat recent onset cough-related syncope.Relatively simple trials of drug therapy can sometimes avoid intensive investigations; in our case, the use of a systemic steroid would probably have avoided many radiological and endoscopic examinations.",
"affiliations": "Department of Cardiology, A. Manzoni Hospital, Lecco, Italy.;Department of Cardiology, A. Manzoni Hospital, Lecco, Italy.;Department of Cardiology, A. Manzoni Hospital, Lecco, Italy.;Department of Cardiology, L. Vanvitelli University of Naples, Caserta, Italy.;Department of Cardiology, A. Manzoni Hospital, Lecco, Italy.",
"authors": "Farina|Andrea|A|;Bassanelli|Giorgio|G|;Bianchi|Alfredo|A|;Coppola|Guido|G|;Savonitto|Stefano|S|",
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"doi": "10.12890/2018_000842",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2018_000842842-1-5225-2-10-20180321ArticlesMalignant Cough Syncope from Idiopathic Vagal Inflammation Farina Andrea 1Bassanelli Giorgio 1Bianchi Alfredo 1Coppola Guido 2Savonitto Stefano 1\n1 Department of Cardiology, A. Manzoni Hospital, Lecco, Italy\n2 Department of Cardiology, L. Vanvitelli University of Naples, Caserta, Italy2018 25 5 2018 5 5 00084208 1 2018 29 1 2018 © EFIM 20182018This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseWe describe the case of a patient with malignant vasodepressive cough syncope. We demonstrated a vaso-vagal mechanism related to left vagal neuritis, by means of laryngoscopy and laryngeal electromyography. The condition resolved with steroid therapy.\n\nLEARNING POINTS\nLeft vagal neuritis should be considered in the differential diagnosis of recent onset repetitive loss of consciousness, in particular if cough related.\n\nSteroids were used to successfully treat recent onset cough-related syncope.\n\nRelatively simple trials of drug therapy can sometimes avoid intensive investigations; in our case, the use of a systemic steroid would probably have avoided many radiological and endoscopic examinations.\n\nSyncopecoughvagalneuritis\n==== Body\nCASE REPORT\nA 74-year-old man was admitted to the emergency department with paroxysmal dry cough attacks complicated by traumatic syncope. He had coronary artery disease with previous angioplasty of the circumflex coronary artery, had a dual-chamber pacemaker for atrio-ventricular block, and was on anticoagulant therapy for paroxysmal atrial fibrillation. Medications included apixaban 5 mg twice daily, enalapril 5 mg once daily, metoprolol 25 mg twice daily, and atorvastatin 20 mg once daily.\n\nAt presentation, blood pressure and heart rate were normal, the patient did not have fever or altered mental status, and clinical examination was unremarkable. Chest x-ray excluded parenchymal consolidation, obstructive pulmonary disease and signs of heart failure, and revealed only mild left diaphragm elevation. The electrocardiogram showed sinus rhythm with first-degree atrio-ventricular block. Pacemaker interrogation and the echocardiogram were normal.\n\nMethods and procedures\nThe patient was admitted to the general medicine department, where he was first treated with antibiotics, cough sedatives and bronchodilators without any improvement; he still experienced up to 20 syncopal episodes per day with jerking movements preceded by cough. Enalapril was stopped. Thorax computed tomography (CT) excluded parenchymal disease or pulmonary embolism.\n\nA bronchoscopy was performed to explore other causes of cough, but cytology, fungal antibody testing and bacterial cultures were all negative. Neurological assessment with a cerebral CT scan, cerebral magnetic resonance imaging (MRI) and supra-aortic trunks Doppler were also negative. The electroencephalogram showed slowing of cerebral waves during jerking movements without critical activity. Laryngoscopy was performed and showed signs of chronic sinusitis. Esophagogastroduodenoscopy (EGDS) did not reveal any signs of gastroesophageal reflux or other pathology.\n\nDuring hospitalization and therapy with enoxaparin, the patient developed haemorrhagic shock due to right shoulder post-traumatic haematoma (haemoglobin fell from 16 to 7 g/dl) with episodes of supraventricular tachycardia. He was transferred to the cardiovascular intensive care unit where he was treated with fluids and administration of blood components resulting in haemodynamic and rhythm stabilization. Over the next few days he presented several new syncopal attacks. During these episodes, invasive pedidial blood pressure monitoring demonstrated a significant drop in blood pressure without changes in heart rate (Fig. 1). To investigate whether syncope was related to an abnormal vagal reflex, atropine 1 mg i.v. was administered as vagolytic treatment, resulting in temporary control of syncopal episodes. Another otolaryngologist assessment with laryngoscopy revealed hypomobility of the left vocal cord. In order to determine if vagal nerve dysfunction was present, laryngeal electromyography was performed and revealed signs of acute neurogenic damage of the cricothyroid and thyroarytenoid left muscles with denervation potentials (Fig. 2).\n\nOnce organic causes were excluded through imaging, under the hypothesis of vagal neuritis we started methylprednisolone 40 mg bid i.v. with rapid improvement in cough and no further syncopal episodes. The steroid was tapered over the next 2 weeks and at the 1-month follow-up visit, clinical evaluation and laryngoscopy were normal.\n\nDISCUSSION\nThe mechanism of cough-related loss of consciousness has been debated since the first description in 1876. An early suggestion that it was a form of epilepsy was excluded in our case as direct electroencephalography during a spontaneous jerking attack demonstrated slowing of cerebral waves without critical activity. Another hypothesis was a rapid increase in liquor pressure with secondary circulatory arrest or cerebral concussion, but cerebral MRI excluded organic causes of altered liquor circulation. Continuous invasive pedidial blood pressure monitoring, avoiding jerk-related artefacts, showed a rapid reduction in blood pressure accompanied loss of consciousness, and demonstrated that the mechanism of syncope was related to a reduction in cerebral perfusion due to systemic hypotension[1]. Possible mechanisms of hypotension could be Valsalva related with a reduction in cardiac output, or rapid fluctuations in intrathoracic pressure during cough attacks that lead to a vaso-vagal reflex secondary to stimulation of aortic baroceptors [2].\n\nIn our case, the absence of syncope during Valsalva manoeuvre and the reproducible prevention of cough-induced syncope attacks by atropine suggested the second mechanism.\n\nThe question was why a patient without any past such history had suddenly developed vaso-vagal syncope. We demonstrated left vagal dysfunction with laryngoscopic evidence of left vocal cord hypomobility and subsequent laryngeal electromyography showed signs of neurogenic damage in the vagal-innervated muscles. The fact that the patient had dysphagia, dysphonia and dry cough, all possible symptoms of vagal neuropathy, further supported this hypothesis. We systematically excluded structural causes of vagal dysfunction by MRI and CT study of the cranial, cervical and thoracic nerves. Several cases of post-viral persistent vagal neuropathy are reported in the literature. We did not obtain biopsy specimens, but the rapid and sustained response to steroid therapy strongly suggests the presence of acute neuritis; negative follow-up laryngoscopy also confirmed an acute and transient event. To our knowledge this is the first report of acute vagal neuritis that manifested as malignant cough syncope with nerve dysfunction, possibly explaining both the cause of the cough and the mechanism of the secondary syncope.\n\nThis case of vaso-vagal reflex may have shown a pure vasodepressive response, as demonstrated by the absence of pacemaker intervention during syncope, because of the isolated left vagal dysfunction; vagal cardiac innervation is asymmetric, with only the right nerve going to the sino-atrial and atrio-ventricular nodes and inducing a cardio-inhibitory response. The most likely neural pathway to explain our case involves as afferent branch the Cyon nerve that carries signals from aortic arch baroceptors to the left vagal nerve. This hypothesis is further supported by the absence of carotid sinus hypersensitivity to neck massage, because in this second reflex the afferent branch is part the of glossopharyngeal nerve. Inflamed afferent nerve fibres may respond to a rise in intrathoracic pressure induced by intermittent cough with an increased baroceptor signal, leading to a severe vagal vasodepressive response.\n\nWhile it was known that cough may be a cause of syncope and that vagal neuropathy may be a cause of persistent cough after respiratory viral infection, what it new in this case is the demonstration of acute left vagal dysfunction as the cause of pure vasodepressive vaso-vagal syncopes. Moreover, for the first time to our knowledge, acute vagal neuritis was strongly suggested by the rapid and sustained response to steroid therapy. The patient was discharged on oral prednisone 37.5 mg once daily with tapering over the following 2 weeks. Laryngoscopy showed normal cord mobility 1 month later and clinical follow-up was uneventful 2 months later.\n\nIn conclusion, cough syncope is an unusual form of situational syncope that may occur in both the standing and supine positions. Its rapid and unpredictable occurrence can have traumatic consequences. In the clinical evaluation of these patients, the first step is to connect loss of consciousness to cough and then to determine the aetiology of cough in order to establish specific treatment, exploring first the more common causes, such as gastroesophageal reflux, obstructive pulmonary disease and ACE inhibitors[3], and then uncommon causes, such as cerebral pathology or post-viral vagal neuropathy. If suspected, this entity can be initially investigated by fibrolaryngoscopy and confirmed by laryngeal electromyograph [4, 5]. A trial of steroid therapy can be initiated.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n\nFigure 1 Invasive blood pressure monitoring through the pedidial left artery, avoiding jerk-related artefacts during cough, demonstrated a significant drop in blood pressure without changes in heart rate during the syncope attack (baseline arterial pressure 125/80 mmHg; immediate post-cough arterial pressure 60/30 mmHg)\n\nFigure 2 Laryngeal electromyography revealed denervation potentials of the cricothyroid and thyroarytenoid left muscles\n==== Refs\nREFERENCES\n1 McIntosh HD Estes EH Warren JV The mechanism of cough syncope Am Heart J 1956 52 70 82 13326836 \n2 Sharpey-Schafer EP The mechanism of syncope after coughing Br Med J 1953 2 860 863 13094038 \n3 Dicpinigaitis PV Lim L Farmakidis C Cough syncope Respir Med 2014 108 244 251 24238768 \n4 Amin MR Koufman JA Vagal neuropathy after upper respiratory infection: a viral etiology? Am J Otolaryngol 2001 22 251 256 11464321 \n5 Tatar Cadall E Ocal B Korkmaz H Unlu E Surenoglu AU Saylam G Postviral vagal neuropathy: what is the role of laryngeal electromyography in improving diagnostic accuracy? J Voice 2015 29 595 599 25510163\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "5(5)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Syncope; cough; neuritis; vagal",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000842",
"pmc": null,
"pmid": "30756033",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "11464321;13094038;13326836;24238768;25510163",
"title": "Malignant Cough Syncope from Idiopathic Vagal Inflammation.",
"title_normalized": "malignant cough syncope from idiopathic vagal inflammation"
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"abstract": "OBJECTIVE\nWe report disease control, survival outcomes, and treatment-related toxicity among adult medulloblastoma patients who received proton craniospinal irradiation (CSI) as part of multimodality therapy.\n\n\nMETHODS\nWe reviewed 20 adults with medulloblastoma (≥ 22 years old) who received postoperative proton CSI ± chemotherapy between 2008 and 2020. Patient, disease, and treatment details and prospectively obtained patient-reported acute CSI toxicities were collected. Acute hematologic data were analyzed.\n\n\nRESULTS\nMedian age at diagnosis was 27 years; 45% of patients had high-risk disease; 75% received chemotherapy, most (65%) after CSI. Eight (40%) patients received concurrent vincristine with radiotherapy. Median CSI dose was 36GyE with a median tumor bed boost of 54GyE. Median duration of radiotherapy was 44 days. No acute ≥ grade 3 gastrointestinal or hematologic toxicities attributable to CSI occurred. Grade 2 nausea and vomiting affected 25% and 5% of patients, respectively, while 36% developed acute grade 2 hematologic toxicity (36% grade 2 leukopenia and 7% grade 2 neutropenia). Those receiving concurrent chemotherapy with CSI had a 38% rate of grade 2 hematologic toxicity compared to 33% among those not receiving concurrent chemotherapy. Among patients receiving adjuvant chemotherapy (n = 13), 100% completed ≥ 4 cycles and 85% completed all planned cycles. With a median follow-up of 3.1 years, 4-year actuarial local control, disease-free survival, and overall survival rates were 90%, 90%, and 95%, respectively.\n\n\nCONCLUSIONS\nProton CSI in adult medulloblastoma patients is very well tolerated and shows promising disease control and survival outcomes. These data support the standard use of proton CSI for adult medulloblastoma.",
"affiliations": "Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, 2015 North Jefferson Street, Jacksonville, FL, 32206, USA.;Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, 2015 North Jefferson Street, Jacksonville, FL, 32206, USA.;Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, USA.;Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, 2015 North Jefferson Street, Jacksonville, FL, 32206, USA.;Department of Neurosurgery and the Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida College of Medicine, Gainesville, FL, USA.;Baptist MD Anderson Cancer Center, Jacksonville, FL, USA.;University of Florida Health Proton Therapy Institute, Jacksonville, FL, USA.;Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, 2015 North Jefferson Street, Jacksonville, FL, 32206, USA.;Department of Neurosurgery, University of Florida College of Medicine Jacksonville, Jacksonville, FL, USA.;Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, 2015 North Jefferson Street, Jacksonville, FL, 32206, USA. mrutenberg@floridaproton.org.",
"authors": "Liu|I-Chia|IC|;Holtzman|Adam L|AL|;Rotondo|Ronny L|RL|;Indelicato|Daniel J|DJ|;Gururangan|Sridharan|S|;Cavaliere|Robert|R|;Carter|Bridgette|B|;Morris|Christopher G|CG|;Tavanaiepour|Daryoush|D|;Rutenberg|Michael S|MS|http://orcid.org/0000-0001-6945-7883",
"chemical_list": null,
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"doi": "10.1007/s11060-021-03783-x",
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"issn_linking": "0167-594X",
"issue": "153(3)",
"journal": "Journal of neuro-oncology",
"keywords": "Central nervous system tumors; Clinical outcomes; Craniospinal irradiation; Particle therapy; Radiation therapy",
"medline_ta": "J Neurooncol",
"mesh_terms": null,
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "467-476",
"pmc": null,
"pmid": "34105033",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
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"title": "Proton therapy for adult medulloblastoma: Acute toxicity and disease control outcomes.",
"title_normalized": "proton therapy for adult medulloblastoma acute toxicity and disease control outcomes"
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"abstract": "BACKGROUND\nIntravenous magnesium sulfate, a rescue therapy added to bronchodilator and systemic steroid therapy for moderate and severe asthma, is uncommonly administered. We hypothesized that nebulized magnesium would confer benefit without undue risk.\n\n\nMETHODS\nPatients aged 2 to 14 y with moderate and severe asthma (PRAM severity score ≥ 4) admitted to infirmary/observation unit care were randomized double-blind on admission to receive 800 mg nebulized magnesium or normal saline placebo after all received intensive therapy with combined nebulized albuterol-ipratropium and intravenous methylprednisolone. Time to medical readiness for discharge was the primary outcome; sample size was chosen to detect a 15% absolute improvement. Improvement over time in PRAM severity score and other secondary outcomes were compared for the overall group and severe asthma subset.\n\n\nRESULTS\nOne hundred and ninety-one magnesium sulfates and 174 placebo patients met criteria for analysis. The groups were similar with mean baseline PRAM scores >7. Blinded active therapy significantly increased blood magnesium level 2 hr post-treatment completion compared to placebo, 0.85 vs 0.82 mmol/L, P = 0.001. There were no important adverse effects. Accelerated failure time analysis showed a non-significantly shortened time to medical readiness for discharge of 14% favoring the magnesium sulfate group, OR = 1.14, 95% CI 0.93 to 1.40, P = 0.20. Mean times until readiness for discharge were 14.7 hr [SD 9.7] versus 15.6 hr [SD 11.3] for the investigational and placebo groups, respectively, P = 0.41.\n\n\nCONCLUSIONS\nAdding nebulized magnesium to combined nebulized bronchodilator and systemic steroid therapy failed to significantly shorten time to discharge of pediatric patients with moderate or severe asthma.",
"affiliations": "Department of Pediatrics, Division of Pediatric Emergency Medicine, Sidra Medical and Research Centre, Doha, Qatar.;Department of Pediatrics, Division of Pediatric Emergency Medicine, Hamad Medical Corporation, Doha, Qatar.;Division of Pulmonary and Critical Care Medicine, University of Washington School of Medicine, Seattle, Washington.;Department of Pediatrics, Division of Pediatric Emergency Medicine, Hamad Medical Corporation, Doha, Qatar.;Department of Pediatrics, Division of Pediatric Emergency Medicine, Hamad Medical Corporation, Doha, Qatar.;Department of Pediatrics, Division of Pediatric Emergency Medicine, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Alansari|Khalid|K|;Ahmed|Wessam|W|;Davidson|Bruce L|BL|;Alamri|Mohamed|M|;Zakaria|Ibrahim|I|;Alrifaai|Mahomud|M|",
"chemical_list": "D001993:Bronchodilator Agents; D005938:Glucocorticoids; D008278:Magnesium Sulfate; D009241:Ipratropium; D008274:Magnesium; D000420:Albuterol; D008775:Methylprednisolone",
"country": "United States",
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"doi": "10.1002/ppul.23158",
"fulltext": null,
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"issn_linking": "1099-0496",
"issue": "50(12)",
"journal": "Pediatric pulmonology",
"keywords": "bronchodilator; nebulization; pediatric emergency",
"medline_ta": "Pediatr Pulmonol",
"mesh_terms": "D000293:Adolescent; D000420:Albuterol; D001249:Asthma; D001993:Bronchodilator Agents; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D009241:Ipratropium; D008274:Magnesium; D008278:Magnesium Sulfate; D008297:Male; D008775:Methylprednisolone; D009330:Nebulizers and Vaporizers; D010351:Patient Discharge; D012720:Severity of Illness Index",
"nlm_unique_id": "8510590",
"other_id": null,
"pages": "1191-9",
"pmc": null,
"pmid": "25652104",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "23235599;24429155;16627836;21235843;24429139;24429154;21175517;10796650;18346499",
"title": "Nebulized magnesium for moderate and severe pediatric asthma: A randomized trial.",
"title_normalized": "nebulized magnesium for moderate and severe pediatric asthma a randomized trial"
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"abstract": "From 16,380 administrations of I.V. fluid in children during a 6-month period, there were 1,800 extravasations (11%) with 40 skin sloughs. All that resulted in either partial or full-thickness skin loss were treated by one of 3 conservative protocols, and no skin grafts were needed in this series. Most of the extravasations resulting in skin loss were associated with hypertonic fluids and the use of infusion pumps. Careful hourly monitoring of such cases seems highly desirable. We found no discernible differences in the healing among the 3 treatment regimens used. The importance of systematic monitoring of children receiving I.V. fluids by nursing personnel, the elevation of an extremity involved in an extravasation, and the care of any resulting wounds are discussed.",
"affiliations": null,
"authors": "Brown|A S|AS|;Hoelzer|D J|DJ|;Piercy|S A|SA|",
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"issue": "64(2)",
"journal": "Plastic and reconstructive surgery",
"keywords": null,
"medline_ta": "Plast Reconstr Surg",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007275:Injections, Intravenous; D008297:Male; D009336:Necrosis; D010289:Parenteral Nutrition, Total; D012871:Skin Diseases",
"nlm_unique_id": "1306050",
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"pubdate": "1979-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Skin necrosis from extravasation of intravenous fluids in children.",
"title_normalized": "skin necrosis from extravasation of intravenous fluids in children"
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"abstract": "Mixed connective tissue disease (MCTD; also known as Sharp's syndrome) is a rare autoimmune inflammatory disorder characterized by high titer of U1 ribonucleoprotein (U1RNP) antibody and clinical and serological overlap of systemic lupus erythematosus, systemic sclerosis, and polymyositis. The diagnosis is based on clinical and serological factors in criteria such as Alarcon-Segovia, Khan, Kusakawa, and Sharps. Cardiac disease can be a complication of connective tissue disease (CTD). There are few reports in Africa.\nTo present MCTD as underlying cause of heart failure with reduced ejection fraction and highlight challenges of investigations and treatment.\nTo highlight the first case in our center and discuss the cardiac, respiratory, and rheumatologic management.\nWe present a 52-year-old woman with 3 weeks history of productive cough with whitish sputum, severe dyspnea, orthopnea, paroxysmal nocturnal dyspnea, right sided abdominal pain, leg swellings, a one year history of recurrent fever, Raynaud's phenomenon, small joint swellings and deformities with pain in both hands.\nOn examination there was microstomia, tethered forehead and lower eyelid skin, tender swelling of the interphalangeal joints and arthritis mutilans. Laboratory findings showed estimated glomerular filtration rate <60 mL/kg/min/1.73 m2, U1RNP antibody levels were eight times upper limit of normal, elevated rheumatoid factor, speckled antinuclear antibody pattern, negative anticentromere antibody, anti Scl-70 and anticyclic citrullinated peptide. Chest X-ray/CT revealed pulmonary fibrosis. Echocardiography findings showed reduced ejection fraction of 40%, elevated pulmonary arterial pressure at rest of 60.16 mmHg. The patient showed improvement on antifailure drugs, but prednisolone was stopped for sudden reversal of previously controlled stage 2 hypertension (HTN), and the patient was discharged in a stable condition. Difficulties ensued in obtaining prompt definite results due to the unavailability of serologic tests in the hospital, and the tests were done outside the state and country.\nIdentifying MCTD is critical, especially in patients requiring steroids that may worsen systemic HTN and heart failure. There is a need to have definitive investigative facilities for such patients in hospitals.",
"affiliations": "Department of Cardiology, dapo3000@gmail.com.;Department of Cardiology, dapo3000@gmail.com.;Department of Rheumatology.;Department of Rheumatology.;Department of Cardiology, dapo3000@gmail.com.;Department of Cardiology, dapo3000@gmail.com.;Department of Cardiology, dapo3000@gmail.com.;Department of Pulmonology.;Department of Radiology, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun, Nigeria.;Department of Cardiology, dapo3000@gmail.com.;Department of Cardiology, dapo3000@gmail.com.;Department of Cardiology, dapo3000@gmail.com.;Department of Cardiology, dapo3000@gmail.com.;Department of Cardiology, dapo3000@gmail.com.;Department of Cardiology, dapo3000@gmail.com.",
"authors": "Adewuya|Oladapo A|OA|;Adebayo|Rasaaq A|RA|;Ajibade|Adeola I|AI|;Odunlami|Gbenga J|GJ|;Akintomide|Anthony O|AO|;Ogunyemi|Suraj A|SA|;Ajayi|Olufemi E|OE|;Adetiloye|Adebola O|AO|;Omisore|Adeleye D|AD|;Olanipekun|Oladipo A|OA|;Owolabi|Adeyinka O|AO|;Amjo|Ifeoluwa|I|;Akinyele|Olumide A|OA|;Bamgboje|Abayomi O|AO|;Balogun|Michael O|MO|",
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"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S151693imcrj-11-307Case ReportMixed connective tissue disease complicated by heart failure in Ile-Ife, Nigeria: management challenges in a resource-limited economy Adewuya Oladapo A 1Adebayo Rasaaq A 1Ajibade Adeola I 2Odunlami Gbenga J 2Akintomide Anthony O 1Ogunyemi Suraj A 1Ajayi Olufemi E 1Adetiloye Adebola O 3Omisore Adeleye D 4Olanipekun Oladipo A 1Owolabi Adeyinka O 1Amjo Ifeoluwa 1Akinyele Olumide A 1Bamgboje Abayomi O 1Balogun Michael O 1\n1 Department of Cardiology, dapo3000@gmail.com\n2 Department of Rheumatology\n3 Department of Pulmonology\n4 Department of Radiology, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun, NigeriaCorrespondence: Oladapo A Adewuya, Cardiology Unit, Ekiti State University Teaching Hospital (EKSUTH), PMB 5355, Ado-Iworoko Road, Ado Ekiti, Nigeria, Tel +234 803 725 5000, Email dapo3000@gmail.com2018 02 11 2018 11 307 312 © 2018 Adewuya et al. This work is published and licensed by Dove Medical Press Limited2018The 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.Background\nMixed connective tissue disease (MCTD; also known as Sharp’s syndrome) is a rare autoimmune inflammatory disorder characterized by high titer of U1 ribonucleoprotein (U1RNP) antibody and clinical and serological overlap of systemic lupus erythematosus, systemic sclerosis, and polymyositis. The diagnosis is based on clinical and serological factors in criteria such as Alarcon-Segovia, Khan, Kusakawa, and Sharps. Cardiac disease can be a complication of connective tissue disease (CTD). There are few reports in Africa.\n\nAims\nTo present MCTD as underlying cause of heart failure with reduced ejection fraction and highlight challenges of investigations and treatment.\n\nObjectives\nTo highlight the first case in our center and discuss the cardiac, respiratory, and rheumatologic management.\n\nPatient and methods\nWe present a 52-year-old woman with 3 weeks history of productive cough with whitish sputum, severe dyspnea, orthopnea, paroxysmal nocturnal dyspnea, right sided abdominal pain, leg swellings, a one year history of recurrent fever, Raynaud’s phenomenon, small joint swellings and deformities with pain in both hands.\n\nResults\nOn examination there was microstomia, tethered forehead and lower eyelid skin, tender swelling of the interphalangeal joints and arthritis mutilans. Laboratory findings showed estimated glomerular filtration rate <60 mL/kg/min/1.73 m2, U1RNP antibody levels were eight times upper limit of normal, elevated rheumatoid factor, speckled antinuclear antibody pattern, negative anticentromere antibody, anti Scl-70 and anticyclic citrullinated peptide. Chest X-ray/CT revealed pulmonary fibrosis. Echocardiography findings showed reduced ejection fraction of 40%, elevated pulmonary arterial pressure at rest of 60.16 mmHg. The patient showed improvement on antifailure drugs, but prednisolone was stopped for sudden reversal of previously controlled stage 2 hypertension (HTN), and the patient was discharged in a stable condition. Difficulties ensued in obtaining prompt definite results due to the unavailability of serologic tests in the hospital, and the tests were done outside the state and country.\n\nConclusion\nIdentifying MCTD is critical, especially in patients requiring steroids that may worsen systemic HTN and heart failure. There is a need to have definitive investigative facilities for such patients in hospitals.\n\nVideo abstract\n\n\n\nKeywords\nmixed connective tissue disorderU1RNParthritis mutilans PAHHFrEFprednisolone\n==== Body\nIntroduction\nMixed connective tissue disease (MCTD) is a rare systemic autoimmune rheumatic disease mainly diagnosed by clinical and serologic criteria.1–3 There are some common underlying causes of heart failure in our environment, and MCTD is a rare cause of heart failure with unknown reports in Africa.4 We hereby present a case of MCTD complicated by heart failure with the associated management challenges in our resource-limited economic environment. The way we overcame the challenges may be useful for others in similar circumstances in addition to adding information to the local and international databases about MCTD. The prevalence of MCTD in Africa is 0.11%.3\n\nCase\nA 52-year-old woman presented with cough productive of whitish sputum, bilateral leg swelling, facial puffiness, right-sided abdominal pain, and severe difficulty in breathing for over 3 weeks prior to presentation. She is a computer operator and had no prior exposure to occupational lung disease hazards.\n\nThere were high-grade intermittent fevers, chills, rigors, headache, and vomiting on several occasions about a week before presentation.\n\nDifficulty in breathing was insidious at onset, initially on exertion, and progressed to become worse at rest, with paroxysmal nocturnal dyspnea, orthopnea, palpitations, easy fatigability, and early satiety.\n\nThere is a year history of recurrent shoulder, fingers, knee, joint, and muscle pains with swellings, Raynaud’s phenomenon, deformities, and stiffness of the hands. She has been postmenopausal for 7 years and not on hormone replacement therapy. Medical history was unremarkable, and review of systems was essentially normal.\n\nOn examination\nThe blood pressure was 180/110 mmHg in the sitting position and 188/115 mmHg in standing position (stage 2 hypertension [HTN]), pulse rate was 120 beats/minute, respiratory rate was 28 breaths/minute, and temperature was 38°C. The patient suffered from microstomia, tethered forehead skin, lower eyelids, tender swelling of the interphalangeal (IP) joints, arthritis mutilans (la main en lorgnette; Figure 1), and bilateral pitting pedal edema up to the midlegs. There were bronchial breath sounds, coarse crepitations in left lower lung zones, bibasal fine crepitations, thickened arterial wall, locomotor brachialis, raised jugular venous pressure of 10 cm H2O, hyperdynamic precordium, apex beat in the sixth left intercostal space anterior axillary line (LICS AAL) heaving, left parasternal heave, and heart sounds (HS) – 1, 2, 3, and P2>A2. There was a tricuspid regurgitation murmur (pansystolic), enlarged liver 6 cm below the right costal margin, with a span of 14cm, tender, firm and a smooth surface.\n\nLaboratory data revealed a hemoglobin level of 10.0 g/dL, hematocrit of 30%, and white blood cell count of 4,300/mm3 with 72% segmented neutrophils and 28% lymphocytes. Film appearance showed anisocytosis, macrocytosis, microcytosis and was positive for Plasmodium falciparum (malaria parasite). Estimated glomerular filtration rate was <60 mL/kg/min/1.73 m2 and rheumatologic tests are shown in Table 1. Chest X-ray revealed features of pulmonary fibrosis secondary to connective tissue disease (CTD), with features of pulmonary arterial hypertension (PAH) as shown in Figure 2, but no pleural effusions. In Figure 3, chest CT showed basal predominance, mosaic pattern, and thickening of intralobular septae. Hand X-rays (not shown) revealed global periarticular osteopenia and soft tissue swelling over the IP joints, complete resorption of the right second and eighth middle phalanges, left third and fifth phalanges, and crowding of the carpal bones. Liver function tests (LFTs) were within normal limits. Electrocardiography showed a rate of 94 beats/minute, left axis deviation, right atrial enlargement, normal ventricles and T wave inversions >2 mm in multiple leads. Echocardiography revealed a hypokinetic interventricular septum, mild aortic, mitral and tricuspid regurgitation, grade 1 diastolic dysfunction, left ventricular systolic dysfunction, an ejection fraction of 40%, no pericardial effusion and pulmonary arterial pressure of 60.1 mmHg.\n\nTreatment\nOn admission the patient was treated immediately for malaria with an adult dose for patients 35 kg or greater which is artemether+lumefantrine 80/480 mg one tab orally two times daily for 3 days. She was commenced on both oral and intravenous antifailure drugs and antibiotics namely, aldactone 25 mg, lisinopril 5 mg, lasix 60 mg, ramipril 10 mg, digoxin 0.125 mg, warfarin 2.5 mg (goal international normalized ratio, 2–3), clexane 40 IU, augmentin 600 mg intravenous q12h, clarithromycin 500 mg IV q12h, with daily weighing and monitoring of fluid input and output.\n\nTreatment with 20 mg prednisolone orally once daily was started on the 18th day of admission, and joint pains, stiffness, and myalgia gradually improved. Two days after commencement of prednisolone, previously controlled blood pressure from 180/110 mmHg to 130/80 mmHg, increased back to 186/100 mmHg with clinical deteriorations evidenced by worsening dyspnea at rest, orthopnea, and palpitations. Prednisolone was discontinued on 22nd day of admission with resultant reduction in blood pressure to 130/70 mmHg and improvement in clinical status. A provisional diagnosis of acute heart failure precipitated by CTD was made but could not be confirmed due to initial lack of serological results. She was discharged home in a stable condition 25 days after admission and was asked to report after 2 weeks to both Cardiology and Rheumatology clinics for follow-up. Serological tests were eventually done outside the state and country because facilities for the tests were not available within the hospital.\n\nDiscussion\nEven though MCTD has generally a good prognosis, significant cardiac involvement is rare.5 Rheumatoid arthritis, systemic lupus erythematosus (SLE), inflammatory myopathies, systemic sclerosis, and sarcoidosis are among CTDs with severe cardiovascular association; this is due to numerous causative features such as micro/macrovascular disease, myopericarditis, myocardial fibrosis, coronary artery disease, pulmonary hypertension (PH), and finally cardiac failure.6,15 Concentric intimal proliferation and plexogenic pulmonary arteriopathy were described at autopsy as evidence for PH in young females who were diagnosed with MCTD.7 Briasoulis et al8 reported a young woman with new-onset heart failure with features suggesting cardiac tamponade and a related diagnosis of progressive MCTD associated with severe hypothyroidism, and despite prompt recognition and rapid management, she worsened and died within 4 weeks. Although MCTD has been known to be widely associated with PH, the pathogenesis of other cardiovascular manifestations such as left heart failure that could lead to right heart failure is not well understood. Kawano-Dourado et al17 in a study of 39 MCTD patients found that functional and radiologic alterations suggestive of interstitial lung disease in long-term MCTD patients were prevalent. Caminati et al18 mentioned that PH is a well-known outcome of ILDs associated with CTDs.\n\nUndiagnosed HTN overtime, in the setting of an unrecognized MCTD, may lead to left heart failure and, with the concomitant PH, culminated in biventricular failure. Ungprasert et al19 reported that cardiac involvement was common among MCTD patients and was one of the leading causes of mortality. Similarly, Schwagten et al9 described combined systolic and diastolic heart failures as the first presentation of MCTD in a middle-aged female, and Gunnarsson et al16 in a nationwide multicenter cohort of 147 adult MCTD patients found that the prevalence of PH is much lower than expected from previous studies but confirm the seriousness of the disease complication. On the other hand, pulmonary manifestations have been drawing attention as they are found in more than 50% of the patients with MCTD.10 However, PAH and Raynaud’s phenomenon of the small vessels of the heart, similar to that observed in the fingers, are some of the most important cardiac lesions in MCTDs.11 Similarly, Hajas et al12 in a prospective study of 280 patients with MCTD found that overall, PAH remained the leading cause of death in patients with MCTD and that the prevalence of cardiovascular morbidity and mortality, malignancy, and thrombotic events increased during the disease course of MCTD.\n\nWhitlow et al13 described a young black woman with clinical and serologic features of MCTD who developed myocarditis, congestive heart failure, and ventricular ectopic activity with high titer of antibody to U1 ribonucleoprotein (U1RNP). The combination of features is the core of criteria by Sharp,20 Alarcón-Segovia and Villareal,21 and Khan and Appeboom22 in the presence of synovitis. MCTD is diagnosed by these criteria with a focus on a high U1RNP titer: synovitis, PAH, and Raynaud’s phenomenon in patients.2 Among the rheumatic diseases, the diagnosis of well-established rheumatoid arthritis, progressive systemic sclerosis (PSS), dermatomyositis–polymyositis, and SLE is usually obvious, even though some cases display the characteristic of more than one rheumatic disease and are referred to as “overlap” syndromes.\n\nMost of these have the features of two to three rheumatic diseases, such as SLE, PSS, and PM or DM. Sharp20 designated an overlap syndrome of SLE, generalized scleroderma, and PM, which they considered to be a novel class of a “rheumatic disease syndrome dissimilar from the overlap syndromes” and termed it “mixed connective tissue disease”. The discrete feature of this model was the high titer of antibodies to a saline extractable nuclear antigen, which were isolated into ribonucleoprotein found in a lesser number of patients with classical PSS and SLE.7 Patients with MCTD may show a favorable response to corticosteroid therapy and a benign course, but the presence of cardiorespiratory complications may spell a rapid devastating clinical course in patients.\n\nIn our case, a major treatment challenge among others was that the onset of MCTD could not be accurately ascertained, so the temporal relationship between MCTD and cardiac problems was unclear, but as she presented with acute decompensated heart failure, there was prompt management with antifailure drugs with clinical improvement, but with persistence of the rheumatologic manifestations, such as fever, polyarthritis, joint swelling, stiffness, and pain, the patient responded positively, but briefly, to the administration of prednisolone with resulting sudden deterioration in clinical status and impending death, which led to its immediate withdrawal.\n\nAnother treatment challenge was the delay in obtaining prompt serology to confirm the suspected CTD at early stage due to the unavailability of the serologic lab tests in our hospital.\n\nFurthermore, a declining renal status prompted consideration for renal replacement therapy. Immune complex glomerulonephritis with MCTD has often been reported; in addition, MCTD associated with myeloperoxidase-anti- neutrophil cytoplasmic antibody positive polyangiitis occurred in a patient with advanced renal failure, anemia, and pulmonary alveolar hemorrhage and died on the 16th day of admission.14\n\nOn echocardiography, our patient had several myocardial involvements, and Lash et al15 reported a relatively poor prognosis in MCTD patients with primary myocardial involvement as in SLE.\n\nWe believe that our patient benefited from the prompt management of acute heart failure complicating MCTD, but we encountered difficulties in establishing an early link between both entities.\n\nConclusion\nIdentifying MCTD is critical, chiefly in patients requiring glucocorticoids or steroids that may worsen systemic HTN and heart failure. There is a need to have definitive investigative facilities for such patients in hospitals.\n\nEthics approval\nThe ethics and research committee approval was obtained before the commencement of the report.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Arthritis mutilans of both hands.\n\nFigure 2 Posteroanterior view of chest X-ray showing reticular interstitial opacities with coalesced cystic lesions giving honeycomb appearance in both lung fields, decreased left lung field, and prominent pulmonary trunk.\n\nFigure 3 (A) Axial chest CT of the lung window showing reticular opacities, honeycombing, thickening of septae, and ground glass attenuation. (B) Coronal reformatted chest CT of the lung window showing honeycombing with basal predominance worse on the left and mosaic pattern, loss of left lung volume, and ground glass attenuation in the right lower lobe.\n\nAbbreviation: CT, computed tomography.\n\nTable 1 Laboratory results and reference values\n\nLaboratory results\tNormal reference values\t\nAnti-U1 RNP >8.0 U/mL (positive)\t<1 U/mL\t\nRheumatoid factor=396 IU/mL (positive)\t0–20 IU/mL\t\nANA pattern speckled\tN/A\t\nACA=1:<80 (negative)\t1:<80\t\nAnti-Scl-70=0.3 U/mL (negative)\t<0.6 U/mL\t\nAnti-CCP=3.5 U/mL (negative)\t<7.0 U/mL\t\nAbbreviations: ACA, anticentromere antibody; ANA, antibodies against nuclear antigen; Anti-CCP, anticyclic citrullinated peptide; Anti-Scl-70, antibodies against topoisomerase 1; Anti-U1RNP, antibodies to U1 ribonucleoprotein complex; N/A, not applicable.\n==== Refs\nReferences\n1 Martínez-Barrio J Valor L López-Longo FJ Facts and controversies in mixed connective tissue disease Med Clin (Barc) 2018 150 1 26 32 28864092 \n2 Alarcón-Segovia D Cardiel MH Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients J Rheumatol 1989 16 3 328 334 2724251 \n3 Missounga L Ba JI Nseng Nseng Ondo IR Mixed connective tissue disease: prevalence and clinical characteristics in African black, study of 7 cases in Gabon and review of the literature Pan Afr Med J 2017 27 162 28904690 \n4 Adebayo RA Akinwusi PO Balogun MO Two-dimensional and Doppler echocardiographic evaluation of patients presenting at Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria: a prospective study of 2501 subjects Int J Gen Med 2013 6 541 544 23861593 \n5 Lundberg IE Cardiac involvement in autoimmune myositis and mixed connective tissue disease Lupus 2005 14 9 708 712 16218472 \n6 Mavrogeni S Markousis-Mavrogenis G Koutsogeorgopoulou L Kolovou G Cardiovascular magnetic resonance imaging: clinical implications in the evaluation of connective tissue diseases J Inflamm Res 2017 10 55 61 28546762 \n7 Ueda N Mimura K Maeda H Mixed connective tissue disease with fatal pulmonary hypertension and a review of literature Virchows Arch A 1984 404 4 335 340 \n8 Briasoulis A Halpern D Bhatti M Dodell G Herzog E Acute biventricular failure as a sequela of multiple autoimmune disorders Can J Cardiol 2012 28 5 611.e7 e9 \n9 Schwagten B Verheye S Van den Heuvel P Combined systolic and diastolic heart failure as the first presentation of mixed connective tissue disease Acta Cardiol 2007 62 4 421 423 17824306 \n10 Derderian SS Tellis CJ Abbrecht PH Welton RC Rajagopal KR Pulmonary involvement in mixed connective tissue disease Chest 1985 88 1 45 48 4006555 \n11 Tani C Carli L Vagnani S The diagnosis and classification of mixed connective tissue disease J Autoimmun 2014 48–49 46 49 \n12 Hajas A Szodoray P Nakken B Clinical course, prognosis, and causes of death in mixed connective tissue disease J Rheumatol 2013 40 7 1134 1142 23637328 \n13 Whitlow PL Gilliam JN Chubick A Ziff M Myocarditis in mixed connective tissue disease. Association of myocarditis with antibody to nuclear ribonucleoprotein Arthritis Rheum 1980 23 7 808 815 7406932 \n14 Kitaura K Miyagawa T Asano K Mixed connective tissue disease associated with MPO-ANCA-positive polyangiitis Intern Med 2006 45 20 1177 1182 17106166 \n15 Lash AD Wittman AL Quismorio FP Jr Myocarditis in mixed connective tissue disease: clinical and pathologic study of three cases and review of the literature Semin Arthritis Rheum 1986 15 4 288 296 2940685 \n16 Gunnarsson R Andreassen AK Molberg Ø Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian cross-sectional multicentre study and review of current literature Rheumatology (Oxford) 2013 52 7 1208 1213 23407386 \n17 Kawano-Dourado L Baldi BG Kay FU Pulmonary involvement in long-term mixed connective tissue disease: functional trends and image findings after 10 years Clin Exp Rheumatol 2015 33 2 234 240 25896472 \n18 Caminati A Cassandro R Harari S Pulmonary hypertension in chronic interstitial lung diseases Eur Respir Rev 2013 22 129 292 301 23997057 \n19 Ungprasert P Wannarong T Panichsillapakit T Cardiac involvement in mixed connective tissue disease: a systematic review Int J Cardiol 2014 171 3 326 330 24433611 \n20 Sharp GC Diagnostic criteria for classification of MCTD Mixed connective tissue disease and antinuclear antibodies Amsterdam Elsevier 1987 23 32 \n21 Alarcon-Segovia D Villareal M Classification and diagnostic criteria for mixed connective tissue disease Kasukawa R Sharp GC Mixed connective tissue disease and antinuclear antibodies Amsterdam Elsevier 1987 33 40 \n22 Kahn MF Appeboom T Syndrome de Sharp Kahn MF Peltier AP Meyer O Piette JC Les Maladies Systemiques 3rd ed Paris Flammarion 1991 545 556\n\n",
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"keywords": "HFrEF; U1RNP; arthritis mutilans PAH; mixed connective tissue disorder; prednisolone",
"medline_ta": "Int Med Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101566269",
"other_id": null,
"pages": "307-312",
"pmc": null,
"pmid": "30464652",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "22542049;2724251;7406932;2940685;23861593;4006555;28904690;28546762;23407386;17106166;23997057;23637328;24461387;24433611;28864092;25896472;16218472;17824306;6437068",
"title": "Mixed connective tissue disease complicated by heart failure in Ile-Ife, Nigeria: management challenges in a resource-limited economy.",
"title_normalized": "mixed connective tissue disease complicated by heart failure in ile ife nigeria management challenges in a resource limited economy"
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"abstract": "The use of illicit drugs has become a worldwide health problem. Substances with the potential to be abused may have direct or indirect effects on physiologic mechanisms that lead to organ system dysfunction and diseases.\nThe present study aims to investigate the structural and reabsorption integrity of the nephron among Egyptian addicts of tramadol alone and coabused with cannabis.\nSixty-five males were included in the study, they were classified into control group (G1=19), tramadol addicts group (G2=18), and tramadol coabused with cannabis addicts group (G3=28). Parameters investigated for structural integrity were urinary levels ofleucineaminopeptidase and N-acetyl-β-D-glucosaminidase, and urinary parameters for reabsorption integrity were levels of copper and zinc as well as calcium, also urinary creatinine was measured. In addition, urinary levels of tramadol and tetrahydrocannabinol were estimated.\nAmong the two addicted groups, all measured parameters were not significantly different in comparison with the control group except for urinary calcium excretion which was found to be significantly increased among the two addicted groups.\nBoth tramadol addiction alone or coabused with cannabis causes increased urinary excretion of calcium, indicating reabsorption dysfunction of calcium without affecting structural integrity along the nephron.",
"affiliations": "Chemistry Department, Faculty of Education, Ain-Shams University, Heliopolis, Roxy, Cairo, Egypt.;Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt.;Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.;Clinical Pathology Department, El-Demerdash Hospital, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.;Atomic Energy Authority, Nasr City, Cairo, Egypt.;Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt.",
"authors": "El-Safty|Ibrahim|I|;Eltamany|Elsayed|E|;Shouman|Ahmed|A|;El-Gamel|Omayma|O|;Nada|Ahmed|A|;Ali|Wesam|W|",
"chemical_list": "D014147:Tramadol; D003300:Copper; D003404:Creatinine; D015032:Zinc; D002118:Calcium",
"country": "Uganda",
"delete": false,
"doi": "10.4314/ahs.v18i3.35",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1680-6905",
"issue": "18(3)",
"journal": "African health sciences",
"keywords": "Enzymuria; calcium; copper; reabsorption impairment; tubular structural integrity; zinc",
"medline_ta": "Afr Health Sci",
"mesh_terms": "D000328:Adult; D002118:Calcium; D016022:Case-Control Studies; D003300:Copper; D003404:Creatinine; D003430:Cross-Sectional Studies; D004534:Egypt; D006801:Humans; D008297:Male; D002189:Marijuana Abuse; D009293:Opioid-Related Disorders; D014147:Tramadol; D055815:Young Adult; D015032:Zinc",
"nlm_unique_id": "101149451",
"other_id": null,
"pages": "767-775",
"pmc": null,
"pmid": "30603010",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": "10617309;10766935;12372948;12388418;15042540;15280159;1554117;15886461;15892169;16011448;17712819;17928409;18294749;18802367;25878616;26384363;26516462;4091874;9722388",
"title": "Effect of tramadol addiction alone and its co-abuse with cannabis on urinary excretion of Copper, Zinc, and Calcium among Egyptian addicts.",
"title_normalized": "effect of tramadol addiction alone and its co abuse with cannabis on urinary excretion of copper zinc and calcium among egyptian addicts"
} | [
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"companynumb": "EG-JNJFOC-20180914910",
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"activesubstance": {
"activesubstancename": "TRAMADOL HYDROCHLORIDE"
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{
"abstract": "We report, to our best knowledge, the first case of treatment of pupil-occluding postoperative organized hyphema anterior to the intraocular lens (IOL) using neodymium: yttrium-aluminum-garnet (Nd:YAG) laser. A 78-year-old Asian female underwent uneventful cataract operation. She had been taking aspirin, which she discontinued 1 week before surgery. Iris prolapse occurred at the end of the surgery, which led to intracameral bleeding. Two weeks later, her best-corrected visual acuity was hand motion. Although hyphema had decreased, pupil-occluding organized hematoma had formed anterior to the IOL. The blood clot anterior to the IOL was removed using Nd:YAG laser. One week later, although the hematoma anterior to the IOL resolved, endocapsular hematoma was observed, which was dispersed with Nd:YAG laser posterior capsulotomy. Two weeks later, her best-corrected visual acuity improved to 20/60. There was no complication associated with Nd:YAG laser. In conclusion, pupil-occluding organized hyphema anterior to the IOL can occur as a complication of cataract surgery, in which Nd:YAG laser can be a useful treatment option.",
"affiliations": "Department of Ophthalmology, Kangwon National University Hospital, Kangwon National University Graduate School of Medicine, Chuncheon.;Department of Ophthalmology, Kangwon National University Hospital, Kangwon National University Graduate School of Medicine, Chuncheon.;Department of Ophthalmology, Kangwon National University Hospital, Kangwon National University Graduate School of Medicine, Chuncheon.;Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.;Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea.",
"authors": "Kim|Moosang|M|;Lee|Seung-Jun|SJ|;Han|Sang Beom|SB|;Yang|Hee Kyung|HK|;Hyon|Joon Young|JY|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IMCRJ.S110113",
"fulltext": "\n==== Front\nInt Med Case Rep JInt Med Case Rep JInternational Medical Case Reports JournalInternational Medical Case Reports Journal1179-142XDove Medical Press 10.2147/IMCRJ.S110113imcrj-9-183Case ReportPupil-occluding organized hyphema anterior to the intraocular lens treated by neodymium: yttrium-aluminum-garnet laser: a case report Kim Moosang 1Lee Seung-Jun 1Han Sang Beom 1Yang Hee Kyung 2Hyon Joon Young 21 Department of Ophthalmology, Kangwon National University Hospital, Kangwon National University Graduate School of Medicine, Chuncheon2 Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South KoreaCorrespondence: Sang Beom Han, Department of Ophthalmology, Kangwon National University Hospital, 156 Baengnyeong-ro, Chuncheon, Kangwon 200-722, South Korea, Tel +82 33 258 9210, Fax +82 33 258 2296, Email m.sangbeom.han@gmail.com2016 07 7 2016 9 183 185 © 2016 Kim 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.We report, to our best knowledge, the first case of treatment of pupil-occluding postoperative organized hyphema anterior to the intraocular lens (IOL) using neodymium: yttrium-aluminum-garnet (Nd:YAG) laser. A 78-year-old Asian female underwent uneventful cataract operation. She had been taking aspirin, which she discontinued 1 week before surgery. Iris prolapse occurred at the end of the surgery, which led to intracameral bleeding. Two weeks later, her best-corrected visual acuity was hand motion. Although hyphema had decreased, pupil-occluding organized hematoma had formed anterior to the IOL. The blood clot anterior to the IOL was removed using Nd:YAG laser. One week later, although the hematoma anterior to the IOL resolved, endocapsular hematoma was observed, which was dispersed with Nd:YAG laser posterior capsulotomy. Two weeks later, her best-corrected visual acuity improved to 20/60. There was no complication associated with Nd:YAG laser. In conclusion, pupil-occluding organized hyphema anterior to the IOL can occur as a complication of cataract surgery, in which Nd:YAG laser can be a useful treatment option.\n\nKeywords\nblood clotcase reporthyphemaNd:YAG laserpostoperative hyphema\n==== Body\nIntroduction\nIn ophthalmologic practice, neodymium: yttrium-aluminum-garnet (Nd:YAG) laser is mainly applied for treatment of posterior capsular opacity.1 It has also been used for a variety of indications, including peripheral iridotomy,2 anterior vitreolysis,3 anterior capsule relaxing incisions,4 anterior capsulotomy in white intumescent cataracts,5 goniopuncture,6 removal of residual cortex,7 and treatment of endocapsular hematoma.8\n\nHowever, to our best knowledge, the treatment of organized hyphema anterior to intraocular lens (IOL) using Nd:YAG laser has never been reported. Pupil-occluding organized hyphema anterior to the IOL conceivably causes serious vision decrease. However, surgical intervention can often be difficult due to the risk of rebleeding, and other treatment options should be considered. Herein we present a case of successful treatment of pupil-occluding organized hyphema anterior to the IOL by direct application of Nd:YAG laser to the hematoma.\n\nCase presentation\nA 78-year-old Asian female underwent cataract surgery in the right eye (oculus dexter [OD]). Preoperatively, her best-corrected visual acuity (BCVA) was 20/400 OD. She had a history of ischemic heart disease and hypertension and, therefore, was taking aspirin. She discontinued aspirin 1 week preoperatively, and coagulation panels were within normal range. Cataract surgery was performed with topical anesthesia and clear corneal incision, and was uneventful until IOL implantation and removal of viscoelastics. However, she had intraoperative floppy iris syndrome and iris prolapse occurred through the main wound at the conclusion of the surgery, which led to intracameral hemorrhage. Although copious irrigation of the anterior chamber combined with aspiration of the blood clot was done, bleeding was not completely controlled, and eventually, hyphema filled half of the intracameral space. Postoperatively, oral prednisolone (30 mg a day for 3 days) and topical prednisolone acetate (1%, six times a day) were prescribed.\n\nOne week later, her BCVA was hand motion, and intraocular pressure (IOP) measured with Goldmann applanation tonometry (GAT) was 15 mmHg. Although hyphema had decreased, organized hyphema anterior to the IOL had occluded the pupil (Figure 1A). One week later, her BCVA was hand motion, and there was no change in the organized hyphema anterior to the IOL. Using Nd:YAG laser (3.0–4.0 mJ), the organized hemorrhage on the IOL was lysed. One week later, her BCVA was 20/400, and IOP was 15 mmHg by GAT. Hematoma anterior to the IOL was completely absorbed. However, endocapsular hematoma that occluded two-thirds of the pupil was observed (Figure 1B). Nd:YAG laser posterior capsulotomy (1.0–2.0 mJ) was performed to disperse the blood clot from the visual axis. Two weeks later, her BCVA improved to 30/60, and IOP was 14 mmHg by GAT. There was no blood occluding the visual axis, and hyphema was completely absorbed (Figure 1C). There was no hemorrhage in the vitreous cavity. No evidence of corneal endothelial decompensation was observed.\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. As this is a single case report and only retrospective review of medical records was needed, ethics approval was waived by the institutional review board of Kangwon National University Hospital.\n\nDiscussion\nHyphema following cataract surgery is uncommon. Studies showed that phacoemulsification of uncomplicated cataract with IOL implantation with topical anesthesia and clear corneal incision can be safe even in patients taking anticoagulants or antiplatelet drugs.9 However, in conditions that may increase the risk of bleeding, such as small pupil, floppy iris syndrome, iris neovascularization, or pseudoexfoliation or interruption of antiplatelet or anticoagulant therapy, the risk of postoperative hematoma should be considered.9 Although aspirin was stopped and coagulation panels were normal in our patient, inadvertent intracameral hemorrhage occurred associated with iris prolapse. Complete removal of the hemorrhage was impossible, which led to blood collection in the anterior chamber and capsular bag. Although the hemorrhage was partly absorbed, remnant organized hyphema anterior to the IOL occluded the pupil and led to substantial decrease in vision. Endocapsular hematoma also caused occlusion of the visual axis. Secondary operation to wash out the hemorrhage could be a treatment option. However, considering that the patient had a risk for iris prolapse, additional surgical manipulation could exacerbate the hyphema. Conservative management until the hemorrhage is completely absorbed could be another option. However, the organized hyphema anterior to the IOL persisted for 2 weeks, and reduced her vision significantly by occluding the pupil. There was also a possibility that the organized hemorrhage anterior to the IOL had formed a persistent fibrin membrane, necessitating intervention to improve the condition. Eventually, the remaining organized hemorrhage anterior and posterior to the IOL was removed using Nd:YAG laser. We chose lysis of the hematoma anterior to the IOL by direct application of Nd:YAG laser because it can deliver strong energy to a small target without the risk of damage to the adjacent tissue.\n\nAs in the present case, intraoperative hyphema cannot be completely prevented, and in these circumstances, secondary operation may often be difficult due to the risk of rebleeding. Surgical intervention of intracameral hemorrhage can sometimes be dangerous also in patients with increased bleeding tendency, such as hemophilia or liver diseases. In these patients, Nd:YAG laser can be a safe option for vision recovery.\n\nNd:YAG laser was also used for the treatment of postoperative endocapsular hematoma.8 However, in these cases, the laser was used to make posterior capsular opening and to drain the blood to the vitreous cavity, as we did for the treatment of endocapsular hematoma.8 For the treatment of organized hyphema anterior to the IOL, we directly applied the Nd:YAG laser for the lysis of the hematoma, and thus used higher energy compared to the energy level used for posterior capsulotomy.\n\nAlthough Nd:YAG laser posterior capsulotomy is relatively safe, complications including retinal detachment, macular edema, optic disc edema, uveitis, glaucoma, macular hole, and endophthalmitis have been reported.10 In the present case, the energy of the laser was concentrated on the blood clot and the possibility of damage to other tissues was low. However, as relatively stronger energy was used, we believe attention should be paid to the possibility of complications.\n\nConclusion\nIn conclusion, pupil-occluding organized hyphema anterior to the IOL can occur as a complication of cataract surgery, although it may be rare. Direct lysis of the hematoma using Nd:YAG laser can be a useful treatment option in this condition, particularly when surgical intervention is difficult due to the risk of rebleeding.\n\nAuthor contributions\n\nMK carried out data acquisition and drafted the manuscript. SJL interpreted the data and drafted the manuscript. SBH interpreted the data and drafted the manuscript. HKY analyzed the data and critically revised the manuscript. JYH analyzed the data and critically revised the manuscript. All authors read and approved the final manuscript, and agree 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.\n\nDisclosure\n\nThe author reports no conflicts of interest in this work.\n\nFigure 1 Change of the hyphema before and after the laser treatment.\n\nNotes: (A) Anterior segment photography taken 1 week postoperatively, demonstrating organized hyphema anterior to the IOL occluding pupil. (B) Anterior segment photography taken at 1 week after the lysis of organized hyphema anterior to the IOL. Although hematoma anterior to the IOL was absorbed, endocapsular hemorrhage remained. (C) Anterior segment photography taken at 2 weeks after the posterior capsulotomy. Hematoma anterior and posterior to the IOL completely resolved.\n\nAbbreviation: IOL, intraocular lens.\n==== Refs\nReferences\n1 Aslam TM Devlin H Dhillon B Use of Nd:YAG laser capsulotomy Surv Ophthalmol 2003 48 594 612 14609706 \n2 Gilbert CM Robin AL Pollack IP Iridotomy using the Q-switched neodymium (Nd):YAG laser Ophthalmology 1984 91 1123 6548558 \n3 Steinert RF Wasson PJ Neodymium:YAG laser anterior vitreolysis for Irvine-Gass cystoid macular edema J Cataract Refract Surg 1989 15 304 307 2732929 \n4 Hayashi K Yoshida M Nakao F Hayashi H Prevention of anterior capsule contraction by anterior capsule relaxing incisions with neodymium:yttrium-aluminum-garnet laser Am J Ophthalmol 2008 146 23 30 18405874 \n5 Coelho RP Martin LF Paula JS Scott IU Comparison of preoperative Nd:YAG laser anterior capsulotomy versus two-stage curvilinear capsulorhexis in phacoemulsification of white intumescent cataracts Ophthalmic Surg Lasers Imaging 2009 40 582 585 19928724 \n6 Anand N Pilling R Nd:YAG laser goniopuncture after deep sclerectomy: outcomes Acta Ophthalmol 2010 88 110 115 19302078 \n7 Hood CT Shtein RM Mian SI Sugar A Neodymium-yttrium-aluminum-garnet laser lysis of retained cortex after phacoemulsification cataract surgery Am J Ophthalmol 2012 154 808 813 e1 22958858 \n8 Hagan JC 3rd Gaasterland DE Endocapsular hematoma. Description and treatment of a unique form of postoperative hemorrhage Arch Ophthalmol 1991 109 514 518 2012552 \n9 Grzybowski A Ascaso FJ Kupidura-Majewski K Packer M Continuation of anticoagulant and antiplatelet therapy during phacoemulsification cataract surgery Curr Opin Ophthalmol 2015 26 28 33 25390860 \n10 Han SB Yang HK Hyon JY Woo SJ Wee WR Transient optic disc edema following neodymium: yttrium-aluminum-garnet laser posterior capsulotomy Can J Ophthalmol 2012 47 e1 2 22333862\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-142X",
"issue": "9()",
"journal": "International medical case reports journal",
"keywords": "Nd:YAG laser; blood clot; case report; hyphema; postoperative hyphema",
"medline_ta": "Int Med Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101566269",
"other_id": null,
"pages": "183-5",
"pmc": null,
"pmid": "27462181",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "25390860;2012552;22333862;18405874;19928724;2732929;14609706;22958858;6548558;19302078",
"title": "Pupil-occluding organized hyphema anterior to the intraocular lens treated by neodymium: yttrium-aluminum-garnet laser: a case report.",
"title_normalized": "pupil occluding organized hyphema anterior to the intraocular lens treated by neodymium yttrium aluminum garnet laser a case report"
} | [
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"companynumb": "KR-BAYER-2016-153697",
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"abstract": "Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing.\n\n\n\nWe included 122 neonates and infants (0-180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200-300 pg ml-1), medium (400-500 pg ml-1), and high (600-700 pg ml-1) DEX plasma concentrations.\n\n\n\nFive of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8-9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min-1 70 kg-1. Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th-95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml-1.\n\n\n\nWhen used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection.\n\n\n\nNCT01915277.",
"affiliations": "Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.;Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.;Department of Anesthesiology, C.S. Mott Children's Hospital, University of Michigan School of Medicine, Ann Arbor, MI, USA.;Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.;Department of Pediatric Anesthesiology, Perioperative and Pain Medicine, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA.;Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, Bethesda, MD, USA.;Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.;New England Research Institutes, Watertown, MA, USA.;New England Research Institutes, Watertown, MA, USA.;Department of Pediatric Anesthesiology, Perioperative and Pain Medicine, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA.;Department of Pediatric Anesthesiology, Perioperative and Pain Medicine, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA. Electronic address: dra@bcm.edu.",
"authors": "Zuppa|Athena F|AF|;Nicolson|Susan C|SC|;Wilder|Nicole S|NS|;Ibla|Juan C|JC|;Gottlieb|Erin A|EA|;Burns|Kristin M|KM|;Stylianou|Mario|M|;Trachtenberg|Felicia|F|;Ni|Hua|H|;Skeen|Tera H|TH|;Andropoulos|Dean B|DB|;|||",
"chemical_list": "D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine",
"country": "England",
"delete": false,
"doi": "10.1016/j.bja.2019.06.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0912",
"issue": "123(6)",
"journal": "British journal of anaesthesia",
"keywords": "anaesthesia; congenital heart surgery; dexmedetomidine; pharmacokinetics; tetralogy of Fallot; transposition of the great arteries; ventricular septal defect",
"medline_ta": "Br J Anaesth",
"mesh_terms": "D006348:Cardiac Surgical Procedures; D020927:Dexmedetomidine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D006993:Hypnotics and Sedatives; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D008297:Male",
"nlm_unique_id": "0372541",
"other_id": null,
"pages": "839-852",
"pmc": null,
"pmid": "31623840",
"pubdate": "2019-12",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "26612740;26170346;31743171;19708909;9270653;27529322;20003127;26218862;27167685;20613720;18613931;21871284;22772516;25653737;17052852;29516704;17693909;26164712;21033018;7254989;19352168;24646706;23628837;23435789;17680275;17267303;20418300;21087426;22891035;25715046;3609115;17053885;16790625;17437131;21965374;19295456;21326289;9391745;17122572;17328581",
"title": "Results of a phase 1 multicentre investigation of dexmedetomidine bolus and infusion in corrective infant cardiac surgery.",
"title_normalized": "results of a phase 1 multicentre investigation of dexmedetomidine bolus and infusion in corrective infant cardiac surgery"
} | [
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"companynumb": "US-HQ SPECIALTY-US-2019INT000289",
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"activesubstancename": "DEXMEDETOMIDINE HYDROCHLORIDE"
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"abstract": "OBJECTIVE\nTo perform a phase II study evaluating a combination of gemcitabine and cisplatin in a population of patients with squamous cell carcinoma (SCC) of the penis and unresected locoregional lymph nodes and/or distant metastases, who had a poor prognosis with no standard of chemotherapy.\n\n\nMETHODS\nEligible patients had histologically confirmed SCC of the penis with unresected locoregional lymph nodes and/or distant metastases, at initial diagnosis or at relapse, and measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Patients were treated with a combination of gemcitabine 1250 mg/m(2) on day 1 over 30 min and cisplatin 50 mg/m(2) on day 1 over 1 h, every 2 weeks. The primary endpoint was the objective response rate; secondary endpoints were time to progression (TTP) and overall survival (OS).\n\n\nRESULTS\nIn all, 25 patients were included in the first phase of the study between February 2004 and January 2010 and received a median of five cycles. For the intent-to-treat population, two patients (95% confidence interval [CI] 0.98-26.0) presented an objective response and 13 patients (52%) had stable disease (95% CI 35.5-76.8). The median TTP was at 5.48 months (95% CI 2.40-11.73). After a median follow-up of 26.97 months (95% CI 17.77, not reached), nine patients were still alive. The median OS and 2-year OS rate were respectively estimated at 14.98 months (95% CI 9.76-32.9) and 39.32% (95% CI 19.15-59.03). Eleven patients had a serious adverse event (44%), 24% being relied to chemotherapy.\n\n\nCONCLUSIONS\nEvery 2 weeks' administration of the combination of gemcitabine and cisplatin showed non-significant responses in patients with unresected locoregional or metastatic penile SCC. Despite manageable side-effects, this combination cannot be recommended as a standard of care, due to disappointing response rates seen in this negative study. Further regimens should be explored to improve the OS of these patients with poor prognosis.",
"affiliations": "Department of Medical Oncology, Nîmes University Hospital, Nîmes, France.;Department of Medical Oncology, Daniel Hollard Institute, Grenoble, France.;Department of Medical Oncology, Léon Bérard Cancer Centre, Lyon, France.;Department of Medical Oncology, Curie Institute, Paris, France.;Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.;Department of Medical Oncology, Eugène Marquis Cancer Center, Rennes, France.;Department of Medical Oncology, Foch University Hospital, Paris, France.;Department of Medical Oncology, Saint-Louis University Hospital, Paris, France.;Clinical Research and Biostatistic Unit, Claudius Régaud Cancer Institute, Toulouse, France.;Department of Medical Oncology, Claudius Régaud Cancer Institute, Toulouse, France.",
"authors": "Houédé|Nadine|N|;Dupuy|Laura|L|;Fléchon|Aude|A|;Beuzeboc|Philippe|P|;Gravis|Gwenaëlle|G|;Laguerre|Brigitte|B|;Théodore|Christine|C|;Culine|Stéphane|S|;Filleron|Thomas|T|;Chevreau|Christine|C|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1111/bju.13054",
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"issn_linking": "1464-4096",
"issue": "117(3)",
"journal": "BJU international",
"keywords": "gemcitabine and cisplatin combination; penile cancer; squamous cell carcinoma",
"medline_ta": "BJU Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D003841:Deoxycytidine; D006801:Humans; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D010412:Penile Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "100886721",
"other_id": null,
"pages": "444-9",
"pmc": null,
"pmid": "25601543",
"pubdate": "2016-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Intermediate analysis of a phase II trial assessing gemcitabine and cisplatin in locoregional or metastatic penile squamous cell carcinoma.",
"title_normalized": "intermediate analysis of a phase ii trial assessing gemcitabine and cisplatin in locoregional or metastatic penile squamous cell carcinoma"
} | [
{
"companynumb": "FR-CIPLA LTD.-2015FR00976",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMycobacterium bovis is an infrequent cause of central nervous system tuberculosis in Spain, with few cases described in the literature. Since compulsory pasteurization of milk and implementation of eradication programs on infected cattle, human sporadic illness with this organism has dramatically declined in developed countries.\n\n\nMETHODS\nA 71-year-old immunocompromised male, who presented a calvarial lytic lesion. A craniotomy for the total resection of the lesion was performed and the microbiology results were positive for M. bovis, therefore antituberculous therapy was initiated. Despite of the correct treatment, the patient developed a tuberculous abscess that required an aggressive surgical management followed by a suppurative fistula. Based on the treatment of tuberculous lymphadenitis, we decided to perform a conservative management with antituberculous therapy (isoniazid + rifampicin + ethambutol + moxifloxacin + steroids during 12 months) and avoided new surgical cleanings of the surgical bed obtaining a good response and a good clinical evolution.\n\n\nCONCLUSIONS\nAs far as we know, this is the first case reported of a suppurative fistula after the resection of a cerebral abscess caused by M. bovis, therefore, there is no report in the literature about the treatment of this complication.",
"affiliations": "Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.;Hospital Universitario 12 de Octubre, Madrid, España.",
"authors": "Panero|I|I|;San-Juan|R|R|;Eiriz|C|C|;García-Pérez|D|D|;Paredes|I|I|;González|C|C|;Recio|R|R|;Carretero|O|O|;Lagares|A|A|;Gómez|P A|PA|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.33588/rn.6910.2019194",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0210-0010",
"issue": "69(10)",
"journal": "Revista de neurologia",
"keywords": null,
"medline_ta": "Rev Neurol",
"mesh_terms": "D000368:Aged; D001922:Brain Abscess; D005402:Fistula; D006801:Humans; D008297:Male; D009163:Mycobacterium bovis; D011183:Postoperative Complications; D013030:Spain; D020306:Tuberculosis, Central Nervous System",
"nlm_unique_id": "7706841",
"other_id": null,
"pages": "417-422",
"pmc": null,
"pmid": "31713228",
"pubdate": "2019-11-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Uncommon case of Mycobacterium bovis brain abscess complicated by suppurative fistula, and review of the literature.",
"title_normalized": "uncommon case of mycobacterium bovis brain abscess complicated by suppurative fistula and review of the literature"
} | [
{
"companynumb": "ES-STADA-212915",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "A 68-year-old woman presented to our hospital with abdominal fullness. Computed tomography(CT)revealed ascites and massive tumors in the abdominal cavity. She was diagnosed with ascending colon cancer with peritoneal dissemination and ovarian metastasis. After ileostomy, panitumumab plus mFOLFOX6 therapy was initiated, but it was discontinued due to adverse events. As the ascites rapidly increased, her chemotherapy was changed to bevacizumab(BV)plus FOLFIRI. BV combination therapy resulted in a dramatic decrease in ascites and improved her quality of life, whereas the therapy did not reduce the primary and metastatic lesions. Our case suggested that BV could decrease ascites by inhibiting vascular endothelial growth factor(VEGF)-induced vascular permeability.",
"affiliations": "Dept. of Oncology, Shinko Hospital.",
"authors": "Kusama|Toshiyuki|T|;Higashida|Akihiro|A|;Komatsubara|Takashi|T|;Nishigori|Hideaki|H|;Kokado|Yujiro|Y|;Ishii|Masayuki|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(9)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001201:Ascites; D000068258:Bevacizumab; D044682:Colon, Ascending; D003110:Colonic Neoplasms; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D010534:Peritoneal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1119-21",
"pmc": null,
"pmid": "26469173",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A Case of Ascending Colon Cancer Showing Marked Reduction of Ascites by Bevacizumab Combination Chemotherapy.",
"title_normalized": "a case of ascending colon cancer showing marked reduction of ascites by bevacizumab combination chemotherapy"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016RR-113244",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEUCOVORIN CALCIUM"
},
... |
{
"abstract": "Antitubercular therapy (ATT)-induced hepatotoxicity is often over looked and active tuberculosis is considered a contraindication for liver transplantation, however it might be the only lifesaving option to certain patients of acute liver failure (ALF) due to ATT. We have assessed the outcome of live donor liver transplantation in ATT-induced ALF. A retrospective analysis of all the cases of ALF that underwent liver transplantation from 2006 to 2014 at the Amrita Institute of Medical Sciences was done. A total of seven (7.7%) patients with ATT-induced ALF who had underwent live donor liver transplantation were included in the study. Out of seven patients, three (42.8%) had established diagnosis of tuberculosis and the remaining (58.2%) patients were started on ATT empirically. The median duration of ATT intake was 2 months. All the patients underwent live donor liver transplant as they met King's College criteria, and their model for end-stage liver disease score was above 35 on admission, receiving graft from first degree relatives. Histopathology of explant liver showed pan acinar necrosis. Restarting of ATT after transplant was individualized. It was restarted only in two (28%) patients with prior sputum-positive pulmonary tuberculosis after a median time of 27 days after transplant. ATT was not restarted in rest of the (72%) patients. Postoperative mortality was seen in two (28%) patients due to conditions that masquerade the ATT-induced acute liver failure. The overall survival rate was 71.4% with a median follow up of 22 months. Live donor-related transplantation is feasible option in ATT-induced acute liver failure. Restarting of ATT post liver transplant is feasible and should be individualized along with frequent monitoring of immunosuppressant levels; however, if the primary diagnosis of tuberculosis was empirical, reintroduction of ATT can be omitted.",
"affiliations": "Department of Gastrointestinal and Multiviceral Transplant Surgery, Amrita Institute of Medical Sciences and Research Centre, Ponnekkara, Kochi, 572 101, India. akshaysge@gmail.com.;Department of Gastrointestinal and Multiviceral Transplant Surgery, Amrita Institute of Medical Sciences and Research Centre, Ponnekkara, Kochi, 572 101, India.;Department of Gastrointestinal and Multiviceral Transplant Surgery, Amrita Institute of Medical Sciences and Research Centre, Ponnekkara, Kochi, 572 101, India.;Department of Gastrointestinal and Multiviceral Transplant Surgery, Amrita Institute of Medical Sciences and Research Centre, Ponnekkara, Kochi, 572 101, India.;Department of Gastrointestinal and Multiviceral Transplant Surgery, Amrita Institute of Medical Sciences and Research Centre, Ponnekkara, Kochi, 572 101, India.;Department of Gastrointestinal and Multiviceral Transplant Surgery, Amrita Institute of Medical Sciences and Research Centre, Ponnekkara, Kochi, 572 101, India.;Department of Gastrointestinal and Multiviceral Transplant Surgery, Amrita Institute of Medical Sciences and Research Centre, Ponnekkara, Kochi, 572 101, India.",
"authors": "Bavikatte|Akshay P|AP|;Sudhindran|S|S|;Dhar|Puneet|P|;Sudheer|O V|OV|;Unnikrishnan|G|G|;Balakrishnan|Dinesh|D|;Menon|Ramachandran N|RN|",
"chemical_list": "D000995:Antitubercular Agents; D007166:Immunosuppressive Agents",
"country": "India",
"delete": false,
"doi": "10.1007/s12664-016-0725-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0254-8860",
"issue": "36(1)",
"journal": "Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology",
"keywords": "Acute liver failure; Antitubercular therapy; Live donor liver transplantation",
"medline_ta": "Indian J Gastroenterol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents; D002648:Child; D002675:Child, Preschool; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D017114:Liver Failure, Acute; D008111:Liver Function Tests; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008991:Monitoring, Physiologic; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8409436",
"other_id": null,
"pages": "56-61",
"pmc": null,
"pmid": "28066854",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": "19642133;20156055;22868013;11870389;18720535;22332331;20196116;26927985;10653382;15841455;15390328;9827281;20879012",
"title": "Live donor liver transplantation for antitubercular drug-induced acute liver failure.",
"title_normalized": "live donor liver transplantation for antitubercular drug induced acute liver failure"
} | [
{
"companynumb": "PHHY2017IN159155",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PYRAZINAMIDE"
},
"drugadditional": null,
"dr... |
{
"abstract": "This case series is to create awareness among clinicians on the importance of Hepatitis B screening prior to administration of chemotherapeutic agents and immunosuppressant in preventing Hepatitis B reactivation (HBVr). We also highlight the importance of identifying patients who are at risk of HBVr and when to initiate antiviral prophylaxis based on the current evidence-based guidelines. The case series consists of four patients seen in Hospital Selayang, Malaysia who developed fulminant liver failure secondary to chemotherapeutic agents or immunosuppressant induced HBVr. HBVr is likely to be of increasing clinical significance as potent immunosuppressive regimens are used more widely across all medical specialties. Clinicians should be made aware of the potential risk of patients developing fulminant liver failure following HBVr and its association with high morbidity and mortality. In the era of inexpensive Hepatitis B blood screening tests and safe potent antivirals, there is now a paradigm shift to make the test compulsory to screen all patient prior to initiation of chemotherapeutic agents or immunosuppressive therapy. Antiviral prophylaxis may be offered to more patients who are at risk of HBVr and the duration of both prophylaxis and subsequent monitoring may be extended until 6 to 18 months following completion of treatment.",
"affiliations": "Hospital Selayang, Acute Internal Medicine, Malaysia. huda.adznan@gmail.com.;Hospital Selayang, Department of Hepatology, Malaysia.",
"authors": "Nida' Ul-Huda|A|A|;Haniza|O|O|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents",
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-5283",
"issue": "76(5)",
"journal": "The Medical journal of Malaysia",
"keywords": null,
"medline_ta": "Med J Malaysia",
"mesh_terms": "D000998:Antiviral Agents; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D007166:Immunosuppressive Agents; D014775:Virus Activation",
"nlm_unique_id": "0361547",
"other_id": null,
"pages": "719-724",
"pmc": null,
"pmid": "34508381",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Lessons learned from chemotherapeutic and immunosuppressant induced Hepatitis B reactivation - a case series.",
"title_normalized": "lessons learned from chemotherapeutic and immunosuppressant induced hepatitis b reactivation a case series"
} | [
{
"companynumb": "MY-PFIZER INC-202101419552",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "Amniotic fluid embolism (AFE) continues to be a rare, enigmatic condition with high maternal mortality. It is characterized by cardiovascular compromise, loss of consciousness or other neurologic symptoms, and coagulopathy. The latter is usually treated according to existing protocols for consumptive coagulopathy.\n\n\n\nSerial analyses of a panel of hemostaseological parameters were performed in three consecutive cases of AFE that occurred at our institution.\n\n\n\nAll mothers and neonates survived without major sequelae. Disproportionately low levels of fibrinogen and factor five, and exorbitantly elevated D-dimers were present in all cases, whereas markers of consumptive coagulopathy, platelets and antithrombin in particular, were only slightly reduced.\n\n\n\nOur results support hyperfibrinolysis as contributing factor of AFE-associated coagulopathy. We, therefore, propose a treatment algorithm which includes early use of tranexamic acid and transfusion of red blood cells and fresh frozen plasma, adding fibrinogen if hemostasis is not readily achieved.",
"affiliations": "Department of Obstetrics and Gynecology, Medical Faculty, University Hospital Cologne, Kerpener Straße 34, 50931, Cologne, Germany. lars_schroed@gmx.net.;Department of Obstetrics and Prenatal Medicine, University Bonn Medical School, Bonn, Germany.;Department of Obstetrics and Prenatal Medicine, University Bonn Medical School, Bonn, Germany.;Department of Obstetrics and Prenatal Medicine, University Bonn Medical School, Bonn, Germany.",
"authors": "Schröder|Lars|L|http://orcid.org/0000-0001-6908-989X;Hellmund|Astrid|A|;Gembruch|Ulrich|U|;Merz|Waltraut Maria|WM|",
"chemical_list": "D015415:Biomarkers",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00404-020-05466-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0932-0067",
"issue": "301(4)",
"journal": "Archives of gynecology and obstetrics",
"keywords": "Amniotic fluid embolism; Critical care; Disseminated intravascular coagulation; Fibrinolysis; Maternal mortality; Pregnancy; Tranexamic acid",
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D000328:Adult; D015415:Biomarkers; D004619:Embolism, Amniotic Fluid; D005260:Female; D006801:Humans; D011247:Pregnancy",
"nlm_unique_id": "8710213",
"other_id": null,
"pages": "923-929",
"pmc": null,
"pmid": "32157417",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21504838",
"title": "Amniotic fluid embolism-associated coagulopathy: a single-center observational study.",
"title_normalized": "amniotic fluid embolism associated coagulopathy a single center observational study"
} | [
{
"companynumb": "DE-MYLANLABS-2020M1043583",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Neuropathic pain is a common and difficult to manage public health problem characterized by frequent treatment failure and high management costs. The variable presentation and response to treatment among patients make it difficult for physicians to apply a single, standardized approach for management. The physician's role in treating neuropathic pain is complex. Clinical decisions must be drawn from personal and shared experience, case reports, and evidence-based, controlled trials performed on selected populations of patients with common, narrowly-defined conditions. Recent advances in our understanding of the mechanisms that underlie the processing of nociceptive stimuli and the perception of pain have led to the increased 'off-label use' of adjuvant medications in an attempt to provide relief for many patients who heretofore have suffered unnecessarily with intractable neuropathic pain. Unfortunately, as with any treatment, sound clinical decisions can occasionally result in an untoward adverse response. It is therefore imperative that potential adverse effects inherent to all medications be considered and weighed against the untoward consequences of withholding treatment prior to incorporating their use in any course of management. This commentary presents a case report that illustrates a particularly devastating consequence that was encountered when a medication was selected for 'off-label use' in the treatment of intractable pain and presents an opinion for consideration in developing guidelines for determining acceptable risk and standard of care based upon rational adherence or deviation from the approved indications offered for the use of a medication at the time of its introduction into practice is granted.",
"affiliations": "Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, LA, United States.;Department of Internal Medicine, Section of Physical Medicine and Rehabilitation, United States.;Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, LA, United States; Department of Internal Medicine, Section of Physical Medicine and Rehabilitation, United States; Department of Anesthesiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States; Department of Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States; Center of Excellence for Oral and Craniofacial Biology, Louisiana State University Health Sciences Center, New Orleans, LA, United States; Pain Mastery Center of Louisiana, Louisiana State University Health Sciences Center, New Orleans, LA, United States. Electronic address: hgould@lsuhsc.edu.",
"authors": "Khursheed|Faraz|F|;Ioffe|Julia|J|;Gould|Harry J|HJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-510X",
"issue": "349(1-2)",
"journal": "Journal of the neurological sciences",
"keywords": "Adjuvant medications; Malpractice; Neuropathic pain; Off-label prescribing; Physicians' Desk Reference; Shared responsibility",
"medline_ta": "J Neurol Sci",
"mesh_terms": "D000328:Adult; D019468:Disease Management; D005260:Female; D006801:Humans; D055118:Medication Adherence; D009437:Neuralgia; D056687:Off-Label Use; D010818:Practice Patterns, Physicians'; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0375403",
"other_id": null,
"pages": "72-6",
"pmc": null,
"pmid": "25579412",
"pubdate": "2015-02-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A plea for rational mitigation of poor outcomes in the 'off-label use' of medications for the management of pain.",
"title_normalized": "a plea for rational mitigation of poor outcomes in the off label use of medications for the management of pain"
} | [
{
"companynumb": "PHHY2015US033360",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nWe report the first teenage case of ketamine-induced transient central diabetes insipidus.\n\n\nMETHODS\nThe patient was an 18-year-old woman with moyamoya disease undergoing an external carotid to internal carotid bypass and given a low-dose ketamine infusion. After approximately 2 hours in the supine position, with 0.5 Minimum Alveolar Concentration (MAC) of sevoflurane, a propofol infusion at 50 μg/kg/min, a remifentanil infusion at 0.5 μg/kg/min, and a ketamine infusion at a dose of 10 μg/kg/min, this patient had an excessive urine output. Initially, the Foley catheter contained 50 mL of urine. She was given 1500 mL of crystalloid during the case but produced 2700 mL of urine output. Increasing urine output was noted 1 hour into the procedure around the time that the patient experienced a 2-minute Cushing-like response characterized by bradycardia and hypertension. Several I-Stat samples revealed a worsening hypernatremia. The decision was made to check the urine osmolality and treat the patient with 4 μg of desmopressin (DDAVP). Urine output began to slow down to a normal rate of 2 mg/kg/h, as the patient was transferred from the operating room to the computed tomographic (CT) scanning room for a CT and CT angiogram; both were unremarkable. The neurosurgery team waited until the next day to complete the procedure. The procedure was completed successfully and uneventfully the next day without a ketamine infusion as part of the general anesthetic plan.\n\n\nCONCLUSIONS\nThe Naranjo Adverse Drug Reaction score of 4 suggested a possible relationship between the patient's ketamine infusion and subsequent central diabetes insipidus. The 2 previous cases on this topic have suggested that ketamine, as an N-methyl-d-aspartate receptor antagonist, inhibits vasopressin release in the neurohypophysis.\n\n\nCONCLUSIONS\nUrine output, urine osmolarity, and serum osmolarity should be monitored in patients given ketamine anesthetic; desmopressin should be present to prevent dangerous long-term sequela.",
"affiliations": "Department of Anesthesiology, Tulane Medical Center, New Orleans, LA, USA. Electronic address: sgaffar@tulane.edu.;Department of Anesthesiology, Tulane Medical Center, New Orleans, LA, USA.;Department of Anesthesiology, Tulane Medical Center, New Orleans, LA, USA.;Department of Anesthesiology, Tulane Medical Center, New Orleans, LA, USA.;Department of Neurosurgery, Tulane Medical Center, New Orleans, LA, USA.;Department of Anesthesiology, Tulane Medical Center, New Orleans, LA, USA.",
"authors": "Gaffar|Sharib|S|;Eskander|Jonathan P|JP|;Beakley|Burton D|BD|;McClure|Brian P|BP|;Amenta|Peter|P|;Pierre|Nakeisha|N|",
"chemical_list": "D000778:Anesthetics, Dissociative; D007649:Ketamine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jclinane.2016.09.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0952-8180",
"issue": "36()",
"journal": "Journal of clinical anesthesia",
"keywords": "Central diabetes insipidus; DI; EC to IC bypass; Intracranial pressure; Ketamine; Moyamoya",
"medline_ta": "J Clin Anesth",
"mesh_terms": "D000293:Adolescent; D000714:Anastomosis, Surgical; D000778:Anesthetics, Dissociative; D002342:Carotid Artery, External; D002343:Carotid Artery, Internal; D020790:Diabetes Insipidus, Neurogenic; D005260:Female; D006801:Humans; D007431:Intraoperative Complications; D007649:Ketamine; D009072:Moyamoya Disease; D014556:Urine",
"nlm_unique_id": "8812166",
"other_id": null,
"pages": "72-75",
"pmc": null,
"pmid": "28183578",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of central diabetes insipidus after ketamine infusion during an external to internal carotid artery bypass.",
"title_normalized": "a case of central diabetes insipidus after ketamine infusion during an external to internal carotid artery bypass"
} | [
{
"companynumb": "US-PFIZER INC-2016571405",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "KETAMINE HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nThe 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides defined drug-associated immune complex vasculitis as a distinct entity included within the category of vasculitis associated with probable etiology. In the present study we assessed the clinical spectrum of patients with drug-associated cutaneous vasculitis (DACV).\n\n\nMETHODS\nCase records were reviewed of patients with DACV treated at a tertiary referral hospital over a 36-year period. A diagnosis of DACV was considered if the drug was taken within a week before the onset of the disease.\n\n\nRESULTS\nFrom a series of 773 unselected cutaneous vasculitis cases, 239 patients (30.9%; 133 men and 106 women; mean age 36 yrs) were diagnosed with DACV. Antibiotics (n=149; 62.3%), mainly β-lactams and nonsteroidal antiinflammatory drugs (NSAID; n=24; 10%) were the most common drugs. Besides skin lesions (100%), the most common clinical features were joint (51%) and gastrointestinal (38.1%) manifestations, nephropathy (34.7%), and fever (23.8%). The most remarkable laboratory data were increased erythrocyte sedimentation rate (40.2%), presence of serum cryoglobulins (26%), leukocytosis (24.7%), positive antinuclear antibodies (21.1%), anemia (18.8%), and positive rheumatoid factor (17.5%). Despite drug discontinuation and bed rest, 108 patients (45.2%) required medical treatment, mainly corticosteroids (n=71) or immunosuppressive drugs (n=7). After a median followup of 5 months, relapses occurred in 18.4% of patients, and persistent microhematuria or renal insufficiency in 3.3% and 5%, respectively.\n\n\nCONCLUSIONS\nDACV is generally associated with antibiotics and NSAID. In most cases it has a favorable prognosis, although a small percentage of patients may develop residual renal damage.",
"affiliations": "From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla.;From the Divisions of Rheumatology, Internal Medicine, Pathology, and Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.F. Ortiz-Sanjuán, MD; R. Blanco, MD, PhD; T. Pina, MD; V. Calvo-Río, MD; J. Loricera, MD; J. Rueda-Gotor, MD; M.A. González-Gay, MD, PhD, Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, University of Cantabria; J.L. Hernández, MD, PhD, División of Internal Medicine, Hospital Universitario Marqués de Valdecilla, University of Cantabria; M.C. González-Vela, MD, PhD, Division of Pathology, Hospital Universitario Marqués de Valdecilla; H. Fernández-Llaca, MD; S. Armesto, MD, PhD; M.A. González-López, MD, PhD, División of Dermatology, Hospital Universitario Marqués de Valdecilla. miguelaggay@hotmail.com.",
"authors": "Ortiz-Sanjuán|Francisco|F|;Blanco|Ricardo|R|;Hernández|José L|JL|;Pina|Trinitario|T|;González-Vela|María C|MC|;Fernández-Llaca|Héctor|H|;Calvo-Río|Vanesa|V|;Loricera|Javier|J|;Armesto|Susana|S|;González-López|Marcos A|MA|;Rueda-Gotor|Javier|J|;González-Gay|Miguel A|MA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.140390",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "41(11)",
"journal": "The Journal of rheumatology",
"keywords": "CUTANEOUS VASCULITIS; DRUG-ASSOCIATED VASCULITIS; DRUGS; HYPERSENSITIVITY VASCULITIS; PALPABLE PURPURA",
"medline_ta": "J Rheumatol",
"mesh_terms": "D000328:Adult; D017677:Age Distribution; D000368:Aged; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001707:Biopsy, Needle; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012017:Referral and Consultation; D012189:Retrospective Studies; D012720:Severity of Illness Index; D017678:Sex Distribution; D018709:Statistics, Nonparametric; D062606:Tertiary Care Centers; D014657:Vasculitis; D055815:Young Adult",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "2201-7",
"pmc": null,
"pmid": "25225278",
"pubdate": "2014-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Drug-associated cutaneous vasculitis: study of 239 patients from a single referral center.",
"title_normalized": "drug associated cutaneous vasculitis study of 239 patients from a single referral center"
} | [
{
"companynumb": "ES-JNJFOC-20150308230",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nThe innate immune system is profoundly dysregulated in paracetamol (acetaminophen)-induced liver injury. The neutrophil-lymphocyte ratio (NLR) is a simple bedside index with prognostic value in a number of inflammatory conditions.\n\n\nOBJECTIVE\nTo evaluate the prognostic accuracy of the NLR in patients with significant liver injury following single time-point and staggered paracetamol overdoses.\n\n\nMETHODS\nTime-course analysis of 100 single time-point and 50 staggered paracetamol overdoses admitted to a tertiary liver centre. Timed laboratory samples were correlated with time elapsed after overdose or admission, respectively, and the NLR was calculated.\n\n\nRESULTS\nA total of 49/100 single time-point patients developed hepatic encephalopathy (HE). Median NLRs were higher at both 72 (P=0.0047) and 96 h after overdose (P=0.0041) in single time-point patients who died or were transplanted. Maximum NLR values by 96 h were associated with increasing HE grade (P=0.0005). An NLR of more than 16.7 during the first 96 h following overdose was independently associated with the development of HE [odds ratio 5.65 (95% confidence interval 1.67-19.13), P=0.005]. Maximum NLR values by 96 h were strongly associated with the requirement for intracranial pressure monitoring (P<0.0001), renal replacement therapy (P=0.0002) and inotropic support (P=0.0005). In contrast, in the staggered overdose cohort, the NLR was not associated with adverse outcomes or death/transplantation either at admission or subsequently.\n\n\nCONCLUSIONS\nThe NLR is a simple test which is strongly associated with adverse outcomes following single time-point, but not staggered, paracetamol overdoses. Future studies should assess the value of incorporating the NLR into existing prognostic and triage indices of single time-point paracetamol overdose.",
"affiliations": "aGastroenterology Department, The James Cook University Hospital, Middlesbrough bDivision of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.",
"authors": "Craig|Darren G|DG|;Kitto|Laura|L|;Zafar|Sara|S|;Reid|Thomas W D J|TW|;Martin|Kirsty G|KG|;Davidson|Janice S|JS|;Hayes|Peter C|PC|;Simpson|Kenneth J|KJ|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000157",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "26(9)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D056486:Chemical and Drug Induced Liver Injury; D062787:Drug Overdose; D005260:Female; D006501:Hepatic Encephalopathy; D006801:Humans; D007958:Leukocyte Count; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008214:Lymphocytes; D008297:Male; D009504:Neutrophils; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D018746:Systemic Inflammatory Response Syndrome; D014218:Triage",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "1022-9",
"pmc": null,
"pmid": "25045842",
"pubdate": "2014-09",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "An elevated neutrophil-lymphocyte ratio is associated with adverse outcomes following single time-point paracetamol (acetaminophen) overdose: a time-course analysis.",
"title_normalized": "an elevated neutrophil lymphocyte ratio is associated with adverse outcomes following single time point paracetamol acetaminophen overdose a time course analysis"
} | [
{
"companynumb": "GB-JNJFOC-20140804761",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "Objective Gastric endoscopic submucosal dissection (ESD) under heparin replacement (HR) of warfarin reportedly has a high risk of delayed bleeding (24-57%). It is possible that the delayed bleeding risk may have changed over the years. We evaluated the current risk of delayed bleeding after gastric ESD under HR of anticoagulant agents. Methods We retrospectively reviewed the delayed bleeding rate and analyzed the risk factors for delayed bleeding. Patients Consecutive patients who underwent gastric ESD under HR of anticoagulant agents from July 2015 to June 2017. Results A total of 32 patients with a solitary early gastric cancer and taking anticoagulant agents were analyzed, including 24 patients on warfarin (the warfarin group) and 8 patients on direct oral anticoagulants (the DOAC group). Three (9.4%) patients experienced delayed bleeding: three (12.5%) patients in the warfarin group and no patients in the DOAC group. Continued aspirin treatment was identified to be a risk factor of delayed bleeding (p=0.01). Conclusion Careful management may be required for patients undergoing gastric ESD under continued aspirin treatment in addition to HR of anticoagulant agents; although the delayed bleeding risk after gastric ESD under HR of anticoagulant agents might have decreased over the years.",
"affiliations": "Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Gastroenterology, Japanese Red Cross Okayama Hospital, Japan.;Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan.;Department of Gastroenterology, Mitoyo General Hospital, Japan.;Department of Internal Medicine, Hiroshima City Hospital, Japan.;Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center, Japan.;Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, Japan.;Department of Internal Medicine, Saiseikai Imabari Hospital, Japan.;Department of Internal Medicine, Sumitomo Besshi Hospital, Japan.;Department of Gastroenterology, Kagawa Prefectural Central Hospital, Japan.;Department of Internal Medicine, Okayama City Hospital, Japan.;Department of Internal Medicine, Tsuyama Chuo Hospital, Japan.;Department of Internal Medicine, Akaiwa Medical Association Hospital, Japan.;Department of Endoscopy, National Hospital Organization Shikoku Cancer Center, Japan.;Department of Internal Medicine, Fukuyama City Hospital, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Endoscopy, Okayama University Hospital, Japan.;Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Japan.;Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.",
"authors": "Hamada|Kenta|K|;Kanzaki|Hiromitsu|H|;Inoue|Masafumi|M|;Ishiyama|Shuhei|S|;Yamauchi|Kenji|K|;Miyahara|Koji|K|;Toyokawa|Tatsuya|T|;Tsuzuki|Takao|T|;Miyaike|Jiro|J|;Matsubara|Minoru|M|;Takahashi|Sakuma|S|;Nishimura|Mamoru|M|;Takenaka|Ryuta|R|;Yunoki|Naoko|N|;Hori|Shinichiro|S|;Kobayashi|Sayo|S|;Yamasaki|Yasushi|Y|;Kawahara|Yoshiro|Y|;Ishikawa|Hideki|H|;Okada|Hiroyuki|H|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D006493:Heparin; D001241:Aspirin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.4998-20",
"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918 1349-7235 The Japanese Society of Internal Medicine \n\n32641658\n10.2169/internalmedicine.4998-20\nOriginal Article\nContinued Aspirin Treatment May Be a Risk Factor of Delayed Bleeding after Gastric Endoscopic Submucosal Dissection under Heparin Replacement: A Retrospective Multicenter Study\nHamada Kenta 1 Kanzaki Hiromitsu 1 Inoue Masafumi 2 Ishiyama Shuhei 3 Yamauchi Kenji 4 Miyahara Koji 5 Toyokawa Tatsuya 6 Tsuzuki Takao 7 Miyaike Jiro 8 Matsubara Minoru 9 Takahashi Sakuma 10 Nishimura Mamoru 11 Takenaka Ryuta 12 Yunoki Naoko 13 Hori Shinichiro 14 Kobayashi Sayo 15 Yamasaki Yasushi 1 Kawahara Yoshiro 16 Ishikawa Hideki 17 Okada Hiroyuki 1 \n1 Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan\n\n2 Department of Gastroenterology, Japanese Red Cross Okayama Hospital, Japan\n\n3 Department of Internal Medicine, Okayama Saiseikai General Hospital, Japan\n\n4 Department of Gastroenterology, Mitoyo General Hospital, Japan\n\n5 Department of Internal Medicine, Hiroshima City Hospital, Japan\n\n6 Department of Gastroenterology, National Hospital Organization Fukuyama Medical Center, Japan\n\n7 Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, Japan\n\n8 Department of Internal Medicine, Saiseikai Imabari Hospital, Japan\n\n9 Department of Internal Medicine, Sumitomo Besshi Hospital, Japan\n\n10 Department of Gastroenterology, Kagawa Prefectural Central Hospital, Japan\n\n11 Department of Internal Medicine, Okayama City Hospital, Japan\n\n12 Department of Internal Medicine, Tsuyama Chuo Hospital, Japan\n\n13 Department of Internal Medicine, Akaiwa Medical Association Hospital, Japan\n\n14 Department of Endoscopy, National Hospital Organization Shikoku Cancer Center, Japan\n\n15 Department of Internal Medicine, Fukuyama City Hospital, Japan\n\n16 Department of Endoscopy, Okayama University Hospital, Japan\n\n17 Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Japan\nCorrespondence to Dr. Kenta Hamada, paosishou@yahoo.co.jp\n\n\n7 7 2020 \n1 11 2020 \n59 21 2643 2651\n1 4 2020 18 5 2020 Copyright © 2020 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Objective \nGastric endoscopic submucosal dissection (ESD) under heparin replacement (HR) of warfarin reportedly has a high risk of delayed bleeding (24-57%). It is possible that the delayed bleeding risk may have changed over the years. We evaluated the current risk of delayed bleeding after gastric ESD under HR of anticoagulant agents. \n\nMethods \nWe retrospectively reviewed the delayed bleeding rate and analyzed the risk factors for delayed bleeding. \n\nPatients \nConsecutive patients who underwent gastric ESD under HR of anticoagulant agents from July 2015 to June 2017. \n\nResults \nA total of 32 patients with a solitary early gastric cancer and taking anticoagulant agents were analyzed, including 24 patients on warfarin (the warfarin group) and 8 patients on direct oral anticoagulants (the DOAC group). Three (9.4%) patients experienced delayed bleeding: three (12.5%) patients in the warfarin group and no patients in the DOAC group. Continued aspirin treatment was identified to be a risk factor of delayed bleeding (p=0.01). \n\nConclusion \nCareful management may be required for patients undergoing gastric ESD under continued aspirin treatment in addition to HR of anticoagulant agents; although the delayed bleeding risk after gastric ESD under HR of anticoagulant agents might have decreased over the years. \n\nanticoagulant agentbleedingendoscopic submucosal dissectiongastric cancerheparin replacementwarfarin\n==== Body\nIntroduction\nPatients with valvular heart disease or atrial fibrillation (AF) with a high CHADS2 or CHA2DS2-VASc score have a high risk of developing thromboembolic diseases (1). Anticoagulant agents are generally recommended for the primary and secondary prevention of such diseases. For the thromboembolic complications associated with warfarin withdrawal in gastroenterological endoscopic procedures, the incidence of stroke was reported in 1.06% of patients (2). The Japan Gastroenterological Endoscopy Society (JGES) guidelines (2012) (3), the British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines (2016) (4), and the American Society for Gastrointestinal Endoscopy (ASGE) guidelines (2016) (5) recommend that patients using warfarin should be treated under heparin replacement (HR) as a bridge therapy to reduce the risk of thromboembolic complications during the perioperative period of therapeutic endoscopy. However, several investigators have reported that gastric endoscopic submucosal dissection (ESD) under HR of warfarin has a high risk of delayed bleeding (24-57%) (6-8). Based on these reports, the JGES guidelines were revised in 2017 (9), which allow for continued warfarin treatment in patients where the prothrombin time international normalized ratio (PT-INR) fell within the therapeutic range, or a temporary switch to direct oral anticoagulant (DOAC) in those with non-valvular atrial fibrillation as an alternative to HR. However, since these studies were small and included old data (6-8), the delayed bleeding risk after gastric ESD under HR might have changed over the years. We therefore planned a retrospective multi-center study to evaluate the current risk of delayed bleeding after gastric ESD under HR of anticoagulant agents, by analyzing data collected during a few years prior to the revision of the JGES guidelines.\n\nMaterials and Methods\nParticipants\nThis was a retrospective, multi-center study conducted at 15 institutes (Okayama Gut Study Group) in Japan, comprising 1 university hospital, 1 cancer center and 13 general hospitals. To determine the study period, a preliminary questionnaire survey was conducted. Based on the survey, as a study group, >50 cases with anticoagulant agents underwent gastric ESD every year. Therefore, the study period was determined for 2 years as >100 cases were expected to be included. The records for all patients who underwent ESD for adenocarcinomas or suspected adenocarcinomas of the stomach from July 2015 to June 2017 were extracted from the database and reviewed. The inclusion and exclusion criteria were determined prior to the data collection. Patients were included if they met the following criteria: (i) under anticoagulant therapy using warfarin or DOAC, (ii) aged 20 years or older, (iii) Eastern Cooperative Oncology Group performance status of 0-2, (iv) hemoglobin ≥9 g/dL, (v) platelet ≥100,000/mm3, (vi) aspartate aminotransferase and alanine aminotransferase ≤150 U/L. The exclusion criteria were as follows: (i) anticoagulant therapy withdrawal or continuance without HR during the perioperative period, (ii) simultaneous ESD for two or more lesions, (iii) dialysis treatment, (iv) the systemic administration of corticosteroids or nonsteroidal anti-inflammatory drugs, (v) a history of gastrectomy or reconstruction of the gastric tube, (vi) pregnant or lactating. Patients taking DOAC were included in the present study since the JGES guidelines (2012) recommended HR of DOAC; although the BSG and ESGE guidelines (2016) and the ASGE guidelines (2016) do not have such a recommendation. As only anonymous retrospective data was used in the present study, the opt-out method was used for obtaining informed consent. The study protocol was approved first by the ethics committee of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, and subsequently by each institutional review board. The ethics committee approved that the present study waived the need for written informed consent as part of the study approval. The study was performed in accordance with the Declaration of Helsinki.\n\nTreatments\nEndoscopic submucosal dissection (ESD)\nAll ESD procedures were performed by either an experienced endoscopist or a resident under the supervision of an experienced endoscopist. The ESD procedure was carried out as previously described (10). The ESD procedure consisted of the following: Marking around a lesion, mucosal incision, submucosal dissection, and lesion removal. Just after the removal of the specimen, the created ulcer was carefully examined, and any visible vessels and adherent clots were coagulated. Clip closure or cover with a polyglycolic acid sheet was not performed in any of the cases. The time for the ESD procedure was measured from the start of marking until the completion of post-ESD coagulation. The ESD procedure was performed using an ITKnife2 (KD-611L; Olympus Medical Systems, Tokyo, Japan), a DualKnife (KD-650L; Olympus), an ITKnife (KD-610L; Olympus), or an ITknife nano (KD-612; Olympus). A Coagrasper (FD-411UR; Olympus) was mainly used as hemostatic forceps and a VIO 300D (ERBE Elektromedizin, Tübingen, Germany) was used as a high-frequency generator. Either a proton pump inhibitor or a vonoprazan was administered for 5 to 8 weeks after the ESD.\n\nManagement of anticoagulant and HR\nIn the present study, anticoagulant agents included warfarin and DOAC such as dabigatran, rivaroxaban, and apixaban. Anticoagulant withdrawal and HR were generally conducted according to the JGES guidelines (2012) (3). In the case of warfarin, warfarin was withdrawn ≥3 days before ESD and the continuous intravenous administration of unfractionated heparin (10,000-20,000 units per day) was started after warfarin withdrawal. The activated partial thromboplastin time (APTT) during HR was controlled from 1.5- to 2-fold higher than the normal value and heparin was discontinued 3-6 hours before ESD. Heparin was re-administered the night of ESD or the day after ESD after the absence of bleeding was confirmed. Warfarin was re-administered after heparin was started. Heparin was discontinued after the PT-INR level had reached the effective range (≥1.50). In the case of DOAC, DOAC was withdrawn ≥24 hours before ESD and heparin was started after DOAC withdrawal. HR was controlled as mentioned before, and heparin was discontinued soon after the DOAC re-administration. Heparin, warfarin, and DOAC were all re-administered with the same dose at the time of discontinuation before the ESD.\n\nManagement of antiplatelet agents\nThe antiplatelet agents included aspirin, ticlopidine, clopidogrel, eicosapentaenoic acid, and limaprost alfadex. The drug holidays of antiplatelet agents before ESD consisted of 5-8 days for aspirin, 7 days for ticlopidine, 9 days for clopidogrel, 6 days for eicosapentaenoic acid, and 5 days for limaprost alfadex. The antiplatelet agent was re-administered 2-8 days after ESD. In cases where the antiplatelet agent could not be withdrawn due to a high risk of thromboembolic complications, aspirin was continued during the perioperative period.\n\nMeasured outcomes\nThe primary endpoint was the delayed bleeding rate after gastric ESD under HR of anticoagulant agents. The delayed bleeding was defined as hematemesis, melena, or a decrease in hemoglobin of ≥2 g/dL; this was endoscopically confirmed as active bleeding from an ESD-induced gastric ulcer or blood in the stomach, occurring from soon after ESD to 28 days after ESD.\n\nThe secondary endpoints were (i) the delayed bleeding rate according to the anticoagulant agent (warfarin or DOAC); (ii) the rate of intra-ESD bleeding requiring transfusion; (iii) the rate of thromboembolic complications from soon after anticoagulant agent withdrawal to 28 days after ESD; and (iv) the timing of the delayed bleeding. A subgroup analysis was conducted to identify the risk factors for delayed bleeding after gastric ESD.\n\nStatistical analysis\nAll continuous variables are expressed as the median with the range. Statistical analyses were conducted using Fisher's exact test for categorical outcomes. The computer software JMP version 12 (SAS, Cary, USA) was used for the data analysis. The significance level was set at p<0.05.\n\nResults\nParticipant flow\nFrom July 2015 to June 2017, 2,480 patients with gastric neoplasms were treated by gastric ESD and were assessed for eligibility. A total of 116 patients took anticoagulant agents and 47 patients were treated under HR during the perioperative period of gastric ESD. Fifteen patients were excluded based on the exclusion criteria, and a total of 32 patients taking anticoagulant agents were thus analyzed; these included 24 patients on warfarin (the warfarin group) and 8 patients on DOAC (the DOAC group), including 4 patients on apixaban, 3 patients on rivaroxaban, and 1 patient on dabigatran (Fig. 1).\n\nFigure 1. Flow diagram of the study participants. HR: heparin replacement, ESD: endoscopic submucosal dissection, NSAID: nonsteroidal anti-inflammatory drug, DOAC: direct oral anticoagulant\n\nCharacteristics of the patients, lesions, perioperative management, and ESD procedures\nThe median age of patients was 79 years (65-91 years), and 88% were male. The most frequent comorbidity associated with cardiovascular disease was hypertension (72%) followed by AF (69%), dyslipidemia (34%), congestive heart failure (31%), and diabetes mellitus (25%). Of these, 31% of the patients were taking an antiplatelet agent. The DOAC group had a higher frequency of AF than the warfarin group since DOAC is usually used for non-valvular AF. While, patients in the warfarin group had more severe comorbidities than those in the DOAC group, such as congestive heart failure, valvular heart disease, prior deep vein thrombosis, pulmonary hypertension, cardiomyopathy, and old myocardial infarction. The median tumor size was 15.5 mm; 41% were located in the antrum, and 13% had an ulcer or scar (Table 1a).\n\nTable 1a. Characteristics of the Patients, Antithrombotic Therapy and Lesions.\n\n\t\tTotal \nn=32\t\tWarfarin \nn=24\t\tDOAC \nn=8\t\nAge (years)\t\t79 (65-91)\t\t80 (65-91)\t\t72.5 (65-83)\t\nMale\t\t28 (88)\t\t21 (88)\t\t7 (88)\t\nComorbidities associated with cardiovascular disease\t\t\t\t\t\t\t\nHypertension\t\t23 (72)\t\t18 (75)\t\t5 (62)\t\nAtrial fibrillation\t\t22 (69)\t\t14 (58)\t\t8 (100)\t\nCHADS2 scorea\t\t2 (0-5)\t\t2 (0-5)\t\t2 (0-3)\t\nCHA2DS2-VASc scorea\t\t5 (1-7)\t\t5 (1-7)\t\t4 (1-5)\t\nDyslipidemia\t\t11 (34)\t\t8 (33)\t\t3 (38)\t\nCongestive heart failure\t\t10 (31)\t\t9 (38)\t\t1 (13)\t\nDiabetes mellitus\t\t8 (25)\t\t7 (29)\t\t1 (13)\t\nValvular heart disease\t\t3 (9)\t\t3 (13)\t\t0 (0)\t\nPulmonary hypertension\t\t2 (6)\t\t2 (8)\t\t0 (0)\t\nCardiomyopathy\t\t2 (6)\t\t2 (8)\t\t0 (0)\t\nPeripheral artery disease\t\t2 (6)\t\t1 (4)\t\t1 (13)\t\nPast history associated with cardiovascular disease\t\t\t\t\t\t\t\nStroke or TIA\t\t6 (19)\t\t4 (17)\t\t2 (25)\t\nDeep vein thrombosis\t\t3 (9)\t\t3 (13)\t\t0 (0)\t\nMyocardial infarction\t\t2 (6)\t\t2 (8)\t\t0 (0)\t\nAntiplatelet agent\t\t10 (31)\t\t7 (29)\t\t3 (38)\t\nAspirin\t\t6 (19)\t\t4 (17)\t\t2 (25)\t\nTiclopidine\t\t1 (3)\t\t1 (4)\t\t0 (0)\t\nClopidogrel\t\t1 (3)\t\t0 (0)\t\t1 (13)\t\nEicosapentaenoic acid\t\t1 (3)\t\t1 (4)\t\t0 (0)\t\nLimaprost alfadex\t\t1 (3)\t\t1 (4)\t\t0 (0)\t\nHelicobacter pylori (positive/negative/unknown)\t\t9/18/5\t\t7/14/3\t\t2/4/2\t\nTumor located in the antrum\t\t13 (41)\t\t10 (42)\t\t3 (38)\t\nPathological tumor size (mm)\t\t15.5 (6-65)\t\t15.5 (6-65)\t\t14.5 (6-30)\t\nTumor with ulcer/scar\t\t4 (13)\t\t2 (8)\t\t2 (25)\t\nData are presented as the median (range) or n (%).\n\naCHADS2 and CHA2DS2-VASc scores were evaluated in 22 patients with atrial fibrillation.\n\nDOAC: direct oral anticoagulant, TIA: transient ischemic attack\n\nContinued aspirin therapy was only used in the warfarin group. Multiple antiplatelet therapy was not used in this study population. A proton pump inhibitor was used in 66% of the patients and vonoprazan was used in 34% of the patients to treat ESD-induced gastric ulcers. The median resected specimen size was 38 mm. The en bloc resection rate and complete resection rate were 100% and 97%, respectively. Second-look endoscopy was performed on all patients either before oral food intake or discharge (Table 1b).\n\nTable 1b. Characteristics of Perioperative Management, ESD Procedures and Outcomes.\n\n\t\tTotal \nn=32\t\tWarfarin \nn=24\t\tDOAC \nn=8\t\nAnticoagulant therapy\t\t\t\t\t\t\t\nPeriod of anticoagulant agent withdrawal before ESD (days)\t\t4 (1-7)\t\t5 (3-7)\t\t2.5 (1-5)\t\nPeriod of HR before ESD (days)\t\t3 (1-6)\t\t4 (2-6)\t\t2 (1-4)\t\nPeriod until HR re-start after ESD (days)\t\t1 (0-2)\t\t1 (0-2)\t\t0 (0-1)\t\nPeriod until anticoagulant agent re-administration after ESD (days)\t\t1 (1-6)\t\t1.5 (1-6)\t\t1 (1-3)\t\nPeriod of HR after ESD (days)\t\t5 (1-15)\t\t5 (1-15)\t\t2 (1-2)\t\nAntiplatelet therapy\t\t\t\t\t\t\t\nContinued aspirin treatmenta\t\t3 (9)\t\t3 (13)\t\t0 (0)\t\nPeriod of aspirin withdrawal before ESD (days)b\t\t6 (5-8)\t\t5.5 (5-6)\t\t7 (6-8)\t\t\nPeriod until antiplatelet agent re-administration after ESD (days)c\t\t7 (2-8)\t\t6 (2-8)\t\t7 (2-8)\t\nAcid suppressant\t\t32 (100)\t\t24 (100)\t\t8 (100)\t\nProton pump inhibitor\t\t21 (66)\t\t16 (67)\t\t5 (62)\t\nVonoprazan\t\t11 (34)\t\t8 (33)\t\t3 (38)\t\nESD\t\t\t\t\t\t\t\nESD procedural items\t\t\t\t\t\t\t\nITKnife2\t\t16 (50)\t\t15 (62)\t\t1 (12.5)\t\nDualKnife\t\t11 (34)\t\t7 (30)\t\t4 (50)\t\nITKnife\t\t4 (13)\t\t2 (8)\t\t2 (25)\t\nITknife nano\t\t1 (3)\t\t0 (0)\t\t1 (12.5)\t\nProcedure time for ESD (min)\t\t65 (23-348)\t\t59 (23-348)\t\t80 (51-250)\t\nResected specimen size (mm)\t\t38 (20-100)\t\t37 (20-100)\t\t40 (24-50)\t\nEn bloc resection\t\t32 (100)\t\t24 (100)\t\t8 (100)\t\nComplete resection\t\t31 (97)\t\t23 (96)\t\t8 (100)\t\nSecond-look endoscopy\t\t32 (100)\t\t24 (100)\t\t8 (100)\t\nTiming of SLE\t\t\t\t\t\t\t\n1-2 days after ESD (before oral food intake)\t\t24 (75)\t\t19 (79)\t\t5 (62)\t\n6-8 days after ESD (before discharge)\t\t8 (25)\t\t5 (21)\t\t3 (38)\t\nProphylactic hemostasis during SLEd\t\t\t\t\t\t\t\nYes\t\t9 (29)\t\t5 (22)\t\t4 (50)\t\nNo\t\t22 (71)\t\t18 (78)\t\t4 (50)\t\nData are presented as the median (range) or n (%).\n\naTiclopidine was switched to aspirin in one patient.\n\nbThe aspirin withdrawal period was evaluated in 4 patients who stopped taking aspirin.\n\ncThe period until antiplatelet agent re-administration was evaluated in 7 patients who stopped taking antiplatelet agents.\n\ndOne patient was excluded from the Warfarin group because the patient experienced delayed bleeding before the scheduled second-look endoscopy.\n\nESD: endoscopic submucosal dissection, DOAC: direct oral anticoagulant, HR: heparin replacement, SLE: second-look endoscopy\n\nDelayed bleeding and other complications\nIn total, three (9.4%) patients experienced delayed bleeding after gastric ESD under HR of anticoagulant agents. In the warfarin group, three (12.5%) patients experienced delayed bleeding and two (8.3%) received transfusion; in the DOAC group, no patients experienced these complications. Delayed bleeding was managed by endoscopic hemostasis using hemostatic forceps with a soft coagulation mode in all the three cases. No patients in either group experienced intra-ESD bleeding requiring transfusion, thromboembolic complications, or perforation (Table 2).\n\nTable 2. Complications of Gastric ESD under Heparin Replacement.\n\n\t\tTotal \nn=32\t\tWarfarin \nn=24\t\tDOAC \nn=8\t\nDelayed bleeding\t\t3 (9.4)\t\t3 (12.5)\t\t0 (0)\t\nTransfusion due to delayed bleeding\t\t2 (6.3)\t\t2 (8.3)\t\t0 (0)\t\nIntra-ESD bleeding requiring transfusion\t\t0 (0)\t\t0 (0)\t\t0 (0)\t\nThromboembolic complications\t\t0 (0)\t\t0 (0)\t\t0 (0)\t\nPerforation\t\t0 (0)\t\t0 (0)\t\t0 (0)\t\nData are presented as n (%).\n\nESD: endoscopic submucosal dissection, DOAC: direct oral anticoagulant\n\nCharacteristics and timing of delayed bleeding\nDelayed bleeding occurred in three patients taking warfarin. Two (67%) patients were taking aspirin and both continued with aspirin therapy because of an old myocardial infarction. The median days until delayed bleeding was 10 days (4-13 days); two (67%) patients experienced delayed bleeding after discharge (5 and 8 days after heparin withdrawal). In all three cases, the delayed bleeding was managed by endoscopic hemostasis using hemostatic forceps with a soft coagulation mode and the same kind and dose of acid suppressant were continued. The detailed information on the patient, lesion, and perioperative management of antithrombotic therapy is shown in Fig. 2.\n\nFigure 2. Patient and lesion characteristics, antithrombotic therapy, and timing of bleeding in three patients with delayed bleeding. yo: years old, DB: delayed bleeding, ESD: endoscopic submucosal dissection, SLE: second-look endoscopy, TLE: third-look endoscopy\n\nSubgroup analysis of the risk factors for delayed bleeding\nIn the subgroup analysis, continued aspirin treatment was identified as a risk factor for delayed bleeding. Two of the 3 (67%) patients under continued aspirin treatment experienced delayed bleeding; however, 1 of 29 (3.4%) patients without continued aspirin treatment experienced delayed bleeding (p=0.01) (Table 3).\n\nTable 3. A Univariable Analysis of the Risk Factors for Delayed Bleeding.\n\n\tDelayed bleeding (+) \nn=3\tDelayed bleeding (-) \nn=29\tp value\t\nAnticoagulant agent\t\t\t0.55\t\nWarfarin\t3 (13)\t21\t\t\nDOAC\t0 (0)\t8\t\t\nAntiplatelet agent including both cases of cessation and aspirin continuation\t\t\t0.22\t\nYes\t2 (20)\t8\t\t\nNo\t1 (5)\t21\t\t\nContinued aspirin treatment\t\t\t0.01\t\nYes\t2 (67)\t1\t\t\nNo\t1 (3)\t28\t\t\nAcid suppressant\t\t\t1.0\t\nProton pump inhibitor\t2 (10)\t19\t\t\nVonoprazan\t1 (9)\t10\t\t\nTumor size\t\t\t0.55\t\n>2 cm\t0 (0)\t11\t\t\n≤ 2 cm\t3 (14)\t18\t\t\nUlcer or scar in the tumor\t\t\t1.0\t\nPresent\t0 (0)\t4\t\t\nAbsent\t3 (11)\t25\t\t\nTumor location\t\t\t1.0\t\nAntrum\t1 (8)\t12\t\t\nBody\t2 (11)\t17\t\t\nTiming of SLE\t\t\t0.14\t\n1-2 days after ESD\t1 (4)\t23\t\t\n6-8 days after ESD\t2 (25)\t6\t\t\nData are presented as n (delayed bleeding rate, %).\n\nDOAC: direct oral anticoagulant, SLE: second-look endoscopy, ESD: endoscopic submucosal dissection\n\nDiscussion\nThis study included only the latest 2 year's data and therefore represented the current risk of delayed bleeding after gastric ESD under HR of anticoagulant agents. The delayed bleeding rate was 9.4%: 12.5% in the warfarin group and 0% in the DOAC group, and no life-threatening complications were observed. Continued aspirin treatment was identified to be a risk factor for delayed bleeding after gastric ESD under HR of anticoagulant agents.\n\nIn the present study, antiplatelet agents as a whole, including both cases of cessation and aspirin continuation, were not identified to be a risk factor of delayed bleeding after gastric ESD under HR of anticoagulant agents, contrary to the findings of previous studies (6,11). However, continued aspirin treatment was identified to be a risk factor of delayed bleeding after gastric ESD under HR. Although it remains controversial as to whether continued aspirin treatment alone increases the bleeding risk after gastrointestinal ESD (12,13), and our results indicate an elevated risk of delayed bleeding with the co-use of HR and aspirin.\n\nThe delayed bleeding rates did not differ significantly between the warfarin and DOAC groups. However, since delayed bleeding only occurred in the warfarin group, DOAC is expected to be an alternative to warfarin. A recent nationwide database analysis from Japan demonstrated that DOAC may reduce delayed bleeding after therapeutic endoscopy, including gastric ESD, compared with warfarin regardless of whether HR was also performed (14). However, since the drug indications were different between warfarin and DOAC, the patient's backgrounds might be different between the patients using warfarin and those with DOAC. In the present study, the same limitation was noted, and the sample size was too small to accurately discuss the safety of DOAC. To date there are few reports describing the delayed bleeding risk after gastric ESD for patients using DOAC (11). Therefore, more data are required to accurately determine the safety of DOAC during the perioperative period of gastric ESD.\n\nIn the present study, the delayed bleeding rate in the warfarin group (12.5%) was lower than that suggested by previous studies (24-57%) (6-8). Although HR of warfarin was identified to be a risk factor of delayed bleeding after gastric ESD (10,11,14-16), the risk may have decreased over the years. Vonoprazan, a novel potassium-competitive acid blocker, is expected to reduce the delayed bleeding rate after gastric ESD based on the results of a single arm observational study (17), because of its rapid, strong, and sustained acid inhibitory effect (18). However, a randomized phase II study showed that the difference in the delayed bleeding rate after gastric ESD between patients using vonoprazan and proton pump inhibitors was only 1.4% (19). In the present study, the difference was almost the same as that reported in the randomized study and did not show significance (Table 3). The effectiveness of vonoprazan may be small in terms of the prevention of the delayed bleeding after gastric ESD in patients under HR, contrary to expectations. Based on our experience in clinical practice, prophylactic coagulation might be carefully performed in patients immediately after gastric ESD under HR of warfarin owing to the high risk of delayed bleeding in such patients from previous studies. This may have contributed to the decrease in delayed bleeding observed in the present study.\n\nPatients who undergo gastric ESD under HR of warfarin are reported to experience delayed bleeding later than those without HR; this tendency has been explained by the effects of warfarin reaching the therapeutic range under HR, that is, the enhanced anticoagulant effect due to dual anticoagulant therapy of warfarin and heparin (6,8,10). In the present study, two of three patients experienced delayed bleeding on postoperative day 10 and 13, and these late onsets were consistent with previous studies (Fig. 2). However, two patients experienced delayed bleeding after discharge, five and eight days after heparin withdrawal. While the other patient who experienced delayed bleeding on postoperative day 4 was under HR at delayed bleeding; however, neither APTT nor PT-INR was abnormally high (Fig. 2). Therefore, the enhanced anticoagulant effect due to dual anticoagulant therapy cannot be applied to the three patients in the present study. From the data, we suspected that the patients who experienced delayed bleeding had a potential bleeding risk regardless of HR. If so, delayed bleeding might have occurred even if HR had not been performed in such cases.\n\nNo thromboembolic complications were observed in the present study. Indeed, some patients who underwent gastric ESD under HR of warfarin experienced thromboembolism during the perioperative period (7,11,14). Thromboembolism can cause critical complications such as cerebral embolism, deep vein thrombosis, pulmonary embolism, or death. From this point of view, continued warfarin may be a more suitable management method if it does not increase the risk of perioperative bleeding. One observational study reported that there was no significant difference in the delayed bleeding rate among patients who underwent gastric ESD under the cessation (10%), HR (12%), and continuation (8%) of anticoagulant agents including warfarin and DOAC (20). These results suggest that HR and the continuation of anticoagulant agents may not increase the perioperative bleeding risk. On the other hand, a large randomized, double-blind, placebo-controlled trial showed that HR of warfarin increased bleeding during the perioperative period of various elective invasive procedures compared to a placebo; however, this study only included 10 patients who underwent a high-bleeding-risk endoscopic procedure (21). It remains controversial as to which management method of anticoagulant agents is most suitable during the perioperative period of high-bleeding-risk endoscopic procedures, including gastric ESD. Therefore, we now need to evaluate these methods based on the data from a well-designed randomized controlled trial.\n\nThe present study is associated with some limitations. First, this was a retrospective study. Second, the treatments were not performed according to a unified protocol, mainly because of restrictions arising from the study's retrospective design. Third, the sample size was smaller than what we had expected, especially in the DOAC group, mainly owing to the number of non-HR cases being unexpectedly large. However, the sample size of the warfarin group was comparable to previous studies (6-8,10,16). Given that there are few reports describing the risk of delayed bleeding after gastric ESD for patients using DOAC, the present study is valuable despite its small sample size. Most previous studies included old data to increase the sample sizes because the number of patients undergoing gastric ESD under HR of anticoagulant agents is not so large (6-8,10,11). We therefore collected only the latest two year's data (2015 to 2017) to elucidate the current situation. This is the greatest strength of the present study, and we also chose to conduct a multi-center study in order to compensate for the short study period. Fourth, as a result of the small sample size and low bleeding rate, the number of delayed bleeding events was lower than what we had expected. Therefore, a multivariable analysis to reduce any confounding bias could not be conducted. Finally, the present study lacked a control group, precluding comparisons with other management methods of anticoagulant agents.\n\nIn conclusion, this latest, retrospective, multi-center study suggests that careful management may be required for patients undergoing gastric ESD under continued aspirin treatment in addition to HR of anticoagulant agents; although the delayed bleeding risk after gastric ESD under HR of anticoagulant agents might have decreased over the years.\n\n\nThe study protocol was approved first by the ethics committee of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital, and subsequently by each institutional review board. As only anonymous retrospective data was used in the present study, the opt-out method was used for the informed consent. The ethics committee approved that the present study waived the need for written informed consent as part of the study approval.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nThe authors thank Dr. Junichiro Nasu (Department of Internal Medicine, Okayama Saiseikai General Hospital), Dr. Masahiro Nakagawa (Department of Internal Medicine, Hiroshima City Hospital), Dr. Masahiro Takatani (Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital), and Dr. Tomoki Inaba (Department of Gastroenterology, Kagawa Prefectural Central Hospital) for their assistance with the data collection.\n==== Refs\n1. \nCamm AJ , Kirchhof P , Lip GY , et al \nGuidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC)\n. Eur Heart J \n31 : 2369 -2429\n, 2010 .20802247 \n2. \nBlacker DJ , Wijdicks EF , McClelland RL \nStroke risk in anticoagulated patients with atrial fibrillation undergoing endoscopy\n. Neurology \n61 : 964 -968\n, 2003 .14557569 \n3. \nFujimoto K , Fujishiro M , Kato M , et al \nGuidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment\n. Dig Endosc \n26 : 1 -14\n, 2014 .\n4. \nVeitch AM , Vanbiervliet G , Gershlick AH , et al \nEndoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines\n. Gut \n65 : 374 -389\n, 2016 .26873868 \n5. \nAcosta RD , Abraham NS , et al; ASGE Standards of Practice Committee . The management of antithrombotic agents for patients undergoing GI endoscopy\n. Gastrointest Endosc \n83 : 3 -16\n, 2016 .26621548 \n6. \nTakeuchi T , Ota K , Harada S , et al \nThe postoperative bleeding rate and its risk factors in patients on antithrombotic therapy who undergo gastric endoscopic submucosal dissection\n. BMC Gastroenterol \n13 : 136 , 2013 .24010587 \n7. \nYoshio T , Nishida T , Kawai N , et al \nGastric ESD under heparin replacement at high-risk patients of thromboembolism is technically feasible but has a high risk of delayed bleeding: Osaka University ESD Study Group\n. Gastroenterol Res Pract \n2013 : 365830 , 2013 .23843783 \n8. \nMatsumura T , Arai M , Maruoka D , et al \nRisk factors for early and delayed post-operative bleeding after endoscopic submucosal dissection of gastric neoplasms, including patients with continued use of antithrombotic agents\n. BMC Gastroenterol \n14 : 172 , 2014 .25280756 \n9. \nKato M , Uedo N , Hokimoto S , et al \nGuidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment: 2017 appendix on anticoagulants including direct oral anticoagulants\n. Dig Endosc \n30 : 433 -440\n, 2018 .29733468 \n10. \nGotoda T , Hori K , Iwamuro M , et al \nEvaluation of the bleeding risk with various antithrombotic therapies after gastric endoscopic submucosal dissection\n. Endosc Int Open \n5 : E653 -E662\n, 2017 .28691050 \n11. \nYoshio T , Tomida H , Iwasaki R , et al \nEffect of direct oral anticoagulants on the risk of delayed bleeding after gastric endoscopic submucosal dissection\n. Dig Endosc \n29 : 686 -694\n, 2017 .28295638 \n12. \nWu W , Chen J , Ding Q , Yang D , Yu H , Lin J \nContinued use of low-dose aspirin may increase risk of bleeding after gastrointestinal endoscopic submucosal dissection: a meta-analysis\n. Turk J Gastroenterol \n28 : 329 -336\n, 2017 .28797987 \n13. \nDong J , Wei K , Deng J , et al \nEffects of antithrombotic therapy on bleeding after endoscopic submucosal dissection\n. Gastrointest Endosc \n86 : 807 -816\n, 2017 .28732709 \n14. \nNagata N , Yasunaga H , Matsui H , et al \nTherapeutic endoscopy-related GI bleeding and thromboembolic events in patients using warfarin or direct oral anticoagulants: results from a large nationwide database analysis\n. Gut \n67 : 1805 -1812\n, 2018 .28874418 \n15. \nSanomura Y , Oka S , Tanaka S , et al \nTaking warfarin with heparin replacement and direct oral anticoagulant is a risk factor for bleeding after endoscopic submucosal dissection for early gastric cancer\n. Digestion \n97 : 240 -249\n, 2018 .29421806 \n16. \nShindo Y , Matsumoto S , Miyatani H , Yoshida Y , Mashima H \nRisk factors for postoperative bleeding after gastric endoscopic submucosal dissection in patients under antithrombotics\n. World J Gastrointest Endosc \n8 : 349 -356\n, 2016 .27076874 \n17. \nKagawa T , Iwamuro M , Ishikawa S , et al \nVonoprazan prevents bleeding from endoscopic submucosal dissection-induced gastric ulcers\n. Aliment Pharmacol Ther \n44 : 583 -591\n, 2016 .27464849 \n18. \nSakurai Y , Mori Y , Okamoto H , et al \nAcid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects: a randomized open-label cross-over study\n. Aliment Pharmacol Ther \n42 : 719 -730\n, 2015 .26193978 \n19. \nHamada K , Uedo N , Tonai Y , et al \nEfficacy of vonoprazan in prevention of bleeding from endoscopic submucosal dissection-induced gastric ulcers: A prospective randomized phase II study\n. J Gastroenterol \n54 : 122 -130\n, 2019 .29943163 \n20. \nIgarashi K , Takizawa K , Kakushima N , et al \nShould antithrombotic therapy be stopped in patients undergoing gastric endoscopic submucosal dissection?\n\nSurg Endosc \n31 : 1746 -1753\n, 2017 .27530896 \n21. \nDouketis JD , Spyropoulos AC , Kaatz S , et al \nPerioperative bridging anticoagulation in patients with atrial fibrillation\n. N Engl J Med \n373 : 823 -833\n, 2015 .26095867\n\n",
"fulltext_license": "CC BY-NC-ND",
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"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "anticoagulant agent; bleeding; endoscopic submucosal dissection; gastric cancer; heparin replacement; warfarin",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001241:Aspirin; D000069916:Endoscopic Mucosal Resection; D005260:Female; D006493:Heparin; D006801:Humans; D007564:Japan; D008297:Male; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D012307:Risk Factors; D013274:Stomach Neoplasms; D014859:Warfarin",
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"title": "Continued Aspirin Treatment May Be a Risk Factor of Delayed Bleeding after Gastric Endoscopic Submucosal Dissection under Heparin Replacement: A Retrospective Multicenter Study.",
"title_normalized": "continued aspirin treatment may be a risk factor of delayed bleeding after gastric endoscopic submucosal dissection under heparin replacement a retrospective multicenter study"
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"abstract": "Nitrofurantoin-induced lung toxicity is relatively common, but rare histologic patterns sometimes occur that may make diagnosis difficult. We present the case of a 69-year-old woman taking prophylactic nitrofurantoin for urinary tract infections, who developed granulomatous interstitial pneumonia. She improved with cessation of nitrofurantoin, without other therapy. To our knowledge, this is the fourth reported case of granulomatous interstitial pneumonia associated with nitrofurantoin, and the first to show complete resolution with cessation of the drug alone, without steroids. It is important to recognize that idiosyncratic reactions to nitrofurantoin can produce a wide spectrum of histologic patterns. Of these patterns, granulomatous interstitial pneumonia is a rarely evidenced manifestation (possibly because few cases undergo a confirmatory lung biopsy). Recognition of granulomatous interstitial pneumonia as a manifestation of nitrofurantoin toxicity can aid in early identification of the reaction and prompt withdrawal of the drug, both of which are essential to prevent long-term complications.",
"affiliations": "Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Rochester, MN, USA.;Mayo Clinic, Rochester, MN, USA.;Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Scottsdale, AZ, USA.;Mayo Clinic, Scottsdale, AZ, USA tazelaar.henry@mayo.edu.",
"authors": "Sakata|Kenneth K|KK|;Larsen|Brandon T|BT|;Boland|Jennifer M|JM|;Palen|Brian|B|;Muhm|John R|JR|;Helmers|Richard A|RA|;Tazelaar|Henry D|HD|",
"chemical_list": "D000892:Anti-Infective Agents, Urinary; D009582:Nitrofurantoin",
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"delete": false,
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"issue": "22(4)",
"journal": "International journal of surgical pathology",
"keywords": "granulomas; lung; nitrofurantoin; toxicity",
"medline_ta": "Int J Surg Pathol",
"mesh_terms": "D000368:Aged; D000892:Anti-Infective Agents, Urinary; D005260:Female; D006099:Granuloma; D006801:Humans; D017563:Lung Diseases, Interstitial; D009582:Nitrofurantoin; D014552:Urinary Tract Infections",
"nlm_unique_id": "9314927",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Nitrofurantoin-Induced Granulomatous Interstitial Pneumonia.",
"title_normalized": "nitrofurantoin induced granulomatous interstitial pneumonia"
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"abstract": "Cirrhotic patients are at a high risk of fungal infections. Voriconazole is widely used as prophylaxis and in the treatment of invasive fungal disease. However, the safety, pharmacokinetics, and optimal regimens of voriconazole are currently not well defined in cirrhotic patients.\n\n\n\nRetrospective pharmacokinetics study.\n\n\n\nTwo large, academic, tertiary-care medical center.\n\n\n\nTwo hundred nineteen plasma trough concentrations (Cmin ) from 120 cirrhotic patients and 83 plasma concentrations from 11 non-cirrhotic patients were included.\n\n\n\nData pertaining to voriconazole were collected retrospectively. A population pharmacokinetics analysis was performed and model-based simulation was used to optimize voriconazole dosage regimens.\n\n\n\nVoriconazole-related adverse events (AEs) developed in 29 cirrhotic patients, and the threshold Cmin for AE was 5.12 mg/L. A two-compartment model with first-order elimination adequately described the data. The Child-Pugh class and body weight were the significant covariates in the final model. Voriconazole clearance in non-cirrhotic, Child-Pugh class A and B cirrhotic (CP-A/B) and Child-Pugh class C cirrhotic (CP-C) patients was 7.59, 1.86, and 0.93 L/hour, respectively. The central distribution volume and peripheral distribution volume was 100.8 and 55.2 L, respectively. The oral bioavailability was 91.6%. Model-based simulations showed that a loading dose regimen of 200 mg/12 hours intravenously or orally led to 65.0-75.7% of voriconazole Cmin in therapeutic range on day 1, and the appropriate maintenance dosage regimens were 75 mg/12 hours and 150 mg/24 hours intravenously or orally for CP-A/B patients, and 50 mg/12 hours and 100 mg/24 hours intravenously or orally for CP-C patients. The predicted probability of achieving the therapeutic target concentration for optimized regimens at steady-state was 66.8-72.3% for CP-A/B patients and 70.3-74.0% for CP-C patients.\n\n\n\nThese results recommended that the halved loading dose regimens should be used, and voriconazole maintenance doses in cirrhotic patients should be reduced to one-fourth for CP-C patients and to one-third for CP-A/B patients compared to that for patients with normal liver function.",
"affiliations": "Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.;School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.;Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Department of Infectious Disease, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.;Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.;School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.;Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.",
"authors": "Wang|Taotao|T|0000-0002-6459-7139;Yan|Miao|M|;Tang|Dan|D|;Dong|Yuzhu|Y|;Zhu|Li|L|;Du|Qian|Q|;Sun|Dan|D|;Xing|Jianfeng|J|;Dong|Yalin|Y|0000-0001-5619-0788",
"chemical_list": null,
"country": "United States",
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"doi": "10.1002/phar.2474",
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"issn_linking": "0277-0008",
"issue": "41(2)",
"journal": "Pharmacotherapy",
"keywords": "Child-Pugh class; adverse events; liver cirrhosis; model-based simulation; population pharmacokinetics; voriconazole",
"medline_ta": "Pharmacotherapy",
"mesh_terms": null,
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "172-183",
"pmc": null,
"pmid": "33064889",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Using Child-Pugh Class to Optimize Voriconazole Dosage Regimens and Improve Safety in Patients with Liver Cirrhosis: Insights from a Population Pharmacokinetic Model-based Analysis.",
"title_normalized": "using child pugh class to optimize voriconazole dosage regimens and improve safety in patients with liver cirrhosis insights from a population pharmacokinetic model based analysis"
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"activesubstancename": "VORICONAZOLE"
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"abstract": "In clinically euthyroid patients presenting with urticaria, a trial period of withholding antithyroid medications can be exercised. In clinically hyperthyroid patients, antithyroid medications may be stopped with close observation of response.",
"affiliations": "Tameside and Glossop Integrated Care NHS Foundation Trust Ashton-Under-Lyne UK.;Tameside and Glossop Integrated Care NHS Foundation Trust Ashton-Under-Lyne UK.",
"authors": "Womack|Nicholas|N|https://orcid.org/0000-0003-2991-6509;Jude|Edward|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3620",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.3620\nCCR33620\nCase Report\nCase Reports\nUrticaria as a manifestation of hyperthyroidism\nWOMACK and JUDE\nWomack Nicholas https://orcid.org/0000-0003-2991-6509\n1 nwomack@doctors.org.uk\n\nJude Edward 1\n1 Tameside and Glossop Integrated Care NHS Foundation Trust Ashton‐Under‐Lyne UK\n* Correspondence\nNicholas Womack, Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton‐Under‐Lyne OL6 9RW, UK.\nEmail: nwomack@doctors.org.uk\n\n05 5 2021\n5 2021\n9 5 10.1002/ccr3.v9.5 e0362008 9 2020\n01 6 2020\n19 9 2020\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nIn clinically euthyroid patients presenting with urticaria, a trial period of withholding antithyroid medications can be exercised. In clinically hyperthyroid patients, antithyroid medications may be stopped with close observation of response.\n\nIn clinically euthyroid patients presenting with urticaria, a trial period of withholding antithyroid medications can be exercised. In clinically hyperthyroid patients, antithyroid medications may be stopped with close observation of response.\n\ncarbimazole\nhyperthyroidism\nurticaria\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:24.05.2021\nWomack N , Jude E . Urticaria as a manifestation of hyperthyroidism. Clin Case Rep.2021;9 :e03620. 10.1002/ccr3.3620\n==== Body\n1 BACKGROUND\n\nUrticaria is a common, pruritic skin condition with multiple causes and can have a significant impact on quality of life. In this paper, we present a case of acute urticaria secondary to hyperthyroidism. This link appears to be due to the autoimmune thyroid cascade (particularly IgE antithyroid peroxidase [TPO] antibodies) sensitizing mast cells for activation and histamine release. Although antihistamines and steroids are first‐line treatment, identifying the “causative” factor is not easy in hyperthyroid patients due to the independent links urticaria shares with both carbimazole and thyrotoxicosis.\n\nUrticaria consists of blanchable, erythematous “wheals” secondary to vasoactive mediators, predominantly histamine release from mast cells. Wheals are usually transient, disappearing from one aspect of the body and reappearing in new areas, and almost always pruritic. Acute urticaria refers to a presentation of <6 weeks; otherwise, the term chronic urticaria is used. Most cases are idiopathic, but known triggers include drugs, infections, foods, and even certain physical factors (such as cold, heat, and sunlight). 1\n\nHyperthyroidism results from an excess state of thyroid hormones caused by excess release and increased synthesis from the thyroid gland, or less commonly, from extrathyroidal sources. Excess thyroid release is often stimulated by specific antibodies, including antithyroid peroxidase (TPO), antithyroglobulin (Tg), and antithyroid‐stimulating hormone receptor (TSHR) antibodies. 2 Graves' disease, the most common cause of hyperthyroidism, is an example of an autoimmune disease where thyroid‐stimulating antibodies activate thyroid‐stimulating hormone receptors, leading to excess hormone release from the thyroid gland. 3\n\nUrticaria and autoimmune hyperthyroidism appear to share an aetiological relationship, although the exact mechanism remains ambiguous. 4 In this report, we discuss a new case of urticaria presenting itself as a manifestation of hyperthyroidism, the pathophysiology to this link is explored and management strategies are discussed.\n\n2 CASE PRESENTATION\n\nA 23‐year‐old female patient with a recent diagnosis of Graves' disease presented to her GP with an urticarial rash localized to her neck. She was prescribed a course of cetirizine and prednisolone. Shortly after, she presented to the emergency department with a spreading urticarial rash extending to her neck, stomach, chest, back, genitals, upper and lower legs, consisting of “extensive excoriations and dermatographia, with blanching and wheals” (Figures 1 and 2). She had given birth to her first child as recently as 4 months ago and the only other medication she took on a regular basis was carbimazole, which was started 1 month prior to her presentation. She had no family history of any autoimmune disorders.\n\nFIGURE 1 Patient presented with acute urticaria\n\nFIGURE 2 Patient presented with acute urticaria\n\nInvestigations revealed normal inflammatory markers (CRP 2 mg/L, WBC 9.3 × 109/L), and her renal and liver function tests all remained within normal limits. No clinical findings were evident on examination of her chest and abdomen, and no focal neurology was elicited. Her FT4 2 weeks prior to admission was 38.4 pmol/L, with a TSH of 0.01 mU/L, although her FT4 on the day of admission was normal at 10.7 pmol/L. She was treated with intravenous chlorphenamine in the emergency department then admitted for observation and referred to the endocrinologist.\n\nOver the next 48 hours, she had a further exacerbation of her rash which now resulted in lip swelling and she was started on intravenous hydrocortisone and oral loratadine. Her carbimazole was stopped due to concerns it may be the cause of the rash. She was reviewed the next day and an urgent dermatology opinion was sought, while a full autoimmune screen was sent (all negative, Table 1). Urinalysis was also negative. Thyroid peroxidase antibody (anti‐TPO) levels were raised at >1000 iU/mL, and thyroid receptor antibodies were unremarkable (0.30 iU/L).\n\nTABLE 1 Autoimmune screening tests\n\nAntibody\tResult\t\nComplement (C3)\t1.26 g/L (negative)\t\nComplement (C4)\t0.14 g/L (negative)\t\nANCA (Antineutrophil cytoplasmic antibody)\t<0.2 iU/mL (negative)\t\nRheumatoid factor\t17.6 iU/mL (negative)\t\nANA (Antinuclear antibody)\tNegative\t\nAnticardiolipin\t<1.6 GPLU/mL (negative)\t\nJohn Wiley & Sons, Ltd\n\nAfter dermatology review, the patient was started on oral chlorphenamine (at triple the normal licensed dose), topical menthol 1% cream and her steroid dose was gradually reduced. After 5 days of treatment, her urticaria was limited to her legs and scalp, and she had symptomatically improved.\n\n3 OUTCOME AND FOLLOW‐UP\n\nOnce the patient's symptoms had improved, she was discharged having stayed in hospital for a total of 1 week. She had an ultrasound of her thyroid 2 weeks after discharge which showed diffuse thyroiditis along with a right U2 thyroid nodule. She was discharged without any further carbimazole and followed up in endocrine clinics to monitor thyroid function and to potentially commence propylthiouracil.\n\n4 DISCUSSION\n\nThe lifetime prevalence of acute urticaria is estimated to be 15%‐23% in adults and up to 14.5% in children. 5 The detriment to quality of life is severe, and applicable to social, recreational, vocational, and emotional aspects of life. 6 , 7 Management consists of high dose antihistamines along with steroid use and avoidance of causative factors. 8\n\nIn rare circumstances, urticaria can be the presenting feature of hyperthyroidism. Rothfield 9 reviewed 108 cases of hyperthyroidism and found two cases of urticaria (1.85%) that varied with the degree of hyperthyroidism. Pruritis was also found in a number of patients, and severity varied along with thyroid state in five out of the 108 cases (4.63%).\n\nThe mechanism linking urticaria and hyperthyroidism is not clearly understood. Chronic urticaria is thought to be triggered by activation and degranulation of mast cells. Although IgG antithyroid auto‐antibodies do not directly activate mast cells, they are postulated to make them more susceptible to activation by other mediators. 10 In this case, thyroid peroxidase antibodies were >1000 iU/mL. Another proposed theory is that IgE anti‐TPO antibodies directly bind to mast cells to cause autoallergic mast cell degranulation and activation. 11 Furthermore, omalizumab, an anti‐IgE therapy, provides particularly good symptomatic improvement in patients with urticaria and positive IgE anti‐TPO antibodies. 12\n\nTreatment for hyperthyroidism consists of medications, surgery, or radioiodine. The currently licensed medications for hyperthyroidism include carbimazole (converted to methimazole) and propylthiouracil, both of which reduce the conversion of thyroxine (T4) to its active form, triiodothyronine (T3). 13 , 14 Specifically, methimazole and propylthiouracil impede iodination of tyrosine residues in thyroglobulin, an important step in conversion of T4 to T3. Propylthiouracil also inhibits peripheral conversion of T4 to T3, although the therapeutic effect of this is unclear. 13\n\nCarbimazole itself is also a known cause of rash and urticaria. 15 , 16 A review of the yellow card scheme between 1981 and 2003 found rashes to be the 4th most common side effect for carbimazole, behind neutropenia, hepatobiliary disorders, and agranulocytosis. Interestingly, angioedema is also a recognized side effect of carbimazole, which could indicate that carbimazole was the underlying cause in our case. 17 Propylthiouracil, the lesser used medication for hyperthyroidism, has a number of adverse effects including urticaria and other skin reactions; skin eruptions occur in 4%‐6% of patients. 18\n\nIn patients that are otherwise clinically euthyroid, a suitable strategy would be to withhold carbimazole (or propylthiouracil) when an urticarial rash first develops. But the correct action in patients with uncontrolled hyperthyroidism is less clear, as withholding antithyroid drugs could result in an exacerbation of thyrotoxicosis and consequently intensify the urticaria. In such patients, a trial period of carbimazole‐free therapy in order to closely assess urticarial response would be justified. Talapatra et al 19 faced the above dilemma in 2007, and opted to withhold carbimazole therapy, resulting in an aggravated thyrotoxicosis with a persistent rash. They then found the urticarial rash to improve once the patient's hyperthyroid state had resolved with propylthiouracil.\n\nIn our patient, the hyperthyroidism developed shortly before urticaria, although she was clinically euthyroid when she presented to hospital. But despite the unremarkable FT4 level, it is likely that the IgE anti‐TPO cascade was still rampant as evidenced by the high anti‐TPO levels. Interestingly, the decision to stop carbimazole did result in symptomatic relief; however, this coincided with high dose antihistamines.\n\nOverall, urticaria is a complication of both autoimmune hyperthyroid disease and the medications used to treat hyperthyroidism. Differentiating between the two is both vital and challenging. In the absence of other clues, it is worth attempting a trial period of withholding antithyroid medications with close assessment of the urticarial rash (see Table 2). At the same time, symptomatic relief can be found with steroids and antihistamines.\n\nTABLE 2 Summary of recommendations\n\nThyroid function tests should be part of routine screening for patients presenting with acute or chronic urticaria.\n\nIn patients that are clinically euthyroid with urticaria or rash, antithyroid drugs can be stopped temporarily.\n\nIn patients with clinical hyperthyroidism and urticaria, a trial of withholding antithyroid drugs can be utilized with close assessment of response.\n\nShort‐term symptomatic relief of urticaria can be found with high dose antihistamines and steroids.\n\n\t\nJohn Wiley & Sons, Ltd\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTION\n\nNW: involved in conception/analysis, drafting of the article, critical revision of the article, and final approval. EJ: involved in conception/analysis, critical revision of the article, and final approval.\n\nETHICAL APPROVAL\n\nHereby, I, Dr Nicholas Womack, consciously assure that for the manuscript “Urticaria as a Manifestation of Hyperthyroidism” the following is fulfilled: (1) This material is the authors' own original work, which has not been previously published elsewhere. (2) The paper is not currently being considered for publication elsewhere. (3) The paper reflects the authors' own research and analysis in a truthful and complete manner. (4) The paper properly credits the meaningful contributions of coauthors and coresearchers. (5) The results are appropriately placed in the context of prior and existing research. (6) All sources used are properly disclosed (correct citation). Literally copying of text must be indicated as such by using quotation marks and giving proper reference. (7) All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content.\n\nACKNOWLEDGMENTS\n\nWith thanks to Tameside and Glossop Integrated Care NHS Foundation Trust. Consent statement: Written and verbal consent provided by patient for the article and related images.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are openly available through Wiley at DOI: https://doi.org/10.22541/au.159112170.04349002.\n==== Refs\nREFERENCES\n\n1 Deacock S . An approach to the patient with urticaria. Clin Exp Immunol. 2008;153 (2 ):151‐161.18713139\n2 Fröhlich E , Wahl R . Thyroid autoimmunity: role of anti‐thyroid antibodies in thyroid and extra‐thyroidal diseases. Front Immunol. 2017;8 :521.28536577\n3 Kravets I . Hyperthyroidism: diagnosis and treatment. Am Fam Physician. 2016;93 (5 ):1‐2.\n4 Isaacs N , Ertel N . Urticaria and pruritus: uncommon manifestations of hyperthyroidism. J Allergy Clin Immunol. 1971;48 (2 ):73‐81.4104292\n5 Lee S , Ha E , Jee H , et al. Prevalence and risk factors of urticaria with a focus on chronic urticaria in children. Allergy Asthma Immunol Res. 2017;9 (3 ):212.28293927\n6 O'Donnell B , Lawlor F , Simpson J , Morgan M , Greaves M . The impact of chronic urticaria on the quality of life. Br J Dermatol. 1997;136 (2 ):197‐201.9068731\n7 Baiardini I , Pasquali M , Braido F , et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire (CU‐Q2oL). Allergy. 2005;60 (8 ):1073‐1078.15969690\n8 Cks.nice.org.uk . Urticaria ‐ NICE CKS [online]. 2019. https://cks.nice.org.uk/urticaria#!scenario. Accessed July 20, 2019.\n9 Rothfeld B . Pruritus as a symptom in hyperthyroidism. JAMA, J Am Med Assoc. 1968;205 (1 ):52.\n10 Selvendran S , Aggarwal N . Chronic urticaria and thyroid autoimmunity: a perplexing association. Oxf Med Case Reports. 2018;2018 (2 ):omx099.29492270\n11 Altrichter S , Peter H , Pisarevskaja D , Metz M , Martus P , Maurer M . IgE mediated autoallergy against thyroid peroxidase – a novel pathomechanism of chronic spontaneous urticaria? PLoS One. 2011;6 (4 ):e14794.21532759\n12 Metz M , Staubach P , Bauer A , et al. Clinical efficacy of omalizumab in chronic spontaneous urticaria is associated with a reduction of FcεRI‐positive cells in the skin. Theranostics. 2017;7 (5 ):1266‐1276.28435464\n13 Abraham P , Acharya S . Current and emerging treatment options for Graves' hyperthyroidism. Ther Clin Risk Manag. 2009;6 :29‐40.\n14 Brent G . Mechanisms of thyroid hormone action. J Clin Invest. 2012;122 (9 ):3035‐3043.22945636\n15 Ponmani C , Mcclatchey M , Kanzaria S , Keane M , Banerjee K . Severe urticaria in graves' disease: is carbimazole to blame? Hormone Research in Paediatrics, [online] 82(P‐D‐2‐2‐599). 2014. http://abstracts.eurospe.org/hrp/0082/hrp0082p2‐d2‐599. Accessed July 20, 2019\n16 Pan S , Wood D , Chatterjee K . Fixed drug eruption in the endocrine clinic: rare presentation of reaction to carbimazole. Endocrine Abstracts, [online] 28(P367). 2012. https://www.endocrine‐abstracts.org/ea/0028/ea0028p367. Accessed July 20, 2019\n17 Pearce S . Spontaneous reporting of adverse reactions to carbimazole and propylthiouracil in the UK. Clin Endocrinol. 2004;61 (5 ):589‐594.\n18 Demir M , Yaylaci S , Tamer A , Ayturk S . Propylthiouracil induced leukocytoclastic vasculitis: a rare manifestation. Indian J Endocrinol Metab. 2013;17 (2 ):339.23776917\n19 Talapatra I , Prabhakar K , Tymms D . Urticaria; an uncommon presentation of thyrotoxicosis. Eur J Gen Med. 2007;4 (4 ):205‐208.\n\n",
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"keywords": "carbimazole; hyperthyroidism; urticaria",
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"title": "Urticaria as a manifestation of hyperthyroidism.",
"title_normalized": "urticaria as a manifestation of hyperthyroidism"
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"abstract": "A fecal microbiota transplant has proved to be an extremely effective method for patients with recurrent infections with Clostridium difficile. We present the case of a 65-year-old female patient with multiple Clostridium difficile infection (CDI) relapses on the rectal remnant, post-colectomy for a CDI-related toxic megacolon. The patient also evidenced associated symptomatic Clostridium difficile vaginal infection. She was successfully treated with serial fecal \"minitransplants\" (self-administered at home) and metronidazole ovules.",
"affiliations": "Lucian Blaga University; Polisano Clinic, Sibiu, Romania. popadaniel1980@yahoo.com.;Department of Gastroenterology, Prof. Dr. Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania.;Department of Gastroenterology, Prof. Dr. Octavian Fodor Regional Institute of Gastroenterology and Hepatology; 3rd Medical Clinic, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania.;Polisano Clinic, Sibiu, Romania.;Lucian Blaga University, Sibiu, Romania.;Department of Gastroenterology, Prof. Dr. Octavian Fodor Regional Institute of Gastroenterology and Hepatology; 3rd Medical Clinic, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania.",
"authors": "Popa|Daniel|D|;Laszlo|Mihaela|M|;Ciobanu|Lidia|L|;Ucenic|Elena|E|;Mihalache|Manuela|M|;Pascu|Oliviu|O|",
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"title": "Self-Administered Home Series Fecal \"Minitransplants\" for Recurrent Clostridium difficile Infection on a Rectal Remnant.",
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"abstract": "Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by failure of superoxide production in phagocytic cells. The disease is characterised by recurrent infections and inflammatory events, frequently affecting the lungs. Improvement of life expectancy now allows most patients to reach adulthood. We aimed to describe the pattern of pulmonary manifestations occurring during adulthood in CGD patients. This was a retrospective study of the French national cohort of adult patients (≥16 years old) with CGD. Medical data were obtained for 67 adult patients. Pulmonary manifestations affected two-thirds of adult patients. Their incidence was significantly higher than in childhood (mean annual rate 0.22 versus 0.07, p=0.01). Infectious risk persisted despite anti-infectious prophylaxis. Invasive fungal infections were frequent (0.11 per year per patient) and asymptomatic in 37% of the cases. They often required lung biopsy for diagnosis (10 out of 30). Noninfectious respiratory events concerned 28% of adult patients, frequently associated with a concomitant fungal infection (40%). They were more frequent in patients with the X-linked form of CGD. Immune-modulator therapies were required in most cases (70%). Respiratory manifestations are major complications of CGD in adulthood. Noninfectious pulmonary manifestations are as deleterious as infectious pneumonia. A specific respiratory monitoring is necessary.",
"affiliations": "Service de Pneumologie, Hôpital Foch, Suresnes, France UPRES EA 220, Suresnes, France Faculté des Sciences de la Santé Simone Veil, Université Versailles-Saint-Quentin-en-Yvelines, Versailles, France h.salvator@hopital-foch.com.;CEREDIH, Centre de Référence des Déficits Immunitaires Héréditaires, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France Service d'Immunologie-Hématologie et Rhumatologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France INSERM UMR 1163, Paris, France.;Service de Pneumologie, Hôpital Foch, Suresnes, France.;Service de Pneumologie, Hôpital Foch, Suresnes, France.;Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.;Service de Pneumologie A, Centre de Compétence Maladies Rares Pulmonaires, DHU FIRE, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France INSERM UMR 1152, Paris, France.;Service de Pneumologie A, Centre de Compétence Maladies Rares Pulmonaires, DHU FIRE, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France INSERM UMR 1152, Paris, France.;Service de Pneumologie, Hôpital Foch, Suresnes, France UPRES EA 220, Suresnes, France Faculté des Sciences de la Santé Simone Veil, Université Versailles-Saint-Quentin-en-Yvelines, Versailles, France.;CEREDIH, Centre de Référence des Déficits Immunitaires Héréditaires, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France INSERM UMR 1163, Paris, France Service d'Hématologie Adulte, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.;Service de Médecine Interne, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.;UF Dysfonctionnements Immunitaires, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France INSERM UMR 1149, Paris, France.;UF Dysfonctionnements Immunitaires, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France INSERM UMR 1149, Paris, France.;Délégation pour la Recherche Clinique et l'Innovation, Hôpital Foch, Suresnes, France.;Service de Médecine Interne, Hospices Civils de Lyon, Groupe Hospitalier Sud, Université de Lyon, Lyon, France.;Service d'Hématologie et Oncologie pédiatrique, Centre Hospitalier Universitaire de Nancy, Nancy, France.;CEREDIH, Centre de Référence des Déficits Immunitaires Héréditaires, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France INSERM UMR 1163, Paris, France Service d'Hématologie Adulte, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.;CEREDIH, Centre de Référence des Déficits Immunitaires Héréditaires, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France INSERM UMR 1163, Paris, France Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker Pasteur, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.;CEREDIH, Centre de Référence des Déficits Immunitaires Héréditaires, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France Service d'Immunologie-Hématologie et Rhumatologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France INSERM UMR 1163, Paris, France Collège de France, Paris, France.;Service de Pneumologie, Hôpital Foch, Suresnes, France UPRES EA 220, Suresnes, France Faculté des Sciences de la Santé Simone Veil, Université Versailles-Saint-Quentin-en-Yvelines, Versailles, France.",
"authors": "Salvator|Hélène|H|;Mahlaoui|Nizar|N|;Catherinot|Emilie|E|;Rivaud|Elisabeth|E|;Pilmis|Benoit|B|;Borie|Raphael|R|;Crestani|Bruno|B|;Tcherakian|Colas|C|;Suarez|Felipe|F|;Dunogue|Bertrand|B|;Gougerot-Pocidalo|Marie-Anne|MA|;Hurtado-Nedelec|Margarita|M|;Dreyfus|Jean-François|JF|;Durieu|Isabelle|I|;Fouyssac|Fanny|F|;Hermine|Olivier|O|;Lortholary|Olivier|O|;Fischer|Alain|A|;Couderc|Louis-Jean|LJ|",
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"country": "England",
"delete": false,
"doi": "10.1183/09031936.00118414",
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"issn_linking": "0903-1936",
"issue": "45(6)",
"journal": "The European respiratory journal",
"keywords": null,
"medline_ta": "Eur Respir J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents; D058070:Asymptomatic Diseases; D001706:Biopsy; D015331:Cohort Studies; D005260:Female; D006105:Granulomatous Disease, Chronic; D006801:Humans; D007155:Immunologic Factors; D008168:Lung; D008171:Lung Diseases; D008172:Lung Diseases, Fungal; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D018410:Pneumonia, Bacterial; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "8803460",
"other_id": null,
"pages": "1613-23",
"pmc": null,
"pmid": "25614174",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pulmonary manifestations in adult patients with chronic granulomatous disease.",
"title_normalized": "pulmonary manifestations in adult patients with chronic granulomatous disease"
} | [
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"activesubstancename": "ITRACONAZOLE"
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{
"abstract": "Six patients developed metastatic merkel-cell carcinoma and were treated with a combination chemotherapy frequently used for small-cell lung cancer. Five of six patients had a complete response for a median of 3.5 months. Overall survival from initiation of chemotherapy was a median of 6.5 months. Two patients died from major complications of therapy.",
"affiliations": "Hematology-Oncology Service, Walter Reed Army Medical Center, Washington D.C.",
"authors": "Redmond|J|J|;Perry|J|J|;Sowray|P|P|;Vukelja|S J|SJ|;Dawson|N|N|",
"chemical_list": "D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D002945:Cisplatin",
"country": "United States",
"delete": false,
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"issn_linking": "0277-3732",
"issue": "14(4)",
"journal": "American journal of clinical oncology",
"keywords": null,
"medline_ta": "Am J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015266:Carcinoma, Merkel Cell; D002945:Cisplatin; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D012074:Remission Induction; D012878:Skin Neoplasms; D015996:Survival Rate; D014750:Vincristine",
"nlm_unique_id": "8207754",
"other_id": null,
"pages": "305-7",
"pmc": null,
"pmid": "1862761",
"pubdate": "1991-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chemotherapy of disseminated Merkel-cell carcinoma.",
"title_normalized": "chemotherapy of disseminated merkel cell carcinoma"
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{
"companynumb": "US-PFIZER INC-2020322919",
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"occurcountry": "US",
"patient": {
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{
"abstract": "Limited data was available for long-term follow-up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all-trans-retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)-based front-line therapy. The aim of this work was to retrospectively analyze the long-term survival rate and frequency of therapy-related myeloid neoplasia (t-MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front-line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non-ATO group). The median duration of follow-up was 7.5 years (1.0-18.3 years). ATO group showed significant superior 10-year estimated relapse-free survival (RFS) up to 90.3% comparing with 65.5% in the non-ATO group (P < 0.0001). In addition, the 10-year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non-ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non-ATO group in both low-to-intermediate-risk (94.2% vs 64.6%, P < 0.0001) and high-risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3-year RFS and OS rates in the chemotherapy-free subgroup of the low-to-intermediate-risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy-related myeloid neoplasms (t-MN). The estimated 5-year cumulative incidence risk of t-MN in the ATO and non-ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long-term outcome of patients treated with ATRA plus ATO-based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.",
"affiliations": "Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, the Ningbo Yinzhou People's Hospital, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, the Ningbo Yinzhou People's Hospital, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.;Department of Hematology, the Ningbo Yinzhou People's Hospital, Zhejiang, People's Republic of China.;Department of Hematology, Leukemia center, The First Affiliated Hospital of Zhejiang University, College of Medicine; Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.",
"authors": "Lou|Yinjun|Y|http://orcid.org/0000-0003-4495-2460;Lu|Ying|Y|;Zhu|Zhijuan|Z|;Ma|Yafang|Y|;Suo|Shanshan|S|;Wang|Yungui|Y|;Chen|Dong|D|;Tong|Hongyan|H|;Qian|Wenbin|W|;Meng|Haitao|H|;Mai|Wenyuan|W|;Yu|Wenjun|W|;Xu|Weilai|W|;Wang|Lei|L|;Mao|Liping|L|;Pei|Renzhi|R|;Jin|Jie|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/hon.2519",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-0232",
"issue": null,
"journal": "Hematological oncology",
"keywords": "acute promyelocytic leukemia; arsenic trioxide; long-term survival; therapy-related myeloid neoplasms",
"medline_ta": "Hematol Oncol",
"mesh_terms": null,
"nlm_unique_id": "8307268",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29862538",
"pubdate": "2018-06-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Improved long-term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide-based front-line therapy.",
"title_normalized": "improved long term survival in all sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide based front line therapy"
} | [
{
"companynumb": "CN-MYLANLABS-2018M1069654",
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "TRETINOIN"
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{
"abstract": "Targeted cancer therapies often induce \"outlier\" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.",
"affiliations": null,
"authors": "Imielinski|Marcin|M|;Greulich|Heidi|H|;Kaplan|Bethany|B|;Araujo|Luiz|L|;Amann|Joseph|J|;Horn|Leora|L|;Schiller|Joan|J|;Villalona-Calero|Miguel A|MA|;Meyerson|Matthew|M|;Carbone|David P|DP|",
"chemical_list": "D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; C482119:BRAF protein, human; D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-9738",
"issue": "124(4)",
"journal": "The Journal of clinical investigation",
"keywords": null,
"medline_ta": "J Clin Invest",
"mesh_terms": "D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000368:Aged; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents; D002471:Cell Transformation, Neoplastic; D004273:DNA, Neoplasm; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D009536:Niacinamide; D009857:Oncogenes; D010671:Phenylurea Compounds; D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D000077157:Sorafenib",
"nlm_unique_id": "7802877",
"other_id": null,
"pages": "1582-6",
"pmc": null,
"pmid": "24569458",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "22663011;17603483;22982658;19755855;18948947;23737487;23401445;22923433;23589544;23224737;22037377;17016424;22980976;20668451;10801873;15520807;22908275;8616716;15870716;22980975;17982442",
"title": "Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma.",
"title_normalized": "oncogenic and sorafenib sensitive araf mutations in lung adenocarcinoma"
} | [
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"companynumb": "US-ROCHE-1390330",
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"occurcountry": "US",
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"abstract": "Few geriatric patients were included in studies on direct oral anticoagulants and data on dabigatran concentration and safety are needed in this population. Our objectives were to evaluate peak and trough dabigatran plasma concentrations over time in a geriatric population and to identify factors associated with dabigatran plasma concentrations and to assess the relationship with bleeding events.\n\n\n\nPeak and trough dabigatran plasma concentration were performed 4,8,15,30,45 days after inception of dabigatran treatment in 68 consecutive patients ≥75 years old hospitalized in a geriatric hospital with atrial fibrillation. Bleeding events were monitored for 1 year.\n\n\n\nMean age was 85.8(5.1) years old and 76.5% were women. Overall, 541 dabigatran plasma measurements (270 peak, 271 trough) were performed. Mean dabigatran concentrations of the 5 sequential measurements ranged 106-146ng/mL for peak and 66-84ng/mL for trough. Renal failure was associated with high peak and trough dabigatran concentration. Inter- and intra-individual coefficients of variation were 59.5% and 44.7% for peak and 74.5% and 44.6% for trough. Participants in the lower two tertiles of dabigatran concentration at day 8 (D8) remained below the 90th percentile (243.9ng/ml) on the next measurements. Bleeding events were associated with high trough dabigatran concentrations. Trough dabigatran concentration at D8>243.9ng/mL significantly predicted bleeding.\n\n\n\nIn this geriatric population, renal function and low albumin were associated with dabigatran concentrations. Despite large variability, participants in the lower two tertiles of dabigatran concentration at D8 remained below the 90th percentile on the following measurements. D8 dabigatran trough concentration≥243.9ng/mL identified patients at risk of bleeding.",
"affiliations": "Prof. Olivier Hanon, Hôpital Broca, 54-56 Pascal, 75013 Paris, France, Tel: +33 1 44 08 30 00, Fax: +33 1 44 08 36 18, Email: olivier.hanon@aphp.fr.",
"authors": "Chaussade|E|E|;Hanon|O|O|;Boully|C|C|;Labourée|F|F|;Caillard|L|L|;Gerotziafas|G|G|;Vidal|J-S|JS|;Elalamy|I|I|",
"chemical_list": "D000991:Antithrombins; D000069604:Dabigatran",
"country": "France",
"delete": false,
"doi": "10.1007/s12603-017-0982-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1279-7707",
"issue": "22(1)",
"journal": "The journal of nutrition, health & aging",
"keywords": "80 and over; Anticoagulants; aged; antithrombins; atrial fibrillation",
"medline_ta": "J Nutr Health Aging",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins; D001281:Atrial Fibrillation; D000069604:Dabigatran; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D012307:Risk Factors",
"nlm_unique_id": "100893366",
"other_id": null,
"pages": "165-173",
"pmc": null,
"pmid": "29300437",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "23769405;14577060;17577005;15582289;7722560;20214409;25464465;24076487;11783668;21788546;21576658;20299623;16527828;25651449;1202204;23369212;15969921;19717844;26672898;1244564;15611490;25995317;19762550;24315724;23010710;20609686;18399711;23718677;25523236;15882252;10460985;16908781;21830957;22227958;25994994;23784008;22111719",
"title": "Real-Life Peak and Trough Dabigatran Plasma Measurements over Time in Hospitalized Geriatric Patients with Atrial Fibrillation.",
"title_normalized": "real life peak and trough dabigatran plasma measurements over time in hospitalized geriatric patients with atrial fibrillation"
} | [
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"companynumb": "FR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-061568",
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"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
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"abstract": "Isoniazid-induced seizures are a rare adverse reaction especially in immunocompetent adults. We report a case of a healthy man with seizures shortly after ingestion of his first therapeutic dose of isoniazid with rifapentine therapy for treatment of latent tuberculosis infection. Only 6 other similar cases are reported in the literature.",
"affiliations": "University of Mississippi Medical Center, Jackson, Mississippi, USA.;University of Mississippi Medical Center, Jackson, Mississippi, USA.;University of Mississippi Medical Center, Jackson, Mississippi, USA.;University of Mississippi Medical Center, Jackson, Mississippi, USA.;University of Mississippi Medical Center, Jackson, Mississippi, USA.",
"authors": "Navalkele|Bhagyashri|B|;Bueno Rios|Maria X|MX|;Wofford|John D|JD|;Kumar|Vijay|V|;Webb|Risa M|RM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa144",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa144\nofaa144\nBrief Report\nAcademicSubjects/MED00290\nSeizures in an Immunocompetent Adult From Treatment of Latent Tuberculosis Infection: Is Isoniazid to Blame?\nNavalkele Bhagyashri Bueno Rios Maria X Wofford John D Kumar Vijay Webb Risa M \nUniversity of Mississippi Medical Center, Jackson, Mississippi, USA\nCorrespondence: Bhagyashri D. Navalkele, MD, FACP, Assistant Professor, Division of Infectious Diseases, Department of Internal Medicine, The University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39110 (bnavalkele@umc.edu ).\n5 2020 \n23 4 2020 \n23 4 2020 \n7 5 ofaa14413 2 2020 17 4 2020 21 4 2020 20 5 2020 © The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2020This 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.comAbstract\nIsoniazid-induced seizures are a rare adverse reaction especially in immunocompetent adults. We report a case of a healthy man with seizures shortly after ingestion of his first therapeutic dose of isoniazid with rifapentine therapy for treatment of latent tuberculosis infection. Only 6 other similar cases are reported in the literature.\n\nisoniazidlatent tuberculosispyridoxineseizurestuberculosis\n==== Body\nLatent tuberculosis infection (LTBI) is defined as Mycobacterium tuberculosis (TB) bacteria infecting an asymptomatic person who does not have risk of transmission to others. Worldwide, approximately 25% of the population has LTBI. According to the US National TB Surveillance System (2011–2015), an estimated 8.9 million persons (3.1%) have LTBI [1]. The Centers for Disease Control and Prevention (CDC) and American Thoracic Society strongly recommend testing and treating LTBI to avoid development of active TB disease. Treatment regimens for LTBI include isoniazid (INH), INH plus rifapentine (RPT), or rifampin (RIF) based therapy. A randomized controlled trial (RCT) published in 2011 demonstrated a once-weekly INH and RPT regimen for 12-weeks (3HP) to be as effective as 9 months of daily INH therapy for treatment of LTBI. Treatment completion rate in the directly observed once-weekly 3HP group was higher (82%) compared with the group receiving self-administered daily INH (69%) (P < .001) [2]. Increased adherence was attributed to directly observed and shorter duration of therapy. According to the recent guidelines published by the National Tuberculosis Controllers Association and CDC, INH is now considered as an alternative LTBI regimen due to long duration of therapy, hepatotoxicity, and potential low treatment completion rate [3]. Currently, the CDC recommends the 3HP regimen in persons that are 2 years or older, including those with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), as the preferred treatment of choice for LTBI [4].\n\nAdverse effects of the 3HP regimen in the RCT indicated a higher number of cases that discontinued the 3HP regimen due to an adverse event (4.9%) compared with those on INH (3.7%) (P = .0009) [2]. However, there was no difference in serious adverse events or risk of death in either treatment group; moreover, the risk for hepatitis was lower with 3HP. A follow-up postmarketing observational study of 3288 US clinic-based patients who successfully completed the 3HP regimen reported adverse drug reaction in 35.7% of the patients [5]. The most common adverse reactions included nausea (15%), fatigue (12%), myalgias (8%), other systemic complaints (8%), and headaches (7%). Approximately 6% of patients complained of fever/chills, dizziness, or abdominal pain. Approximately 5% or less had rash/hives, appetite loss, neuropathy, diarrhea, or jaundice as reported reactions. No serious adverse reactions (including seizures) were reported. Despite the adverse reactions, 79% of the patients successfully completed LTBI treatment. Thus, the 3HP regimen is recognized as an effective, safe treatment with high treatment completion rates and potential to further decrease TB disease in the United States. In this study, we report the first case of seizures after the first dose of the 3HP regimen in an immunocompetent adult.\n\nCASE\nA 28-year-old man, originally from Pakistan, presented to the Employee Health for a pre-employment health screening. His QuantiFERON-TB Gold test was positive. Subsequent evaluation was negative for any signs or symptoms of active TB. Chest radiograph was negative for any pulmonary disease. Laboratory screening test was negative for HIV antigen/antibody with normal renal and hepatic function test. Diagnosis of LTBI was established. The patient had no other comorbidities, and he denied history of seizures. He did not have previous or active history of alcohol consumption or illicit drug use. He was not taking any medications or herbals at that time. He was initiated on the 3HP regimen (oral INH 900 mg with RPT 900 mg once weekly for 12 weeks). After ingestion of his first dose of 3HP, he returned to work. Approximately 1–2 hours postingestion, he had a medical doctor-witnessed generalized tonic-clonic (GTC) seizure lasting approximately 2 minutes. No tongue-biting, bowel, or bladder incontinence was observed. He was transferred to the emergency department (ED) in a postictal state. In the ED, vital signs were stable with blood pressure of 136/82 mmHg, pulse 106/minute, temperature 98.3°F, respiratory rate of 18/minute, oxygen saturation of 97% on room air, and weight of 70.8 kg. Physical examination was normal with the exception of altered mentation. While in the ED, he experienced another episode of GTC seizure lasting approximately 1minute. Point-of-care laboratory tests showed a blood glucose level of 143 mg/dL and normal serum electrolytes. Urine drug screen was not performed. He received 2 mg of lorazepam and was given 1 gram of levetiracetam. Due to concerns for potential INH toxicity, initially 250 mg of vitamin B6 was administered. Subsequently, toxicology was consulted and he received a loading dose of 4750 mg of vitamin B6. Serum vitamin B6 level was not collected before loading. All diagnostic tests per neurology recommendation were negative including computed tomography of the head, magnetic resonance imaging of the brain, and electroencephalography. Infectious diseases (ID) experts recommended withholding further LTBI treatment during hospitalization. He had no further seizures during the 24-hour observation period and was discharged home when mentation was back to baseline. He was seen in the outpatient ID clinic 10 days after the event. He denied any history of prior TB including close contact with persons with active TB, prior treatments for TB, or any further seizure activity since discharge. He had self-initiated oral vitamin B6 postdischarge with intermittent adherence, and the subsequent serum B6 level was 78 mcg/L (normal value 5–50 mcg/L). Due to concern for INH-induced seizures, he was initiated on RIF 600 mg oral daily regimen for 4 months. He successfully completed LTBI treatment with RIF without any reported adverse events.\n\nDiscussion\nSeizures are a rare but serious adverse reaction related to medication ingestion. Up to 6% of new-onset seizures are associated with drug toxicity [6]. Exposure to medications, including but not limited to opiods, antidepressants, antibiotics, stimulants, and immunosuppressants, can increase excitatory or reduce inhibitory neuronal activity inducing seizures. Most events are self-limited without serious consequences.\n\nAmong medications used to treat LTBI, there are currently no reports of RPT or RIF causing seizures in the adult population. The most common adverse reaction secondary to INH is elevation of serum transaminases, and the most severe and at times fatal reaction is hepatitis. Isoniazid diffuses readily across all body fluids including the cerebrospinal fluid (CSF) [7]. Isoniazid is associated with adverse reactions involving central nervous system (CNS), such as paresthesia, peripheral neuropathy, psychosis, and seizure, with undefined frequency. Usually, overdose or ingestion of a toxic dose of INH has been associated with these CNS reactions. A dose over 30 mg/kg may be associated with hallucinations, recurrent seizures, metabolic acidosis, hypotension, and coma. Death may occur at doses of over 80 mg/kg [8]. Isoniazid mainly acts by inhibiting pyridoxal-5-phosphate or pyridoxine phosphokinase enzyme, thus reducing gamma amino butyric acid (GABA) levels, an inhibitory neurotransmitter, and thus precipitating seizure activity. Pyridoxine is a cofactor in GABA synthesis and its deficiency can further enhance INH-induced seizures. Pyridoxine deficiency can be present in patients with underlying medical conditions such as pregnancy, cancer, uremia, alcoholism, chronic liver disease, and advanced age. In patients at high risk for peripheral neuropathy and other INH toxicities, concomitant supplementation of oral pyridoxine (25–50 mg daily) with INH is recommended [9]. Pyridoxine causes immediate cessation of seizures by rapidly binding to INH and restoring GABA production. The recommended pyridoxine treatment dose for an unknown INH overdose is a maximum of 5 grams intravenously to an adult or child [8]. Alternatively, in cases of the known ingested dose, a pyridoxine dose equivalent to the amount of INH ingested (gram for gram) is recommended.\n\nIn our case, the patient was immunocompetent with no known underlying risk factors to precipitate pyridoxine deficiency, and he did not consume a toxic dose of INH. Even though current literature reviews indicate that most cases of INH-induced seizures have been reported secondary to overdose or toxicity, it is worth noting that our patient received a dose 3 times higher than the usual daily dosing but consistent with intermittent dosing regimen per guidelines. He developed seizures 1–2 hours after INH and RPT ingestion. Plasma levels of INH usually peak 0.75 to 2 hours after dosing; meanwhile, CNS peak concentration occurs approximately 4 hours after ingestion [10, 11]. Peak plasma concentration of RPT occurs approximately 5 hours after ingestion, and overall CSF penetration is estimated to be low (lipophilic and plasma protein binding of 80%) [10, 12, 13]. These findings favor INH as the most likely culprit given its shorter peak time and good CSF penetration. To further determine causality, the Naranjo adverse drug reaction probability scale was applied and validated INH as probable cause for the seizures (score = 6) [14]. Due to concern for INH-induced seizures, th patient received the maximum dose of pyridoxine, which possibly prevented further seizures.\n\nTo our knowledge, only 6 case reports are published on INH-induced seizures after receiving a therapeutic INH dose (Table 1). Of the 6 reports, 67% cases were receiving INH treatment for active TB [15–18]. Of the 2 LTBI cases, 1 was an elderly patient with end-stage renal disease and 1 was an adult with HIV infection [19, 20]. All 6 reported cases had underlying medical conditions, except for 1 elderly man receiving treatment for pulmonary TB. Pyridoxine treatment was successful in achieving cessation of refractory seizures in two thirds of the reported cases. One did not respond to any treatments and died. One did not receive pyridoxine, but TB treatment was stopped.\n\nTable 1. Literature Review of Six Case Reports on INH-Induced Seizures\n\nCases\tAge (years) \tSex\tUnderlying Illness\tDiagnosis\tOngoing Treatment\tTime to Seizure \tType of Seizure\tSeizure Response\tOutcome\t\n1\t67 \tM\tHypertension, Chronic kidney disease\tDisseminated TB \tINH 200 mg daily, pyridoxine 25 mg daily, Streptomycin 250 mg daily \t13 days\tGTC\tNo response to phenytoin, pyridoxine 500 mg, diazepam, phenobarbital\tDied\t\n2\t35\tM\tAlcohol and tobacco abuse\tPulmonary TB\tINH 600 mg+RIF 450 mg+PZ 1500 mg+ETM 1200 mg (thrice weekly)\tWithin 24 hrs\tGTC\tResponse to cessation of TB treatment\tSurvived\t\n3\t65 \tM\tNone\tPulmonary TB\tINH 600 mg+RIF 450 mg+ETM 1200 mg+PZ 1500 mg (thrice weekly regimen) \t1 hour after first dose\tGTC\tUnresponsive to phenytoin, diazepam. Response to pyridoxine 100 mg bid\tSurvived\t\n4\t86\tF\tHypertension, Pleuritis, Diabetes mellitus\tDisseminated TB\tINH 200 mg+RIF 450 mg+ETM 750 mg daily\t7 days\tGTC\tNo response to diazepam, phenobarbital, phenytoin. Response to pyridoxal phosphate 60 mg/day\tSurvived\t\n5\t66\tF\tEnd-stage renal disease on peritoneal dialysis\tLTBI\tINH 300 mg daily\t24 hours–2 days\tFocal \tResponse to pyridoxine 50 mg \tSurvived\t\n6\t44 \tF\tHIV\tLTBI\tINH 300 mg daily\t2 months\tGTC, Status epilepticus\tNo response to lorazepam, phenytoin, Response to pyridoxine 5 g\tSurvived\t\nAbbreviations: ETM, ethambutol; F, female; g, gram; GTC, generalized tonic-clonic; HIV, human immunodeficiency virus; INH, isoniazid; LTBI, latent tuberculosis infection; M, male; PZ, pyrazinamide; RIF, rifampin/rifampicin; RPT, rifapentine; TB, tuberculosis. \n\nConclusions\nOur case is unique and illustrates the possibility of risk of seizures while treating an immunocompetent adult with therapeutic doses of INH. Our patient did not have comorbidities or evidence of malnutrition. Healthcare providers should be cognizant of this uncommon but potentially severe adverse reaction and consider concomitant therapy with vitamin B6 during INH treatment and administering appropriate pyridoxine dosing if a seizure occurs.\n\nAcknowledgments\nWe thank the clinicians and staff at the University of Mississippi Medical Center who supported the clinical care of this patient through expert advice and consultation.\n\n\nPotential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1. \nHaddad MB , Raz KM , Lash TL , et al \nSimple estimates for local prevalence of latent tuberculosis infection, United States, 2011–2015\n. Emerg Infect Dis 2018 ; 24 :1930 –3\n.30226174 \n2. \nSterling TR , Villarino ME , Borisov AS , et al. ; TB Trials Consortium PREVENT TB Study Team \nThree months of rifapentine and isoniazid for latent tuberculosis infection\n. N Engl J Med 2011 ; 365 :2155 –66\n.22150035 \n3. \nSterling TR , Njie G , Zenner D , et al. \nGuidelines for the treatment of latent tuberculosis infection: recommendations from the National Tuberculosis Controllers Association and CDC, 2020\n. MMWR Recomm Rep 2020 ; 69 :1 –11\n.\n4. \nBorisov AS , Bamrah Morris S , Njie GJ , et al. \nUpdate of recommendations for use of once-weekly isoniazid-rifapentine regimen to treat latent mycobacterium tuberculosis infection\n. MMWR Morb Mortal Wkly Rep 2018 ; 67 :723 –6\n.29953429 \n5. \nSandul AL , Nwana N , Holcombe JM , et al. \nHigh rate of treatment completion in program settings with 12-dose weekly isoniazid and rifapentine for latent mycobacterium tuberculosis infection\n. Clin Infect Dis 2017 ; 65 :1085 –93\n.28575208 \n6. \nChen HY , Albertson TE , Olson KR \nTreatment of drug-induced seizures\n. Br J Clin Pharmacol 2016 ; 81 :412 –9\n.26174744 \n7. \nDonald PR \nCerebrospinal fluid concentrations of antituberculosis agents in adults and children\n. Tuberculosis (Edinb) 2010 ; 90 :279 –92\n.20709598 \n8. \nGlatstein M , Carbell G , Scolnik D , et al. \nPyridoxine for the treatment of isoniazid-induced seizures in intentional ingestions: the experience of a national poison center\n. Am J Emerg Med 2018 ; 36 :1775 –8\n.29397257 \n9. \nThe selection and use of essential medicines\n. World Health Organ Tech Rep Ser 2015 ; vii-xv :1 –546\n.\n10. \nPeloquin CA \nTherapeutic drug monitoring in the treatment of tuberculosis\n. Drugs 2002 ; 62 :2169 –83\n.12381217 \n11. \nEllard GA , Humphries MJ , Allen BW \nCerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis\n. Am Rev Respir Dis 1993 ; 148 :650 –5\n.8368635 \n12. \nNau R , Sörgel F , Eiffert H \nPenetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections\n. Clin Microbiol Rev 2010 ; 23 :858 –83\n.20930076 \n13. \nJarvis B , Lamb HM \nRifapentine\n. Drugs 1998 ; 56 :607 –16\n; discussion 17.9806107 \n14. \nNaranjo CA , Busto U , Sellers EM , et al. \nA method for estimating the probability of adverse drug reactions\n. Clin Pharmacol Ther 1981 ; 30 :239 –45\n.7249508 \n15. \nAach R , Kissane J \nGeneralized seizures following isoniazid therapy for tuberculosis in a patient with uremia\n. Am J Med 1972 ; 53 :765 –74\n.4628883 \n16. \nAiwale AS , Patel UA , Barvaliya MJ , et al. \nIsoniazid induced convulsions at therapeutic dose in an alcoholic and smoker patient\n. Curr Drug Saf 2015 ; 10 :94 –5\n.25859682 \n17. \nPuri MM , Kumar L , Vishwakarma PD , Behera D \nSeizures with single therapeutic dose of isoniazid\n. Indian J Tuberc 2012 ; 59 :100 –2\n.22838208 \n18. \nTsubouchi K , Ikematsu Y , Hashisako M , et al. \nConvulsive seizures with a therapeutic dose of isoniazid\n. Intern Med 2014 ; 53 :239 –42\n.24492693 \n19. \nAsnis DS , Bhat JG , Melchert AF \nReversible seizures and mental status changes in a dialysis patient on isoniazid preventive therapy\n. Ann Pharmacother 1993 ; 27 :444 –6\n.8477121 \n20. \nTajender V , Saluja J \nINH induced status epilepticus: response to pyridoxine\n. Indian J Chest Dis Allied Sci 2006 ; 48 :205 –6\n.18610679\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "7(5)",
"journal": "Open forum infectious diseases",
"keywords": "isoniazid; latent tuberculosis; pyridoxine; seizures; tuberculosis",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa144",
"pmc": null,
"pmid": "32462048",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": "9806107;30226174;12381217;8477121;29397257;4628883;22150035;28575208;27183787;7249508;24492693;22838208;26174744;25859682;8368635;20709598;20930076;32053584;29953429;18610679",
"title": "Seizures in an Immunocompetent Adult From Treatment of Latent Tuberculosis Infection: Is Isoniazid to Blame?",
"title_normalized": "seizures in an immunocompetent adult from treatment of latent tuberculosis infection is isoniazid to blame"
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"activesubstancename": "RIFAPENTINE"
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"abstract": "The safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).\n\n\n\nThis was a single-institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.\n\n\n\nWe identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non-small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1-2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).\n\n\n\nAdverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.\n\n\n\nThe safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors' institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.",
"affiliations": "The MetroHealth System Campus of Case Western Reserve University, Cleveland, Ohio, USA.;The MetroHealth System Campus of Case Western Reserve University, Cleveland, Ohio, USA.",
"authors": "Alkrekshi|Akram|A|0000-0001-7418-4883;Tamaskar|Ila|I|",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1002/onco.13739",
"fulltext": "\n==== Front\nOncologist\nOncologist\n10.1002/(ISSN)1549-490X\nONCO\ntheoncologist\nThe Oncologist\n1083-7159\n1549-490X\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n33655663\n10.1002/onco.13739\nONCO13739\n43\nImmuno‐Oncology\nImmuno‐Oncology\nSafety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection\nSafety of ICI in Cancer Patients with HCV\nAlkrekshi and Tamaskar\nAlkrekshi Akram https://orcid.org/0000-0001-7418-4883\n1 aalkrekshi@metrohealth.org\n\nTamaskar Ila 1\n1 The MetroHealth System Campus of Case Western Reserve University Cleveland Ohio USA\n* Correspondence: Akram Alkrekshi, M.D., The MetroHealth System Campus of Case Western Reserve University, 2500 MetroHealth Drive, Cleveland, Ohio 44109, USA. Telephone: 216‐778 ‐7800; e‐mail: aalkrekshi@metrohealth.org\n20 3 2021\n5 2021\n26 5 10.1002/onco.v26.5 e827e830\n12 4 2020\n08 2 2021\n© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ 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.\n\nAbstract\n\nBackground\n\nThe safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).\n\nMaterials and Methods\n\nThis was a single‐institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.\n\nResults\n\nWe identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1–2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).\n\nConclusion\n\nAdverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.\n\nImplications for Practice\n\nThe safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors’ institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.\n\nThe absence of immune checkpoint inhibitor (ICI) safety data in cancer patients with hepatitis C virus infection (HCV) makes it challenging to assess the risk‐benefit ratio of the therapy and to advise patients on the likelihood of adverse events to help them make informed decisions. This article reports a retrospective study of cancer patients with HCV untreated and resolved who received ICI therapy.\n\nImmune checkpoint inhibitor\nHepatitis C\nImmune‐related adverse events\nImmunotherapy\nRetrospective study\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:06.05.2021\n==== Body\nIntroduction\n\nImmune checkpoint inhibitors (ICIs), namely programmed death receptor‐1 (PD‐1) and programmed death receptor‐1 ligand (PD‐1L) inhibitors and cytotoxic T‐lymphocytic antigen 4 (CTLA‐4), have changed the cancer therapy paradigm and are approved for various malignancies: melanoma, lung cancer, hepatocellular carcinoma, and many others (Table 1). CTLA‐4 and PD‐1L are intrinsic downregulators of immunity that dampen the immune regulatory response. Cancer cells hijack this system to evade the immune system. ICIs, by blocking these cell surface proteins, enhance the antitumor immune response. In hepatitis C virus (HCV) infection, the expression of PD‐1/PD‐1L contributes to the persistence of infection [1]. Therefore, to avoid unforeseen adverse events (AEs; e.g., viral reactivation), patients with HCV infections were excluded from most clinical trials evaluating ICI even though HCV is a major health care problem, with a prevalence of 0.5%–2.3% worldwide [2]. Absence of ICI safety data in patients with cancer with HCV makes it challenging to adequately assess the risk‐benefit of ICI and to advise the patient on the likelihood of AEs to assist them in making an informed decision. This may result in ICIs being denied or delayed pending treatment of the underlying HCV. In this article, we conducted a retrospective study of all patients with cancer with HCV untreated and resolved who received ICI at our institution.\n\nTable 1 Immune checkpoint inhibitor indications\n\nMelanoma; adjuvant, unresectable, or metastatic\t\nNon‐small cell lung cancer; metastatic\t\nSmall cell lung cancer; metastatic\t\nHepatocellular carcinoma\t\nRenal cell carcinoma; advanced, or metastatic\t\nHodgkin lymphoma\t\nHead and neck squamous cell carcinoma; recurrent or metastatic\t\nUrothelial carcinoma; locally advanced or metastatic\t\nBreast cancer; triple‐negative locally advanced or metastatic\t\nColon cancer, metastatic (MSI‐H or dMMR)\t\nGlioblastoma\t\nCutaneous squamous cell carcinoma; locally advanced or metastatic\t\nGastric cancer; recurrent locally advanced or metastatic\t\nAnal cancer; metastatic\t\nMerkel cell carcinoma\t\nPrimary mediastinal large B‐cell lymphoma\t\nMesothelioma\t\nAbbreviations: dMMR mismatch repair deficient; MSI‐H, microsatellite instability‐high.\n\nMaterials and Methods\n\nThis was a single‐institution retrospective electronic chart review of all patients with active or resolved hepatitis C viral infection who were treated with an immune checkpoint inhibitor (ICI) for cancer of any type and stage from January 2012 to December 2019. Data collected included age, gender, ethnicity, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at the time of cancer diagnosis, cancer type and stage, hepatitis C status (specified as untreated chronic infection if the viral load was detected at the time of cancer diagnosis, treated if a history of treatment with undetectable viral load was documented, and spontaneously resolved if only hepatitis C virus antibody was present with undetectable viral load and absence of treatment history), viral genotype, presence of cirrhosis, liver function test before and throughout treatment, type of ICI, length of therapy in weeks, the reason for discontinuation of therapy, and toxicities. Patients with coinfection with hepatitis B virus or human immunodeficiency virus were excluded. The severity of immune‐mediated toxicities was graded using National Cancer Institute CTCAE, Version 5.0 [3]. The study was approved by the institutional review board.\n\nResults\n\nWe identified 40 cases, 30 (75%) men and 10 (25%) women, with median age of 64 years (range, 51–80). The largest ethnicity was Black (22; 55%), followed by White (17; 42.5%) and others (1; 2.5%). ECOG was 0–1 in 36 patients (90%) and 2 in four patients (10%). Median BMI was 24.3 kg/m2 (range, 16.7–42.8). Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (1; 2.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 patients (35%), and spontaneously resolved in 9 (22.5%) patients. Hepatitis C genotype was 1a in 25 patients (62.5%), 1b in 1 patient (2.5%), 3 in 1 (2.5%) patients, and unavailable for the rest. Viral load in untreated patients ranged from 45 to 7,620 × 103 copies per mL. Cirrhosis was documented in 22 patients (55%). None of the untreated patients received treatment for HCV at the time of cancer diagnosis before the commencement of ICI. ICIs used were nivolumab alone in 23 patients (57.5%), pembrolizumab in 10 (25%), atezolizumab in 4 (10%), durvalumab in 2 (5%), and combination of ipilimumab and nivolumab in 1 (2.5%). The median length of therapy with ICI was 16 weeks (range, 2–199). AEs noted (see Table 2) were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab, grade 3 colitis in one patient (2.5%) on nivolumab, hepatotoxicity in two patients (5%) on nivolumab (one patient with grade 1 and the other had grade 2), grade 1–2 fatigue in three patients (7.5%), and hypothyroidism in one patient (2.5%).\n\nTable 2 Characteristics of patients with HCV with adverse events while on immune checkpoint inhibitors\n\nCase\tAge, years\tSex\tEthnicity\tECOG PS\tCancer\tHCV status\tGenotype\tViral Load\tCirrhosis\tTherapy\tLength of therapy, weeks\tReason for discontinuation\tToxicities\t\n1\t65\tM\tBlack\t0\tNSCLC\tUntreated\t1a\t385 × 103\tNo\tNivolumab\t78\tToxicities\tPneumonitis, grade 3\t\n2\t61\tF\tBlack\t1\tNSCLC\tUntreated\t1a\t744 × 103\tNo\tNivolumab\t5\tPD\tFatigue grade, 1\t\n3\t64\tF\tBlack\t0\tNSCLC\tTreated\t1a\t0\tNo\tNivolumab and ipilimumab\t24\tOngoing\tHypothyroidism, grade 1 and fatigue, grade 2\t\n4\t55\tF\tWhite\t1\tSCLC\tUntreated\t1a\t152 × 103\tNo\t1\t9\tToxicities\tColitis, grade 3\t\n5\t74\tF\tOther\t1\tHCC\tTreated\t1a\t0\tYes\tNivolumab\t25\tPD\tFatigue, grade 1\t\n6\t66\tM\tWhite\t0\tHCC\tUntreated\t1a\t557 × 103\tYes\tNivolumab\t12\tPD\tHepatotoxicity, grade 1\t\n7\t59\tM\tBlack\t1\tHCC\tUntreated\t1b\t3,190 × 103\tYes\tNivolumab\t16\tPD\tHepatotoxicity, grade 2\t\nAbbreviations: ECOG, Eastern Cooperative Oncology Group Performance Status; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; NSCLC, non‐small cell lung cancer; PD, progressive disease; SCLC, small cell lung cancer.\n\nThe patient with grade 2 hepatotoxicity was a 55‐year‐old African American man with HCC. He had liver cirrhosis with MELD score of 7, ascites, and HCV with genotype 1b. The hepatotoxicity occurred after the first dose of nivolumab. Hepatotoxicity was marked by transaminitis, whereas alkalyine phosphatase, bilirubin, albumin, and clotting factors remained within the normal range. He was treated with prednisone 1 mg/kg with a taper over 2 weeks with a return of liver function test to baseline. He was continued on nivolumab with no further recurrence of hepatotoxicity, for timeline, and degree of transaminitis (see Fig. 1).\n\nFigure 1 Timeline of the patient with grade 2 hepatotoxicity due to nivolumab.\n\nAbbreviations: ALT alanine transaminase; AST aspartate transaminase.\n\nDiscussion\n\nChronic hepatitis C infection is a major health problem, with a prevalence of approximately 1% in the U.S., with higher rates in states with a worse opioid crisis, likely owing to increased injection drug use [4]. Although effective therapy for HCV is now present, challenges in prevention, case detection, treatment affordability, and access propose that HCV burden will continue to be a significant health care issue in the foreseeable future [4]. Population‐based studies concerning cancer risk in HCV‐infected patients showed an increased risk for hepatocellular carcinoma, non‐Hodgkin lymphoma, and lung cancer [5, 6]. Along with the expanding indications for ICI, the coexistence of HCV and potentially ICI‐responsive cancer will be encountered more frequently. Two landmark trials that studied PD‐1 inhibitors in hepatocellular carcinoma included treated and untreated HCV patients: a phase I–II study of nivolumab in hepatocellular carcinoma included 50 patients with HCV, CheckMate‐40 (NCT01658878), and a phase II study of pembrolizumab in hepatocellular carcinoma that included 26 patients with HCV, Keynote‐224 (NCT02702414) [7, 8]. However, trials investigating ICIs in cancers other than hepatocellular carcinoma have excluded patients with HCV infection, as it is unknown how the ICIs will interplay with the underlying chronic infection (e.g., the potential for a flare of chronic HCV infection or higher rate of AEs).\n\nIn this article, we report our case series of 40 patients covering the past 8 years addressing the safety of ICIs in patients with HCV. The predominance of men in our study may be explained by predominant tumor subtypes in our cohort, namely, non‐small cell lung cancer and hepatocellular carcinoma, both of which are more common in men, which is likely attributed to an increased likelihood of adapting high‐risk behaviors in men that increase their risk for these cancers (e.g., smoking and injectable drug use) [6, 9]. Ethnicities reported were reflective of the background population [10].\n\nIn our study, PD‐1/PD‐L1 inhibitor AE rates were comparable to those reported in clinical trials that excluded 1%–3% of patients with HCV [11, 12]. No deaths related to ICI were identified. Only two patients suffered grade 3 AEs: one with colitis on nivolumab and another with pneumonitis on pembrolizumab, with resultant discontinuation of treatment in both. There were only two cases of hepatotoxicity, with the worst being grade 2 in a patient with genotype 1b; however, the patient was able to continue ICI following glucocorticoid course. Both patients with hepatotoxicity had hepatocellular carcinoma, untreated HCV, and liver cirrhosis and were treated with nivolumab. Viral load was not checked at the time of liver enzyme derangement; therefore, it is not possible to comment if an HCV flare was contributing. In the aforementioned trials of PD‐1 inhibitors in hepatocellular carcinoma, CheckMate‐40 and Keynote‐224, no HCV flares were reported [7, 8].\n\nStudy limitations include single‐center study and all the limitations of a retrospective design; selection bias and lack of rigorousness in documenting all possible treatment toxicities compared with a prospective study. The majority of patients were male, and the prevailing genotype was 1a. HCV genotype varies racially and geographically; therefore, our findings may not be generalizable [13]. Interestingly, the patient with grade 2 hepatotoxicity had HCV genotype 1b, which was under‐represented in our cohort. Further studies, including all HCV genotypes, are needed to evaluate if certain genotypes carry a higher risk of ICI‐related AEs. Other areas of study include characterization of PD‐L1 expression in the liver and its effect on AE rates, the safety of ICIs in patients with HCV coinfected with hepatitis B virus and/or human immunodeficiency virus, and cancer registry studies to explore possible health disparities should patients with HCV and cancer be less likely to receive ICI.\n\nConclusion\n\nIn the lack of randomized controlled trials to address the safety of ICI in HCV and other major chronic viral infections across different cancers, observational studies may help to illustrate if such populations tend to have higher rates of ICI AEs. This observational study showed no deaths related to ICIs, and AE profiles in untreated and resolved patients with HCV were comparable to rates of non‐HCV patients. ICI was not delayed in our cohort pending treatment for active HCV. These findings may aid the oncologist in discussing ICI toxicities in patients with cancer with untreated and resolved HCV.\n\nAuthor Contributions\n\nConception/design: Akram Alkrekshi, Ila Tamaskar\n\nProvision of study material or patients: Akram Alkrekshi, Ila Tamaskar\n\nCollection and/or assembly of data: Akram Alkrekshi, Ila Tamaskar\n\nData analysis and interpretation: Akram Alkrekshi, Ila Tamaskar\n\nManuscript writing: Akram Alkrekshi, Ila Tamaskar\n\nFinal approval of manuscript: Akram Alkrekshi, Ila Tamaskar\n\nDisclosures\n\nThe authors indicated no financial relationships\n==== Refs\nReferences\n\n1 Gardiner D , Lalezari J , Lawitz E et al. A randomized, double‐blind, placebo‐controlled assessment of BMS‐936558, a fully human monoclonal antibody to programmed death‐1 (PD‐1), in patients with chronic hepatitis C virus infection. PLoS One 2013;22 :e63818.\n2 Hepatitis C fact sheet. World Health Organization. Available at https://www.who.int/news‐room/fact‐sheets/detail/hepatitis‐c. Accessed Feb 9, 2020.\n3 Common Terminology Criteria for Adverse Events (CTCAE): protocol development. CTEP. Available at https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. Accessed January 5, 2020.\n4 Rosenberg ES , Rosenthal EM , Hall EW et al. Prevalence of Hepatitis C Virus Infection in US States and the District of Columbia, 2013 to 2016. JAMA Netw Open 2018;1 :e186371.30646319\n5 Swart A , Burns L , Mao L et al. The importance of blood‐borne viruses in elevated cancer risk among opioid‐dependent people: A population‐based cohort study. BMJ Open 2012;2 :e001755.\n6 Liu X , Chen Y , Wang Y et al. Cancer risk in patients with hepatitis C virus infection: a population‐based study in Sweden. Cancer Med 2017;6 :1135–1140.28374973\n7 El‐Khoueiry AB , Sangro B , Yau T et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open‐label, non‐comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389 :2492–2502.28434648\n8 Zhu AX , Finn RS , Edeline J et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE‐224): A non‐randomised, open‐label phase 2 trial. Lancet Oncol 2018;19 :940–952.29875066\n9 Donington JS , Colson YL . Sex and gender differences in non‐small cell lung cancer. Semin Thorac Cardiovasc Surg 2011;23 :137–145.22041044\n10 Diversity Data at Cleveland, OH. DataUSA . Available at https://datausa.io/profile/geo/cleveland-oh/. Accessed January 5, 2020.\n11 Leroy V , Templier C , Faivre JB et al. Pembrolizumab‐induced pneumonitis. ERJ Open Res 2017;3 .\n12 Reddy HG , Schneider BJ , Tai AW . Immune checkpoint inhibitor‐associated colits and hepatitis. Clin Transl Gastroenterol 2018;9 :180.30228268\n13 Gordon SC , Trudeau S , Li J et al. Race, age, and geography impact hepatitis C genotype distribution in the United States. J Clin Gastroenterol 2020;53 :40–50.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1083-7159",
"issue": "26(5)",
"journal": "The oncologist",
"keywords": "Hepatitis C; Immune checkpoint inhibitor; Immune-related adverse events; Immunotherapy; Retrospective study",
"medline_ta": "Oncologist",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007680:Kidney Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012189:Retrospective Studies",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "e827-e830",
"pmc": null,
"pmid": "33655663",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": "22041044;28737649;29875066;30228268;28374973;30646319;23045358;28434648;23717490;28480216",
"title": "Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection.",
"title_normalized": "safety of immune checkpoint inhibitors in patients with cancer and hepatitis c virus infection"
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"abstract": "Synthetic cannabinoid use has risen at alarming rates. This case series describes 11 patients exposed to the synthetic cannabinoid, MAB-CHMINACA who presented to an emergency department with life-threatening toxicity including obtundation, severe agitation, seizures and death. All patients required sedatives for agitation, nine required endotracheal intubation, three experienced seizures, and one developed hyperthermia. One developed anoxic brain injury, rhabdomyolysis and died. A significant number were pediatric patients. The mainstay of treatment was aggressive sedation and respiratory support. Synthetic cannabinoids pose a major public health risk. Emergency physicians must be aware of their clinical presentation, diagnosis and treatment.",
"affiliations": "Department of Emergency Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania.;Department of Emergency Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania.;Department of Emergency Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania.;Department of Emergency Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania.;Department of Emergency Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania.;NMS Labs, Willow Grove, Pennsylvania.;Pediatric Critical Care, Lehigh Valley Health Network, Allentown, Pennsylvania.",
"authors": "Katz|Kenneth D|KD|;Leonetti|Adam L|AL|;Bailey|Blake C|BC|;Surmaitis|Ryan M|RM|;Eustice|Eric R|ER|;Kacinko|Sherri|S|;Wheatley|Scott M|SM|",
"chemical_list": "D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D013287:Illicit Drugs; D007191:Indazoles; C000614303:MAB-CHMINACA",
"country": "United States",
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"doi": "10.5811/westjem.2016.2.29519",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 10.5811/westjem.2016.2.29519wjem-17-290Behavioral HealthCase ReportCase Series of Synthetic Cannabinoid Intoxication from One Toxicology Center Katz Kenneth D. MD*Leonetti Adam L. DO*Bailey Blake C. DO*Surmaitis Ryan M. DO*Eustice Eric R. DO*Kacinko Sherri PhD†Wheatley Scott M. MD‡* Department of Emergency Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania† NMS Labs, Willow Grove, Pennsylvania‡ Pediatric Critical Care, Lehigh Valley Health Network, Allentown, PennsylvaniaAddress for Correspondence: Kenneth D. Katz, MD, Lehigh Valley Health Network, Department of Emergency Medicine, 2545 Schoenersville Road, 4th Floor, South Wing, Bethlehem, PA 18017. Email: katzkd1@gmail.com.5 2016 26 4 2016 17 3 290 294 17 12 2015 22 2 2016 © 2016 Katz et al.2016This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Synthetic cannabinoid use has risen at alarming rates. This case series describes 11 patients exposed to the synthetic cannabinoid, MAB-CHMINACA who presented to an emergency department with life-threatening toxicity including obtundation, severe agitation, seizures and death. All patients required sedatives for agitation, nine required endotracheal intubation, three experienced seizures, and one developed hyperthermia. One developed anoxic brain injury, rhabdomyolysis and died. A significant number were pediatric patients. The mainstay of treatment was aggressive sedation and respiratory support. Synthetic cannabinoids pose a major public health risk. Emergency physicians must be aware of their clinical presentation, diagnosis and treatment.\n==== Body\nINTRODUCTION\nSynthetic cannabinoids (SCs) were synthesized to mimic the effects of Δ-9 Tetrahydrocannabinol (THC), the psychoactive component of the Cannabis sativa plant. Due to excessive cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) receptor agonism, use of SCs has been associated with unexpected and significant toxicity, including lethargy, agitation, tachycardia, hyperthermia, acute tubular necrosis, myocardial infarction, seizure and even death.1 Marketed as “Spice” and “K2,” its popularity among adolescents and adults has risen substantially and is the second most common drug of abuse (after marijuana) among high school students.2\n\nIn April 2015, an unprecedented, massive nationwide surge in SC cases was reported to regional poison control centers. The American Association of Poison Control Centers reported a 562% increase in April compared to March (1,512 versus 269).3 The state of New York issued a health alert after more than 160 citizens were hospitalized between April 8–17 for suspected SC toxicity. Health departments in Alabama, Mississippi, Connecticut, Maryland and the National Institute on Drug Abuse issued similar warnings.4 Tyndall et al. recently reported an outbreak of MAB (or ADB)-CHMINACA toxicity in multiple patients at the University of Florida Health Medical Center.5 Northeastern Pennsylvania simultaneously witnessed an epidemic of SC exposures.\n\nThe following cases describe 11 patients presenting to a tertiary care medical facility between April 20 and June 6 of 2015, who had serologic confirmed exposure to a novel, carboxamide indazole SC, MAB-CHMINACA (N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1 H-indazole-3-carboxamide).6 This case series received expedited approval from the hospital’s institutional review board.\n\nCASE REPORTS\nCase #1: An 18-year-old man without prior medical history was found by police, unresponsive in a parking lot after smoking “K2.” The patient became agitated and was brought into the emergency department (ED). He was tachycardic and admitted to the tertiary care intensive care unit (TCICU). His EKG showed sinus tachycardia and rightward axis. Pupil examination was 4mm bilaterally with sluggish reactivity. The patient recovered uneventfully and was discharged later that day.\n\nCase #2: A 28-year-old man with a history of substance abuse and hepatitis presented to an outside healthcare facility (OHF) unresponsive, hallucinating and tachycardic. The patient was endotracheally intubated for airway protection and then transferred to a TCICU. Although he developed aspiration pneumonia, he was treated and discharged uneventfully on hospital day (HD) six.\n\nCase #3: A 17-year-old woman without medical history was transferred to the TCICU from an OHF for agitation, delirium and tachycardia after exposure to SC. She was treated with benzodiazepines, but did not require intubation. he patient was discharged uneventfully on HD two.\n\nCase #4: A 14-year-old boy without medical history was transferred from an OHF to the tertiary care pediatric intensive care unit (TCPICU) after being found unresponsive on the street. The patient became agitated and combative at the OHF, and was endotracheally intubated. The patient admitted to using “K2” and was eventually extubated and discharged on HD two.\n\nCase #5: A 13-year-old girl with a history of marijuana abuse was transferred from an OHF to a TCPICU after ingesting SC. The patient was found intermittently responsive and combative at home. Her pupils were 3mm bilaterally and sluggish, but reactive. At the OHF, she was tachycardic and--after being administered benzodiazepines--became obtunded with hypoventilation. She was endotracheally intubated and transferred to the TCPICU. The patient was extubated and discharged on HD two.\n\nCase #6: A 13-year-old boy without medical history was found unresponsive in a park. On examination, his pupils were 3mm bilaterally and reactive. At the OHF, the patient was endotracheally intubated and transferred to a TCPICU. He required significant amounts of sedatives due to periods of agitation and combativeness. During his hospitalization the patient developed aspiration pneumonia, but was discharged uneventfully on HD three.\n\nCase #7: A 50-year-old man with a history of polysubstance abuse was transported to the ED after using SCs and being found unresponsive by his roommate. The patient was apneic and cyanotic, and--after endotracheal intubation--was transferred to the TCICU. He was extubated, and discharged to an inpatient drug and rehabilitation facility on HD eight.\n\nCase #8: A 40-year-old woman with a history of bipolar disorder presented to the ED with a witnessed seizure after smoking SC. Her EKG demonstrated sinus tachycardia with an incomplete right bundle branch block. The patient was tachycardic, administered benzodiazepines and endotracheally intubated. In the TCICU, the patient was extubated, had an unremarkable electroencephalogram and discharged on HD two.\n\nCase #9: A 19-year-old woman with a history of epilepsy, bipolar disorder and substance abuse presented to an OHF after suffering a seizure after smoking SC. Her EKG showed sinus rhythm with sinus arrhythmia and nonspecific T-wave abnormality. The patient was found unresponsive; she was endotracheally intubated and transferred to a TCICU. She was also treated for a wound infection secondary to intravenous drug abuse. The patient was extubated and discharged on HD four.\n\nCase #10: A 14-year-old boy with a history of substance abuse was found by his mother, agitated after exposure to SC and transported to an OHF. His pupils were 4mm bilaterally and sluggishly reactive on examination. The patient’s EKG demonstrated sinus bradycardia; early repolarization was noted. The patient demonstrated periods of unresponsiveness followed by severe agitation and combativeness requiring sedation and endotracheal intubation. He was transferred to the TCICU and eventually extubated and discharged on HD two.\n\nCase #11: A 20-year-old man without medical history was found unresponsive by family members after SC exposure and transported to an OHF. The patient had been without medical care for approximately 24 to 36 hours. He was hyperthermic, tachycardic and demonstrated decorticate posturing along with areas of trunk and extremity edema on examination. He was endotracheally intubated. Laboratory analysis demonstrated significant rhabdomyolysis and acute renal failure. He was transferred to the TCICU where clinical examination was consistent with anoxic brain injury. A brain magnetic resonance imaging (MRI) scan confirmed these findings. Care was eventually withdrawn due to the grim prognosis, and the patient died on HD seven.\n\nThese 11 patients were all exposed to the SC, MAB-CHMINACA, and presented to the ED with significant, life-threatening toxicity, ranging from obtundation to severe agitation, seizures and death. All had serum samples drawn upon arrival to the hospital that were sent to a contracted laboratory for further identification of specific SCs. All patients had expanded toxicologic analysis (liquid chromatography/mass spectroscopy, LC/MS) to determine any potential adulterants or other substances to which each patient was exposed. All patients required benzodiazepines or other sedatives for agitation. Nine of 11 patients required endotracheal intubation for either control of severe agitation or decreased responsiveness. Three experienced seizures. One patient presented with hyperthermia, and six of the 11 had tachycardia. One patient developed rhabdomyolysis and died. The majority suffered from mental illness or substance abuse. A significant number were pediatric patients, the youngest of whom was only 13. Common chemistries and laboratory values were unremarkable for these patients; pupil size examination and/or EKG results were not available for five of the cases. The results are summarized in Table.\n\nAny drug material recovered from patients was analyzed by the county criminal investigative laboratories to determine the presence of SCs (see Figure). Results confirmed MAB-CHMINACA in all samples tested.\n\nDISCUSSION\nTo date, this is the largest SC case series describing MAB-CHMINACA toxicity. In the fall of 2014, MAB-CHMINACA was responsible for more than 125 patients seeking hospital care in Baton Rouge, LA.7 It is a highly potent SC, which was just recently added to the Schedule 1 Controlled Substance Act in late 2015.8 The clinical manifestations observed in these patients appear similar to those described with other SC toxicities.5,9\n\nThe exact mechanism of MAB-CHMINACA toxicity is unknown. Affinities of SCs and their metabolites are multifold higher at the CB1 and CB2 receptors than that of Δ-9 THC and are thought responsible for such severe clinical manifestations.9 CB1 receptors are mostly located in the brain and regulate the central nervous system effects of Δ-9 THC and other cannabinoids; they are also expressed peripherally in adipocytes and skeletal muscle.1 The identification of CB1 receptors presynaptically on GABA and glutamatergic terminals with increased excitatory and decreased inhibitory tone may be responsible.10 Other postulated mechanisms include activation of non-cannabinoid receptors and drug-drug synergistic effects.1\n\nSome patients demonstrated stimulant and serotonergic agent use as detected by comprehensive urine drug LC/MS testing that could have contributed to their clinical presentation, such as sympathomimetic or serotonergic toxidromes. However, this was not universal and would not explain the fairly consistent clinical presentation of all of these patients. Further, the relative concentrations of MAB-CHMINACA do not necessarily correlate with toxicity and may demonstrate the potential lipophilic distribution of the drug to tissue at the time of blood draw. For example, patient #11 had a relatively low concentration, yet expired. Interestingly, post-mortem analysis of a patient who died from MAB-CHMINACA toxicity demonstrated a relatively low amount in the adipose tissue, atypical of other SCs. The authors hypothesized the compound may require time to distribute to that tissue, and that may have been the salient issue regarding patient #11 given the length of time from medical attention.11\n\nLimitations in real-time detection by routine toxicologic immunoassay screening appear to be a factor in SC use.12 The reasons for the abrupt, recent increase in exposures, however, remain unclear. The celebration of “4/20” (a counterculture holiday celebrating Cannabis) correlated with this surge and might have influenced users.\n\nManagement of the SC-intoxicated patient centers on meticulous supportive care, as no specific antidote currently exists. Decontamination is of little value. Given their beneficial pharmacokinetic profile, administration of benzodiazepines titrated to clinical effect can control agitation, delirium, hyperthermia and seizures. Cooling measures without antipyretic administration can also be implemented for hyperthermic patients. Administration of intravenous fluids is helpful for associated rhabdomyolysis. Endotracheal intubation may be required for the severely intoxicated patient.9\n\nCONCLUSION\nSCs pose a substantial and dangerous public health risk. Emergency physicians must be aware of their clinical presentation, difficulties in identification and treatment. Further studies are required to elucidate the exact mechanism of SCs and, more specifically, MAB-CHMINACA toxicity.\n\nSection Editor: Rick A. McPheeters, DO\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.\n\nFigure Sample synthetic cannabinoid packaging.\n\nTable Summary of case reports of 11 patients presenting to the emergency department with life-threatening toxicity after exposure to synthetic cannabinoids.\n\nCase\tHospital day\tClinical presentation\tIntubated\tOutcome\tVital signs\tQualitative serum level, SC screen*\tComprehensive urine drug screen findings (LC/MS)\t\n#1. 18yo male\tDay 1\tAltered mental status, combative, agitated\tNo\tDischarged same day.\tHR 113bpm, BP 95/53mmHg, temp 99.9°F, RR 20rpm, pulse ox 100%, room air\tX1\tCaffeine\t\n#2. 28yo male\tDay 3\tCombative and hallucinating\tYes\tDeveloped aspiration pneumonia. Discharged hospital day 6.\tHR 102bpm, BP 119/88mmHg, temp 96°F, RR 15rpm, pulse ox 100%, vent\tX10\tCaffeine, morphine, midazolam, lorazepam\t\n#3. 17yo female\tDay 2\tAgitated and delirious\tNo\tDischarged following day.\tHR 110bpm, BP 112/63mmHg, temp 97.3°F, RR 16rpm, pulse ox 98%, room air\tX8\tLorazepam\t\n#4. 14yo male\tDay 2\tIntermittent unresponsiveness followed by agitation\tYes\tDischarged following day.\tHR 96bpm, BP 123/58mmHg, temp 96.7°F, RR 19rpm, pulse ox 98%, vent\tX45\tNorfentanyl\t\n#5. 13yo female\tDay 2\tAltered mental status with unresponsiveness\tYes\tDischarged hospital day 2.\tHR 115bpm, BP 98/46mmHg, temp 98.9°F, RR 17rpm, Ppulse ox 100%, vent\tX20\tPhenylephrine, midazolam, fentanyl, norfentanyl, diphenhydramine, cotinine\t\n#6. 13yo male\tDay 0\tFound unresponsive\tYes\tDeveloped aspiration pneumonia. Discharged on hospital day 3.\tHR 81bpm, BP 131/80mmHg, temp 97.1°F, RR 16rpm, pulse ox 99%, room air\tX30\tLorazapam, hydroxymidazolam\t\n#7. 50yo male\tDay 1\tFound unresponsive\tYes\tDischarged to inpatient drug rehabilitation facility.\tHR 59bpm, BP 93/57mmHg (patient prescribed Lopressor), temp 98.7°F, RR 14rpm, pulse ox 95%, vent\tX36\tEthanol, naloxone, metoprolol, caffeine\t\n#8. 40yo female\tDay 1\tCombative, delirious, seizures\tYes\tDischarged hospital day 2.\tHR 114bpm, BP 120/62mmHg, temp 99.4°F, RR 18rpm, pulse ox 84%, room air (improved after intubation)\tX32\tAcetaminophen\t\n#9. 19yo female\tDay 3\tFound unresponsive; seizure-like activity\tYes\tTreated for infected right forearm wound secondary to IV drug use. Discharged hospital day 4.\tHR 74bpm, BP 118/85mmHg, temp 97.6°F, RR 14rpm, pulse ox 100%, 40% oxygen\tX55\tMorphine, norfentanyl, cocaine, amphetamine, methamphetamine, codeine, midazolam, lorazepam\t\n#10. 14yo male\tDay 2\tAgitated and combative\tYes\tDischarged following day.\tHR 95bpm, BP 114/66mmHg, temp 99.9°F, RR 22rpm, pulse ox 100% vent\tX13\tSertraline\t\n#11. 20yo male\tDay 3\tFound unresponsive and posturing; approximate down-time was 24–36 hours\tYes\tExpired. Anoxic brain injury. Family withdrew care on hospital day 7\tHR 146bpm, BP 200/74mmHg, temp 104.1°F, RR 33rpm, pulse ox 100%, vent (outside facility)\nHR 75bpm, BP 138/55mmHg, temp 99.5°F, RR 17rpm, pulse ox 100%, vent (upon ICU arrival)\tX1.5\tSertraline\t\nSC, synthetic cannabinoids; LC, liquid chromatography; MS, mass spectroscopy; HR, heart rate; BP, blood pressure; RR, respiratory rate; RPM, respirations per minute; yo, year old\n\n* Value represents the number of times higher each case was in comparison to Case #1, which had the lowest relative concentration.\n\nSC, synthetic cannabinoids; LC, liquid chromatography; MS, mass spectroscopy; IV, intravenous; HR, heart rate; BP, blood pressure; RR, respiratory rate; RPM, respirations per minute; ICU, intensive care unit\n==== Refs\nREFERENCES\n1 Zhao A Tan M Maung A Rhabdomyolysis and acute kidney injury requiring dialysis as a result of concomitant use of atypical neuroleptics and synthetic cannabinoids Case Rep Nephrol 2015 2015 235982 26550500 \n2 NIH National Institute on Drug Abuse Media Guide: Most Commonly Used Addictive Drugs Available at: http://www.drugabuse.gov/publications/media-guide/most-commonly-used-addictive-drugs Accessed on Jan 23, 2016 \n3 Synthetic Marijuana Data American Association of Poison Control Centers Web site Available at: https://aapcc.s3.amazonaws.com/files/library/Syn_Marijuana_Web_Data_through_7.6.15.pdf Accessed on Nov 17, 2015 \n4 Schwartz A Potent “Spice” drug fuels rise in visits to emergency room New York Times (New York Ed.) 4 25 2015 Available at: http://www.nytimes.com/2015/04/25/health/surge-in-hospital-visits-linked-to-a-drug-called-spice-alarms-health-officials.html?_r=0 Accessed on Nov 17, 2015 \n5 Tyndall JA Gerona R De Portu G An outbreak of acute delirium from exposure to the synthetic cannabinoid AB-CHMINACA Clin Toxicol (Phila) 2015 53 10 950 6 26555732 \n6 Debruyne D Le Boissilier R Emerging drugs of abuse: Current perspectives on synthetic cannabinoids Subst Abuse Rehabil 2015 6 113 29 26543389 \n7 DHH Bans Another Synthetic Drug WAFB, Baton Rouge, Louisiana Web site Available at: http://www.wafb.com/story/27157019/dhh-bans-another-synthetic-drug Accessed on Nov 19, 2015 \n8 Schedules of Controlled Substances: Temporary Placement of the Synthetic Cannabinoid MAB-CHMINACA into Schedule I (A Proposed Rule) Drug Enforcement Administration, Washington DC Web site Available at: https://www.federalregister.gov/articles/2015/09/16/2015-23198/schedules-of-controlled-substances-temporary-placement-of-the-synthetic-cannabinoid-mab-chminaca Accessed on Nov 19, 2015 \n9 Nelson ME Bryant SM Aks SE Emerging drugs of abuse Emerg Med Clin North Am 2014 32 1 1 28 24275167 \n10 Lapoint J James LP Moran CL Severe toxicity following synthetic cannabinoid ingestion Clin Toxicol (Phila) 2011 49 8 760 4 21970775 \n11 Hasegawa K Wurita A Minakata K Postmortem distribution of MAB-CHMINACA in body fluids and solid tissues of a human cadaver Forensic Toxicol 2015 33 2 380 7 26257834 \n12 Tait RJ Caldicott D Mountain D A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment Clin Toxicol (Phila) 2015 2015 1 13 26567470\n\n",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D005260:Female; D005334:Fever; D006801:Humans; D013287:Illicit Drugs; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D019064:Product Packaging; D011634:Public Health; D012640:Seizures; D019966:Substance-Related Disorders; D055815:Young Adult",
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"title": "Case Series of Synthetic Cannabinoid Intoxication from One Toxicology Center.",
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"abstract": "A 69-year-old man, previously treated with pyridostigmine for myasthenia gravis (manifesting as ptosis and diplopia) was evaluated for several concomitant bilateral anterior orbital masses. Imaging revealed 3 discrete, solid masses within and around the orbits. An incisional biopsy demonstrated atypical lymphocytes positive for CD20 and Cyclin-D1, consistent with mantle cell lymphoma. The patient received induction chemotherapy with a rituximab-based regimen. He experienced resolution of his diplopia and ptosis after one cycle of chemotherapy and achieved complete remission of the orbital masses and myasthenia symptoms after 6 cycles. Myasthenia gravis is most commonly associated with thymoma, but may also be observed with other malignancies. Recognition that orbital lymphoma may coexist with myasthenia gravis will help in expediting the diagnosis of future cases and in guiding treatment decisions.",
"affiliations": "a Department of Ophthalmology , University of Virginia , Charlottesville , Virginia , USA.;a Department of Ophthalmology , University of Virginia , Charlottesville , Virginia , USA.;b Department of Pathology , University of Virginia , Charlottesville , Virginia , USA.;c Division of Hematology and Oncology , University of Virginia , Charlottesville , Virginia , USA.;a Department of Ophthalmology , University of Virginia , Charlottesville , Virginia , USA.",
"authors": "Karlin|Justin|J|;Peck|Travis|T|;Prenshaw|Karyn|K|;Portell|Craig A|CA|;Kirzhner|Maria|M|",
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"mesh_terms": "D000368:Aged; D018951:Antigens, CD20; D000074322:Antineoplastic Agents, Immunological; D019938:Cyclin D1; D003937:Diagnosis, Differential; D004172:Diplopia; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D009157:Myasthenia Gravis; D009918:Orbital Neoplasms; D000069283:Rituximab",
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"title": "Orbital mantle cell lymphoma presenting as myasthenia gravis.",
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"abstract": "Eosinophilic gastroenteritis (EGE) is a rare disease occurring commonly in patients with a history of allergies, asthma, food sensitivities, or parasite exposure. The condition has been postulated to occur when eosinophils accumulate at the intestinal epithelium resulting in inflammation, recruitment and degranulation of mast cells, and further propagation of eosinophil activation. While laboratory and microbiological data may point to the diagnosis, the condition is only confirmed via biopsy demonstrating the eosinophilic infiltration of the intestinal epithelium. Multiple medications have previously been implicated in causing EGE; however, this is the first documented case associated with emtricitabine/tenofovir.",
"affiliations": "Internal Medicine, University of Miami, Holy Cross Hospital, Fort Lauderdale, USA.;Internal Medicine, University of Miami, Holy Cross Hospital, Fort Lauderdale, USA.;Internal Medicine, University of Miami, Holy Cross Hospital, Fort Lauderdale, USA.",
"authors": "Lozier|Matthew R|MR|;Sanchez|Alexandra M|AM|;Reyes|Ricardo|R|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3498Internal MedicineGastroenterologyInfectious DiseaseEosinophilic Colitis Associated with Emtricitabine/Tenofovir Muacevic Alexander Adler John R Lozier Matthew R 1Sanchez Alexandra M 1Reyes Ricardo 1\n1 \nInternal Medicine, University of Miami, Holy Cross Hospital, Fort Lauderdale, USA \nMatthew R. Lozier mrl160@miami.edu26 10 2018 10 2018 10 10 e349821 9 2018 24 10 2018 Copyright © 2018, Lozier et al.2018Lozier et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/15236-eosinophilic-colitis-associated-with-emtricitabinetenofovirEosinophilic gastroenteritis (EGE) is a rare disease occurring commonly in patients with a history of allergies, asthma, food sensitivities, or parasite exposure. The condition has been postulated to occur when eosinophils accumulate at the intestinal epithelium resulting in inflammation, recruitment and degranulation of mast cells, and further propagation of eosinophil activation. While laboratory and microbiological data may point to the diagnosis, the condition is only confirmed via biopsy demonstrating the eosinophilic infiltration of the intestinal epithelium. Multiple medications have previously been implicated in causing EGE; however, this is the first documented case associated with emtricitabine/tenofovir.\n\neosinophilic gastroenteritishivemtricitabine/tenofoviratopic disorderseosinophilscrptemporal associationThe 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\nEosinophilic gastroenteritis (EGE) is a rare disease that is challenging to diagnose based on clinical findings, especially in patients without a history of allergies, asthma, food sensitivities, or parasite exposure. We report a biopsy-confirmed case of EGE likely related to treatment with the combination of emtricitabine/tenofovir. Repeat administration of the drug resulted in abdominal symptoms and imaging findings consistent with colitis, which resolved following the cessation of therapy.\n\nCase presentation\nA 54-year-old male with previously diagnosed human immunodeficiency virus (HIV) had recurrent presentations for colitis since initiating emtricitabine/tenofovir. In the past, he had self-discontinued this medication, resulting in the resolution of gastrointestinal (GI) complaints, but subsequent re-initiation of the medication led to a recurrence of symptoms and hospitalization. The abdominal computed tomography (CT) scan reported focal colitis in the descending colon, as seen in Figure 1. The patient was started on empiric antibiotics with a progressive worsening of symptoms. He was taken to the operating room for exploratory laparoscopy, resulting in colonic resection and diverting colostomy. The pathological specimen, as seen in Figure 2, demonstrated eruptive pseudomembranes, edema, and mixed inflammation, including numerous eosinophils within the colon wall consistent with eosinophilic colitis. Upon reviewing his laboratory and microbiological data, it was noted that the patient did not have peripheral eosinophilia and that stool cultures, fecal leukocytes, and stool ova and parasites were all negative. However, an elevated C-reactive protein (CRP) of 37.6 mg/L was noted on admission that trended up to 61.0 mg/L. Outpatient screening for HLA-B*57:01 was negative and his previous HIV medication regimen was switched to the combination of abacavir, dolutegravir, and lamivudine. No symptom recurrence has been noted since the treatment regimen was adjusted.\n\nFigure 1 Focal colitis\nAxial (top) and coronal (bottom) views of the computed tomography scan of the abdomen with evidence of fecalith in the proximal and mid-descending colon associated with focal colonic wall thickening, pericolonic inflammatory stranding, and pericolonic fluid consistent with focal colitis\n\nFigure 2 Pathologic findings\nLow-power microscopic views (top and lower left) of a pathologic specimen of the colon demonstrating numerous eosinophils infiltrating throughout. High-power microscopic view (lower right) demonstrating similar findings\n\nDiscussion\nThe diagnosis of EGE is based on the presence of eosinophilic infiltration of the stomach, duodenum, esophagus, and colon without any known cause of eosinophilia [1]. While peripheral eosinophilia is a common finding in EGE, it is not necessary for the diagnosis [2]. The pathogenesis of EGE is not well understood, but epidemiologic and clinical features suggest an allergic component. It has been postulated that eosinophils accumulate at the intestinal surface and release multiple toxic cationic proteins. These proteins cause the destruction of the intestinal epithelium, resulting in recruitment and degranulation of mast cells, further propagating eosinophil activation [3]. This case of EGE is unique, as the patient had no history of allergies or atopic disorders, no peripheral eosinophilia, and negative microbiological tests (stool cultures, fecal leukocytes, and stool ova and parasites). Even with all these unremarkable findings, the biopsy specimen demonstrated marked eosinophilic infiltration of the mucosal layers. While other possible causes (allergic, inflammatory, parasitic infection, and more) of EGE were considered, the temporal association of GI symptoms matching the use of emtricitabine/tenofovir and resolution following the adjustment of the HIV regimen implicate this medication as the cause in this clinical scenario. Although multiple medications have previously been implicated in causing EGE [3-9], this is the first documented case associated with emtricitabine/tenofovir.\n\nConclusions\nThis case should raise awareness that there are more undocumented medications that can cause EGE. We propose that EGE be considered in the differential diagnosis of patients taking emtricitabine/tenofovir who develop recurring gastrointestinal symptoms and have imaging findings consistent with colitis even if peripheral eosinophilia is not noted. Colonoscopy and biopsy may be warranted during the evaluation in order to definitively diagnose or rule out the disease.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Eosinophilic gastroenteritis and colitis: a comprehensive review Clin Rev Allergy Immunol Uppal V Kreiger P Kutsch E 175 188 50 2016 https://www.ncbi.nlm.nih.gov/pubmed/?term=Uppal+V%2C+Kreiger+P%2C+Kutsch+E%3A+Eosinophilic+Gastroenteritis+and+Colitis%3A+a+Comprehensive+Review.+Clin+Rev+Allergy+Immunol.+2016+Apr%2C+50(2)%3A175-88. 26054822 \n2 Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues Gut Talley NJ Shorter RG Phillips SF Zinsmeister AR 54 58 31 1990 https://gut.bmj.com/content/31/1/54 2318432 \n3 Allergic reaction to gemfibrozil manifesting as eosinophilic gastroenteritis South Med J Lee JY Medellin MV Tumpkin C 807 808 South Med J 93 2000 https://sma.org/southern-medical-journal/article/allergic-reaction-to-gemfibrozil-manifesting-as-eosinophilic-gastroenteritis/ 10963515 \n4 Pentostatin-induced hypereosinophilia with eosinophilic gastroenteritis Leuk Lymphoma 8 2019 Shouval R Duffield A Gocke C Lee L Brodsky RA 1567 1569 PMID 51 2010 https://www.ncbi.nlm.nih.gov/pubmed/?term=Pentostatin-induced+hypereosinophilia+with+eosinophilic+gastroenteritis.+Shouval+R%2C+Duffield+A%2C+Gocke+C%2C+Lee+L%2C+Brodsky+RA.+Leuk+Lymphoma.+2010 20496999 \n5 Enalapril-induced eosinophilic gastroenteritis J Clin Gastroenterol Barak N Hart J Sitrin MD 157 158 33 2001 https://journals.lww.com/jcge/pages/articleviewer.aspx?year=2001&issue=08000&article=00014&type=abstract 11468446 \n6 Eosinophilic gastroenteritis as an allergic reaction to a trimethoprim-sulfonamide preparation [Article in German, English] Dtsch Med Wochenschr Wienand B Sanner B Liersch M 371 374 116 1991 https://www.ncbi.nlm.nih.gov/pubmed/?term=Eosinophilic+gastroenteritis+as+an+allergic+reaction+to+a+trimethoprim-sulfonamide+preparation 2001640 \n7 Carbamazepine-induced eosinophilic colitis Epilepsia Anttila VJ Valtonen M 119 121 33 1992 https://www.ncbi.nlm.nih.gov/pubmed/?term=Anttila%2C+V.-J.+and+Valtonen%2C+M.+(1992)%2C+Carbamazepine-Induced+Eosinophilic+Colitis.+Epilepsia%2C+33%3A+119-121.+doi%3A10.1111%2Fj.1528-1157.1992.tb02293.x 1733744 \n8 Eosinophilic colitis due to rifampicin Lancet Lange P Oun H Fuller S Turney JH 1296 1297 344 1994 https://www.ncbi.nlm.nih.gov/pubmed/?term=Eosinophilic+colitis+due+to+rifampicin+Lancet+Lange%2C+P.+and+Oun%2C+H.+and+Fuller%2C+S. \n9 Clozapine-induced eosinophilic colitis Am J Psychiatry Karmacharya R Mino M Pirl WF 1386 1387 162 2005 https://www.ncbi.nlm.nih.gov/pubmed/15994729\n\n",
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"abstract": "Immune thrombocytopenic purpura (ITP) is characterized by a decreased platelet count caused by excess destruction of platelets and inadequate platelet production. In many cases, the etiology is not known, but the viral illness is thought to play a role in the development of some cases of ITP. The current (2011) American Society of Hematology ITP guidelines recommend initial diagnostic studies to include testing for HIV and Hepatitis C. The guidelines suggest that initial treatment consist of observation, therapy with corticosteroids, IVIG or anti D. Most cases respond to the standard therapy such that the steroids may be tapered and the platelet counts remain at a hemostatically safe level. Some patients with ITP are dependent on long-term steroid maintenance, and the thrombocytopenia persists with the tapering of the steroids. Recent case reports demonstrate that ITP related to cytomegalovirus (CMV) can persist in spite of standard therapy and that antiviral therapy may be indicated. Herein we report a case of a 26-year-old female with persistent ITP that resolved after the delivery of a CMV-infected infant and placenta. Furthermore, we review the current literature on CMV-associated ITP and propose that the current ITP guidelines be amended to include assessment for CMV, even in the absence of signs and symptoms, as part of the work-up for severe and refractory ITP, especially prior to undergoing an invasive procedure such as splenectomy.",
"affiliations": "Department of Hematology and Oncology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030.;Department of Pathology and Laboratory Services, Manchester Memorial Hospital, 71 Haynes Street, Manchester, CT 06040.;Department of Hematology and Oncology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030.",
"authors": "Shimanovsky|Alexei|A|;Patel|Devbala|D|;Wasser|Jeffrey|J|",
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"fulltext": "\n==== Front\nMediterr J Hematol Infect DisMediterr J Hematol Infect DisMediterranean Journal of Hematology and Infectious DiseasesMediterranean Journal of Hematology and Infectious Diseases2035-3006Università Cattolica del Sacro Cuore 2674087110.4084/MJHID.2016.010mjhid-8-1-e2016010Case ReportRefractory Immune Thrombocytopenic Purpura and Cytomegalovirus Infection: A Call for a Change in the Current Guidelines Shimanovsky Alexei 1Patel Devbala 2Wasser Jeffrey 1\n1 Department of Hematology and Oncology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030\n2 Department of Pathology and Laboratory Services, Manchester Memorial Hospital, 71 Haynes Street, Manchester, CT 06040Correspondence to: Alexei Shimanovsky MD. Department of Hematology and Oncology, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030. E-mail: Shimanovsky@resident.uchc.edu2016 01 1 2016 8 1 e201601023 8 2015 11 11 2015 2016This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Immune thrombocytopenic purpura (ITP) is characterized by a decreased platelet count caused by excess destruction of platelets and inadequate platelet production. In many cases, the etiology is not known, but the viral illness is thought to play a role in the development of some cases of ITP. The current (2011) American Society of Hematology ITP guidelines recommend initial diagnostic studies to include testing for HIV and Hepatitis C. The guidelines suggest that initial treatment consist of observation, therapy with corticosteroids, IVIG or anti D. Most cases respond to the standard therapy such that the steroids may be tapered and the platelet counts remain at a hemostatically safe level. Some patients with ITP are dependent on long-term steroid maintenance, and the thrombocytopenia persists with the tapering of the steroids. Recent case reports demonstrate that ITP related to cytomegalovirus (CMV) can persist in spite of standard therapy and that antiviral therapy may be indicated. Herein we report a case of a 26-year-old female with persistent ITP that resolved after the delivery of a CMV-infected infant and placenta. Furthermore, we review the current literature on CMV-associated ITP and propose that the current ITP guidelines be amended to include assessment for CMV, even in the absence of signs and symptoms, as part of the work-up for severe and refractory ITP, especially prior to undergoing an invasive procedure such as splenectomy.\n==== Body\nIntroduction\nImmune thrombocytopenic purpura (ITP) is a common cause of acquired thrombocytopenia caused by auto-anti-platelet antibodies that destroy platelets, damage megakaryocytes and inhibit platelets production. Viral infection such as rubella, varicella, mumps, cytomegalovirus (CMV) and Epstein-Barr virus are linked to ITP and thrombocytopenia.1 While the infections can be relatively asymptomatic, they can trigger an autoimmune process. In the past several years, cases of ITP have been reported secondary to unsuspected, persistent infections such as hepatitis C, HIV and Helicobacter pylori (H. pylori). The successful treatment of ITP in such cases may require recognition and eradication of the underlying infection.\n\nSeveral cases of thrombocytopenia and ITP, secondary to persistent CMV infection, in immunocompetent adults, have been reported in the literature.2 While the majority of cases describe patients that responded to standard ITP therapy, some reports describe patients who are dependent upon or worsen with corticosteroids.2–5 In a small case-series of four patients, steroids appeared to worsen CMV-associated ITP and improvement in the platelet counts occurred after starting gancyclovir and Cytogam with steroid taper.6 Herein we describe a case of an immunocompetent adult female diagnosed with ITP, refractory to standard therapy, during her first pregnancy. The ITP improved following delivery of a CMV-infected neonate and the products of conception. The placenta demonstrated evidence of active CMV infection by PCR. Furthermore, we review current literature and propose a modification to the current ITP guidelines.\n\nCase Report\nA healthy 26-year-old G1P0 female of Asian-Indian descent was referred to our clinic for a second opinion of her thrombocytopenia. During her initial visit to the obstetrician, she was asymptomatic and had a platelet count of 3 x 109/l (normal 150-450 x 109/l). She initially received intravenous immunoglobulin (IVIG) at 1 g/kg, prednisone 140 mg/day and a trial of anti-D. Her platelet count improved temporarily, returning to 10–30×109//l after a few weeks (Figure 1). She was on maintenance prednisone (40 mg/day) when she first presented to our clinic.\n\nThe patient denied having an abnormal menstrual cycle, mucosal bleeding, and family history of blood disorders. On physical exam, the patient appeared cushingoid with normal vital signs. She had no petechiae or ecchymosis. Uterus was gravid. She had no palpable hepatosplenomegaly. The rest of her exam was normal. The leucocyte count was 24,500/uL, with 7% band forms, 88% neutrophils, and 4% lymphocytes. The hemoglobin was 13 g/dL with a hematocrit of 37%. Her platelet count was 30×109/l. Coagulation screen, liver profile, and blood chemistry values were normal. Bone marrow biopsy showed megakaryocyte hyperplasia with normal morphology, consistent with ITP. Her ANA, Hepatitis B, C, and HIV were negative. Stool H. pylori antigen was positive.\n\nThe patient was treated with pantoprazole 40 mg daily, amoxicillin 1000 mg daily and clarithromycin 500 mg twice daily. After treatment, her platelet count remained between 10–40×109//l. As resistance to H. pylori treatment is common, the patient received a second course of antibiotic therapy. Subsequently, the H. pylori stool antigen became negative with no improvement in platelet count. After receiving appropriate vaccinations, she underwent a splenectomy with no improvement in platelet count. She was maintained on prednisone 40 mg/day and intermittent IVIG until her delivery.\n\nShe delivered a healthy baby girl with a platelet count of 15×109//l and no significant hemorrhage or bleeding. During a routine screen, the infant was diagnosed with congenital CMV via urine PCR. The newborn was treated with ganciclovir 10mg/kg, leading to improvement in platelet count. Placental pathology demonstrated focal chorionic chorionitis without any chorionic villinits. The corresponding segment of the placenta was positive for CMV by PCR. The mother was positive for CMV IgG. Interestingly, one week after delivery, the patient’s platelet count began to improve. She was no longer taking prednisone or IVIG and her platelet count normalized to 192×109/l ten months after delivery (Figure 1).\n\nDiscussion\nOur patient presented with severe thrombocytopenia in her first trimester of pregnancy. While gestational thrombocytopenia accounts for 70–80% of cases during pregnancy, our patient did not meet the clinical criteria for this diagnosis. Her platelet count was less than 100 x 109/l and she presented early in pregnancy, findings that are less consistent with gestational thrombocytopenia.7 While type 2B von Willebrand was considered in the differential of thrombocytopenia in our patient, it is less likely in our patient as she did not have any personal or family history of abnormal bleeding. Given the normal vital signs and liver function, pregnancy-specific causes of thrombocytopenia such as preeclampsia, eclampsia, HELLP syndrome and acute fatty liver are less likely. Moreover, the patient’s bone marrow was consistent with ITP and the temporary response to corticosteroids and IVIG supports the diagnosis of ITP.\n\nITP is a rare cause of thrombocytopenia during pregnancy, occurring only 1 in 10,000 pregnancies. While ITP can occur at any point in pregnancy, it is one of the few causes of thrombocytopenia that can become apparent during the first trimester.8 Primary ITP is caused by a complex mechanism that is caused by autoantibodies against platelets and T-cell mediated platelet destruction.9 Conversely, secondary ITP develops in a setting of autoimmune disease, lymphoma, and infection with H. pylori or viral infection such as HIV, hepatitis C, or CMV.7\n\nThe current ITP guidelines from the American Society of Hematology recommend testing for Hepatitis C and HIV, as they are known to cause secondary ITP.10 Both were negative in our patient. Testing for H. pylori is also recommended in patients with isolated thrombocytopenia. The stool antigen for H. pylori positive in our patient and we considered H. pylori-associated ITP however; the patients’ platelets did not improve after two courses of triple antibiotic therapy. The patient was treated based on the current guidelines with corticosteroids, IVIG, and splenectomy. Except a temporary spike in her platelet count (Figure 1) after IVIG administration, the patient failed to have a durable response to standard therapy.\n\nAfter delivery, the patient’s newborn was diagnosed with congenital CMV. While CMV is known to cause secondary ITP, isolated thrombocytopenia, and fetal damage, in most countries pregnant women are not routinely screened for CMV.11 Indeed, neither the American Society of Obstetrics and Gynecology (ACOG) nor the Centers for Disease Control and Prevention (CDC) recommend routine serologic screening for CMV in pregnant women.12 Furthermore, the current ITP guidelines from the American Society of Hematology do not require CMV testing.10 Consequently, medical insurance companies may refuse to cover the costs of CMV testing in patients that have isolated thrombocytopenia and do not exhibit symptoms that suggest CMV. Indeed, in the United States, isolated thrombocytopenia is not considered to be reimbursable indication for CMV testing by Medicare and insurers may refuse payment for asymptomatic patients.\n\nWhile some experts recommend testing for CMV in thrombocytopenic patients that have lymphocytosis, atypical lymphocytes, toxic granulation or neutrophilia, our patient had none of these signs of CMV infection.7 As such, our patient was not tested for CMV during her pregnancy and the diagnosis of CMV-associated ITP was only considered in our patient postpartum, when the fetal urine and placenta tested positive for CMV infection.\n\nThe patient’s clinical course and bone marrow findings suggest that the persistent thrombocytopenia was due to secondary ITP caused by CMV infection. We propose that the mother either acquired CMV infection early in pregnancy or had a reactivation of the virus leading to symptomatic CMV causing her to have thrombocytopenia and ITP. Moreover, we hypothesize that the placenta was a reservoir for CMV, thus causing persistent ITP that was refractory to standard therapy, resolving only after delivery. Indeed, mammalian models have demonstrated that the placenta can act as a reservoir for CMV long after it is cleared from the maternal blood.13 Soon after the delivery, the CMV reservoir was removed, and maternal platelet count returned to normal levels.\n\nCytomegalovirus infection in an immunocompetent host is frequently asymptomatic and detected retrospectively.14 Increasing evidence from the recent literature suggests that CMV infection may be associated with ITP, especially refractory ITP.2 A study by Sheng Yu et al. showed that CMV infection, especially the gB1 genotype, was the cause of ITP in children.15 A recent review by DiMaggio et al., suggests that CMV may be the cause of severe and refractory ITP and that CMV PCR should be ordered if there is a strong clinical suspicion of an infection.6,16 To date, 9 cases of severe, steroid-resistant CMV-associated thrombocytopenia and ITP have been reported (Table 1) in immunocompetent adults.2–6,17–20 In some of the cases, thrombocytopenia associated with CMV-induced ITP worsened after administration of steroid therapy.6,15\n\nAlthough the mechanism of CMV-induced thrombocytopenia is unclear, several hypotheses have been proposed. Molecular mimicry leading to the production of anti-platelet antibodies causing immune dysregulation and platelet destruction is one such mechanism.21 Additionally, CMV directly infects megakaryocytes leading maturation arrest causing decreased platelet production and thrombocytopenia.21 Indeed, this has been described as the cause of delayed platelet recovery following allogeneic bone marrow transplant.22 Furthermore, the latter better explains the lack of a durable response with corticosteroids, as this therapy is aimed at blocking platelet destruction and not increasing platelet production.23 Accordingly, in non-pregnant patients, a trial of a thrombomimetic agent may be useful in severe refractory cases of ITP. Moreover, treatment with ganciclovir and Cytogam to optimize rapid suppression of CMV may provide greater efficacy and faster clinical improvement. Indeed, treatment with anti-CMV therapy has produced a rise in platelet count and improvement in clinical outcome in some patients with CMV-associated ITP.5,6,19,20\n\nThe current case and literature reports (Table 1) suggest that CMV-associated ITP can cause severe thrombocytopenia refractory to standard therapy and treatment of the underlying CMV infection may improve thrombocytopenia. However, while some clinicians check for CMV in patients with thrombocytopenia, the current American Society of Hematology (2011) guidelines for the diagnosis and management of ITP recommend checking and treating only for Hepatitis C and HIV; they do not recommend testing for CMV as part of the diagnostic workup, representing a gap in the current guidelines.10 We believe it is appropriate to test for CMV infection if there is a high clinical suspicion of CMV exposure, steroid-dependent ITP or before splenectomy. Moreover, treatment with ganciclovir and Cytogam should be further investigated in non-pregnant individuals where CMV-associated ITP is suspected. Accordingly, modification of the American Society of Hematology ITP guidelines and those of other organizations may be warranted. Those modifications should include recommendations for CMV testing in pregnancy and prior to splenectomy since treatment of CMV may improve ITP and eliminate the need for invasive surgery. In addition, this would lead to increase physician awareness of CMV-induced ITP and may encourage reimbursement for CMV testing in patients with isolated ITP, who lack other signs and symptoms of CMV infection. Lastly, clinical trials are needed to investigate the risk-benefit of treating CMV-induced ITP with anti-viral agents in pregnant and non-pregnant individuals.\n\nFigure 1 Patients’ clinical course. Time-points of administration of high-dose steroids, intravenous Immunoglobulin (IVIG), splenectomy and delivery of the infant are indicated. The patient was maintained on prednisone 40 mg PO daily until the day of delivery. After delivery, the prednisone was tapered off.\n\nTable 1 Cases of Steroid-Resistant Thrombocytopenia and ITP associated with CMV infection in immunocompetent adults.\n\nCases of Cytomegalovirus-Associated Steroid-Resistant Thrombocytopenia and ITP in Immunocompetent Adults\n\t\nSource\tAge (yr)\tSex\tPlatelet Count (×109/l)\tDiagnostic Test\tTreatment and Outcome\t\nSugioka et al., 20124\t30\tM\t10\tSerum PCR (titers 310 copies/106 cells)\tPrednisone (85 mg/day) with no response. Responded to IVIG (0.4 g/kg/day)\t\nDiMaggio et al., 20096\t50\tM\t5\tUrine cultures and serum PCR\tNo response to IV methylprednisolone, IV anti-D, IVIG, or IV vincristine.\t\n\t72\tM\t1\tSerum PCR, titers 111 copies/106 cells\tNo response to prednisone or IVIG. Responded to ganciclovir (5 mg/kg, i.v.) twice daily and cytogam twice weekly\t\nVon Spronsen and Breed, 19965\t63\tF\t5\tCMV IgM\tDexamethasone (8 mg/d) with no response. Platelet count improved with ganciclovir (5 mg/kg, i.v.) twice daily.\t\nSahud and Bachelor, 19783\t21\tM\t12\tCMV viral titers (1:1024)\tRefractory to high-dose steroids. Improved after splenectomy.\t\nShimm et al., 1980 17\t20\tM\t<10\tCMV culture in blood\tRefractory to high-dose steroids; Platelet count improved after splenectomy.\t\nAlliot and Barrios, 20052\t80\tM\t8\tCMV IgM\tMethylprednisolone (120mg/day) and prednisone (60 mg/day) with minimal response; patient improved with IVIG (1g/kg/day).\t\nShrestha et al., 201420\t22\tM\t6\tNot Described\tFailed therapy with steroids and IVIG. Splenectomy did not improve platelet count. Improvement was seen when treated with foscarnet and valganciclovir.\t\nGural et al., 199818\t27\tM\t2\tCMV IgM and IgG; spleen tissue PCR\tHydrocortisone (300 mg/day) and IVIG (1g/kg) with no response. Improvement after splenectomy.\t\nArruda et al., 199719\t34\tM\t12\tCMV IgM and IgG\tPrednisone (1–2 mg/kg/day) with minimal response. Recovery with ganciclovir 5 mg/kg twice daily × 21 days.\n==== Refs\nReferences\n1 Wright JF Blanchette VS Wang H Characterization of platelet-reactive antibodies in children with varicella-associated acute immune thrombocytopenic purpura (ITP) Br J Haematol 1996 95 145 152 10.1046/j.1365-2141.1996.d01-1872.x 8857953 \n2 Alliot C Barrios M Cytomegalovirus-induced thrombocytopenia in an immunocompetent adult effectively treated with intravenous immunoglobulin: a case report and review Hematology 2005 10 277 279 10.1080/10245330500093658 16085539 \n3 Sahud MA Bachelor MM Cytomegalovirus-induced thrombocytopenia. An unusual case report Arch Intern Med 1978 138 1573 1575 10.1001/archinte.1978.03630350095027 213040 \n4 Sugioka T Kubota Y Wakayama K Severe steroid-resistant thrombocytopenia secondary to cytomegalovirus infection in an immunocompetent adult Intern Med 2012 51 1747 1750 10.2169/internalmedicine.51.7193 22790138 \n5 van Spronsen DJ Breed WP Cytomegalovirus-induced thrombocytopenia and haemolysis in an immunocompetent adult Br J Haematol 1996 92 218 220 10.1046/j.1365-2141.1996.00288.x 8562398 \n6 DiMaggio D Anderson A Bussel JB Cytomegalovirus can make immune thrombocytopenic purpura refractory Br J Haematol 2009 146 104 112 10.1111/j.1365-2141.2009.07714.x 19438507 \n7 Gernsheimer T James AH Stasi R How I treat thrombocytopenia in pregnancy Blood 2013 121 38 47 10.1182/blood-2012-08-448944 23149846 \n8 McCrae KR Thrombocytopenia in pregnancy Hematology Am Soc Hematol Educ Program 2010 2010 397 402 21239825 \n9 Provan D Stasi R Newland AC International consensus report on the investigation and management of primary immune thrombocytopenia Blood 2010 115 168 186 10.1182/blood-2009-06-225565 19846889 \n10 Neunert C Lim W Crowther M The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia Blood 2011 117 4190 4207 10.1182/blood-2010-08-302984 21325604 \n11 Ross SA Novak Z Pati S Overview of the diagnosis of cytomegalovirus infection Infect Disord Drug Targets 2011 11 466 474 10.2174/187152611797636703 21827433 \n12 Nyholm JL Schleiss MR Prevention of maternal cytomegalovirus infection: current status and future prospects Int J Womens Health 2010 2 23 35 21072294 \n13 Griffith BP McCormick SR Fong CK The placenta as a site of cytomegalovirus infection in guinea pigs J Virol 1985 55 402 409 2991565 \n14 Wright JG Severe thrombocytopenia secondary to asymptomatic cytomegalovirus infection in an immunocompetent host J Clin Pathol 1992 45 1037 1038 10.1136/jcp.45.11.1037 1333493 \n15 Sheng Yu Z Tang LF Zou CC Cytomegalovirus-associated idiopathic thrombocytopenic purpura in Chinese children Scand J Infect Dis 2008 40 922 927 10.1080/00365540802238471 18618335 \n16 Ding Y Zhao L Mei H Role of myeloid human cytomegalovirus infection in children’s idiopathic thrombocytopenic purpura Pediatr Hematol Oncol 2007 24 179 188 10.1080/08880010601166421 17454787 \n17 Shimm DS Logue GL Rosse WF Recurrent thrombocytopenia following idiopathic thrombocytopenic purpura. The importance of platelet-bound IgG in establishing cause Arch Intern Med 1980 140 855 857 10.1001/archinte.1980.00330180129043 6247987 \n18 Gural A Gillis S Gafanovich A Massive intracranial bleeding requiring emergency splenectomy in a patient with CMV-associated thrombocytopenia Haemostasis 1998 28 250 255 10.1159/000022439 10420074 \n19 Arruda VR Rossi CL Nogueira E Cytomegalovirus infection as cause of severe thrombocytopenia in a nonimmunosuppressed patient Acta Haematol 1997 98 228 230 10.1159/000203630 9401503 \n20 Shreshta Rajsha RD Mingma Sherpa Cytomegalovirus: A possible cause of Persistent Refractory Immune Thrombocytopenic Purpura Journal of Advances in Internal Medicine 2014 3 42 45 \n21 Papagianni A Economou M Tsoutsou E CMV-related immune thrombocytopenic purpura or CMV-induced thrombocytopenia? Br J Haematol 2010 149 454 455 10.1111/j.1365-2141.2009.08064.x 20096016 \n22 Verdonck LF de Gast GC van Heugten HG Cytomegalovirus infection causes delayed platelet recovery after bone marrow transplantation Blood 1991 78 844 848 1650265 \n23 Psaila B Bussel JB Refractory immune thrombocytopenic purpura: current strategies for investigation and management Br J Haematol 2008 143 16 26 10.1111/j.1365-2141.2008.07275.x 18573111\n\n",
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"title": "Refractory Immune Thrombocytopenic Purpura and Cytomegalovirus Infection: A Call for a Change in the Current Guidelines.",
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"abstract": "Bisphosphonates (BP) are the most commonly prescribed effective form of osteoporosis treatment with adverse effects associated with prolonged use such as atypical femoral fractures (AFF). Asians have an elevated risk of AFF at 5 to 6 times those of whites and Hispanics. In this study, we characterize factors associated with AFF and its mortality in a single center in Singapore. We conducted a cohort study of subjects older than 50 years admitted to Changi General Hospital (CGH), Singapore, with fragility subtrochanteric femoral fractures from 2009 to 2015. Using the ASBMR 2014 criteria, fractures are classified into atypical and typical subtrochanteric femoral fractures. CGH uses a nationalized electronic health record that allows review of information on patients' demographics, clinical history and previous investigations. Mortality was assessed as of December 31, 2019. Between 2009 and 2015, there were 3097 hip fractures, of which 393 were subtrochanteric femoral fractures and 69 were classified as AFF by ASBMR 2014 criteria. A total of 52.2% of AFF occurred with BP exposure of median duration 56.5 (28 to 66) months. Multivariate regression showed that BP exposure was associated with the highest risk of AFF (odds ratio [OR] = 6.65 [2.35-18.9]). AFF patients had higher 5-year survival (0.85 versus 0.62, p = 0.001) compared with typical subtrochanteric fracture patients. However, after adjusting for variables, the type of subtrochanteric femoral fractures were no longer significantly associated with progression to death, whereas older age, higher mean Charlson comorbidity score, and Malay ethnicity were the strongest predictors of death. AFF constitutes a small proportion of hip and femoral fractures with prolonged BP use being the highest risk factor for its development. There is no evidence of increased mortality or morbidity in patients with AFF compared with the typical subtrochanteric fracture. The fear of AFF should not impede treatment of typical osteoporotic fractures in this population. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.",
"affiliations": "Department of Endocrinology Department of Medicine Changi General Hospital 2 Simei Street 3 529889 Singapore Singapore.;Department of Endocrinology Department of Medicine Changi General Hospital 2 Simei Street 3 529889 Singapore Singapore.;Department of Endocrinology Department of Medicine Changi General Hospital 2 Simei Street 3 529889 Singapore Singapore.;Centre of Trial Research Unit Changi General Hospital Singapore Singapore.;Department of Radiology Changi General Hospital Singapore Singapore.;Department of Endocrinology Department of Medicine Changi General Hospital 2 Simei Street 3 529889 Singapore Singapore.",
"authors": "Gani|Linsey|L|https://orcid.org/0000-0002-3699-2406;Anthony|Natasha|N|https://orcid.org/0000-0003-4928-6380;Dacay|Lily|L|;Tan|Pei|P|;Chong|Le Roy|LR|https://orcid.org/0000-0002-8374-3760;King|Thomas Fj|TF|https://orcid.org/0000-0002-0383-3433",
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"fulltext": "\n==== Front\nJBMR Plus\nJBMR Plus\n10.1002/(ISSN)2473-4039\nJBM4\nJBMR Plus\n2473-4039\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n10.1002/jbm4.10515\nJBM410515\nOriginal Article\nOriginal Articles\nIncidence of Atypical Femoral Fracture and Its Mortality in a Single Center in Singapore\nINCIDENCE OF ATYPICAL FEMORAL FRACTURES\nGani et al.\nGani Linsey https://orcid.org/0000-0002-3699-2406\n1 Linsey.u.gani@singhealth.com.sg\n\nAnthony Natasha https://orcid.org/0000-0003-4928-6380\n1\nDacay Lily 1\nTan Pei 2\nChong Le Roy https://orcid.org/0000-0002-8374-3760\n3\nKing Thomas FJ https://orcid.org/0000-0002-0383-3433\n1\n1 Department of Endocrinology Department of Medicine Changi General Hospital 2 Simei Street 3 529889 Singapore Singapore\n2 Centre of Trial Research Unit Changi General Hospital Singapore Singapore\n3 Department of Radiology Changi General Hospital Singapore Singapore\n* Address correspondence to: Dr Linsey Gani Department of Endocrinology, Department of Medicine Changi General Hospital, 2 Simei Street 3, Singapore 529889. E‐mail: linsey.u.gani@singhealth.com.sg\n\n19 6 2021\n8 2021\n5 8 10.1002/jbm4.v5.8 e1051530 4 2021\n17 2 2021\n13 5 2021\n© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\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\nBisphosphonates (BP) are the most commonly prescribed effective form of osteoporosis treatment with adverse effects associated with prolonged use such as atypical femoral fractures (AFF). Asians have an elevated risk of AFF at 5 to 6 times those of whites and Hispanics. In this study, we characterize factors associated with AFF and its mortality in a single center in Singapore. We conducted a cohort study of subjects older than 50 years admitted to Changi General Hospital (CGH), Singapore, with fragility subtrochanteric femoral fractures from 2009 to 2015. Using the ASBMR 2014 criteria, fractures are classified into atypical and typical subtrochanteric femoral fractures. CGH uses a nationalized electronic health record that allows review of information on patients' demographics, clinical history and previous investigations. Mortality was assessed as of December 31, 2019. Between 2009 and 2015, there were 3097 hip fractures, of which 393 were subtrochanteric femoral fractures and 69 were classified as AFF by ASBMR 2014 criteria. A total of 52.2% of AFF occurred with BP exposure of median duration 56.5 (28 to 66) months. Multivariate regression showed that BP exposure was associated with the highest risk of AFF (odds ratio [OR] = 6.65 [2.35–18.9]). AFF patients had higher 5‐year survival (0.85 versus 0.62, p = 0.001) compared with typical subtrochanteric fracture patients. However, after adjusting for variables, the type of subtrochanteric femoral fractures were no longer significantly associated with progression to death, whereas older age, higher mean Charlson comorbidity score, and Malay ethnicity were the strongest predictors of death. AFF constitutes a small proportion of hip and femoral fractures with prolonged BP use being the highest risk factor for its development. There is no evidence of increased mortality or morbidity in patients with AFF compared with the typical subtrochanteric fracture. The fear of AFF should not impede treatment of typical osteoporotic fractures in this population. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n\nOSTEOPOROSIS\nBISPHOSPHONATE\nATYPICAL FEMORAL FRACTURES\nASIAN\nMORTALITY\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:02.08.2021\n==== Body\n1 Introduction\n\nOsteoporosis is a chronic degenerative disease that causes degradation of normal bone structure. It renders an individual to be at higher risk of major fractures. It is projected that more than 50% of all osteoporotic fractures will occur in Asia by the year 2050.( 1 ) Since their introduction in the 1990s, bisphosphonates (BP) have been the mainstay of osteoporosis treatment. BPs inhibit osteoclast‐mediated resorption and remodeling of bone.( 2 ) Many large randomized controlled trials have established the efficacy of BP, showing their ability to increase bone mineral density (BMD) and decrease the risk of hip and vertebral fractures by as much as 40% to 70%.( 3 ) In Singapore, oral BP is still the first line of treatment for osteoporosis for most patients. Its affordable cost and oral route of administration render the drug a viable option to most patients.\n\nCase reports of unusual fragility fractures in the subtrochanteric region and along the femoral diaphysis in BP‐treated patients emerged in the literature about 15 years ago. Singapore was one of the first countries in the world to have reported these fractures.( 4 ) This was followed by larger studies of these fractures (now known as atypical femur fractures [AFF]) and their relation to BP.( 5 , 6 , 7 ) The pathogenesis of AFF is currently unclear; BP may alter intrinsic bone properties and healing of microcracks, leading to accumulation of microdamage and stress fracture. Other individual specific risk factors may increase susceptibility, either through alterations in bone geometry or microarchitecture, by interacting with antiresorptives, or by increasing biomechanical stress on the femur. These include ethnicity, younger age, higher body mass index (BMI), genetic factors, comorbidities, and concomitant drugs such as corticosteroid use.( 6 ) A recent large network analysis in California reported that Asian race formed half of their AFF cohorts; risk of AFF in Asians was 4.84 versus whites after adjusting for potential confounding variables.( 8 ) Another recent AFF study in Australia also found that among all Asian patients with AFF, Southeast Asian patients may display the highest risk.( 9 )\n\nAlthough increased mortality associated with typical fragility fractures of the femur is known,( 10 , 11 ) the rate of death associated with AFF has not been well established. A previous study in Sweden found lower mortality in AFF compared with ordinary fractures, (12 ) whereas another study in an elderly population in UK found no difference in mortality at 30 days.( 13 ) No previous studies in the Southeast Asian population have been performed. Given the likely higher risk of AFF in this population, we set out to study the incidence of AFF in our Southeast Asian population and its related demographic and clinical risk factors. We also assessed mortality rate of patients who have sustained AFF versus those with typical subtrochanteric femoral fractures.\n\n2 Materials and Methods\n\nWe conducted a cohort study of all patients admitted to Changi General Hospital (CGH) with acute fragility hip, subtrochanteric, and femur fractures from 2009 to 2015. CGH is a regional hospital serving the eastern population of Singapore estimated at 1.3 million. It employs a nationalized electronic health record that stores demographic information, past biochemical and radiological investigations, and prescription records, which can be accessed from all public health institutions in Singapore. All fragility fractures presenting to CGH between 2009 and 2015 were extracted from the electronic medical records with discharge diagnosis “fracture” and “osteoporosis.” Exclusion criteria include traumatic fractures (eg, motor vehicle car accident), and non‐osteoporotic or non‐fragility fracture and age younger than 50 years. We then separated all hip and subtrochanteric femur fractures and further extracted all subtrochanteric femoral fractures for further evaluation. Radiographs were obtained for patients with subtrochanteric or femoral shaft fractures to reclassify them into AFF according to the ASBMR 2014( 14 ) guideline for AFF (Fig. 1). Clinical and demographic data were extracted from the electronic medical records; this includes ethnicity data as listed in the patient's Singapore NRIC (National Registration Identity Card). Baseline clinical data were obtained on all patients at the time of presentation for fragility subtrochanteric and femoral shaft fractures. Information regarding medical history, including previous fragility fractures, parental history of fragility fractures, history of rheumatoid arthritis, current or previous steroid use in the last 12 months or prednisolone equivalent dose of 5 mg/d for >3 months at the time the fracture was recorded, and history of type 2 diabetes mellitus (DM2), was collected from the electronic medical records. Medication data collected include use of oral antidiabetic drugs, calcium and vitamin D supplementation, glucocorticoid use of more than 3 months’ duration, and anti‐osteoporosis drugs. Singapore has a national electronic health record that documents prescriptions across all public health institutions; duration of medication used was obtained from these prescription records. Duration of antiresorptive used was calculated as duration before the subtrochanteric femoral fractures. Antiresorptive use was analyzed if this was within 5 years of the fracture date and of continuous duration without a break of more than 6 months. Sequential treatment was observed in 15 patients, 11 patients had sequential oral BP (either alendronate or risedronate), and 4 patients were transitioned from oral BP to denosumab. Total exposures within 5 years were added together to constitute duration of BP exposure for each patient. There were no patients that were solely on denosumab for their documented antiresorptive treatment history. We further recorded data on smoking status and alcohol intake (>3 units/d). Smoking and alcohol intake were recorded if this was documented in the medical history before the fracture. Baseline anthropometric data were extracted from the electronic medical record and BMI was calculated as weight divided by height squared (kg/m2). All data were collected at time of presentation of the fracture.\n\nFig 1 Flow chart of identification of atypical femoral fracture (AFF) and subtrochanteric femur fractures.\n\n2.1 Biochemical evaluation\n\nHemoglobin A1c (HbA1c) level (%) was determined by immunoturbidimetric assay (Cobas 8000, Roche Diagnostics, Basel, Switzerland). HbA1C values within 6 months of admitted date were included in this analysis. Serum creatinine (μmol/L) was measured using indirect ion‐specific electrode (Roche Diagnostics) and estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology (CKD‐EPI) Eq. 25‐hydroxyvitamin D (25‐OHD) was measured by radioimmunoassay (Roche Diagnostics), and thyroid‐stimulating hormone (TSH) levels were also measured by immunoassay (Abbot Affinity, Chicago, IL, USA). Baseline biochemical data were collected at the time of presentation for the fracture.\n\n2.2 Radiological evaluation\n\nAll femoral radiographs performed at the time of patient presentation with acute fractures were retrospectively analyzed by adjudicating the radiographic findings with the reporting radiologist and our study member (CLR, a musculoskeletal radiologist with 20 years' experience), who was blinded to patients' identity and clinical characteristics, and classified according to the ASBMR 2014 criteria to ascertain if the radiographic appearances fulfill the definitions of AFF. Periprosthetic fractures were excluded from AFF cases. Healing of fracture was assessed through electronic records to the first documented radiographic report of callus formation or union of fracture during orthopedic clinic follow‐up visit post fracture admission. All BMD scans were performed on a single densitometer (Hologic QDR Discovery, Marlborough, MA, USA). The region of interest (ROI) was set as the total hip (non‐fractured hip site), femoral neck, and first to fourth lumbar vertebrae. We excluded vertebrae with fractures or degeneration causing >1 standard deviation greater areal BMD from the immediately adjacent vertebrae in accordance with the International Society for Clinical Densitometry guidelines for individual vertebrae exclusion. The BMD precision error (percentage of coefficient variation) was 1% for the total hip with a least significant change of 0.034 g/cm2, 2.3% for the femoral neck with a least significant change of 0.041 g/cm2, and 1% for the lumbar spine with a least significant change of 0.022 g/cm2. BMD results analyzed for the study were those that were documented within 6 months of the fracture event.\n\n2.3 Statistical analysis\n\nAll statistical analysis was performed using STATA 16 (Stata Corporation, College Station, TX, USA). Data were expressed as mean ± standard deviation (SD) for numerical data or frequency (percentage) for categorical data. Binary logistic regression was used to assess univariate and multivariate regression analysis in demographic and clinical variables between patients with AFF and typical subtrochanteric femoral fractures. Variables that showed statistical significance (p < 0.05) in univariate analysis were included in the multivariate logistics regression to identify the independent factor that was associated with AFF risk.\n\n2.4 Mortality\n\nPatients were followed up until December 31, 2019, to assess their mortality rate. Date of death was accessed through the electronic health record, and whenever possible, the cause of death was recorded. We calculated Kaplan–Meier curves for death by categories of fracture types at 5 years. We then compared the risk of death between AFF and typical subtrochanteric femoral fractures with potential variables that may affect the progression of death in the follow‐up to assess both unadjusted and adjusted HR for death. This was done using Cox proportional hazard ratio to adjust for age, sex, eGFR status, DM2, race, and bisphosphonate used. To understand the excess mortality rate compared with the age‐standardized mortality of the general population, we compared the rate of death after an AFF and typical subtrochanteric femoral fractures to the rate of death in the general population. National death rates and age‐standardized death rates were accessed on the website from the department of statistics in Singapore (https://www.singstat.gov.sg/find-data/search-by-theme/population/death-and-life-expectancy/latest-data).\n\nStandardized mortality ratios (SMR) were performed using STDRATE procedure in SAS University Edition (SAS Institute, Cary, NC, USA). A two‐tailed p < 0.05 was considered statistically significant. The study received approval by our institutional ethics board.\n\n3 Results\n\nSixty‐nine cases of AFF were identified by the ASBMR 2014 criteria; 5 cases had bilateral AFFs and 3 had incomplete fractures. AFF made up 2.0% of 3097 total hip, femur, and subtrochanteric fractures between 2009 and 2015. Patients presenting with bilateral AFFs were counted as a single AFF case for the purpose of this analysis. Indeterminate cases were excluded from this analysis. The percentage of AFF within subtrochanteric femur fractures in our population has also remained similar over 2009 to 2015 with the proportion of BP‐related AFF being stable (Fig. 2). The baseline demographic and clinical characteristics of the patients with subtrochanteric femoral fractures in the study are shown in Table 1. There were no statistically significant differences between the age of patients with AFF and typical subtrochanteric femoral fractures (71.2 versus 73.8 years old, p = 0.087). AFF patients had a lower mean Charlson comorbidity score (3.2 versus 3.9, p = 0.002) and lower prevalence of type 2 diabetes mellitus (13.0% versus 38.9%, p < 0.001) compared with typical subtrochanteric femoral fractures. There was a higher proportion of females in patients with AFF (87.0% versus 75.1%, p = 0.03), and there were no significant differences in the ethnicity of patients with AFF compared with the typical subtrochanteric femoral fractures. Data for 25‐OHD were only present for 76.4% (n = 353) of the cohort, TSH were recorded in 60% (n = 277), while among DM2 patients (n = 131), 80% had a recently documented HbA1C. There were no statistically significant differences between creatinine, eGFR, TSH, 25‐OHD, HbA1C, prevalence of smokers between patients with AFF, and typical subtrochanteric femoral fractures. There was no documented history of alcohol intake in any patients, and hence this data was excluded from the analysis. However, there was a higher rate of BP use (52.2% versus 11.2%, p < 0.001) and higher rate of surgical intervention (94.2% versus 73.9%, p < 0.001). There were no significant differences between prevalence of previous fragility fractures in the AFF and typical subtrochanteric femoral fracture group. There was no difference in the time to healing as documented by X‐ray, although there was higher prevalence of prodromal symptoms and bilateral fractures in AFF—this was not statistically significant. There were no differences in ethnicity groups between patients with AFF and typical subtrochanteric femoral fractures. Alendronate and risedronate were the most frequently prescribed BP; a small number of patients in both AFF and typical subtrochanteric groups had sequential treatments of oral BP (alendronate and risedronate) and sequential treatment to denosumab. Only one patient was exposed to zoledronic acid. Median duration of BP use was significantly longer in those with AFF (56.5 versus 15.5 months, p < 0.001). Glucocorticoid use was notably higher in patients with AFF (7.3 versus 1.3%, p = 0.002). Table 2 shows the BMD results of patients with AFF and typical subtrochanteric femoral fracture. It shows significantly higher BMD and T‐scores in total hip (0.70 g/cm2 versus 0.61 g/cm2, p = 0.008; −1.90 versus −2.73, p = 0.003) and femoral neck (0.61 g/cm2 versus 0.54 g/cm2, p = 0.028; −1.88 versus −2.54, p = 0.023) in patients with AFF versus those with typical subtrochanteric femoral factures. There were no significant differences in BMD of the lumbar spine.\n\nFig 2 Percentage of atypical femoral fracture (AFF) among subtrochanteric femoral fractures from 2009 to 2015, with percentages of AFF with bisphosphonate (BP) use.\n\nTable 1 Demographics and Clinical Variables of Patients With Atypical Femoral Fracture (AFF) and Typical Subtrochanteric Femoral Fracture\n\n\tAtypical femoral fracture (n = 69)\tTypical subtrochanteric femoral fracture (n = 393)\tp Value\t\nn (%)\tn (%)\t\nAge (years), mean (SD)\t71.2 (8.7)\t73.8 (12.3)\t0.087\t\nBMI (kg/m2), mean (SD)\t23.5 (3.8)\t23.9 (5.9)\t0.754\t\nFemale\t60 (87.0)\t295 (75.1)\t0.031\t\nRace\t\nChinese\t51 (83.6)\t266 (74.3)\t0.144\t\nMalay\t5 (8.2)\t66 (18.4)\t\nIndian/others\t5 (8.2)\t26 (7.3)\t\neGFR mean (SD)\t76.5 (21.5)\t75.8 (35.1)\t0.870\t\nCreatinine median (IQR)\t73 (62, 88)\t77 (60, 100)\t0.262\t\n25OHD (μg/L), mean (SD) (n = 353)\t28.6 (8.3)\t22.3 (11.5)\t0.061\t\nCharlson comorbidity score, mean (SD)\t3.2 (1.4)\t3.9 (2.0)\t0.002\t\nSmokers\t1 (1.5)\t14 (3.7)\t0.354\t\nFragility fracture history\t15 (22.7)\t105 (27.3)\t0.433\t\nRheumatoid arthritis\t5 (7.3)\t4 (1.0)\t0.001\t\nType 2 diabetes mellitus (DM2)\t9 (13.0)\t153 (38.9)\t<0.001\t\nHbA1c (%) in DM2, mean (SD) (n = 131)\t6.52 (0.51)\t7.25 (2.5)\t0.257\t\nTSH (mIU/L), median (IQR) (n = 277)\t1.19 (0.56, 3.95)\t1.50 (0.92, 2.50)\t0.439\t\nProdromal symptoms\t7 (10.1)\t18 (4.6)\t0.060\t\nBilateral fracture\t3 (4.4)\t10 (2.5)\t0.403\t\nDelayed healing\t2 (2.9)\t2 (2.3)\t0.760\t\nSurgical management\t65 (94.2)\t289 (73.9)\t<0.001\t\nRepeat surgical procedure\t2 (2.9)\t8 (2.1)\t0.643\t\nTime to healing (months), median (IQR)\t2 (1, 3)\t3 (1, 3)\t0.480\t\nAntiresorptive drug use (either oral BP/zoledronic acid/denosumab)\t35 (50.7)\t44 (11.2)\t<0.001\t\nOral BP (either alendronate or risedronate)\n\n\t28\t35\t\t\nOral BP sequential (alendronate and risedronate)\n\n\t5\t6\t\t\nOral BP to denosumab\n\n\t2\t2\t\t\nZoledronic acid\n\n\t0\t1\t\t\nDuration of BP use (months), median (IQR)\t56.5 (28, 66)\t15.5 (4, 36)\t<0.001\t\nGlucocorticoid use\t5 (7.3)\t5 (1.3)\t0.002\t\nSD = standard deviation; BMI = body mass index; eGFR = estimated glomerular filtration rate; IQR = interquartile range; 25‐OHD = 25‐hydroxyvitamin D; HbA1C = hemoglobin A1c; TSH = thyroid‐stimulating hormone; BP = bisphosphonate.\n\nTable 2 Bone Mineral Density (BMD) and T‐Scores of Patients With Atypical Femoral Fracture and Typical Subtrochanteric Femoral Fracture\n\n\tAtypical femoral fracture (n = 69)\tTypical subtrochanteric femoral fracture (n = 393)\tp Value\t\nBMD L spine, mean (SD)\t0.79 (0.16)\t0.78 (0.19)\t0.791\t\nBMD total hip, mean (SD)\t0.70 (0.15)\t0.61 (0.18)\t0.008\t\nBMD femoral neck, mean (SD)\t0.61 (0.14)\t0.54 (0.17)\t0.028\t\nT‐score L spine, mean (SD)\t−1.58 (1.49)\t−1.87 (1.57)\t0.353\t\nT‐score total hip, mean (SD)\t−1.90 (1.35)\t−2.73 (1.39)\t0.003\t\nT‐score femoral neck, mean (SD)\t−1.88 (1.27)\t−2.54 (1.45)\t0.023\t\n\nMultivariate regression analysis was performed to assess clinical variables that were significantly associated with AFF (Table 3) in patients presenting with subtrochanteric femoral fractures. There was a significant degree of collinearity between total hip T‐scores and FN T‐scores with similar odds ratio (OR) values observed in repeated regression. Creatinine and eGFR also yielded similar OR with significant degree of collinearity. Hence T‐score total hip and creatinine were selected for the final model. Exposure to bisphosphonate exhibits the strongest association with occurrence of AFF (OR = 6.65 [2.35–18.9], p < 0.001). A higher T‐score at the total hip (OR = 1.59 [1.06–2.39], p = 0.026) was also significantly associated with the incidence of AFF compared with typical subtrochanteric femoral fractures. Denosumab use was not significantly associated with AFF occurrence. A non‐DM2 status was also significantly associated with incidence of AFF compared with typical subtrochanteric femoral fractures.\n\nTable 3 Multivariate Regression of Variables Associated With Atypical Femoral Fracture\n\n\tUnadjusted OR (95% CI)\tAdjusted OR (95% CI)\t\nAge (years)\t0.98 (0.96, 1.00) a\t1.00 (0.93, 1.07)\t\nFemale\t2.21 (1.06, 4.63) a\t1.94 (0.41, 9.16)\t\nCreatinine\t0.99 (0.98, 0.99) a\t0.99 (0.98, 1.01)\t\nCharlson comorbidity score\t0.79 (0.68, 0.92) a\t0.89 (0.57, 1.41)\t\nRheumatoid arthritis\t7.58 (1.98, 28.97) a\t0.29 (0.01, 6.59)\t\nType 2 diabetes mellitus\t0.24 (0.11, 0.49) a\t0.23 (0.06, 0.95) a\t\nBisphosphonate\t8.17 (4.63, 14.4) a\t6.65 (2.35, 18.9) a\t\nDenosumab\t5.84 (0.81, 42.1)\t1.09 (0.05, 23.5)\t\nSurgical management\t5.74 (2.04, 16.1) a\t5.91 (0.63, 55.7)\t\nGlucocorticoid use\t6.06 (1.71, 21.5) a\t0.33 (0.03, 3.83)\t\nT total hip\t1.53 (1.14, 2.05) a\t1.57 (1.04, 2.37) a\t\nOR = odds ratio; CI = confidence interval.\n\na p < 0.05.\n\nMortality outcomes were assessed for patients with AFF versus typical subtrochanteric femoral fractures with censored date of December 31, 2019. There was a significant difference in mean survival time between AFF and typical subtrochanteric femoral fractures with probability of 5 years’ survival (0.85 versus 0.62, p = 0.001) (Fig. 3). In a multivariate analysis of factors associated with progression to death, older age, higher Charlson comorbidity score, and Malay ethnicity were most significantly associated with the highest risk of death (Table 4). The type of fracture (AFF or typical subtrochanteric femoral fracture) were not significantly associated with risk of death, implying that comorbidities of the patient rather than the fracture type were more important in the progression of death.\n\nFig 3 Kaplan–Meier curve for 5‐year survival in atypical femoral fracture versus typical subtrochanteric femoral fracture.\n\nTable 4 Unadjusted and Adjusted Hazard Ratio (HR) of Progression to Death in Atypical and Typical Subtrochanteric Femoral Fractures\n\n\tUnadjusted HR (95% CI)\tAdjusted HR (95% CI)\t\nAtypical fracture\t0.45 (0.27, 0.74) a\t0.71 (0.40, 1.26)\t\nAge\t1.06 (1.05, 1.08) a\t1.04 (1.02, 1.06) a\t\nFemale\t1.48 (1.04, 2.11) a\t0.92 (0.59, 1.44)\t\neGFR >60\t0.54 (0.41, 0.72) a\t0.87 (0.64, 1.20)\t\nCharlson comorbidity score\t1.53 (1.43, 1.63) a\t1.44 (1.32, 1.58) a\t\nType 2 diabetes mellitus\t1.17 (0.88, 1.56)\t0.80 (0.57, 1.12)\t\nRace\t\nChinese\t1.00\t1.00\t\nMalay\t1.40 (0.98, 2.02)\t1.50 (1.02, 2.22) a\t\nIndian/other\t0.95 (0.54, 1.69)\t1.18 (0.63, 2.20)\t\nBisphosphonate\t0.90 (0.62, 1.30)\t1.13 (0.73, 1.76)\t\nCI = confidence interval; eGFR = estimated glomerular filtration rate.\n\na p < 0.05.\n\nWe compared standardized mortality rates of AFF patients to rates of death in the general population with similar age groups by dividing the patients and comparison groups into chronological 5‐year increments. We found that patients with AFF had a lower mortality rate (SMR = 0.66 [0.34–0.97], p = 0.03) compared with the national standardized age mortality rate, while those with typical subtrochanteric femoral fractures have an excess mortality rate compared with the national standardized age mortality rate (SMR = 6.80 [5.79–7.80], p < 0.001). To assess if there are subgroups within AFF and the typical subtrochanteric fractures that may have differing SMR, subgroup analyses were performed. SMR remained lower within subgroups of AFF patients stratified into sex, bisphosphonate use, and age. Within the group of patients with typical subtrochanteric femoral fractures, SMR remained higher in all subgroups except for men and BP users, which showed no differences in their SMR compared with the national standardized age mortality rate (Table 5).\n\nTable 5 Age‐ and Sex‐Standardized Mortality Ratios (SMR) with 95% Confidence Intervals (CI) of Subgroups of Patients With Atypical Femoral Fracture and Typical Subtrochanteric Femoral Fracture\n\n\tSMR\t95% CI\tp Value\t\nAtypical femoral fracture\t\nAny\t0.66\t0.34–0.97\t0.030\t\nWomen\t0.58\t0.29–0.87\t0.005\t\nMen\t0.08\t0.00–0.18\t<0.001\t\nBisphosphonate users\t0.39\t0.15–0.63\t<0.001\t\nNon‐bisphosphonate users\t0.27\t0.07–0.47\t<0.001\t\nAge <80 years\t0.46\t0.20–0.73\t<0.001\t\nAge ≥80 years\t0.19\t0.02–0.36\t<0.001\t\nTypical subtrochanteric femoral fracture\t\nAny\t6.80\t5.79–7.80\t<0.001\t\nWomen\t5.44\t4.55–6.34\t<0.001\t\nMen\t1.35\t0.90–1.80\t0.124\t\nBisphosphonate users\t0.81\t0.46–1.58\t0.285\t\nNon‐bisphosphonate users\t5.98\t5.04–6.93\t<0.001\t\nAge <80 years\t3.17\t2.48–3.85\t<0.001\t\nAge ≥80 years\t3.63\t2.90–4.36\t<0.001\t\n\n4 Discussion\n\nStudies have shown that Asian patients are at higher risk of AFF, with a possibility of highest risk in Southeast Asian (SEA) patients.( 8 , 9 ) In this study, we set out to assess demographic and clinical characteristics of AFF patients in our population. To our knowledge, this is the first study in the SEA population assessing clinical demographic characteristics and mortality post AFF. Our study found that AFF constitutes a small part of the overall cause of all hip and femoral fractures in our population at 2.0%. The percentage of AFF among subtrochanteric femoral fractures has remained stable from 2009 to 2015. The number of BP‐related AFF have also remained stable. However, the percentage of BP use in our population was very low during this time, as we have shown in a previous study the osteoporosis treatment gap in our population is very high, which points to the integral need of secondary fracture prevention.( 15 ) We also found, consistent with the current literature,( 6 , 16 , 17 ) that AFF patients are less likely to have concurrent comorbidity with a higher rate of glucocorticoid use. However, when we adjusted the odds ratio of AFF development considering all potential significant variables, only exposure to BP and absence of DM2 were associated with development of AFF. The lower incidence of DM2 in the AFF population was similarly reported in other studies.( 18 ) The strongest risk factor for development of AFF in our population was found to be exposure to bisphosphonate with a median duration of 56.5 months. This is consistent with a recent study that found increasing risk present at 3 to 5 years of BP exposure in the Asian population.( 8 ) However, our study also found that nearly half of AFF in our population were in patients not exposed to bisphosphonates; 47.8% of patients with AFF had no previously documented exposure to BP. This was similar to a previous Korean study that found 64.7% of their cohort with no previous BP exposure( 19 ) and past case series from Singapore,( 20 ) in contrast to studies in the ethnic white population that have shown that the majority of AFF occur in the context of BP exposure.( 21 ) It is also interesting to note that in our study a higher T‐score of the hip was associated with the incidence of AFF. This further supports the hypothesis that AFF is a separate category of fracture that resembles stress fractures, and a predisposition to these stress fractures in the Asian population even without exposure to BP may be related to geometrical differences and other factors discussed below. A stress fracture is thought to occur from excessive loading of a relatively healthy bone, whereas an insufficiency fracture occurs with normal loading of an abnormal or weakened bone.( 8 ) This may also explain why incidence of AFF was higher in the younger population with less comorbidity as they may be more mobile and engage in physical activity that may contribute to these stress fractures. BPs may potentially impact stress fracture healing and cause a propagation of microdamage and impending microcrack, which may progress to create a stress fracture. A growing number of studies support the association of femoral geometry, particularly greater femoral bowing and varus alignment, and AFFs.( 22 , 23 , 24 , 25 ) These may be influenced by race or ethnicity and could explain the higher incidence of AFFs in the Asian population.( 8 ) It would also be important to consider other factors such as genetic predisposition with previous studies supporting the role of genetic influence of AFFs. Studies on whole‐exome sequencing in a family revealed a mutation in the enzymatic site inhibited by BP that may increase predisposition to AFFs.( 26 ) Other studies also support the presence of genetic variants that may be more common in the AFF patients with evidence suggesting that the risk may be polygenic with accumulation of at‐risk genetic variants.( 27 ) It would be important to study these variants in the Asian population to understand the underlying risk of AFF and how exposure to BP further increases this risk. Future studies are needed to better characterize underlying rates and physiology of AFF in both BP‐ and non‐BP‐exposed patients in these population as well.\n\nWe also sought to study the morbidity and mortality associated with AFF. Although surgical management in AFF patients is higher and there is a higher rate of bilateral fracture, our study found that time to healing and repeat surgery rates are not significantly different from typical fractures. In our follow‐up, we found that there was a higher probability of 5‐year survival for AFF patients compared with those with typical subtrochanteric femoral fractures (0.85 versus 0.62, p = 0.001). Factors associated with higher risk of progression to death were older age, higher Charlson comorbidity score, and Malay ethnicity. Indeed, when hazard ratios for death were adjusted for these variables at 10‐year follow‐up, the differences in mortality between AFF and typical subtrochanteric femoral fractures became non‐significant. This implies that comorbidities in patients presenting with these fractures are more important in predicting their mortality outcomes compared with the fracture type alone. The higher mortality rate in the Malay ethnic group compared with the Chinese is also consistent with observations from a previous hip registry study from Singapore.( 28 ) Other studies looking at mortality post AFF have shown no differences or reduced mortality compared with patients with typical subtrochanteric femoral fractures. A previous study in Sweden found lower mortality in patients with AFF in follow‐up duration of a mean of 4 years.( 12 ) Another study found no differences in mortality in a 30‐day follow‐up.( 13 ) When we compared the mortality rates of patients with AFF and typical subtrochanteric femoral fractures to the national standardized age mortality rate in the population in chronological 5‐year increments, we found that mortality risks for AFF patients were lower compared with the age‐standardized mortality in the general population; however, patients with typical fractures remain at a higher mortality risk compared with the general population. Data on comorbidities in the general population are not included in this comparison and thus the SMR should be interpreted in light of this. To assess the influence of factors such as sex, older age category, and bisphosphonate use, we performed further analysis to ascertain if there are differences in SMR in these subgroups. SMR remains lower in the AFF group compared with the age‐standardized mortality in the general population within the different subgroup analysis. In the typical subtrochanteric femoral fracture group, SMR remains higher compared with the age‐standardized mortality in the general population within the different subgroups except for men and those with BP use, which showed no significant difference in their mortality compared with the general population. This points to the fact that typical osteoporotic fracture such as the typical subtrochanteric femoral fracture remains a very high‐risk event when compared with the age‐standardized mortality rate. Bisphosphonates have been shown to reduce mortality post osteoporotic fracture( 29 , 30 ) with increasing evidence of both skeletal and non‐skeletal pathways with benefits observed in cancer and cardiovascular outcomes.( 31 , 32 , 33 ) This may explain the lack of difference in the SMR in the typical subtrochanteric group compared with the general population in those who were BP users.\n\nTaken together, these data imply that patients who sustain AFF are inherently different from those with typical subtrochanteric fracture. Despite higher rates of surgery within the AFF group, they show a higher 5‐year survival compared with patients with typical subtrochanteric fractures. Hazard ratio for progression to death shows that older age, comorbidities, and Malay ethnicity were the strongest predictors for death and that the type of fracture (AFF or typical subtrochanteric femoral fracture) was not significantly associated with progression to death. SMR of AFF is also lower than that of the age‐standardized mortality rate in the general population compared with typical subtrochanteric femoral fractures. There is also no evidence of increased morbidity or need for repeated surgical interventions. These data are reassuring for our population given the much higher risk of AFF that is known in the Asian population. Continued effort to reduce mortality in typical osteoporosis fractures should be pursued with the use of bisphosphonates and other anti‐osteoporotic drugs. The fear of AFF should not impede prevention of typical osteoporotic fractures.\n\nThe main strength of the study was long duration follow‐up of the patient and the link‐up of the electronic medical record for patients in Singapore, which allows us to accurately document a patient's clinical and medication history. We were able through this linkage to ascertain the date of death to provide accurate mortality data. We were also able to identify AFF by adjudication of the radiograph according to the ASBMR 2014 guideline. Limitations include the observational study design and the potential for residual confounding owing to differences in factors related to frailty, socioeconomic status, BMI, and BMD. There were missing data on 25‐OHD, TSH, and HbA1C, which may not accurately reflect differences present within the study population. There were very small numbers of patients on denosumab, and these patients were all previously exposed to BP. This may imply that we are unable to accurately ascertain the independent association of denosumab with AFF occurrence in this analysis. We also relied on the accuracy of the documented electronic health record for smoking and alcohol intake. There was no documented alcohol history intake in any patients, and we were unable to analyze this as a factor in contribution to the association with AFF and mortality. Ever‐smoker and current smokers were treated similarly in our analysis regardless of their last history of smoking. This may not accurately reflect the effect of smoking on the association of AFF and mortality as recency of exposure may play a significant part in the contribution of smoking as a pathological factor. We were also not fully able to ascertain the cause of death in most patients because the cause of death was not listed. There were also low numbers of patients in the older age groups and as such the interpretation of the results in these older groups should be done with caution. This study is also performed in a Southeast Asian population and as such its results may not be applicable in a different ethnicity setting. Comparison of the SMR with the general population is also limited by data on comorbidities present in the general population that was not adjusted for in the model.\n\nIn summary, AFF constitutes a small number of fractures in our population, and long‐term bisphosphonate exposure remains the strongest risk factor for its development. A total of 52.2% of AFF occur in BP users, and long‐term bisphosphonate use is the strongest risk factor for the incidence of AFF with median duration use of 56.5 months. Despite higher rates of surgery with AFF, there is no evidence of increased mortality or morbidity in this population compared with the typical subtrochanteric fracture. There was a lower risk of mortality in AFF compared with national age‐ and‐sex standardized mortality rate, but there was a higher mortality rate in the typical subtrochanteric fractures. The fear of AFF should not impede prevention of typical osteoporotic fractures, which carry a high risk of mortality. Further studies would be important to understand risk factors and physiology of the increased risk of AFF in the Asian population.\n\nDisclosures\n\nAll authors state that they have no conflict of interest.\n\nAUTHOR CONTRIBUTIONS\n\nLinsey Gani: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; validation; writing‐original draft; writing‐review & editing. Le Roy Chong: Data curation; investigation; validation; writing‐original draft; writing‐review & editing. Natasha Anthony: Data curation; project administration. Lily Dacay: Data curation; investigation; project administration. Pei Tan: Formal analysis; methodology; validation; writing‐original draft; writing‐review & editing. Thomas King: Conceptualization; formal analysis; investigation; methodology; project administration; supervision; validation; writing‐original draft; writing‐review & editing.\n\n5 PEER REVIEW\n\nThe peer review history for this article is available at https://publons.com/publon/10.1002/jbm4.10515.\n==== Refs\nReferences\n\n1 Cooper C , Campion G , Melton LJ 3rd. Hip fractures in the elderly: a world‐wide projection. Osteoporos Int. 1992;2 :285‐289.1421796\n2 Khosla S , Bilezikian JP , Dempster DW , et al. Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab. 2012;97 :2272‐2282.22523337\n3 Black DM , Cummings SR , Karpf DB , et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996;348 :1535‐1541.8950879\n4 Goh SK , Yang KY , Koh JS , et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br. 2007;89 :349‐353.17356148\n5 Gedmintas L , Solomon DH , Kim SC . Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta‐analysis. J Bone Miner Res. 2013;28 :1729‐1737.23408697\n6 Black DM , Abrahamsen B , Bouxsein ML , Einhorn T , Napoli N . Atypical femur fractures: review of epidemiology, relationship to bisphosphonates, prevention, and clinical management. Endocr Rev. 2019;40 :333‐368.30169557\n7 Schilcher J , Michaëlsson K , Aspenberg P . Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364 :1728‐1737.21542743\n8 Black DM , Geiger EJ , Eastell R , et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383 :743‐753.32813950\n9 Nguyen HH , Lakhani A , Shore‐Lorenti C , et al. Asian ethnicity is associated with atypical femur fractures in an Australian population study. Bone. 2020;135 :115319.32179169\n10 Haentjens P , Magaziner J , Colón‐Emeric CS , et al. Meta‐analysis: excess mortality after hip fracture among older women and men. Ann Intern Med. 2010;152 :380‐390.20231569\n11 Michaëlsson K , Nordström P , Nordström A , et al. Impact of hip fracture on mortality: a cohort study in hip fracture discordant identical twins. J Bone Miner Res. 2014;29 :424‐431.23821464\n12 Kharazmi M , Hallberg P , Schilcher J , Aspenberg P , Michaëlsson K . Mortality after atypical femoral fractures: a cohort study. J Bone Miner Res. 2016;31 :491‐497.26676878\n13 Davenport D , Duncan J , Duncan R , Dick A , Bansal M , Edwards MR . Outcomes for elderly patients with atypical femoral fractures compared to typical femoral fractures for length of stay, discharge destination, and 30‐day mortality rate. Geriatr Orthop Surg Rehabil. 2018;9 :2151459318820222.30627473\n14 Shane E , Burr D , Abrahamsen B , et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2014;29 :1‐23.23712442\n15 Gani L , Reddy SK , Alsuwaigh R , Khoo J , King TFJ . High prevalence of missed opportunities for secondary fracture prevention in a regional general hospital setting in Singapore. Arch Osteoporos. 2017;12 :60.28656564\n16 Koh JH , Myong JP , Yoo J , et al. Predisposing factors associated with atypical femur fracture among postmenopausal Korean women receiving bisphosphonate therapy: 8 years' experience in a single center. Osteoporos Int. 2017;28 :3251‐3259.28748389\n17 Starr J , Tay YKD , Shane E . Current understanding of epidemiology, pathophysiology, and management of atypical femur fractures. Curr Osteoporos Rep. 2018;16 :519‐529.29951870\n18 Schilcher J , Koeppen V , Aspenberg P , Michaëlsson K . Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop. 2015;86 :100‐107.25582459\n19 Lee YK , Kim TY , Ha YC , et al. Atypical subtrochanteric fractures in Korean hip fracture study. Osteoporos Int. 2017;28 :2853‐2858.28612307\n20 Tan SC , Koh SB , Goh SK , Howe TS . Atypical femoral stress fractures in bisphosphonate‐free patients. Osteoporos Int. 2011;22 :2211‐2212.20838769\n21 Dell RM , Adams AL , Greene DF , et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. 2012;27 :2544‐2550.22836783\n22 Jang SP , Yeo I , So S‐Y , et al. Atypical femoral shaft fractures in female bisphosphonate users were associated with an increased anterolateral femoral Bow and a thicker lateral cortex: a case‐control study. Biomed Res Int. 2017;2017 :5932496.28459066\n23 Soh HH , Chua ITH , Kwek EBK . Atypical fractures of the femur: effect of anterolateral bowing of the femur on fracture location. Arch Orthop Trauma Surg. 2015;135 :1485‐1490.26286640\n24 Hyodo K , Nishino T , Kamada H , Nozawa D , Mishima H , Yamazaki M . Location of fractures and the characteristics of patients with atypical femoral fractures: analyses of 38 Japanese cases. J Bone Miner Metab. 2017;35 :209‐214.27026435\n25 Sasaki S , Miyakoshi N , Hongo M , Kasukawa Y , Shimada Y . Low‐energy diaphyseal femoral fractures associated with bisphosphonate use and severe curved femur: a case series. J Bone Miner Metab. 2012;30 :561‐567.22610061\n26 Roca‐Ayats N , Balcells S , Garcia‐Giralt N , et al. GGPS1 mutation and atypical femoral fractures with bisphosphonates. N Engl J Med. 2017;376 :1794‐1795.28467865\n27 Pérez‐Núñez I , Pérez‐Castrillón JL , Zarrabeitia MT , et al. Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study. Mol Cell Biochem. 2015;409 :45‐50.26160281\n28 Yong E‐L , Ganesan G , Kramer MS , et al. Risk factors and trends associated with mortality among adults with hip fracture in Singapore. JAMA Network Open. 2020;3 :e1919706.32058551\n29 Bliuc D , Tran T , van Geel T , et al. Reduced bone loss is associated with reduced mortality risk in subjects exposed to nitrogen bisphosphonates: a mediation analysis. J Bone Miner Res. 2019;34 :2001‐2011.31402509\n30 Reid IR , Horne AM , Mihov B , et al. Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med. 2018;379 :2407‐2416.30575489\n31 Center JR , Lyles KW , Bliuc D . Bisphosphonates and lifespan. Bone. 2020;141 :115566.32745686\n32 Wolfe F , Bolster MB , O'Connor CM , Michaud K , Lyles KW , Colón‐Emeric CS . Bisphosphonate use is associated with reduced risk of myocardial infarction in patients with rheumatoid arthritis. J Bone Miner Res. 2013;28 :984‐991.23074131\n33 Kranenburg G , Bartstra JW , Weijmans M , et al. Bisphosphonates for cardiovascular risk reduction: a systematic review and meta‐analysis. Atherosclerosis. 2016;252 :106‐115.27513349\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2473-4039",
"issue": "5(8)",
"journal": "JBMR plus",
"keywords": "ASIAN; ATYPICAL FEMORAL FRACTURES; BISPHOSPHONATE; MORTALITY; OSTEOPOROSIS",
"medline_ta": "JBMR Plus",
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"nlm_unique_id": "101707013",
"other_id": null,
"pages": "e10515",
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"pmid": "34368607",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": "28748389;26286640;1421796;32813950;22610061;26676878;32179169;20231569;26160281;27513349;28656564;17356148;32058551;30627473;30169557;22836783;28612307;28459066;20838769;23821464;25582459;23408697;21542743;28467865;31402509;32745686;8950879;23074131;30575489;22523337;23712442;29951870;27026435",
"title": "Incidence of Atypical Femoral Fracture and Its Mortality in a Single Center in Singapore.",
"title_normalized": "incidence of atypical femoral fracture and its mortality in a single center in singapore"
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"abstract": "Identifying the culprit medication in cases of perioperative anaphylaxis can be extremely challenging. A detailed and accurate history, coupled with the appropriate testing, plays a key role in discovering the etiology of perioperative anaphylaxis. We present the case of a 48-year-old woman with a cranial meningioma who was scheduled for surgery. Chlorhexidine, midazolam, lidocaine, propofol, fentanyl, rocuronium, and furosemide were administered during the perioperative period. She developed hypotension, urticaria, bronchospasm, and other symptoms of anaphylaxis soon after general anesthesia. The serum tryptase level obtained during anaphylaxis was 119 ng/mL (normal, <11.4 ng/mL). Epinephrine was administered, and the surgery was canceled, with no cause identified. For the next surgical attempt, she was pretreated with diphenhydramine and ranitidine, and the neuromuscular blocker was withheld. Again, she developed hypotension consistent with anaphylaxis, and epinephrine was administered. She was referred for consultation. A detailed and accurate history was obtained. The baseline serum tryptase level was 6.4 ng/mL. Skin-prick puncture tests were completed, and a diagnosis was made. The surgical team was instructed to avoid the culprit medication, and the cranial surgery was successful. Although difficult, cases of perioperative anaphylaxis can be solved with a detailed history, keen detective work, and appropriate testing.",
"affiliations": "From the Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida; and.;University of South Florida Morsani College of Medicine, Tampa, Florida.",
"authors": "Kolinsky|Nicholas C|NC|;Lockey|Richard F|RF|",
"chemical_list": null,
"country": "United States",
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"doi": "10.2500/aap.2021.42.200060",
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"journal": "Allergy and asthma proceedings",
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"nlm_unique_id": "9603640",
"other_id": null,
"pages": "257-259",
"pmc": null,
"pmid": "33752780",
"pubdate": "2021-05-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A 48-year-old female with perioperative anaphylaxis.",
"title_normalized": "a 48 year old female with perioperative anaphylaxis"
} | [
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"activesubstancename": "FENTANYL CITRATE"
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{
"abstract": "OBJECTIVE\nThe off-label use of vedolizumab (VDZ) for inflammatory bowel disease in children is increasing. We report on possibly the first case of VDZ-associated pulmonary manifestations in paediatrics.\n\n\nMETHODS\nThis report details the case of a 13-year-old child with ulcerative colitis who was initiated on VDZ due to persistent active disease. After the first three doses, he developed a persistent and productive cough. Microbiological work-up was normal. VDZ discontinuation led to the resolution of symptoms.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first case report of VDZ-associated pulmonary manifestations in paediatrics. A direct, pro-inflammatory effect of VDZ has been hypothesized, but further studies are warranted.",
"affiliations": "Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood \"G. Barresi\", University of Messina, Messina, Italy.;Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood \"G. Barresi\", University of Messina, Messina, Italy.;Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood \"G. Barresi\", University of Messina, Messina, Italy.;Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood \"G. Barresi\", University of Messina, Messina, Italy.;Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood \"G. Barresi\", University of Messina, Messina, Italy.;Pediatric Gastroenterology and Cystic Fibrosis Unit, Department of Human Pathology in Adulthood and Childhood \"G. Barresi\", University of Messina, Messina, Italy.",
"authors": "Cucinotta|Ugo|U|;Dipasquale|Valeria|V|;Costa|Stefano|S|;Pellegrino|Salvatore|S|;Ramistella|Vincenzo|V|;Romano|Claudio|C|https://orcid.org/0000-0001-8827-2091",
"chemical_list": null,
"country": "England",
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"doi": "10.1111/jcpt.13494",
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"keywords": "adverse effects; children; inflammatory bowel disease; respiratory tract infection; ulcerative colitis; vedolizumab",
"medline_ta": "J Clin Pharm Ther",
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"nlm_unique_id": "8704308",
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"pmid": "34278581",
"pubdate": "2021-07-18",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Vedolizumab-associated pulmonary manifestations in children with ulcerative colitis.",
"title_normalized": "vedolizumab associated pulmonary manifestations in children with ulcerative colitis"
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"companynumb": "IT-TAKEDA-2021TUS046863",
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"activesubstancename": "CLARITHROMYCIN"
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"abstract": "Altered mental status can have many causes ranging from emergent intracranial pathologies to more insidious, systemic toxic aetiologies. We report a rare case of dermato-neuro syndrome in a 71-year-old man with a known history of scleromyxoedema. The patient initially presented with encephalopathy which quickly progressed to generalised tonic-clonic seizures and coma. While his presentation fits with other, although rare, cases of dermato-neuro syndrome, it is imperative to rule out lethal, more common causes of altered mentation. Due to the rarity and difficulty in diagnosis of dermato-neuro syndrome, there is a significant debate regarding the optimal management as there are no standardised treatment protocols. In our case, the patient was successfully treated with plasmapheresis resulting in improved neurologic function.",
"affiliations": "Department of Internal Medicine, Providence-Providence Park Hospital, Southfield, Michigan, USA jose.larios@ascension.org.;Department of Internal Medicine, Providence-Providence Park Hospital, Southfield, Michigan, USA.;Department of Internal Medicine, Providence-Providence Park Hospital, Southfield, Michigan, USA.;Hematology and Oncology, Providence Park Hospital, Novi, Michigan, USA.",
"authors": "Larios|Jose Maciel|JM|;Ciuro|Jordan|J|;Sam Varghese|Thomson|T|;Lyons|Susan Elizabeth|SE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237170",
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"issn_linking": "1757-790X",
"issue": "13(12)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; coma and raised intracranial pressure; dermatology; haematology (incl blood transfusion)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D001927:Brain Diseases; D000075902:Clinical Deterioration; D003128:Coma; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D009460:Neurologic Examination; D010346:Patient Care Management; D010956:Plasmapheresis; D012121:Respiration, Artificial; D053718:Scleromyxedema; D012640:Seizures; D013577:Syndrome; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
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"pmid": "33376089",
"pubdate": "2020-12-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of dermato-neuro syndrome with plasmapheresis.",
"title_normalized": "successful treatment of dermato neuro syndrome with plasmapheresis"
} | [
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"companynumb": "US-PFIZER INC-2021487607",
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"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
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{
"abstract": "The ability of a hospital's adverse drug reaction (ADR) database to identify common and repeated patterns of preventable adverse drug events (ADEs) was analyzed. ADR reports collected from 1994 through 2000 were extracted from a teaching hospital's ADR database. Reports were assessed concurrently in accordance with seven previously published explicit criteria for preventability. Only cases considered clinically significant were included in this analysis. Events that occurred in the ambulatory care setting were excluded. Preventable ADEs were categorized by drug or drug class, type of medication error, and the subsequent adverse outcome. Novel in this analysis was the linking of these three descriptors. Of the 2571 ADR reports assessed, 415 ADEs were deemed preventable. Of the preventable ADEs, 98 were not analyzed because they occurred in the ambulatory care setting, leaving 317 preventable ADEs in 275 inpatients (mean age +/- S.D., 48.5 +/- 23.9 years) for analysis. Although 93 drugs were associated with these ADEs, only 10 drugs accounted for more than 60% of the events. Analysis and categorization by type of error and outcome suggested that three high-priority preventable ADEs accounted for 50% of all reports: (1) overdoses of anticoagulants or insufficient monitoring and adjustments (according to laboratory test values) were associated with hemorrhagic events, (2) overdosing or failure to adjust for drug-drug interactions of opiate agonists was associated with somnolence and respiratory depression, and (3) inappropriate dosing or insufficient monitoring of insulins was associated with hypoglycemia. Analysis of a hospital ADR database identified prevalent and preventable clinically significant ADEs.",
"affiliations": "Department of Pharmacy Health Care Administration, College of Pharmacy, University of Florida, P.O. Box 100496, Suite P111, 1600 S.W. Archer Road, Gainesville, FL 32610, USA. almut@cop.ufl.edu",
"authors": "Winterstein|Almut G|AG|;Hatton|Randy C|RC|;Gonzalez-Rothi|Ricardo|R|;Johns|Thomas E|TE|;Segal|Richard|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ajhp/59.18.1742",
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"issue": "59(18)",
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"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D016208:Databases, Factual; D004342:Drug Hypersensitivity; D004347:Drug Interactions; D016903:Drug Monitoring; D064420:Drug-Related Side Effects and Adverse Reactions; D006785:Hospitals, University; D006801:Humans; D008508:Medication Errors; D012189:Retrospective Studies; D012308:Risk Management",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1742-9",
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"pubdate": "2002-09-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Identifying clinically significant preventable adverse drug events through a hospital's database of adverse drug reaction reports.",
"title_normalized": "identifying clinically significant preventable adverse drug events through a hospital s database of adverse drug reaction reports"
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"companynumb": "US-PFIZER INC-2020021508",
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"activesubstancename": "PROMETHAZINE HYDROCHLORIDE"
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"abstract": "This is the third case, reported in the literature, of transient cortical blindness that occurred during treatment of testicular carcinoma with cisplatinum, vinblastine and bleomycin. The presence of transiently pathological computerized tomography and brain scan suggests that this alarming event may not only be a toxic side effect of chemotherapy, but also a symptom related to eradicable subclinical metastases.",
"affiliations": null,
"authors": "Crispino|S|S|;Pizzocaro|G|G|;Solero|C L|CL|;Rodari|A|A|;Monfardini|S|S|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D002945:Cisplatin",
"country": "Italy",
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"issue": "3(5)",
"journal": "Chemioterapia : international journal of the Mediterranean Society of Chemotherapy",
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"medline_ta": "Chemioterapia",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D001932:Brain Neoplasms; D002945:Cisplatin; D006423:Hemianopsia; D006801:Humans; D008297:Male; D013736:Testicular Neoplasms; D014747:Vinblastine",
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"title": "Transient left homonymous hemianopsia during treatment of testicular carcinoma with cisplatinum, vinblastine, and bleomycin.",
"title_normalized": "transient left homonymous hemianopsia during treatment of testicular carcinoma with cisplatinum vinblastine and bleomycin"
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"abstract": "OBJECTIVE\nTo assess the risk of cardiac death associated with the use of clarithromycin and roxithromycin.\n\n\nMETHODS\nCohort study.\n\n\nMETHODS\nDenmark, 1997-2011.\n\n\nMETHODS\nDanish adults, 40-74 years of age, who received seven day treatment courses with clarithromycin (n = 160,297), roxithromycin (n = 588,988), and penicillin V (n = 4,355,309).\n\n\nMETHODS\nThe main outcome was risk of cardiac death associated with clarithromycin and roxithromycin, compared with penicillin V. Subgroup analyses were conducted according to sex, age, risk score, and concomitant use of drugs that inhibit the cytochrome P450 3A enzyme, which metabolises macrolides.\n\n\nRESULTS\nA total of 285 cardiac deaths were observed. Compared with use of penicillin V (incidence rate 2.5 per 1000 person years), use of clarithromycin was associated with a significantly increased risk of cardiac death (5.3 per 1000 person years; adjusted rate ratio 1.76, 95% confidence interval 1.08 to 2.85) but use of roxithromycin was not (2.5 per 1000 person years; adjusted rate ratio 1.04, 0.72 to 1.51). The association with clarithromycin was most pronounced among women (adjusted rate ratios 2.83 (1.50 to 5.36) in women and 1.09 (0.51 to 2.35) in men). Compared with penicillin V, the adjusted absolute risk difference was 37 (95% confidence interval 4 to 90) cardiac deaths per 1 million courses with clarithromycin and 2 (-14 to 25) cardiac deaths per 1 million courses with roxithromycin.\n\n\nCONCLUSIONS\nThis large cohort study found a significantly increased risk of cardiac death associated with clarithromycin. No increased risk was seen with roxithromycin. Given the widespread use of clarithromycin, these findings call for confirmation in independent populations.",
"affiliations": "Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen S, Denmark htr@ssi.dk.;Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen S, Denmark.;Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen S, Denmark.",
"authors": "Svanström|Henrik|H|;Pasternak|Björn|B|;Hviid|Anders|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D015575:Roxithromycin; D017291:Clarithromycin; D010404:Penicillin V",
"country": "England",
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"doi": "10.1136/bmj.g4930",
"fulltext": "\n==== Front\nBMJBMJbmjThe BMJ0959-81381756-1833BMJ Publishing Group Ltd. 25139799svah01907610.1136/bmj.g4930ResearchUse of clarithromycin and roxithromycin and risk of cardiac death: cohort study Svanström Henrik statisticianPasternak Björn postdoctoral fellowHviid Anders senior investigator1 Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen S, DenmarkCorrespondence to: H Svanström htr@ssi.dk2014 19 8 2014 349 g493021 7 2014 © Svanström et al 20142014Svanström et alThis is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/.Objective To assess the risk of cardiac death associated with the use of clarithromycin and roxithromycin.\n\nDesign Cohort study.\n\nSetting Denmark, 1997-2011.\n\nParticipants Danish adults, 40-74 years of age, who received seven day treatment courses with clarithromycin (n=160 297), roxithromycin (n=588 988), and penicillin V (n=4 355 309).\n\nMain outcome measures The main outcome was risk of cardiac death associated with clarithromycin and roxithromycin, compared with penicillin V. Subgroup analyses were conducted according to sex, age, risk score, and concomitant use of drugs that inhibit the cytochrome P450 3A enzyme, which metabolises macrolides.\n\nResults A total of 285 cardiac deaths were observed. Compared with use of penicillin V (incidence rate 2.5 per 1000 person years), use of clarithromycin was associated with a significantly increased risk of cardiac death (5.3 per 1000 person years; adjusted rate ratio 1.76, 95% confidence interval 1.08 to 2.85) but use of roxithromycin was not (2.5 per 1000 person years; adjusted rate ratio 1.04, 0.72 to 1.51). The association with clarithromycin was most pronounced among women (adjusted rate ratios 2.83 (1.50 to 5.36) in women and 1.09 (0.51 to 2.35) in men). Compared with penicillin V, the adjusted absolute risk difference was 37 (95% confidence interval 4 to 90) cardiac deaths per 1 million courses with clarithromycin and 2 (–14 to 25) cardiac deaths per 1 million courses with roxithromycin.\n\nConclusions This large cohort study found a significantly increased risk of cardiac death associated with clarithromycin. No increased risk was seen with roxithromycin. Given the widespread use of clarithromycin, these findings call for confirmation in independent populations.\n\nWeb Extra Extra material supplied by the author\nClick here for additional data file.\n==== Body\nIntroduction\nAcute cardiac toxicity is an increasingly recognised potential adverse effect of antimicrobial drug treatment.1\n2\n3 Several agents of the macrolide class of antibiotics are known to interfere with the delayed rectifier potassium current (IKr), which results in accumulation of potassium ions in cardiac myocytes and thereby delays cardiac repolarisation.1\n3\n4 Evident on the common electrocardiogram as a prolongation of the QT interval, this mechanism is thought to underlie an increase in the risk of torsade de pointes, a potentially fatal arrhythmia, with macrolides.1\n3\n4\n\nAlthough numerous case reports and spontaneous reports support this notion,1\n5\n6\n7\n8\n9\n10\n11\n12\n13 evidence from controlled studies to confirm and quantify a potential increase in serious cardiac events risk is limited. Two cohort studies of US Medicaid beneficiaries have found increased risks of sudden cardiac death and cardiovascular death associated with erythromycin and azithromycin, respectively.14\n15 Both studies reported increases in risk in periods of current use of these antibiotics, supporting an acute mechanism. Whereas these studies were performed in cohorts at relatively high baseline cardiovascular risk, a recent population based cohort study of young and middle aged adults at low baseline risk did not find a significantly increased risk of cardiovascular death associated with azithromycin.16 The cardiovascular risks associated with exposure to macrolides other than erythromycin and azithromycin are largely unknown, although a small Dutch case-control study pointed towards the possibility of an association between sudden cardiac death and clarithromycin.17 Like erythromycin, clarithromycin is metabolised by the cytochrome P450 3A enzyme, thus introducing the potential for a pharmacological interaction with other drugs interfering with this enzyme.1\n3\n18\n19 Roxithromycin is similarly metabolised by the cytochrome P450 3A enzyme,18\n19 but it is known to be less susceptible to cytochrome P450 3A inhibition.19\n\nGiven this background, the cardiac safety profiles of individual macrolides need to be elucidated in greater detail to help guide clinical treatment decisions. We did a nationwide registry based cohort study to investigate the risk of cardiac death associated with clarithromycin and roxithromycin, compared with another antibiotic with similar indications and no known cardiac risk, penicillin V.\n\nMethods\nWe did a prospective study in a historical cohort of users of macrolides and penicillin V in the period 1997-2011. The primary study outcome was cardiac death associated with the use of clarithromycin and roxithromycin, compared with penicillin V. Apart from erythromycin and azithromycin, clarithromycin and roxithromycin are the only macrolides available in Denmark. In subgroup analyses, we additionally assessed the risk of cardiac death according to sex, age, an empirically derived risk score for cardiac death, and concomitant use of cytochrome P450 3A inhibiting drugs.\n\nWe took several measures to minimise the potential for confounding. Firstly, to reduce the potential for confounding by indication, we analysed the risk of cardiac death associated with the respective macrolides relative to an active comparator; penicillin V is the most commonly used antibiotic in Denmark with indications similar to clarithromycin and roxithromycin. The indications for clarithromycin, roxithromycin, and penicillin V overlap with respect to upper and lower respiratory tract infections and skin and soft tissue infections. Both macrolides are additionally used for chlamydia, mycoplasma, and legionella infections; clarithromycin alone is used for the treatment of peptic ulcer. Secondly, to further reduce the potential for confounding and to increase the likelihood of isolating an effect attributable to the previously hypothesised pro-arrhythmic mechanism, we excluded participants with serious disease, who may be at high baseline risk of death from non-cardiac causes. Thirdly, to account for baseline differences in the risk of cardiac death, we adjusted all analyses for propensity scores, incorporating a wide range of potential confounders. Finally, to assess whether the choice of study drug may be associated with health status at baseline, which could bias the analyses of cardiac death, we also analysed the outcome of other non-cardiovascular death. An increased risk in death due to other causes for any of the study drugs would indicate differential health status at baseline.\n\nWe defined the study source population on the basis of the Danish Civil Registration System,20 including all people aged 40-74 years living in Denmark during the study period. Using the participants’ unique civil registration number, we linked individual level information on drug use, causes of death, and potential confounders. We identified use of macrolides and penicillin V from the nationwide Danish National Prescription Registry.21 We included information on all filled prescriptions for study antibiotics during the study period. We considered each prescription to be a separate event, and each participant could contribute multiple prescriptions to the study. For inclusion in the study, the person filling the prescription was required not to have been admitted to hospital and not to have had previous antibiotic treatment within 30 days before and including the prescription fill date. To assure adequate capture of covariate information, participants were required to have been continuously registered in Denmark for at least two years before the prescription fill date. Supplementary table A lists exclusion criteria. We identified cardiac deaths from the Danish Register of Causes of Death,22 which is based on death certificates and holds information on causes of all deaths occurring in Denmark, coded according to the International Classification of Diseases (supplementary table B). We collected data on potential confounders at the time of starting treatment (demographic characteristics, medical history and healthcare use, and previous use of other selected drugs) from the Civil Registration System,20 the Danish National Patient Register,23 and the National Prescription Registry,21 respectively (details in supplementary table C).\n\nStatistical analysis\nFor the primary analysis, follow-up started on the date when the prescription was filled and ended on the date of the participant becoming 75 years of age, loss to follow-up (disappearance, emigration), end of study (31 December 2011), switch to any other antibiotic, hospital admission, 37 days after the date of filling the prescription, or cardiac or non-cardiac death, whichever occurred first. In the analyses of death due to other causes, hospital admission and switch to another antibiotic were not included as censoring criteria. Given that the study drugs are generally administered in seven day treatment regimens, a follow-up of 37 days allowed effects of treatment to be evaluated for time periods up to 30 days after treatment had ended. Using Poisson regression, we estimated rate ratios comparing individual macrolides with penicillin V during time periods of current use (0-7 days from start of treatment) and past use (8-37 days). An increase in risk that occurred during current use and disappeared during past use would support the hypothesis of a transient toxic effect; conversely, an increased risk in periods of past use would instead support an alternative mechanism or confounding by baseline characteristics. We also estimated the adjusted absolute difference in risk per 1 million treatment courses with clarithromycin and roxithromycin ((adjusted rate ratio–1)×crude rate among users of penicillin V).\n\nTo control for confounding, we adjusted the analyses for the propensity score for starting treatment with, respectively, clarithromycin and roxithromycin.24 We derived the propensity scores from two separate logistic regression models, including all courses with the respective study drug and penicillin V and with all potential confounders listed in table 1 included as predictors. We then grouped the study participants according to tenths of propensity score distribution, included as adjustment factors in the regressions of the individual macrolides on cardiac death. To account for possible non-independence between multiple courses in the same participants, we used generalised estimating equations for all analyses.\n\nTable 1 Baseline characteristics of participants with use of clarithromycin, roxithromycin, and penicillin V included in analysis. Values are numbers (percentages) unless stated otherwise\n\nCharacteristics\tRoxithromycin (n=588 988)\tClarithromycin (n=160 297)\tPenicillin V (n=4 355 309)\t\nNo of patients\t350 575\t108 767\t1 519 324\t\nMale sex\t208 343 (35.4)\t58 608 (36.6)\t1 813 475 (41.6)\t\nMean (SD) age, years \t56.6 (9.7)\t57.2 (9.6)\t55.7 (9.5)\t\nAge group, years:\t\t\t\t\n 40-44\t88 353 (15.0)\t21 506 (13.4)\t734 320 (16.9)\t\n 45-49\t86 122 (14.6)\t22 078 (13.8)\t680 620 (15.6)\t\n 50-54\t90 525 (15.4)\t24 833 (15.5)\t720 663 (16.5)\t\n 55-59\t95 888 (16.3)\t26 947 (16.8)\t723 566 (16.6)\t\n 60-64\t91 146 (15.5)\t25 386 (15.8)\t625 358 (14.4)\t\n 65-69\t75 181 (12.8)\t21 512 (13.4)\t485 806 (11.2)\t\n 70-74\t61 773 (10.5)\t18 035 (11.3)\t384 976 (8.8)\t\nPlace of birth*:\t\t\t\t\n Denmark\t547 639 (93.0)\t148 842 (92.9)\t4 049 249 (93.0)\t\n Rest of Europe\t14 855 (2.5)\t4 127 (2.6)\t102 731 (2.4)\t\n Outside Europe\t26 494 (4.5)\t7 328 (4.6)\t203 329 (4.7)\t\nCalendar year:\t\t\t\t\n 1997-2001\t106 094 (18.0)\t53 559 (33.4)\t1 387 050 (31.8)\t\n 2002-06\t189 820 (32.2)\t54 146 (33.8)\t1 486 866 (34.1)\t\n 2007-11\t293 074 (49.8)\t52 592 (32.8)\t1 481 393 (34.0)\t\nSeason:\t\t\t\t\n March-May\t142 047 (24.1)\t40 446 (25.2)\t1 107 762 (25.4)\t\n June-August\t100 223 (17.0)\t26 194 (16.3)\t937 113 (21.5)\t\n September-November\t150 821 (25.6)\t39 991 (24.9)\t1 053 135 (24.2)\t\n December-February\t195 897 (33.3)\t53 666 (33.5)\t1 257 299 (28.9)\t\nMedical history:\t\t\t\t\n Acute coronary syndrome\t24 156 (4.1)\t6 739 (4.2)\t163 197 (3.7)\t\n Other ischaemic heart disease\t49 934 (8.5)\t13 629 (8.5)\t307 176 (7.1)\t\n Heart failure/cardiomyopathy\t13 178 (2.2)\t3 772 (2.4)\t79 434 (1.8)\t\n Valve disorders\t5 047 (0.9)\t1 262 (0.8)\t32 987 (0.8)\t\n Cerebrovascular disease\t20 403 (3.5)\t5 367 (3.3)\t135 715 (3.1)\t\n Arterial disease\t18 310 (3.1)\t5 167 (3.2)\t113 997 (2.6)\t\n Arrhythmia\t29 728 (5.0)\t7 625 (4.8)\t181 694 (4.2)\t\n Renal disease\t5 515 (0.9)\t1 419 (0.9)\t32 776 (0.8)\t\n Serious respiratory disease\t6 919 (1.2)\t2 449 (1.5)\t29 406 (0.7)\t\n Other respiratory disease\t78 485 (13.3)\t24 642 (15.4)\t335 736 (7.7)\t\n Psychiatric disorder\t24 346 (4.1)\t6 254 (3.9)\t141 921 (3.3)\t\n Cardiac surgery in previous year\t2 098 (0.4)\t656 (0.4)\t17 584 (0.4)\t\nPrescription drug use in previous year:\t\t\t\t\n ARB/ACE-I\t105 302 (17.9)\t25 884 (16.1)\t642 512 (14.8)\t\n Dihydropyridine CCB\t50 266 (8.5)\t12 022 (7.5)\t317 213 (7.3)\t\n Non-dihydropyridine CCB\t12 236 (2.1)\t3 787 (2.4)\t80 466 (1.8)\t\n Loop diuretics\t39 307 (6.7)\t11 835 (7.4)\t227 858 (5.2)\t\n Other diuretics\t90 091 (15.3)\t23 503 (14.7)\t572 287 (13.1)\t\n β blockers\t65 721 (11.2)\t16 661 (10.4)\t446 204 (10.2)\t\n Anti-arrhythmics class I and III\t2 159 (0.4)\t636 (0.4)\t14 857 (0.3)\t\n Digoxin\t6 704 (1.1)\t2 019 (1.3)\t48 771 (1.1)\t\n Nitrates\t16 894 (2.9)\t5 093 (3.2)\t107 981 (2.5)\t\n Platelet inhibitors\t74 129 (12.6)\t18 861 (11.8)\t459 602 (10.6)\t\n Anticoagulants\t11 655 (2.0)\t2 754 (1.7)\t81 964 (1.9)\t\n Lipid lowering drugs\t87 153 (14.8)\t19 087 (11.9)\t495 742 (11.4)\t\n Oral anti-diabetes drugs\t27 058 (4.6)\t6 282 (3.9)\t174 266 (4.0)\t\n Insulin\t11 999 (2.0)\t2 936 (1.8)\t83 053 (1.9)\t\n Antidepressants\t81 350 (13.8)\t21 213 (13.2)\t510 268 (11.7)\t\n Antipsychotics\t18 141 (3.1)\t4 974 (3.1)\t138 339 (3.2)\t\n Anxiolytics, hypnotics, and sedatives\t125 545 (21.3)\t38 501 (24.0)\t844 880 (19.4)\t\n β2 agonist inhalants\t92 409 (15.7)\t29 464 (18.4)\t434 233 (10.0)\t\n Corticosteroid inhalants\t101 348 (17.2)\t32 736 (20.4)\t441 846 (10.1)\t\n Xantines\t8 248 (1.4)\t3 537 (2.2)\t37 856 (0.9)\t\n Anticholinergic inhalants\t20 875 (3.5)\t6 490 (4.0)\t67 306 (1.5)\t\n Oral corticosteroids\t61 815 (10.5)\t19 598 (12.2)\t305 743 (7.0)\t\n NSAIDs\t196 256 (33.3)\t51 520 (32.1)\t1 414 481 (32.5)\t\n Opiates\t83 453 (14.2)\t23 073 (14.4)\t521 681 (12.0)\t\n Systemic hormone replacement therapy\t79 431 (13.5)\t25 331 (15.8)\t519 201 (11.9)\t\n Anti-osteoporotic drugs\t13 403 (2.3)\t3 874 (2.4)\t63 089 (1.4)\t\n PPI/H2 blocker\t104 313 (17.7)\t35 083 (21.9)\t592 932 (13.6)\t\nNo of prescription drugs used in previous year:\t\t\t\t\n 1-5\t323 735 (55.0)\t83 350 (52.0)\t2 871 871 (65.9)\t\n 6-9\t146 273 (24.8)\t40 501 (25.3)\t921 393 (21.2)\t\n ≥10\t118 980 (20.2)\t36 446 (22.7)\t562 045 (12.9)\t\nUse of healthcare in previous six months:\t\t\t\t\n Cardiovascular ED visit/hospital admission\t10 680 (1.8)\t3 084 (1.9)\t71 770 (1.6)\t\n Other ED visit/hospital admission\t62 136 (10.5)\t17 310 (10.8)\t450 149 (10.3)\t\n Cardiovascular outpatient contact\t14 350 (2.4)\t3 849 (2.4)\t95 501 (2.2)\t\n Other outpatient contact\t155 873 (26.5)\t40 786 (25.4)\t910 646 (20.9)\t\n ED visit in previous 7 days\t2 309 (0.4)\t512 (0.3)\t49 416 (1.1)\t\nACE-I=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; CCB=calcium channel blocker; ED=emergency department; NSAID=non-steroidal anti-inflammatory drug; PPI=proton pump inhibitor.\n\n*Missing values on place of birth (0.5%) were replaced with mode imputation.\n\nCardiac risk score\nWe estimated the cardiac risk score for subgroup analysis by using a logistic regression model, including as predictors all potential confounders (table 1) and a set of dummy variables indicating the treatment received. We then calculated the risk score by multiplying the regression coefficients obtained from the logistic regression model by the respective covariate value at the time of starting treatment for all included factors but the treatment dummy variables, which were all set to 0.25 This produced a summarising single value risk score for each treatment course included in the study. We then categorised all courses into three strata according to the score’s distribution: low (tenths 1-5), medium (6-8), and high (9-10).\n\nConcomitant use of cytochrome P450 3A inhibiting drugs\nFor the subgroup analysis according to concomitant use of cytochrome P450 3A inhibitors, we identified prescriptions for drugs included in the Indiana University School of Medicine cytochrome P450 drug interaction table and defined as strong or moderate inhibitors of cytochrome P450 3A (supplementary table D)26; a strong inhibitor is defined as a drug that causes a greater than fivefold increase in the area under the plasma concentration curve of the substrate or a greater than 80% decrease in clearance and a moderate inhibitor as a drug that causes a greater than twofold increase in area under the curve or a 50-80% decrease in clearance. We defined concomitant cytochrome P450 3A inhibitor use as a prescription that overlapped with the start of antibiotic treatment and the duration of cytochrome P450 3A inhibitor use by the number of defined daily doses in the prescription, with 14 days added to account for irregular drug intake habits.\n\nWe considered rate ratios to be statistically significant if the 95% interval confidence did not overlap 1. We assessed subgroup homogeneity by using the generalised score statistic. We used SAS 9.4 software for all analyses.\n\nResults\nFrom a source population of 3 379 788 people, we identified 8 910 459 treatment courses with the study antibiotics. After application of the exclusion criteria, the final study cohort included a total of 5 104 594 courses: 588 988 courses of roxithromycin, 160 297 courses of clarithromycin, and 4 355 309 courses of penicillin V (fig 1).\n\nFig 1 Enrolment of participants in cohort of users of clarithromycin, roxithromycin, and penicillin V. *People living in Denmark, aged 40-74 years, 1997-2011. †Numbers do not sum because some participants were excluded for more than one reason. ‡Including cancer, serious neurological disease, congenital anomalies/childhood conditions, liver disease,\n\nTable 1 shows participants’ characteristics at baseline. Supplementary table E shows standardised differences between participants with use of the different study drugs. Compared with users of penicillin V, users of clarithromycin and roxithromycin were less likely to be male, were on average slightly older, were less likely to have started treatment in June-August and more likely to have started in December-February, were more likely to have a history of respiratory disease, were more likely to have used drugs for the treatment of asthma and chronic obstructive pulmonary disease, were more likely to have used proton pump inhibitors and H2 blockers, had used a higher number of prescription drugs, were more likely to have had an outpatient hospital contact for non-cardiovascular causes in the previous six months, and were less likely to have had a recent emergency visit. Comparing users of the two macrolides, the groups were well balanced on medical history and use of healthcare; users of clarithromycin were more likely to have started treatment in the early part of the study period and were more likely to have used proton pump inhibitors and H2 blockers. Odds ratio estimates for all potential confounders included in the propensity score models and the cardiac risk score model are shown in tables F and G.\n\nTable 2 shows the risk of cardiac death associated with current and past use of clarithromycin and roxithromycin, compared with penicillin V. During follow-up, the proportions censored owing to, respectively, switch to another antibiotic and hospital admission were 19% and 3% in courses with clarithromycin, 18% and 3% in courses with roxithromycin, and 18% and 2% in courses with penicillin V. Among a total of 285 cardiac deaths observed during current use of the study drugs, 18 occurred during use of clarithromycin (incidence rate 5.3 per 1000 person years), 32 during use of roxithromycin (2.5 per 1000 person years), and 235 during use of penicillin V (2.5 per 1000 person years). In unadjusted analysis, current use of clarithromycin was associated with a significantly increased risk of cardiac death (rate ratio 2.07, 95% confidence interval 1.28 to 3.35); this association persisted after propensity score adjustment (1.76, 1.08 to 2.85). The adjusted absolute risk difference for current use of clarithromycin, compared with use of penicillin V, was 37 (95% confidence interval 4 to 90) cardiac deaths per 1 million treatment courses (fig 2). With regard to past use, clarithromycin was not associated with an increased risk of cardiac death. Current use of roxithromycin was not associated with an increased risk of cardiac death in adjusted analysis (rate ratio 1.04, 0.72 to 1.51). Compared with penicillin V, the adjusted absolute risk difference for current use of roxithromycin was 2 (–14 to 25) cardiac deaths per 1 million courses (fig 2). We observed no increased risk of cardiac death with past use of roxithromycin in either unadjusted or adjusted analysis. In the analyses of mortality due to other causes, we observed no significantly increased risk with clarithromycin (adjusted rate ratio 0.71, 0.49 to 1.03) or roxithromycin (1.14, 0.95 to 1.36).\n\nTable 2 Risk of cardiac death associated with use of clarithromycin and roxithromycin compared with penicillin V\n\n\tCardiac deaths\tIncidence rate/1000 patient years\tRate ratio (95% CI)\t\nUnadjusted\tPropensity score adjusted\t\nCurrent use\t\nClarithromycin\t18\t5.3\t2.07 (1.28 to 3.35)\t1.76 (1.08 to 2.85)\t\nRoxithromycin\t32\t2.5\t1.00 (0.69 to 1.44)\t1.04 (0.72 to 1.51)\t\nPenicillin V\t235\t2.5\t1.00 (reference)\t1.00 (reference)\t\nPast use\t\nClarithromycin\t14\t1.3\t1.24 (0.73 to 2.13)\t1.06 (0.62 to 1.82)\t\nRoxithromycin\t42\t1.0\t1.01 (0.73 to 1.40)\t1.06 (0.76 to 1.46)\t\nPenicillin V\t308\t1.0\t1.00 (reference)\t1.00 (reference)\t\nFig 2 Rate of cardiac death and number of excess cardiac deaths with clarithromycin and roxithromycin, compared with penicillin V. *As calculated from unadjusted rate of cardiac death. †Adjusted for propensity scores\n\nFigure 3 shows the risk of cardiac death associated with the use of clarithromycin and roxithromycin in subgroups according to sex, age, cardiac risk score, and concomitant use of cytochrome P450 3A inhibiting drugs. For clarithromycin, the relative risk was higher in women than in men (adjusted rate 1.09 (0.51 to 2.35) in men and 2.83 (1.50 to 5.36) in women), although not significantly so (P for homogeneity=0.07). We observed no significant differences across subgroups according to age (adjusted rate ratio 2.04 (0.88 to 4.74) among participants aged 40-64 years and 1.61 (0.89 to 2.91) among those aged ≥65 years; P=0.67) or concomitant use of cytochrome P450 3A inhibitors (adjusted rate ratio 1.76 (1.05 to 2.93) without concomitant use of cytochrome P450 3A inhibitors and 1.62 (0.38 to 7.00) with concomitant use; P=0.92). Estimates were similar across levels of cardiac risk score. For roxithromycin, we observed no significant difference in relative risk between men and women (adjusted rate ratio 0.97 (0.59 to 1.59) in men and 1.13 (0.63 to 2.00) in women; P=0.71) or between those younger than 65 years and those aged 65 years or older (adjusted rate ratio 1.64 (0.95 to 2.85) among participants aged 40-64 years and 0.75 (0.45 to 1.25) among those aged ≥65 years; P=0.06). We observed no cardiac deaths among users of roxithromycin with concomitant use of cytochrome P450 3A inhibitors; accordingly, the effect of concomitant use of cytochrome P450 3A inhibitors with roxithromycin could not be estimated. The relative risk was similar across levels of cardiac risk score.\n\nFig 3 Subgroup analyses of risk of cardiac death associated with clarithromycin and roxithromycin, compared with penicillin V. *Cardiac risk score was covariate summary score aiming to capture baseline risk of cardiac death and derived from all variables shown in table 1; score was categorised according to tenths of score’s distribution and strata defined as low (tenths 1-6), medium (6-8), and high (9-10). †Adjusted for propensity score, categorised according to tenths of score’s distribution; analyses stratified according to cardiac risk score were not adjusted for propensity scores\n\nSensitivity analyses\nIn sensitivity analyses, courses with use of clarithromycin and roxithromycin were matched (1:2) on the propensity score to courses with use of penicillin V. With respect to both clarithromycin and roxithromycin, the resulting matched cohorts were well balanced on all covariates (supplementary tables H and I). In propensity score matched analysis for cardiac death, the rate ratio associated with current use of clarithromycin was 1.63 (0.87 to 3.03) and the rate ratio associated with current use of roxithromycin was 0.92 (0.60 to 1.39).\n\nWe also analysed the risk of cardiac death associated with clarithromycin and roxithromycin according to the number of previous courses included in the study for each participant. The distribution for the number of previous courses according to study drug is shown in supplementary table J. For clarithromycin, the rate ratio was 2.07 (1.00 to 4.27) in people who had no previous courses and 0.94 (0.49 to 1.82) in those who had one or more previous courses. For roxithromycin, the rate ratio was 0.87 (0.44 to 1.73) in people who had no previous courses and 0.84 (0.52 to 1.35) in those with previous courses included.\n\nDiscussion\nIn this study, we investigated the risk of cardiac death associated with the use of clarithromycin and roxithromycin, compared with penicillin V. Use of clarithromycin was associated with a significant 76% higher risk of cardiac death. We observed no significant increase in risk with roxithromycin. In terms of absolute risk, use of clarithromycin would account for an estimated 37 excess cardiac deaths per 1 million courses. In subgroup analyses, the increase in risk with clarithromycin seemed to be driven by a strong association among women.\n\nComparison with previous studies\nOnly limited data exist on the risk of cardiac death associated with clarithromycin and roxithromycin. To our knowledge, no controlled observational studies have been published on the association between roxithromycin and cardiac death. In a Dutch case-control study, use of clarithromycin was found to be associated with a non-significant increased risk of sudden cardiac death, although this analysis was based on only three clarithromycin exposed cases.17 In an observational study among Tennessee Medicaid beneficiaries in the United States, the macrolide erythromycin was associated with a significant twofold increased risk of sudden cardiac death.14 As in the Medicaid study, the association between clarithromycin use and cardiac death in our study was present with current use of the drug and disappeared in periods of past use. If the association is true, this observation supports an acute toxic mechanism.\n\nIn the Medicaid study, a greater than fivefold increase in risk was observed in erythromycin users with concomitant use of cytochrome P450 3A inhibiting drugs. Similar to erythromycin, clarithromycin is metabolised by the cytochrome P450 3A enzyme.14 In our study, we did not find an increase in risk among users of clarithromycin with concomitant use of cytochrome P450 3A inhibiting drugs; this analysis, however, was limited by a small number of cases given the uncommon use of cytochrome P450 3A inhibitors. We were unable to examine the possibility that the risk of cardiac death might be increased in users of roxithromycin with concomitant use of cytochrome P450 3A inhibitors. Consequently, the possibility of an increase in risk with concomitant use of cytochrome P450 3A inhibiting drugs (as observed in the study of erythromycin14) may not be excluded and should be considered in future studies. \n\nOf note, the results suggested that the overall increase in risk with clarithromycin was largely driven by a strong association in women, although the difference in risk compared with men narrowly failed to reach statistical significance. This finding is consistent with female sex being a known risk factor for drug induced cardiac arrhythmia in general and macrolide induced arrhythmia in particular.1\n13\n27\n28 In the previous studies that found increased risk of sudden cardiac death and cardiovascular death with macrolides, subgroup analyses by sex were not reported.14\n15 In our subgroup analysis by predicted risk score, the rates of cardiac death increased considerably with increasing risk score. No indication of a differential risk according to levels of baseline risk was, however, observed.\n\nIn sensitivity analysis, we observed an increase in risk with clarithromycin only in people with no previous antibiotic courses during the study period. This increased risk in first time users could point towards the possibility of a genetic predisposition, which has previously been suggested to underlie drug induced torsade de pointes.3 Prolongation of the QT interval and subsequent serious arrhythmia are thought to be the underlying mechanisms for acute cardiac toxicity with macrolides. Individual macrolides vary in their potency of IKr inhibition and thus potential for QT prolongation and, therefore, potentially have different pro-arrhythmic properties.29 Notably, available mechanistic data comparing individual macrolides suggest that clarithromycin has higher potency of IKr inhibition compared with roxithromycin.30\n31 If true, the observed increased risk with clarithromycin but not roxithromycin may represent a clinical manifestation of these differing pharmacodynamic properties. Our study expands on the available knowledge of the cardiac safety of macrolides, being the first large scale population based observational study to show significantly increased cardiac risk with clarithromycin and the relative cardiac safety of roxithromycin.\n\nStrengths and weaknesses of study\nOur study has several strengths that merit attention. Firstly, owing to the nationwide coverage of the study, the results are probably widely generalisable. Secondly, the comparative design allowed us to assess roxithromycin and clarithromycin relative to an antibiotic with similar indications, thereby reducing the potential for confounding by indication. Thirdly, to increase the probability of isolating an effect attributable to roxithromycin and clarithromycin, we restricted the study population to people free from serious disease, with no recent use of antibiotics, and no recent hospital admission.\n\nThe study also has some limitations. We lacked information on several important lifestyle and health factors that are known to influence the risk of cardiac death, such as smoking and body mass index. Thus, despite propensity score adjustment, residual confounding cannot be ruled out. In propensity score matched analysis, which might provide more robust control for confounders than adjustment, the results, although less precise, were similar to the main findings. Furthermore, the fact that the risk of cardiac death was similar between penicillin V and both clarithromycin and roxithromycin in periods of past use would indicate that baseline differences between the groups are unlikely to have influenced the results significantly; whereas the incidence of cardiac death during current use of antibiotics is influenced by acute infection (for which the antibiotic was prescribed), the incidence during past use probably resembles the study participants’ baseline risk of cardiac death. The fact that no significant differences were observed for mortality due to other causes should further lessen concerns about systematic differences in health status at baseline as an explanation for the observed association; the relatively low risk of death from other causes associated with clarithromycin may indicate that the observed association for cardiac death might be stronger than what was estimated. Data on specific infections for which the drugs were prescribed were not available for this study; however, the fact that clarithromycin and roxithromycin have essentially identical indications should reduce concerns about the results being influenced through an effect of infection rather than the prescribed treatment (that is, confounding by indication). The absence of an association between roxithromycin exposure and cardiac death can be viewed as a negative control for the positive association between clarithromycin and cardiac death. Furthermore, the primary outcome definition of cardiac death may not have been sufficiently specific to fully capture an increased risk attributable to the postulated pro-arrhythmic effect; any resulting bias would be in the direction of the null and would not explain the association found with clarithromycin. Finally, the rate of cardiac death in this study was low and results were, accordingly, based on few events. The power to detect differences in subgroup analysis may have been limited.\n\nImplications of findings\nIn absolute terms, 37 (95% confidence interval 4 to 90) excess cardiac deaths occurred per 1 million treatment courses associated with current use of clarithromycin compared with current penicillin V use in this study. Interpretation of the clinical importance of this finding, if confirmed, is delicate. One the one hand, the absolute risk is small, so this finding should probably have limited, if any, effect on prescribing practice in individual patients (with the possible exception of patients who have strong risk factors for drug induced arrhythmia). On the other hand, clarithromycin is one of the more commonly used antibiotics in many countries and many millions of people are prescribed this drug each year; thus, the total number of excess (potentially avoidable) cardiac deaths may not be negligible. These factors need to be considered when assessing the overall benefit/risk profile of macrolides (clarithromycin specifically), an important area for future work by, for example, regulatory agencies and other public health officials.\n\nConclusion\nThis nationwide cohort study found a significantly increased risk of cardiac death associated with current use of clarithromycin but not roxithromycin. The observed association for clarithromycin seemed to be largely attributable to women. Before these results are used to guide clinical decision making, confirmation in independent populations is an urgent priority given the widespread use of macrolide antibiotics.\n\nWhat is already known on this topic\nMacrolide antibiotics prolong the QT interval and are therefore thought to increase the risk of potentially fatal arrhythmias\n\nWhat this study adds\nThis register based cohort study found a significantly increased risk of cardiac death associated with current use of clarithromycin, which was most pronounced among women\n\nNo increased risk of cardiac death was found with roxithromycin\n\nContributors: All authors contributed to conception and design of the study and to the analysis and interpretation of the study results. HS acquired the data and conducted the statistical analyses. HS and BP drafted the manuscript. All authors critically revised the manuscript and approved the final version for submission. AH supervised the study and is the guarantor. \n\nFunding: None.\n\nCompeting interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.\n\nEthical approval: The study was approved by the Danish Data Protection Agency. Ethics approval is not required for register based research in Denmark.\n\nTransparency declaration: AH affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.\n\nData sharing: No additional data available.\n\nCite this as: BMJ 2014;349:g4930\n==== Refs\n1 Justo D, Zeltser D. Torsades de pointes induced by antibiotics. Eur J Intern Med 2006 ;17 :254 -9.16762774 \n2 Mosholder AD, Mathew J, Alexander JJ, Smith H, Nambiar S. Cardiovascular risks with azithromycin and other antibacterial drugs. N Engl J Med 2013 ;368 :1665 -8.23635046 \n3 Owens RC Jr, Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006 ;43 :1603 -11.17109296 \n4 Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003 ;89 :1363 -72.14594906 \n5 Hensey C, Keane D. Clarithromycin induced torsade de pointes. Ir J Med Sci 2008 ;177 :67 -8.17618400 \n6 Huang BH, Wu CH, Hsia CP, Yin CC. Azithromycin-induced torsade de pointes. Pacing Clin Electrophysiol 2007 ;30 :1579 -82.18070319 \n7 Kamochi H, Nii T, Eguchi K, Mori T, Yamamoto A, Shimoda K, et al. Clarithromycin associated with torsades de pointes. Jpn Circ J 1999 ;63 :421 -2.10943628 \n8 Katapadi K, Kostandy G, Katapadi M, Hussain KM, Schifter D. A review of erythromycin-induced malignant tachyarrhythmia—torsade de pointes: a case report. Angiology 1997 ;48 :821 -6.9313632 \n9 Kezerashvili A, Khattak H, Barsky A, Nazari R, Fisher JD. Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors. J Interv Card Electrophysiol 2007 ;18 :243 -6.17546486 \n10 Koh TW. Risk of torsades de pointes from oral erythromycin with concomitant carbimazole (methimazole) administration. Pacing Clin Electrophysiol 2001 ;24 :1575 -6.11707056 \n11 Piquette RK. Torsade de pointes induced by cisapride/clarithromycin interaction. Ann Pharmacother 1999 ;33 :22 -6.9972380 \n12 Promphan W, Khongphatthanayothin A, Horchaiprasit K, Benjacholamas V. Roxithromycin induced torsade de pointes in a patient with complex congenital atrioventricular block. Pacing Clin Electrophysiol 2003 ;26 :1424 -6.12822762 \n13 Shaffer D, Singer S, Korvick J, Honig P. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System. Clin Infect Dis 2002 ;35 :197 -200.12087527 \n14 Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med 2004 ;351 :1089 -96.15356306 \n15 Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012 ;366 :1881 -90.22591294 \n16 Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med 2013 ;368 :1704 -12.23635050 \n17 Straus SM, Sturkenboom MC, Bleumink GS, Dieleman JP, van der Lei J, de Graeff PA, et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur Heart J 2005 ;26 :2007 -12.15888497 \n18 Rubinstein E. Comparative safety of the different macrolides. Int J Antimicrob Agents 2001 ;18 :S71 -6.11574199 \n19 Yamazaki H, Shimada T. Comparative studies of in vitro inhibition of cytochrome P450 3A4-dependent testosterone 6beta-hydroxylation by roxithromycin and its metabolites, troleandomycin, and erythromycin. Drug Metab Dispos 1998 ;26 :1053 -7.9806945 \n20 Pedersen CB. The Danish civil registration system. Scand J Public Health 2011 ;39 (7 suppl):22 -5.21775345 \n21 Kildemoes HW, Sorensen HT, Hallas J. The Danish national prescription registry. Scand J Public Health 2011 ;39 (7 suppl):38 -41.21775349 \n22 Helweg-Larsen K. The Danish register of causes of death. Scand J Public Health 2011 ;39 (7 suppl):26 -9.\n23 Lynge E, Sandegaard JL, Rebolj M. The Danish national patient register. Scand J Public Health 2011 ;39 (7 suppl):30 -3.21775347 \n24 Brookhart MA, Wyss R, Layton JB, Sturmer T. Propensity score methods for confounding control in nonexperimental research. Circ Cardiovasc Qual Outcomes 2013 ;6 :604 -11.24021692 \n25 Sturmer T, Schneeweiss S, Brookhart MA, Rothman KJ, Avorn J, Glynn RJ. Analytic strategies to adjust confounding using exposure propensity scores and disease risk scores: nonsteroidal antiinflammatory drugs and short-term mortality in the elderly. Am J Epidemiol 2005 ;161 :891 -8.15840622 \n26 Indiana University School of Medicine. P450 drug interaction table: Abbreviated “clinically relevant” table. 2013. http://medicine.iupui.edu/clinpharm/ddis/clinical-table/.\n27 Kannankeril P, Roden DM, Darbar D. Drug-induced long QT syndrome. Pharmacol Rev 2010 ;62 :760 -81.21079043 \n28 Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004 ;350 :1013 -22.14999113 \n29 Owens RC Jr. QT prolongation with antimicrobial agents: understanding the significance. Drugs 2004 ;64 :1091 -124.15139788 \n30 Ohtani H, Taninaka C, Hanada E, Otaki H, Sato H, Sawada Y, et al. Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats. Antimicrob Agents Chemother 2000 ;44 :2630 -7.10991836 \n31 Volberg WA, Koci BJ, Su W, Lin J, Zhou J. Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. J Pharmacol Exp Ther 2002 ;302 :320 -7.12065733\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0959-8138",
"issue": "349()",
"journal": "BMJ (Clinical research ed.)",
"keywords": null,
"medline_ta": "BMJ",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D002318:Cardiovascular Diseases; D017291:Clarithromycin; D015331:Cohort Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D003718:Denmark; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010404:Penicillin V; D057216:Propensity Score; D012042:Registries; D015575:Roxithromycin; D012737:Sex Factors",
"nlm_unique_id": "8900488",
"other_id": null,
"pages": "g4930",
"pmc": null,
"pmid": "25139799",
"pubdate": "2014-08-19",
"publication_types": "D016428:Journal Article",
"references": "10991836;22591294;24021692;9806945;15840622;12065733;14594906;11574199;15139788;12822762;9972380;21775347;9313632;21775346;10943628;21079043;17109296;17546486;14999113;15888497;23635050;16762774;21775345;15356306;21775349;23635046;12087527;18070319;11707056;17618400",
"title": "Use of clarithromycin and roxithromycin and risk of cardiac death: cohort study.",
"title_normalized": "use of clarithromycin and roxithromycin and risk of cardiac death cohort study"
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{
"companynumb": "DK-RANBAXY-2015R1-92791",
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"activesubstancename": "CLARITHROMYCIN"
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{
"abstract": "Despite improvements in standard therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for patients with untreated, diffuse large B-cell lymphoma, up to 40% of these patients relapse. Lenalidomide alone or in combination with rituximab has been shown to be active in relapsed/refractory aggressive lymphomas. In this phase I study we determined the maximum tolerated dose of lenalidomide plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone in untreated, elderly (median age 68 years) patients with diffuse large B-cell lymphoma. Four lenalidomide doses (5, 10, 15, and 20 mg/day on days 1-14) allocated using the continual reassessment method were planned to be administered for 14 days in combination with each course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone for a total of six courses. Seven cohorts of patients (n=3 in each cohort) were treated (total n=21) at 10, 20, 15, 15, 15, 10, and 10 mg of lenalidomide. Dose-limiting toxicities occurred in seven patients during the first three courses of treatment. The third dose-level of lenalidomide (15 mg/day) was selected as the maximum tolerated dose, with an estimated probability of dose-limiting toxicities of 0.345 (95% credibility interval 0.164-0.553). Grade 3-4 hematologic adverse events were: neutropenia in 28% of the courses, thrombocytopenia in 9%, and anemia in 3%. Non-hematologic toxicities were moderate: grade 4 increase of creatinine phosphokinase (n=1), grade 3 cardiac (n=2), grade 3 neurological (n=3), and grade 3 gastrointestinal (n=1). In this phase I study, the overall response rate was 90%, with 81% achieving complete remission. This combination regimen appears safe in elderly patients with diffuse large B-cell lymphoma and its efficacy will be assessed in the ongoing phase II trial. This trial was registered at www.clinicaltrials.gov as NCT00907348.",
"affiliations": "uvitolo@cittadellasalute.to.it.",
"authors": "Chiappella|Annalisa|A|;Tucci|Alessandra|A|;Castellino|Alessia|A|;Pavone|Vincenzo|V|;Baldi|Ileana|I|;Carella|Angelo Michele|AM|;Orsucci|Lorella|L|;Zanni|Manuela|M|;Salvi|Flavia|F|;Liberati|Anna Marina|AM|;Gaidano|Gianluca|G|;Bottelli|Chiara|C|;Rossini|Bernardo|B|;Perticone|Sonia|S|;De Masi|Pasqualina|P|;Ladetto|Marco|M|;Ciccone|Giovannino|G|;Palumbo|Antonio|A|;Rossi|Giuseppe|G|;Vitolo|Umberto|U|;|||",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D013792:Thalidomide; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000077269:Lenalidomide; D011241:Prednisone",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2013.085134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6078",
"issue": "98(11)",
"journal": "Haematologica",
"keywords": null,
"medline_ta": "Haematologica",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D064146:Chemotherapy-Induced Febrile Neutropenia; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007558:Italy; D000077269:Lenalidomide; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D013792:Thalidomide; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0417435",
"other_id": null,
"pages": "1732-8",
"pmc": null,
"pmid": "23812930",
"pubdate": "2013-11",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "17576924;15955905;16434987;12660941;19586937;11807147;21859554;16648042;17360935;21030533;22733106;18226581;21720383;18606983;17400393;21495023;23578722;16150940;12941516;2702835;19565649;21504290;16115943;15867204;20548096;18334676;16434377;16754935;16840727;20629527;12384400;20665890;11568943;22160081;19245430;15618473;21228334;21895543;16750358",
"title": "Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi.",
"title_normalized": "lenalidomide plus cyclophosphamide doxorubicin vincristine prednisone and rituximab is safe and effective in untreated elderly patients with diffuse large b cell lymphoma a phase i study by the fondazione italiana linfomi"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1009813",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
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{
"abstract": "A 19-year-old female diagnosed with Graves' disease had treatment initiated with propylthiouracil (PTU). Pretreatment complete blood count and liver-associated enzymes (LAEs) were normal, but no further LAEs were obtained, reflecting U.S. guidelines written in 1995. Three months later, she presented with nausea, vomiting, abdominal pain, and jaundice. LAEs were markedly elevated with: total bilirubin, 6.5 mg/dl; aspartate aminotransferase (AST), 1747 IU/L; and alanine aminotransferase (ALT) 1589 UL/L. After 6 days at an outside hospital, she was transferred to our tertiary care center in acute liver failure with coagulopathy and stage II encephalopathy. Liver transplant evaluation was promptly initiated and she was listed as status 1. PTU was the only medication she had taken; and all serologic, autoimmune, and metabolic studies were negative. She demonstrated rapid clinical deterioration, and on hospital day 7 she underwent orthotopic liver transplant but succumbed to tonsillar herniation immediately after surgery. Pathology from her explanted liver revealed marked necrosis and collapse, consistent with her acute liver failure. PTU-associated hepatotoxicity and myelotoxicity have been well-recognized serious adverse effects for more than 50 years. However, as deaths related to hepatic injury from PTU are rare, American Thyroid Association guidelines do not call for routine monitoring of LAEs, although monitoring of white blood cell count levels is advised. Given the wide spectrum of PTU-related liver injury, ranging from asymptomatic elevations in ALT to fatal acute liver failure, we urge consideration of an LAE monitoring program to prevent irreversible liver damage and call for a reappraisal of monitoring guidelines in the United States.",
"affiliations": "Department of Internal Medicine, Georgetown University Hospital, Washington, DC 20007, USA. jxp163@gunet.georgetown.edu",
"authors": "Primeggia|Jennifer|J|;Lewis|James H|JH|",
"chemical_list": "D013956:Antithyroid Agents; D011441:Propylthiouracil",
"country": "United States",
"delete": false,
"doi": "10.1016/s0027-9684(15)30564-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0027-9684",
"issue": "102(6)",
"journal": "Journal of the National Medical Association",
"keywords": null,
"medline_ta": "J Natl Med Assoc",
"mesh_terms": "D013956:Antithyroid Agents; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006980:Hyperthyroidism; D017093:Liver Failure; D008111:Liver Function Tests; D011441:Propylthiouracil; D055815:Young Adult",
"nlm_unique_id": "7503090",
"other_id": null,
"pages": "531-4",
"pmc": null,
"pmid": "20575220",
"pubdate": "2010-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gone (from the Physicians' desk reference) but not forgotten: propylthiouracil-associated hepatic failure: a call for liver test monitoring.",
"title_normalized": "gone from the physicians desk reference but not forgotten propylthiouracil associated hepatic failure a call for liver test monitoring"
} | [
{
"companynumb": "US-ACTAVIS-2016-00806",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PROPYLTHIOURACIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPerampanel (PER) is a novel antiepileptic drug (AED) which employs a completely different mechanism of action compared to existing medications. Overall, PER is considered to be safe up to a dose of 12 mg per day. When used to treat refractory and super-refractory status epilepticus, PER seems to be extremely well tolerated; this is true even when used at doses of up to 32 mg. There are currently only three case reports on the effects of acute PER overdose in epilepsy patients.\n\n\nMETHODS\nWe report a 16-year-old Thai woman with a low body weight, who took PER at a dose of 40 times that of the prescribed daily dose. She experienced only an alteration of consciousness, without any systemic medical effects, and made a full recovery within 3 days without gastric lavage or specific treatment.\n\n\nCONCLUSIONS\nOur report demonstrates that an acute PER overdose may not produce serious adverse systemic effects. Individuals with adverse central nervous system (CNS) effects, such as altered consciousness, can experience a rapid recovery.",
"affiliations": "Neurology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand. pkanitpo@gmail.com.;Neurology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand.",
"authors": "Phabphal|Kanitpong|K|http://orcid.org/0000-0003-1723-7525;Koonalintip|Prut|P|",
"chemical_list": "D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-021-02759-9",
"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n2759\n10.1186/s13256-021-02759-9\nCase Report\nPerampanel overdose in low body mass index patients with epilepsy: a case report and review of the literature\nhttp://orcid.org/0000-0003-1723-7525\nPhabphal Kanitpong pkanitpo@gmail.com\n\nKoonalintip Prut\ngrid.7130.5 0000 0004 0470 1162 Neurology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110 Thailand\n29 3 2021\n29 3 2021\n2021\n15 14728 9 2020\n23 2 2021\n© The Author(s) 2021\nOpen 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.\nBackground\n\nPerampanel (PER) is a novel antiepileptic drug (AED) which employs a completely different mechanism of action compared to existing medications. Overall, PER is considered to be safe up to a dose of 12 mg per day. When used to treat refractory and super-refractory status epilepticus, PER seems to be extremely well tolerated; this is true even when used at doses of up to 32 mg. There are currently only three case reports on the effects of acute PER overdose in epilepsy patients.\n\nCase presentation\n\nWe report a 16-year-old Thai woman with a low body weight, who took PER at a dose of 40 times that of the prescribed daily dose. She experienced only an alteration of consciousness, without any systemic medical effects, and made a full recovery within 3 days without gastric lavage or specific treatment.\n\nConclusion\n\nOur report demonstrates that an acute PER overdose may not produce serious adverse systemic effects. Individuals with adverse central nervous system (CNS) effects, such as altered consciousness, can experience a rapid recovery.\n\nKeywords\n\nPerampanel\nOverdose\nEpilepsy\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nAmong the currently available antiepileptic drugs (AEDs), perampanel (PER) is a novel AED with a completely different mechanism of action. It is the first selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist used to treat epilepsy. Clinical trials have shown that PER is generally well tolerated, though dose-dependent central nervous system (CNS) effects occur. In the short term, the most commonly reported treatment-emergent adverse events (TEAEs) leading to dose reductions or treatment interruptions are dizziness, somnolence, headache, and fatigue [1]. PER, at 2 mg/day, has been demonstrated to have similar effects and side effects as those of a placebo [2]. At doses of 4 mg/day, dizziness, somnolence, and irritability have been reported as adverse events (AEs). TEAEs are generally more often reported at doses of 8 or 12 mg/day [3]. An extension study of a trial held over a period of 4 years revealed that the most common TEAEs leading to PER therapy discontinuation were dizziness (4.1%), irritability (1.2%), and fatigue (1.1%) [4]. The efficacy of perampanel has been evaluated extensively in various phase II, randomized placebo-controlled phase III [1, 2], and open-label extension trials [5]. The patients recruited in these studies were ≥12 years of age, had refractory partial seizures with or without secondary generalization, and were on 1–3 additional AEDs [2, 4, 6].\n\nThe usual starting dose of PER for focal and generalized seizures in adult patients who are not concomitantly taking an enzyme-inducing antiepileptic drug is 2 mg/day before sleep. Additionally, it is recommended that the dose be increased by 2 mg/day biweekly to reach the maximum tolerable dose (usually 4–8 mg/day), which provides excellent seizure control. Overall, PER is considered to be safe up to a daily dose of 12 mg per day. When used to treat refractory and super-refractory status epilepticus (SE), PER seems to be extremely well tolerated; the same holds true even when used at doses of up to 32 mg. However, currently, very little has been published about incidents where PER is taken above the recommended dosages [7–10]. Three patients with epilepsy [7–9] and one patient with depression and anxiety [10] have been reported to have experienced PER intoxication. Those reports included adult patients aged 34, 39, 40, and 54 years. None of the four studies on PER intoxication reported the body mass index (BMI) of the participants. However, all participants enrolled in the core study investigating the efficacy of PER had a normal BMI. With regard to the pharmacokinetics, PER undergoes extensive hepatic metabolism (>90%) to form 13 major metabolites of hydroxylated perampanel and various glucuronide conjugates. The isoenzyme CYP3A4 is considered to be primarily involved in the metabolism of PER [11]. In a recent study on the correlation between body weight and CYP3A activity, [12] Sandvik et al. reported that the enzyme activity of CYP3A4 was higher in patients with anorexia nervosa compared to a control group consisting of individuals with normal weight, and that CYP3A4 activity was negatively correlated with body weight [13]. Also, CYP3A4 activity was found to decrease with increasing body weight in healthy volunteers [14].\n\nHerein, we describe the clinical findings in a low-BMI patient with epilepsy, who ingested an estimated 80 mg of PER in a suicide attempt. This study was approved by the institutional review board of the Faculty of Medicine, Prince of Songkla University (REC.62-396-14-3).\n\nCase presentation\n\nThe patient was a 16-year-old Thai female who had suffered from refractory epilepsy since the age of 10. She had a focal onset with impaired awareness and motor predominance at least five times per month. Magnetic resonance imaging studies revealed a non-enhancing diffuse enlargement of the right amygdala, hippocampus, and parahippocampal gyrus, and electroencephalography showed occasional spikes in the corresponding areas. She weighed 32 kg (BMI = 19). She had been on multiple antiepileptic drugs, which include valproate 2000 mg/day, levetiracetam 1500 mg/day, and lamotrigine 50 mg/day. At the age of 16, she experienced multiple attacks of convulsive SE, so she was transferred to our hospital for more specialized treatment. A mood disorder was detected on that visit, but no relevant mood conditions before or during treatment at our department were reported by either the patient or her family. Moreover, neither suicidal thoughts nor previous suicide attempts were reported. The patient was initially treated by increasing the lamotrigine dose to 100 mg/day, but her seizures persisted. Two milligrams per day of PER before sleep was added as adjunctive therapy; the dose was up-titrated to 4 mg/day after 2 weeks. Subsequently, she was seizure-free for 6 months. The seizures were controlled with combination therapy consisting of 4 mg/day of PER, the withdrawal of valproate and levetiracetam, and the tapering of lamotrigine to 25 mg/day. We then decided to switch to PER monotherapy by tapering off lamotrigine. The patient had been seizure-free for 8 months when she was found drowsy in her bedroom by her friends, with an empty bottle of PER; there were approximately 40 tablets missing (80 mg). On physical examination, her mental status was described as a state of confusion, and she exhibited signs of withdrawal in response to painful stimuli. Her Glasgow Coma Scale (GCS) score was 8. The other physical findings were as follows: normal vital signs; skin that felt warm to the touch; and pupils that were equal, round, and reactive to light. In addition, her reflexes were normal, there were no focal neurological signs or symptoms, and her mucous membranes were moist. Moreover, no tremors were noted, and her gag reflex was intact. No specific treatment was administered in the emergency room; specifically, no gastric lavage was performed because the time of ingestion was more than 3 hours prior to presentation. It is known that oral PER is rapidly and almost completely absorbed (time to maximum concentration [Tmax], 0.5–2.5 hours), is not subject to any significant first-pass metabolism, and has a bioavailability of almost 100%. Her initial laboratory results were normal, and comprised the findings of a complete blood count, electrolyte test, liver function test, and renal function test. A urine drug and toxic substance screen was negative for benzodiazepines, amphetamine, and ethanol. Additional testing including head computed tomography (CT), chest X-ray, and electrocardiography showed no acute abnormalities. An electroencephalogram performed on the day after admission demonstrated a diffuse slowing and disorganization of the background, consistent with generalized dysfunction. Unfortunately, we were unable to determine serum concentrations due to the unavailability of the technology to measure the blood levels of PER in Thailand.\n\nDuring the patient’s hospital stay, her symptom of drowsiness changed to a qualitative impairment of consciousness involving disorientation and misjudgment of situations, which resolved in 2 days (full GCS score). Her vital signs and other laboratory results remained stable during the first 2 days of admission, and there was no evidence of perampanel-induced systemic AEs such as hepatic or renal toxicity, hypotension, or respiratory suppression. Throughout hospitalization, her vital signs remained within normal parameters. She was discharged on admission day 3 with a normal level of consciousness as well as other neurological and general medical parameters. Once medically cleared, she voluntarily agreed to transfer to the psychiatry ward. During her time there, she was diagnosed with severe depression induced by familial problems. During consultation with the attending staff there, she said, “It was just a blind rage; I did not mean to do that. I am so sorry.” The psychiatric condition leading to her suicide attempt was the diagnosed major depressive syndrome. She was put on an antidepressant, and her depressive symptoms partially resolved. She was deemed psychiatrically stable and was discharged with a prescription of sertraline 50 mg daily and outpatient psychiatric follow-up care. At the initial follow-up 2 weeks after discharge, she reported mood changes with depressive symptoms, which had begun after the tapering off of lamotrigine, and at the same time she was experiencing some family problems; she did not notify her doctor about this. Two months after discharge, she was taking lamotrigine 100 mg/day and sertraline 50 mg/day.\n\nDiscussion\n\nThere is sparse information regarding the effects of PER in cases of an acute overdose. Hence, the definition of PER overdose is not clear. However, we defined it as having received more than 32 mg/day of PER. Herein, we report on a patient from Thailand with a low BMI who overdosed on PER 80 mg/day. Our patient was prescribed a relatively low dose (4 mg/day), so the dose she ingested (80 mg/day) was 20 times higher than the upper limit of her daily dose. The neurological signs in this case involved a significantly depressed mental status manifested by her symptom of drowsiness. Interestingly, her symptoms persisted for 2 days, after which a rapid and complete recovery of her clinical condition was observed. These findings are in contrast to those reported by Kim et al. involving a 39-year-old woman admitted due to altered consciousness and stupor after taking 10 times the daily dose of both PER and valproic acid (she had been taking 4 mg/day of PER and 2000 mg of valproate). In that case, the patient began to regain consciousness on hospitalization day 6 and returned to her baseline mental status on day 8 [7]. Likewise, Li et al. reported prolonged stupor in a 54-year-old man who had experienced PER intoxication [8].\n\nOur patient ingested 20 times the prescribed PER dosage, which is double that reported by Kim et al. The reason why our patient recovered so quickly from altered consciousness may be the fact that she took only PER without any concomitant drugs, especially enzyme inhibitors, whereas the case reported by Kim et al. had taken PER and valproic acid (an enzyme inhibitor antiepileptic drug). There are at least three routes of valproate metabolism: glucuronidation (50%), β oxidation (40%) in the mitochondria, and cytochrome P450 (CYP)-mediated oxidation (10%) [15]—then did not effect PER metabolism. Kim et al. believed that the prolonged stupor in that case was due to the prolonged half-life of PER, not the result of valproate encephalopathy. Another possible explanation is the low BMI of our patient. A previous study reported a negative correlation between BMI and CYP3A4 levels. CYP3A4 is a major metabolite of PER, and an increase in the level of CYP3A4 results in an increase in PER metabolism. Nevertheless, a comprehensive understanding of this mechanism is lacking and requires further study. According to clinical trials, the most commonly reported AEs from therapeutic dosing are dizziness, somnolence, fatigue, and irritability [3, 4]. However, little information on the effects of PER overdose is available. Case reports on PER overdose have revealed that the most frequent clinical presentations involve altered consciousness (stupor) and severe aggression (Table 1) [7–10].Table 1 Characteristics of perampanel overdose patients from different case reports\n\nCase report\tAge (years)\tPrevious diagnosis\tWeight\tDose of perampanel\tCo-medications\tVital signs\tInitial neurological manifestation\tSystemic manifestation\tDuration to recovery\tSpecific treatment\tFull recovery\t\nHoppner et al.\t35\tRefractory epilepsy\tNA\t204 mg (25.5 times her daily dose)\tLevetiracetam\n\nTopiramate\n\nPregabalin\n\n\tNA\tDysarthria followed by stupor\tNo\t2 days\tNoa\tYesb\t\nLi et al.\t54\tRefractory epilepsy\tNA\t300 mg\tDivalproex sodium\n\nLamotrigine\n\nLevetiracetam\n\n\tHeart rate 58/minute\n\nOther findings were unremarkable\n\n\tMarked somnolence\n\nDisconjugate gaze with 3 mm reactive pupils bilaterally\n\n\tSerum sodium 128 mEq/L\t4 days\tNoc\tLost to follow-up\t\nKim et al.\t39\tEpilepsy\tNA\t40 mg (10 times her daily dose)\tValproic acid\tNormal\tStupor\tNormald\t8 dayse\tNoc\tYesb\t\nWu et al.\t40\tDepression and anxiety disorders, polysubstance abuse\tNA\t60 mgf\tNA\tRespiratory rate 6/minuteg\tUnresponsive then extremely agitated next day\tNormal\t5 days\tNoc\tNA\t\nOur report\t\tRefractory epilepsy\t\t80 mg (40 times her daily dose)\tLamotrigine\tNormal\tDrowsiness\tNormal\t3 days\tNoa\tYesb\t\nNA not available\n\naInvolved gastric lavage\n\nbFull recovery to baseline before perampanel overdose\n\ncNo report of gastric lavage\n\ndPulmonary embolism on day 3\n\neDuration to recovery comprised the time required for recovery from both perampanel overdose and pulmonary embolism\n\nfFirst time of perampanel ingestion\n\ngUrine screening positive for benzodiazepine and ethanol\n\nWith respect to the systemic AEs of PER, data related to vital signs, clinical laboratory parameters, and electrocardiographic findings [1, 2, 16] have revealed that patients taking PER in combination therapy are more likely to experience AEs than those on PER monotherapy. Additionally, a dose–response relationship was discovered. Overall, most reported TEAEs were considered mild or moderate in severity; no deaths were recorded, but severe TEAEs were reported by 22 patients (5.0%) receiving placebo and 57 (5.5%) receiving PER at any dose. The serious TEAEs included falls, nephrolithiasis, cholelithiasis, hemorrhagic cystitis, urinary incontinence, and thrombocytopenia. There have been no reports of unstable vital signs, liver toxicity, abnormal complete blood count findings, or cardiac conduction defects. In terms of PER overdose cases, Wu et al. reported a psychiatric patient with a PER overdose and a urine screen that was positive for benzodiazepine and ethanol. They described a patient with severe respiratory depression, who was unresponsive. He was intubated due to concerns related to his airway protection [10]. Another report by Li et al. involving epileptic patients with PER overdose described findings of asymptomatic bradycardia and hyponatremia with spontaneous recovery without specific treatment [8]. Our patient reportedly ingested up to 80 mg of PER (40 times her daily dose) and experienced a short period of drowsiness with a significantly depressed mental status and minimal reaction to painful stimuli while maintaining her airway reflexes, which did not warrant endotracheal intubation. In addition, our report points out that an acute PER overdose may not produce serious adverse systemic effects such as cardiac toxicity, respiratory depression, or other metabolic derangement symptoms. This finding is supported by the results reported by Hopper et al. [9] and Kim et al. [7], which involved patients that had intentionally overdosed on PER as a suicide attempt and experienced symptoms such as impaired consciousness and agitation, without any significant systemic AEs.\n\nAs of now, there is no specific treatment for PER overdose. With regard to its pharmacokinetic properties, the PER concentration has been found to peak after 60 minutes. In phase I studies among healthy male volunteers, the mean plasma half-life of PER was found to range from 52 to 129 hours following a single-dose administration; this could explain our patient’s short duration of coma. If patients present to the hospital more than 60 minutes after ingestion, gastric lavage may not be necessary. According to previous single-case reports, patients recover 2 to 5 days after admission [7–10] without gastric lavage or specific treatment. However, the plasma half-life of PER may be shorter or longer than that of a single dose of PER in the presence of co-medication with cytochrome P450 enzyme inducers or inhibitors.\n\nConclusion\n\nOur report demonstrates that an acute PER overdose may not produce serious adverse systemic effects such as cardiac toxicity, respiratory depression, or other metabolic derangement symptoms. In addition, adverse CNS side effects such as altered consciousness may experience rapid recovery.\n\nAbbreviations\n\nAEDs Antiepileptic drugs\n\nAMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid\n\nPER Perampanel\n\nSE Status epilepticus\n\nAcknowledgements\n\nWe would like to thank Mr. Edmond Subashi for editing the English manuscript.\n\nAuthors' contributions\n\nAll authors contributed to the care of this patient. All authors contributed to the original draft and revisions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding.\n\nAvailability of data and materials\n\nNot applicable.\n\nEthics approval and consent to participate\n\nInstitutional review board approval was obtained from the Ethics Committee, Faculty of Medicine, Prince of Songkla University\n\nConsent for publication\n\nWritten informed consent was obtained from the patient’s legal guardian(s) for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal upon request.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\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. French J Krauss G Biton V Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304 Neurology 2012 79 589 596 10.1212/WNL.0b013e3182635735 22843280\n2. Krauss GL Serratosa JM Villanueva V Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures Neurology 2012 78 1408 1415 10.1212/WNL.0b013e318254473a 22517103\n3. Serratosa JM Villanueva V Kerling F Kasper BS Safety and tolerability of perampanel: a review of clinical trial data Acta Neurol Scand Suppl 2013 197 30 35 10.1111/ane.12102\n4. Krauss G Perucca E Kwan P Final safety, tolerability, and seizure outcomes in patients with focal epilepsy treated with adjunctive perampanel for up to 4 years in an open-label extension of the phase III randomized trials: study 307 Epilepsia 2018 59 866 876 10.1111/epi.14044 29574701\n5. Montouris G Yang H Williams B Zhou S Laurenza A Fain R Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel Epilepsy Res. 2015 114 131 140 10.1016/j.eplepsyres.2015.04.011 26088896\n6. Montouris G Yang H Williams B Zhou S Laurenza A Fain R Efficacy and safety of perampanel in patients with drug-resistant partial seizure after conversion from double-blind placebo to open-label perampanel Epilepsy Res 2015 114 131 140 10.1016/j.eplepsyres.2015.04.011 26088896\n7. Kim S Kim TE Kim D Kim DW Prolonged stupor in perampanel overdose and pharmacokinetic considerations J Epilepsy Res. 2018 8 87 89 10.14581/jer.18014 30809502\n8. Li K Lasoff DR Smollin CG Ly BT Perampanel overdose causing a prolonged coma Clin Toxicol (Phila). 2018 56 677 678 10.1080/15563650.2017.1422743 29299938\n9. Hoppner AC Falser S Kerling F Clinical course of intoxication with the new anticonvulsant drug perampanel Epileptic Disord 2013 15 362 364 10.1684/epd.2013.0598 24001596\n10. Wu CC McShane M Huttlin EA Novoa KC Severe aggression after perampanel overdose: case report Psychosomatics 2019 60 321 324 10.1016/j.psym.2018.07.002 30181001\n11. Patsalos PN The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist Epilepsia 2014 56 12 27 10.1111/epi.12865 25495693\n12. Krogstad V Peric A Robertsen I Correlation of body weight and composition with hepatic activities of cytochrome P450 enzymes J Pharm Sci. 2021 110 432 437 10.1016/j.xphs.2020.10.027 33091408\n13 Sandvik P Lydersen S Hegstad S Spigset O Association between low body weight and cytochrome P-450 enzyme activity in patients with anorexia nervosa Pharmacol Res Perspect. 2020 8 00615 10.1002/prp2.615\n14. Ulvestad M Skotheim IB Jakobsen GS Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects Clin Pharmacol Ther. 2013 93 275 282 10.1038/clpt.2012.261 23361102\n15 Davis R Peters DH McTavish D Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy Drugs 1994 47 332 372 10.2165/00003495-199447020-00008 7512905\n16 French JA Krauss GL Steinhoff BJ Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305 Epilepsia 2013 54 117 125 10.1111/j.1528-1167.2012.03638.x 22905857\n\n",
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"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D015992:Body Mass Index; D004827:Epilepsy; D005260:Female; D006801:Humans; D009570:Nitriles; D011728:Pyridones; D016896:Treatment Outcome",
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"title": "Perampanel overdose in low body mass index patients with epilepsy: a case report and review of the literature.",
"title_normalized": "perampanel overdose in low body mass index patients with epilepsy a case report and review of the literature"
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"abstract": "We discuss the challenges associated with diagnosing neurodegenerative disorders in older adults living with HIV, illustrated through a case report where neurologic co-diagnosis of Alzheimer's disease (AD) and HIV-associated Neurocognitive Disorder (HAND) are considered. The patient was followed and evaluated for over 4 years and underwent post-mortem neuropathologic evaluation. Further work is needed to identify diagnostic tests that can adequately distinguish HAND from early stage neurodegenerative disorders among older adults living with HIV and cognitive changes.",
"affiliations": "a Memory and Aging Center, Department of Neurology , University of California, San Francisco , California, CA , USA.;a Memory and Aging Center, Department of Neurology , University of California, San Francisco , California, CA , USA.;b Departments of Neurosciences and Pathology , University of California, San Diego , California, CA, USA.;c University of Toronto, Tanz Centre for Research in Neurodegenerative Diseases , Toronto , Canada.;d Department of Internal Medicine , University of California, San Francisco , California, CA, USA.;e Department of Psychiatry , University of California, San Diego , California, CA,USA.;a Memory and Aging Center, Department of Neurology , University of California, San Francisco , California, CA , USA.;a Memory and Aging Center, Department of Neurology , University of California, San Francisco , California, CA , USA.;a Memory and Aging Center, Department of Neurology , University of California, San Francisco , California, CA , USA.",
"authors": "Hellmuth|Joanna|J|;Milanini|Benedetta|B|;Masliah|Eliezer|E|;Tartaglia|Maria Carmela|MC|;Dunlop|Miranda B|MB|;Moore|David J|DJ|;Javandel|Shireen|S|;DeVaughn|Saskia|S|;Valcour|Victor|V|",
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"issue": "24(4)",
"journal": "Neurocase",
"keywords": "Alzheimer’s disease; HIV-associated neurocognitive disorder; dementia; neuropathology; neuropsychological testing",
"medline_ta": "Neurocase",
"mesh_terms": "D015526:AIDS Dementia Complex; D000369:Aged, 80 and over; D000544:Alzheimer Disease; D001921:Brain; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests",
"nlm_unique_id": "9511374",
"other_id": null,
"pages": "213-219",
"pmc": null,
"pmid": "30304986",
"pubdate": "2018-08",
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"references": "3422548;19462243;25860316;24121968;21339907;16275845;28779301;27489872;15788276;27995575;23110543;23432363;25880550;22474609;28485492;25860317;19907013;14505582;18989814;25988463;27295036;27435879;22302554;26175795;27206721;7576038;25840462;11867313;12570353;20534887;27251676;21052077;23549585;21135382;21174240;24156898;9932303;17914061;25362201",
"title": "A neuropathologic diagnosis of Alzheimer's disease in an older adult with HIV-associated neurocognitive disorder.",
"title_normalized": "a neuropathologic diagnosis of alzheimer s disease in an older adult with hiv associated neurocognitive disorder"
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"abstract": "Macrolide resistance (MR) in group A Streptococcus (GAS) has been well documented in several countries and has become clinically significant since the large increases in macrolide usage during the 1970s. Macrolides are recommended as an alternative therapy for GAS pharyngitis, the most common cause of bacterial pharyngitis. Macrolide resistance has been associated with certain emm types, a sequence-based typing system of the hypervariable region of the GAS M-protein gene. Clinical failure of macrolide treatment of GAS infections can be associated with complications including acute rheumatic fever and rheumatic heart disease, the leading cause of acquired heart disease in children worldwide. Here we report 2 pediatric cases of MR and/or treatment failure in the treatment of GAS pharyngitis with the subsequent development of acute rheumatic fever. We also review the literature on worldwide MR rates, molecular classifications, and emm types, primarily associated with GAS pharyngeal isolates between the years of 2000 and 2010. The use of macrolides in the management of GAS pharyngitis should be limited to patients with significant penicillin allergy.",
"affiliations": "Section of Pediatric Infectious Diseases, Department of Pediatrics, Rush University Medical Center, Rush Medical College, Chicago, IL 60612, USA. latania_logan@rush.edu",
"authors": "Logan|Latania K|LK|;McAuley|James B|JB|;Shulman|Stanford T|ST|",
"chemical_list": "D005029:Ethylenediamines; D018942:Macrolides; D010406:Penicillins; C010044:benzathine",
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"delete": false,
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"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D002648:Child; D024881:Drug Resistance, Bacterial; D005029:Ethylenediamines; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D018942:Macrolides; D008297:Male; D010406:Penicillins; D010612:Pharyngitis; D012213:Rheumatic Fever; D018570:Risk Assessment; D012720:Severity of Illness Index; D013290:Streptococcal Infections; D013297:Streptococcus pyogenes; D017211:Treatment Failure",
"nlm_unique_id": "0376422",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Macrolide treatment failure in streptococcal pharyngitis resulting in acute rheumatic fever.",
"title_normalized": "macrolide treatment failure in streptococcal pharyngitis resulting in acute rheumatic fever"
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"companynumb": "US-PFIZER INC-2018019901",
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"occurcountry": "US",
"patient": {
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"activesubstancename": "AZITHROMYCIN ANHYDROUS"
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"drugadditional": n... |
{
"abstract": "The public subsidy in Australia of bortezomib (Velcade) for untreated non-transplant multiple myeloma patients was based on the VISTA trial.\n\n\n\nTo ascertain the health outcomes of bortezomib in 'real world' transplant-ineligible elderly patients, compared to trial data.\n\n\n\nPatient and treatment data were extracted from an oncology information system, laboratory information system and medical chart audits for three Queensland public hospitals.\n\n\n\nWe identified 74 patients; the median age was 75 years. Our cohort comprised 47% patients who were International Staging System stage III, 45% at stage II and 8% at stage I. Patients who had comorbidities, such as cardiac disease (41%), pulmonary disease (14%), diabetes (22%), peripheral neuropathy (14%) and other comorbidities (41%) at baseline were included. The common regimens prescribed were VMP, CVD and VD, and most patients (n = 73) received bortezomib on a once-weekly or twice-a-week basis. The overall response rate was 81%. Half (53%) of the patients did not complete their planned therapy due to toxicity (30%), suboptimal response or disease progression (15%), or death on treatment (8%). Overall survival was 40.7 months and progression free survival was 17.7 months.\n\n\n\nOur patients were older, had worse disease characteristics and more comorbidities than patients in the VISTA trial. While response rates were similar, survival outcomes appeared worse. Bortezomib-based treatment in the real world setting still carries a high risk of toxicity in the elderly population.",
"affiliations": "School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.;Department of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Department of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Department of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Department of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.;Toowoomba Hospital, Darling Downs Hospital and Health Services, Toowoomba, Queensland, Australia.;Toowoomba Hospital, Darling Downs Hospital and Health Services, Toowoomba, Queensland, Australia.;Regional Cancer Care, Cancer Care Services, Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia.;Regional Cancer Care, Cancer Care Services, Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia.;School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.",
"authors": "Loke|Crystal|C|0000-0002-4639-1428;Mollee|Peter|P|;McPherson|Ian|I|;Walpole|Euan|E|;Yue|Mimi|M|;Mutsando|Howard|H|;Wong|Phillip|P|;Weston|Helen|H|;Tomlinson|Ross|R|;Hollingworth|Samantha|S|0000-0002-5226-5663",
"chemical_list": "D000069286:Bortezomib; D008558:Melphalan; D011241:Prednisone",
"country": "Australia",
"delete": false,
"doi": "10.1111/imj.14886",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1444-0903",
"issue": "50(9)",
"journal": "Internal medicine journal",
"keywords": "bortezomib; first-line therapy; multiple myeloma; survival",
"medline_ta": "Intern Med J",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001315:Australia; D000069286:Bortezomib; D006801:Humans; D008558:Melphalan; D009101:Multiple Myeloma; D011241:Prednisone; D011793:Queensland; D016896:Treatment Outcome",
"nlm_unique_id": "101092952",
"other_id": null,
"pages": "1059-1066",
"pmc": null,
"pmid": "32369254",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bortezomib use and outcomes for the treatment of multiple myeloma.",
"title_normalized": "bortezomib use and outcomes for the treatment of multiple myeloma"
} | [
{
"companynumb": "AU-BAUSCH-BL-2021-007297",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
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"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo evaluate motion artifacts, breath-hold failure, acute transient dyspnea, and clinical parameters during hepatic arterial phase of gadoxetate disodium-enhanced magnetic resonance (MR) imaging.\n\n\nMETHODS\nThis was an institutional review board-approved observational prospective study (written informed consent acquired) performed in 250 consecutive patients, who underwent liver MR with a multiarterial phase technique. Oxygen saturation (SatO2) and heart rate (HR) were monitored, while patients reported subjective symptoms. Breath-holds were assessed using prospective acquisition correction technique (PACE) monitors. Three readers independently analyzed all images to establish the presence of motion artifacts. Nonparametric statistical testing and Fleiss' kappa were used.\n\n\nRESULTS\nNo statistical differences in SatO2 and HR values were observed during the entire length of MR examination. The PACE graphs showed an altered breath-hold in 16/250 patients (6.4%), however only 6 patients self-reported symptoms during the procedure, and among these 6 subjects, only 2 suffered from acute transient dyspnea (0.8%). Motion-related artifacts increased mostly in the third arterial phase of gadoxetate disodium acquisition (p < 0.0001): The artifacts incidence was 2.9% in the first phase; 4.0% in the second; and 19.5% in the third. This increase was mainly due to patients' inability to hold their breath for the entire duration of the examination. However, at least one gadoxetate disodium arterial phase without motion artifacts and adequate for acquisition timing, was acquired in all MR examinations.\n\n\nCONCLUSIONS\nThe incidence of breath-hold failure and acute transient dyspnea after gadoxetate disodium administration increased during the third arterial phase only. Our protocol allowed the acquisition of at least one arterial phase not compromised by motion artifacts and adequate for acquisition timing, in all patients.",
"affiliations": "Department of Radiology, Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123, Brescia, Italy.;Department of Surgical Sciences, Radiology Institute, University of Turin, Via Genova 3, 10126, Turin, Italy. riccardo.faletti@unito.it.;Department of Radiology, Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123, Brescia, Italy.;Department of Surgical Sciences, Radiology Institute, University of Turin, Via Genova 3, 10126, Turin, Italy.;Department of Radiology, Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123, Brescia, Italy.;Department of Radiology, Spedali Civili di Brescia, P.le Spedali Civili, 1, 25123, Brescia, Italy.;Department of Surgical Sciences, Radiology Institute, University of Turin, Via Genova 3, 10126, Turin, Italy.;Department of Surgical Sciences, Radiology Institute, University of Turin, Via Genova 3, 10126, Turin, Italy.",
"authors": "Grazioli|Luigi|L|;Faletti|Riccardo|R|;Frittoli|Barbara|B|;Battisti|Giacomo|G|;Ambrosini|Roberta|R|;Romanini|Laura|L|;Gatti|Marco|M|;Fonio|Paolo|P|",
"chemical_list": "D003287:Contrast Media; C073590:gadolinium ethoxybenzyl DTPA; D019786:Gadolinium DTPA",
"country": "Italy",
"delete": false,
"doi": "10.1007/s11547-018-0927-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-8362",
"issue": "123(12)",
"journal": "La Radiologia medica",
"keywords": "Arterial phase; Artifact; Gadoxetate disodium; Liver; Magnetic resonance imaging; Motion artifact",
"medline_ta": "Radiol Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016477:Artifacts; D062485:Breath Holding; D003287:Contrast Media; D005260:Female; D019786:Gadolinium DTPA; D006801:Humans; D015994:Incidence; D008113:Liver Neoplasms; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies",
"nlm_unique_id": "0177625",
"other_id": null,
"pages": "910-917",
"pmc": null,
"pmid": "30084108",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "26795574;26807896;27183413;26473642;25811243;26099474;26194455;25055154;25478742;24475864;25903709;28027748;27977329;24617733;23192781;25162310;22334493;25740243;26001231;27509544;20677259",
"title": "Evaluation of incidence of acute transient dyspnea and related artifacts after administration of gadoxetate disodium: a prospective observational study.",
"title_normalized": "evaluation of incidence of acute transient dyspnea and related artifacts after administration of gadoxetate disodium a prospective observational study"
} | [
{
"companynumb": "IT-BAYER-2018-221745",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GADOXETATE DISODIUM"
},
"drugadditional": null,
... |
{
"abstract": "A 62-year-old woman underwent upper endoscopy in January 2009 to reveal the presence of an extrinsic compression measuring approximately 3 cm in the anterior wall of the gastric antrum. Further examinations suggested that it was caused by peritoneal cancer of an unknown origin; thus, staging laparoscopy was performed in May 2009. Multiple white nodules of varying sizes were found scattered throughout the right upper quadrant of the abdomen and the right abdomen. Based on a biopsy of the greater omentum, the patient was diagnosed with papillary serous adenocarcinoma. As no abnormalities were observed in the uterus and ovary, it was suspected that the patient had primary peritoneal cancer. Hence, in July 2009, the patient underwent resection of the greater omentum, gastric pylorus, gall bladder, and right hemicolon where the tumors were localized, as well as bilateral adnexectomy. Based on intraoperative findings and postoperative histology, the patient was diagnosed with high-grade primary peritoneal serous adenocarcinoma and received paclitaxel and carboplatin therapy. Subsequent follow-up examinations, including positron emission tomography-computed tomography(PET-CT), indicated repeated recurrences in the mesentery, the pelvic floor, and around the remnant stomach. After identifying these recurrences, the patient was treated with platinum-based drugs, experiencing repeated response and cessation cycles. Since September 2019, the patient has received olaparib therapy. PET-CT examination performed in September 2020 indicated that the patient remained in complete remission.",
"affiliations": "Dept. of Surgery, Okitama Public General Hospital.",
"authors": "Higashi|Takayuki|T|;Ozawa|Koichiro|K|;Takei|Saki|S|;Takagi|Shinya|S|;Yokoyama|Moriyoshi|M|;Mase|Kenji|K|;Moriya|Toshiyuki|T|;Takeshita|Akiko|A|;Mizutani|Masaomi|M|;Fuyama|Shigemi|S|",
"chemical_list": "D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "48(6)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009852:Omentum; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D000072078:Positron Emission Tomography Computed Tomography",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "829-832",
"pmc": null,
"pmid": "34139733",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary Peritoneal Carcinoma with Long Term Survival-A Case Report.",
"title_normalized": "primary peritoneal carcinoma with long term survival a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-309028",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
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"dru... |
{
"abstract": "BACKGROUND\nEssential thrombocythemia (ET) is a myeloproliferative disorder characterized by thrombocytosis and a propensity for both thrombotic and hemorrhagic events. ET rarely occurs simultaneously with colorectal cancer. Here, we report a case of colorectal cancer in an ET patient treated using laparoscopic ileocecal resection.\n\n\nMETHODS\nA 40-year-old woman was admitted to our hospital after presenting with liver dysfunction. She had been previously diagnosed with ET; aspirin and anagrelide had been prescribed. Subsequent examination at our hospital revealed cecal cancer. Distant metastasis was absent; laparoscopic ileocecal resection was performed. Anagrelide was discontinued only on the surgery day. She was discharged on the seventh postoperative day without thrombosis or hemorrhage. However, when capecitabine and oxaliplatin were administered as adjuvant chemotherapy with continued anagrelide administration, she experienced hepatic dysfunction and thrombocytopenia; thus, anagrelide was discontinued. Five days later, her platelet count recovered. Subsequently, anagrelide and aspirin administration was resumed, without any adjuvant chemotherapy. Her liver function normalized gradually in 4 months. One-year post operation, she is well without tumor recurrence or new metastasis.\n\n\nCONCLUSIONS\nTo our knowledge, this is the first report of laparoscopic colectomy performed on an ET patient receiving anagrelide. Our report shows that complications such as bleeding or thrombosis can be avoided by anagrelide administration. Contrastingly, thrombocytopenia due to anagrelide intake should be considered when chemotherapy that could cause bone marrow suppression is administered.",
"affiliations": "Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. masahitosou@gmail.com.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.;Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.;Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.",
"authors": "Hiyoshi|Masaya|M|http://orcid.org/0000-0001-6661-5647;Nozawa|Hiroaki|H|;Inada|Kentaro|K|;Koseki|Takayoshi|T|;Nasu|Keiichi|K|;Seyama|Yasuji|Y|;Wada|Ikuo|I|;Murono|Koji|K|;Emoto|Shigenobu|S|;Kaneko|Manabu|M|;Sasaki|Kazuhito|K|;Shuno|Yasutaka|Y|;Nishikawa|Takeshi|T|;Tanaka|Toshiaki|T|;Hata|Keisuke|K|;Kawai|Kazushige|K|;Maeshiro|Tsuyoshi|T|;Miyamoto|Sachio|S|;Ishihara|Soichiro|S|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1186/s40792-019-0660-3",
"fulltext": "\n==== Front\nSurg Case RepSurg Case RepSurgical Case Reports2198-7793Springer Berlin Heidelberg Berlin/Heidelberg 66010.1186/s40792-019-0660-3Case ReportCecal cancer with essential thrombocythemia treated by laparoscopic ileocecal resection: a case report http://orcid.org/0000-0001-6661-5647Hiyoshi Masaya +81-3-5800-8653masahitosou@gmail.com 12Nozawa Hiroaki NOZAWAH-SUR@h.u-tokyo.ac.jp 1Inada Kentaro inaina0401ken.taro.s51@docomo.ne.jp 2Koseki Takayoshi pon.pon.pon.310@gmail.com 2Nasu Keiichi k1nacha@gmail.com 2Seyama Yasuji seyamaysur-tky@umin.ac.jp 2Wada Ikuo wadaikuo@gmail.com 2Murono Koji MURONOK-SUR@h.u-tokyo.ac.jp 1Emoto Shigenobu EMOTOS-SUR@h.u-tokyo.ac.jp 1Kaneko Manabu KANEKOM-SUR@h.u-tokyo.ac.jp 1Sasaki Kazuhito SASAKIK-SUR@h.u-tokyo.ac.jp 1Shuno Yasutaka SHUNOY-SUR@h.u-tokyo.ac.jp 1Nishikawa Takeshi NISHIKAWATA-SUR@h.u-tokyo.ac.jp 1Tanaka Toshiaki toshi-t@venus.dti.ne.jp 1Hata Keisuke qyp11547@gmail.com 1Kawai Kazushige kz-kawai@mvd.biglobe.ne.jp 1Maeshiro Tsuyoshi tsuyoshi_maeshiro@tmhp.jp 2Miyamoto Sachio sachio_miyamoto@tmhp.jp 2Ishihara Soichiro soichiro.ishihara@gmail.com 11 0000 0001 2151 536Xgrid.26999.3dDepartment of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan 2 0000 0004 1764 8129grid.414532.5Department of Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan 21 6 2019 21 6 2019 12 2019 5 10112 3 2019 12 6 2019 © The Author(s). 2019Open 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.Background\nEssential thrombocythemia (ET) is a myeloproliferative disorder characterized by thrombocytosis and a propensity for both thrombotic and hemorrhagic events. ET rarely occurs simultaneously with colorectal cancer. Here, we report a case of colorectal cancer in an ET patient treated using laparoscopic ileocecal resection.\n\nCase presentation\nA 40-year-old woman was admitted to our hospital after presenting with liver dysfunction. She had been previously diagnosed with ET; aspirin and anagrelide had been prescribed. Subsequent examination at our hospital revealed cecal cancer. Distant metastasis was absent; laparoscopic ileocecal resection was performed. Anagrelide was discontinued only on the surgery day. She was discharged on the seventh postoperative day without thrombosis or hemorrhage. However, when capecitabine and oxaliplatin were administered as adjuvant chemotherapy with continued anagrelide administration, she experienced hepatic dysfunction and thrombocytopenia; thus, anagrelide was discontinued. Five days later, her platelet count recovered. Subsequently, anagrelide and aspirin administration was resumed, without any adjuvant chemotherapy. Her liver function normalized gradually in 4 months. One-year post operation, she is well without tumor recurrence or new metastasis.\n\nConclusions\nTo our knowledge, this is the first report of laparoscopic colectomy performed on an ET patient receiving anagrelide. Our report shows that complications such as bleeding or thrombosis can be avoided by anagrelide administration. Contrastingly, thrombocytopenia due to anagrelide intake should be considered when chemotherapy that could cause bone marrow suppression is administered.\n\nKeywords\nAnagrelideColorectal cancerEssential thrombocythemiaLaparoscopic surgeryissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nEssential thrombocythemia (ET) is a myeloproliferative disorder characterized by thrombocytosis and a propensity for both thrombotic and hemorrhagic events [1]. ET treatment aims to prevent thrombotic and hemorrhagic complications and alleviate symptoms [2]. Low-dose aspirin is administered to reduce arterial thrombotic event risk [1]. Hydroxyurea and anagrelide are used for controlling platelet counts [2].\n\nColorectal cancer concurrent with ET is extremely rare. Here, we report a case of colorectal cancer in an ET patient treated using laparoscopic ileocecal resection.\n\nCase Presentation\nA 40-year-old female presenting with mild hepatic dysfunction was referred to our hospital. She did not smoke but had a drinking habit. At age 28 years, she had presented with elevated platelet counts (> 100 × 104/μL); ET had been diagnosed based on bone marrow biopsy results. She was prescribed aspirin (100 mg/day) and anagrelide (2.5 mg/day). She had also been prescribed ebastine for itching a while ago.\n\nOn admission to our hospital, laboratory examination revealed slightly elevated alanine aminotransferase (ALT) levels (82 IU/L), although the patient’s ALT level had improved from that recorded previously. Her platelet count was slightly elevated (62.4 × 104/μL). Prothrombin time and activated partial thromboplastin time were normal. Abdominal ultrasonography revealed a cecal tumor. Colonoscopy revealed advanced cecal cancer (Fig. 1). Computed tomography (CT) indicated cecal wall thickening (Fig. 2).Fig. 1 Colonoscopy showing a type 2 tumor in the cecum\n\nFig. 2 Abdominal computed tomography showing cecal wall thickening\n\n\n\nThe patient recovered from liver dysfunction without treatment. She stopped taking oral aspirin 1 week prior to surgery but continued anagrelide until the day before surgery. To prevent thrombosis, she wore elastic stockings; furthermore, intermittent pneumatic compression was performed during surgery. Laparoscopic-assisted ileocecal resection was performed. We used a soft coagulation system to achieve complete hemostasis. The operative duration was 202 min; blood loss was 34 mL.\n\nFrom the first postoperative day, the patient started walking, drinking water, and resumed oral anagrelide intake. She resumed oral aspirin intake on the fifth postoperative day. Her perioperative platelet count was controlled to approximately 40–60 × 104/μL (Fig. 3). Prothrombin time and activated partial thromboplastin time also did not show abnormal values during the perioperative period. The postoperative course was uneventful and she was discharged on the seventh postoperative day.Fig. 3 Transition of platelet counts and transaminase levels from surgery to end of adjuvant chemotherapy. Anagrelide was discontinued only on the operation day and restarted on the first postoperative day. After one course of intravenous oxaliplatin plus oral capecitabine, platelets decreased and hepatic transaminase level increased. Thus, aspirin and anagrelide were discontinued; platelet count recovered to 50 × 104/μL after 5 days. She resumed internal use of anagrelide and aspirin but did not restart adjuvant chemotherapy; liver transaminase levels normalized gradually\n\n\n\nThe tumor pathological stage was T3N1M0 (Stage IIIB). The patient received intravenous oxaliplatin plus oral capecitabine (CapeOX) as postoperative adjuvant chemotherapy (oxaliplatin 130 mg/m2, capecitabine 1000 mg/m2). However, after one course, she again experienced liver dysfunction (aspartate aminotransferase [AST] level, 388 IU/L; ALT level, 531 IU/L); because of anagrelide, her platelet count decreased to 17.8 × 104/μL. Therefore, we asked her to discontinue anagrelide and aspirin that day onwards; 5 days later, her platelet count recovered to 50 × 104/μL. Subsequently, she resumed taking anagrelide and aspirin; however, she refused to resume any adjuvant chemotherapy after this incident. Her liver function normalized gradually in 4 months. There were no clinical signs of thrombosis, and there was no appearance of a new thrombus on contrast-enhanced CT 6 months after the operation. One-year post operation, she is well without tumor recurrence or new metastasis.\n\nConclusions\nET is a myeloproliferative disorder characterized by excess platelet production [2]. ET patients have increased risk of postoperative bleeding and thrombosis [3]. Riggeri et al. reported a retrospective survey of postoperative outcomes of polycythemia vera and ET patients [4]. In their cohort, 23 (7.3%) of 311 patients who underwent surgical interventions experienced major hemorrhagic episodes [4]. This rate was higher than that observed in normal cancer surgery (about 1%) [5]. Zhu et al. reported a case involving an ET patient with sigmoid colon cancer. Plateletpheresis was performed before surgery but anastomotic bleeding complicated the postoperative course. A systematic review of abdominal operations in four ET patients revealed that two of four patients experienced bleeding complications on the first postoperative day [3].\n\nIn laparoscopic surgery, pneumoperitoneum, the Trendelenburg position, and long surgical time could be risk factors for lower extremity venous stasis [6]. However, a meta-analysis of trials comparing laparoscopic surgery with open surgery demonstrated that laparoscopic surgery could achieve the same outcome as open surgery with regards to presence of postoperative venous thromboembolism [6]. However, to prevent thrombosis, we performed laparoscopic surgery in the leg-open position, instead of lithotomy, using an elastic stocking and intermittent pneumatic compression with pneumoperitoneum pressure of up to 8 mmHg. Small amounts of bleeding have been reported in laparoscopic surgery due to pneumoperitoneum pressure; however, treatment for ET patients involves a high bleeding risk as described above, so we also performed careful hemostasis confirmation before closing. The patient’s wound was small and less painful; she resumed walking on the first postoperative day and recovered quickly after surgery. Postoperative administration of Xa inhibitors was not generally indicated at the time, as was she, but she was fortunately discharged without complications. However, the optimal perioperative management of ET patients remains unclear, especially in the context of abdominal malignancy.\n\nA high platelet count (> 60 × 104/μL), age > 60 years, and thrombosis history are high-risk factors for major thrombosis in ET patients [7]. Patients at high thrombosis risk should be treated with cytoreductive therapy (CRT) to reduce thrombosis risk. Presently, two CRT treatments are licensed in Japan: hydroxyurea and anagrelide [2]. Anagrelide is an orally active, platelet-lowering agent approved for first-line treatment of high-risk ET in Japan [2]. Hydroxyurea is most widely used for CRT, although long-term use may be associated with a high secondary leukemia incidence [2]. Recently, Kanakura et al. reported anagrelide efficacy in high-risk ET patients in Japan [2]. Anagrelide was approved for ET treatment in the US and Europe in 1997 and 2004, respectively, but it was not licensed in Japan until 2014. Our patient was prescribed anagrelide about 1 year before surgery; her platelet count was properly controlled. To our knowledge, ours is the first case involving laparoscopic colectomy in a patient who used anagrelide for platelet count management.\n\nCapeOX as adjuvant therapy has a manageable tolerability profile and should be considered as a standard adjuvant treatment option in stage III colorectal cancer patients. Transient thrombocytopenia is relatively common in oxaliplatin-treated patients. Hepatotoxicity is another adverse event observed with oxaliplatin-based chemotherapy [8]. Here, we encountered a considerably decreased platelet count on starting chemotherapy with ongoing anagrelide intake. Hashiba et al. reported the outcome of discontinuing CRT in an ET patient during chemotherapy for esophageal cancer. They administered preoperative chemotherapy (cisplatin + 5-fluorouracil) accompanied by hydroxyurea discontinuation; however, platelet count increased to 116 × 104/μL after therapy [9]. Since our patient was relatively young, we suggested a method of carefully re-administering fluoropyrimidine monotherapy as adjuvant chemotherapy. However, she did not wish to resume treatment because of concerns about adverse events. Thus, the tolerability of fluoropyrimidine monotherapy is unknown as well. Chemotherapeutic strategies for ET patients should consider various events such as bone marrow suppression due to chemotherapy, thrombocytopenia caused by CRT, and elevated platelet count due to drug withdrawal.\n\nThus, we reported on a patient with colon cancer and ET, which are rarely observed together, who required careful perioperative management for laparoscopic surgery. We found that complications such as bleeding or thrombosis during control of the platelet count can be avoided by anagrelide administration. Contrastingly, thrombocytopenia due to anagrelide intake should be considered when chemotherapy that could cause bone marrow suppression is administered. Further studies involving this unique group of patients should focus on developing appropriate treatment strategies.\n\nAbbreviations\nALTAlanine aminotransferase\n\nASTAspartate aminotransferase\n\nCTComputed tomography\n\nCapeOXIntravenous oxaliplatin plus oral capecitabine\n\nCRTCytoreductive therapy\n\nETEssential thrombocythemia\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthors’ contributions\nMH carried out the studies and data analyses and drafted the manuscript. KI, TK, KN, YS, and IW developed the study design and performed data collection. TM, SM, and SI conceived the study, participated in developing its design and coordination, and helped to draft the manuscript. KM, SE, MK, KS, YS, TN, TT, KH, KK, and HN provided significant advice. All authors read and approved the final manuscript.\n\nFunding\nThe authors declare no financial or any other type of support.\n\nAvailability of data and materials\nThe authors declare that all the data related to this article are available in this manuscript.\n\nEthics approval and consent to participate\nAll procedures were performed in accordance with the ethical standards of the responsible committee on human study and with the Helsinki Declaration and later revisions. Informed consent was obtained from the patient for this report.\n\nConsent for publication\nThe patient has consented to the publication of this manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Chu DK Hillis CM Leong DP Anand SS Siegal DM Benefits and risks of antithrombotic therapy in essential thrombocythemia: A Systematic Review Ann Intern Med. 2017 167 170 180 10.7326/M17-0284 28632284 \n2. Kanakura Y Shirasugi Y Yamaguchi H Koike M Chou T Okamoto S A phase 3b, multicenter, open-label extension study of the long-term safety of anagrelide in Japanese adults with essential thrombocythemia Int J Hematol. 2018 108 491 498 10.1007/s12185-018-2510-7 30121892 \n3. Zhu Y Jiang H Chen Z Lu B Wu J Abdominal surgery in patients with essential thrombocythemia: a case report and systematic review of literature Medicine. 2017 96 e8856 10.1097/MD.0000000000008856 29381999 \n4. Ruggeri M Rodeghiero F Tosetto A Castaman G Scognamiglio F Finazzi G Postsurgery outcomes in patients with polycythemia vera and essential thrombocythemia: a retrospective survey Blood. 2008 111 666 671 10.1182/blood-2007-07-102665 17909074 \n5. Leonardi MJ McGory ML Ko CY A systematic review of deep venous thrombosis prophylaxis in cancer patients: implications for improving quality Ann Surg Oncol. 2007 14 929 936 10.1245/s10434-006-9183-9 17103259 \n6. Cui G Wang X Yao W Li H Incidence of postoperative venous thromboembolism after laparoscopic versus open colorectal cancer surgery: a meta-analysis Surg Laparosc Endosc Percutan Tech. 2013 23 128 134 10.1097/SLE.0b013e3182827cef 23579505 \n7. Ruggeri M Finazzi G Tosetto A Riva S Rodeghiero F Barbui T No treatment for low-risk thrombocythaemia: results from a prospective study Br J Haematol. 1998 103 772 777 10.1046/j.1365-2141.1998.01021.x 9858229 \n8. Hoff PM Saad ED Costa F Coutinho AK Caponero R Prolla G Literature review and practical aspects on the management of oxaliplatin-associated toxicity Clin Colorectal Cancer. 2012 11 93 100 10.1016/j.clcc.2011.10.004 22154408 \n9. Hashiba R Lee S Kishida S A case of video-assisted thoracoscopic radical esophagectomy for cancer in a patient with essential thrombocythemia Esophagus. 2016 13 369 373 10.1007/s10388-016-0535-7\n\n",
"fulltext_license": "CC BY",
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"keywords": "Anagrelide; Colorectal cancer; Essential thrombocythemia; Laparoscopic surgery",
"medline_ta": "Surg Case Rep",
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"nlm_unique_id": "101662125",
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"pages": "101",
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"pmid": "31227949",
"pubdate": "2019-06-21",
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"title": "Cecal cancer with essential thrombocythemia treated by laparoscopic ileocecal resection: a case report.",
"title_normalized": "cecal cancer with essential thrombocythemia treated by laparoscopic ileocecal resection a case report"
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"abstract": "BACKGROUND\nComplex spinal deformities are a common issue in pediatric patients with an underlying neurologic diagnosis or syndrome. Management of neuromuscular scoliosis is an awesome responsibility, because these patients present with the most challenging pathologies of the deformed spine. Along with surgical correction of the underlying deformity, an intrathecal baclofen (ITB) pump is considered effective in managing the associated spasticity.\n\n\nMETHODS\nWe present the case of an 11-year-old female who sustained an episode of severe ischemic encephalopathy accompanied by hydrocephalus and severe spastic quadriplegia. An ITB pump was inserted to manage spasticity. Two years later, a very severe decompensated spinal curvature developed. In addition, malfunction of the pump was noted, and the decision was made to perform revision along with open hemilaminectomy at the L3-4 level. The inability of cerebrospinal fluid (CSF) to access the pump was verified intraoperatively, with the absence of CSF glow through the intrathecal space demonstrating blockage of CSF flow.\n\n\nCONCLUSIONS\nThe association of cerebral palsy and relevant disorders with the relentless progression of scoliosis is analyzed, along with the possible offending mechanisms. The efficacy of an ITB pump in controlling intractable spasticity associated with neuromuscular scoliosis is reviewed, as well as its potential to accentuate the clinical progression of neuromuscular scoliosis. Although this is an extremely infrequent situation, we must always bear in mind the possibility that malfunction of an ITB pump could be related to obstruction of CSF flow, owing to the extreme severity of the curves established during the course of, most likely untreated, neuromuscular scoliosis.",
"affiliations": "Neurosurgical Department, Pediatric Hospital of Athens, Agia Sophia, Athens, Greece. Electronic address: dimpanayop@gmail.com.;Neurosurgical Department, Pediatric Hospital of Athens, Agia Sophia, Athens, Greece.;Neurosurgical Department, Pediatric Hospital of Athens, Agia Sophia, Athens, Greece.",
"authors": "Panagopoulos|Dimitrios|D|;Apostolopoulou|Katerina|K|;Themistocleous|Marios|M|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
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"journal": "World neurosurgery",
"keywords": "Cerebrospinal fluid blockage; Intrathecal baclofen pump; Neuromuscular scoliosis",
"medline_ta": "World Neurosurg",
"mesh_terms": "D001418:Baclofen; D002648:Child; D004868:Equipment Failure; D005260:Female; D006801:Humans; D002534:Hypoxia, Brain; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D009125:Muscle Relaxants, Central; D009128:Muscle Spasticity; D012600:Scoliosis",
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"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Severe Neuromuscular Scoliosis Implicated by Dysfunction of Intrathecal Baclofen Pump: Case Report and Review of the Literature.",
"title_normalized": "severe neuromuscular scoliosis implicated by dysfunction of intrathecal baclofen pump case report and review of the literature"
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"abstract": "Reversible cerebral vasoconstriction syndrome (RCVS) is a syndrome characterized by severe headache with segmental vasoconstriction of the cerebral arteries that resolves within 12 weeks. A 16-year-old girl with refractory cytopenia of childhood, who was receiving the immunosuppressant cyclosporine, developed severe headache and was diagnosed with RCVS using magnetic resonance imaging, including magnetic resonance angiography (MRA). MRA is a non-invasive and very effective technique for diagnosing RCVS. MRA should be performed at the onset of severe headache during immunosuppressant administration for children with hematological disorders and may prevent sequelae such as posterior reversible encephalopathy syndrome or ischemic attack.",
"affiliations": "Department of Pediatric Hematology and Oncology, Japanese Red Cross Narita Hospital , Narita, Chiba, Japan.;Department of Radiology, Japanese Red Cross Narita Hospital , Narita, Chiba, Japan.;Department of Pediatric Hematology and Oncology, Japanese Red Cross Narita Hospital , Narita, Chiba, Japan.;Department of Pediatric Hematology and Oncology, Japanese Red Cross Narita Hospital , Narita, Chiba, Japan.;Department of Pediatric Hematology and Oncology, Japanese Red Cross Narita Hospital , Narita, Chiba, Japan.;Department of Pediatric Hematology and Oncology, Japanese Red Cross Narita Hospital , Narita, Chiba, Japan.",
"authors": "Ueki|Hideaki|H|;Sanayama|Yasushi|Y|;Miyajima|Akiyo|A|;Tsuchimochi|Taichiro|T|;Igarashi|Shunji|S|;Sunami|Shosuke|S|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2016.6673",
"fulltext": "\n==== Front\nHematol RepHematol RepHRHematology Reports2038-83222038-8330PAGEPress Publications, Pavia, Italy 2799483810.4081/hr.2016.6673Case ReportReversible Cerebral Vasoconstriction Syndrome Promptly Diagnosed with Magnetic Resonance Imaging Including Magnetic Resonance Angiography During Immunosuppressive Therapy in a 16-Year-Old Girl with Refractory Cytopenia of Childhood Ueki Hideaki 1Sanayama Yasushi 2Miyajima Akiyo 1Tsuchimochi Taichiro 1Igarashi Shunji 1Sunami Shosuke 11 Department of Pediatric Hematology and Oncology, Japanese Red Cross Narita Hospital, Narita, Chiba, Japan2 Department of Radiology, Japanese Red Cross Narita Hospital, Narita, Chiba, JapanDepartment of Pediatric Hematology and Oncology, Japanese Red Cross Narita Hospital, 90-1, Iida-cho, Narita, Chiba 286-8523, Japan +81.476.22.2311 - +81.476.22.6477. uekih0209@gmail.comContributions: HU treated the patient and wrote the manuscript; YS contributed diagnosing the patient radiologically; AM, TT and SI treated the patient as members of clinical team; SS considerably advised me on writing this manuscript.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n17 11 2016 02 11 2016 8 4 667329 6 2016 11 10 2016 ©Copyright H. Ueki et al.2016Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Reversible cerebral vasoconstriction syndrome (RCVS) is a syndrome characterized by severe headache with segmental vasoconstriction of the cerebral arteries that resolves within 12 weeks. A 16-year-old girl with refractory cytopenia of childhood, who was receiving the immunosuppressant cyclosporine, developed severe headache and was diagnosed with RCVS using magnetic resonance imaging, including magnetic resonance angiography (MRA). MRA is a non-invasive and very effective technique for diagnosing RCVS. MRA should be performed at the onset of severe headache during immunosuppressant administration for children with hematological disorders and may prevent sequelae such as posterior reversible encephalopathy syndrome or ischemic attack.\n\nKey words\nReversible cerebral vasoconstriction syndromeImmunosuppressive therapyMagnetic resonance angiographyRefractory cytopenia of childhoodChildren\n==== Body\nIntroduction\nReversible cerebral vasoconstriction syndrome (RCVS) is a syndrome characterized by the sudden onset of severe headache, often called thunderclap headache, with multifocal segmental vasoconstriction of cerebral arteries, identifiable as a beaded appearance on imaging modalities. Reversibility of these angiographic abnormalities is seen within 12 weeks after onset under appropriate therapy, including cessation of causative medicines and administration of a calcium blocker such as lomerizine.1-7 The pathophysiology of RCVS remains uncertain, although alterations in cerebrovascular tone are thought to represent a key underlying mechanism.1 Many substances, including immunosuppressants, vasoactive substances, and blood products, are thought to cause onset of RCVS.8 Timely and accurate diagnosis of RCVS is required for appropriate care. Delays in diagnosis may cause deterioration of symptoms and concomitant excessive diagnostic tests. However, diagnosis can be difficult because of signs and symptoms overlapping with those of better known disorders of the central nervous system, such as posterior reversible encephalopathy syndrome (PRES).3,4,9-13 In patients with hematological disease, calcineurin inhibitors such as cyclosporine and tacrolimus have been used in immunosuppressive therapy (IST) for the treatment of aplastic anemia, and the related disorder, refractory cytopenia of childhood (RCC), and in prophylactic treatment for graft-versus-host disease after hematopoietic cell transplantation. As one of the disorders leading to headache during the use of calcineurin inhibitors, PRES has often been reported. Although PRES is sometimes complicated by RCVS,13 very few reports have described RCVS in patients under 18 years old with hematological disease. We report the case of a 16-year-old girl with RCVS that developed during immunosuppressive therapy for RCC and was promptly diagnosed using magnetic resonance angiography (MRA), a group of techniques based on magnetic resonance imaging (MRI), and successfully treated.\n\nCase Report\nA 13-year-old girl visited our hospital with a 3-day history of fever and abdominal pain. Blood examinations revealed pancytopenia, and she was admitted to our hospital. Bone marrow findings showed hypoplasia and dysplasia of more than 10% of myeloid lineage. G-banding of marrow cells revealed a 46,XX karyotype in all of the 10 cells analyzable, and fluorescence in situ hybridization detected neither monosomy 7 nor trisomy 8. Based on these findings, RCC (a subtype of myelodysplastic syndrome) was diagnosed. Because cytopenia was not severe, she was observed in our outpatient clinic without treatment. After observation for 41 months, at 16 years old, the cytopenia worsened to the point of dependency on blood transfusion and the patient was admitted to our hospital for IST. From day 2 of hospitalization, IST was performed using rabbit antithymocyte globulin (Thymoglobulin; Sanofi K.K., Tokyo, Japan) at 3.5 mg/kg/day (for 5 days), cyclosporine A (CsA) started at 6 mg/kg/day and adjusted to the range of 100-200 ng/mL (for 180 days), and methylprednisolone at 2 mg/kg (full dose for 7 days, tapered down for 3 weeks, then suspended). On day 13 of hospitalization, throbbing headache arose in the left frontal to posterior region of the head. This headache was not severe at onset but gradually worsened over 4 days to 7/10 on the numeric rating scale, leading to sleep disturbance. On day 17 of hospitalization, MRI including MRA was performed. MRA detected segmental constriction as the beaded appearance of bilateral internal carotid arteries and bilateral anterior cerebral arteries (Figure 1). T1- and T2-weighted imaging, fluid-attenuated inversion recovery imaging, and diffusion-weighted imaging as other MRI techniques revealed no abnormalities of the brain. On day 18 of hospitalization, CsA was suspended and administration of the calcium blocker lomerizine was started at 10 mg/day. Headache promptly improved, resolving by day 23 of hospitalization (5 days after starting lomerizine administration). MRA on day 26 of hospitalization showed regression of vasoconstriction (Figure 2). CsA was restarted on day 57 of hospitalization (day 44 after onset of headache) with continuation of lomerizine, because of the need for this agent in the treatment of RCC. No recurrence of headache has been seen for one year after discharge.\n\nDiscussion\nWe promptly diagnosed and successfully treated RCVS during IST in this 16-year-old girl with RCC using MRI, including MRA. Imaging modalities used in the management of RCVS include transcranial Doppler ultrasonography, non-contrast computed tomography (CT), CT angiography, MRA, vessel wall imaging, and catheter angiography.2 Cerebral angiography is the standard criterion for the detection of cerebral vasoconstriction, but noninvasive techniques such as MRA are increasingly being used in clinical practice. MRA is an effective technique for diagnosing and monitoring the evolution of RCVS-related vasoconstriction.14 We used MRI including MRA for screening our patient with severe headache, and MRA revealed segmental vasoconstriction as a beaded appearance of the left internal carotid artery, leading to a diagnosis of RCVS, but T1- and T2-weighted, fluid-attenuated inversion recovery imaging, and diffusion-weighted imaging revealed no abnormalities. MRA is in relatively widespread use and is a non-invasive modality, which is useful in screening for headache. However, when PRES is suspected as a cause of headache, MRA is not generally performed for screening, because PRES can be diagnosed by MRI sequences without MRA. As a result, some cases of RCVS may be misdiagnosed as PRES not complicated with RCVS.\n\nRCVS is closely related to PRES and ischemic stroke. Ducros and colleagues reported that 9-38% of patients with RCVS had PRES-like lesions.15 Chen and colleagues found that vasoconstrictions are important determinants for PRES and ischemic stroke.14 Timely diagnosis and appropriate treatment for RCVS may prevent the onset of these clinical problems.\n\nReports of RCVS in children with hematological disease are very rare. A PubMed search for cases of RCVS in children with hematological diseases, using the search terms reversible cerebral vasoconstriction syndrome [Title/Abstract], and children [Title/Abstract] or pediatric [Title/Abstract], yielded only one report of RCVS.16 However, some cases of RCVS may go unrecognized, considering the relationship between RCVS and PRES. Surveys of cases from multiple centers are needed to clarify the actual incidence of RCVS in children with hematological disease.\n\nConclusions\nMRA should be included in diagnostic modalities for severe headache during administration of causative medicines such as calcineurin inhibitors, for the purpose of prompt diagnosis and treatment of RCVS.\n\nAcknowledgements\nWe wish to thank the staff of our institution who participated in the treatment of this patient.\n\nFigure 1. Magnetic resonance angiography (MRA) on day 17 of hospitalization (4 days after onset of headache). MRA shows segmental constriction (beaded appearance) of bilateral internal carotid arteries and bilateral anterior cerebral arteries (arrows).\n\nFigure 2. Magnetic resonance angiography (MRA) on day 26 of hospitalization (13 days after onset of headache). MRA shows regression of vasoconstriction.\n==== Refs\nReferences\n1. Miller TR Shivashankar R Mossa-Basha M Gandhi D. \nReversible cerebral vasoconstriction syndrome, part 1: epidemiology, pathogenesis, and clinical course . AJNR Am J Neuroradiol \n2015 ;36 :1392 -9 .25593203 \n2. Miller TR Shivashankar R Mossa-Basha M Gandhi D. \nReversible cerebral vasoconstriction syndrome, part 2: diagnostic work-up, imaging evaluation, and differential diagnosis . AJNR Am J Neuroradiol \n2015 ;36 :1580 -8 .25614476 \n3. Ducros A \nL37. Reversible cerebral vasoconstriction syndrome: distinction from CNS vasculitis . Presse Med \n2013 ;42 :602 -4 .23481360 \n4. Ducros A Bousser MG \nReversible cerebral vasoconstriction syndrome . Pract Neurol \n2009 ;9 :256 -67 .19762885 \n5. Gupta S Zivadinov R Ramasamy D Ambrus JL Jr \nReversible cerebral vasoconstriction syndrome (RCVS) in antiphospholipid antibody syndrome (APLA): the role of centrally acting vasodilators. Case series and review of literature . Clin Rheumatol \n2014 ;33 :1829 -33 .24277114 \n6. Marder CP Donohue MM Weinstein JR Fink KR \nMultimodal imaging of reversible cerebral vasoconstriction syndrome: a series of 6 cases . Am J Neuroradiol \n2012 ;33 :1403 -10 .22422190 \n7. Sheikh HU Mathew PG \nReversible cerebral vasoconstriction syndrome: updates and new perspectives . Curr Pain Headache Rep \n2014 ;18 :414 .24658747 \n8. Ducros A Bousser MG \nReversible cerebral vasoconstriction syndrome . Pract Neurol \n2009 ;9 :256 -67 .19762885 \n9. Calabrese LH Dodick DW Schwedt TJ Singhal AB \nNarrative review: reversible cerebral vasoconstriction syndromes . Ann Intern Med \n2007 ;146 :34 -4 .17200220 \n10. Calic Z Choong H Schlaphoff G Cappelen-Smith C. \nReversible cerebral vasoconstriction syndrome following indomethacin . Cephalalgia \n2014 ;34 :1181 -6 .24723675 \n11. Edlow BL Kasner SE Levine JM \nReversible cerebral vasoconstriction syndrome associated with subarachnoid hemorrhage . Neurocrit Care \n2007 ;7 :203 -10 .17901935 \n12. Grooters GS Sluzewski M Tijssen CC \nHow often is thunderclap headache caused by the reversible cerebralvasoconstriction syndrome? \nHeadache \n2014 ;54 :732 -5 .24822246 \n13. Akazawa Y Inaba Y Koike K \nReversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome in a boy with Loeys-Dietz syndrome . Am J Med Genet A \n2015 ;167A :2435 -9 .26096872 \n14. Chen SP Fuh JL Wu JC \nMagnetic resonance angiography in reversible cerebral vasoconstriction syndromes . Ann Neurol \n2010 ;67 :648 -56 .20437562 \n15. Ducros A \nReversible cerebral vasoconstriction syndrome . Lancet Neurol \n2012 ; 11 :906 -17 .22995694 \n16. Kazato Y Fujii K Oba H \nReversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage . Brain Dev \n2012 ;34 :696 -9 .22386063\n\n",
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"issue": "8(4)",
"journal": "Hematology reports",
"keywords": "Children; Immunosuppressive therapy; Magnetic resonance angiography; Refractory cytopenia of childhood; Reversible cerebral vasoconstriction syndrome",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "6673",
"pmc": null,
"pmid": "27994838",
"pubdate": "2016-11-02",
"publication_types": "D002363:Case Reports",
"references": "24723675;17200220;25593203;24658747;26096872;22995694;23481360;22422190;20437562;19762885;24277114;22386063;25614476;24822246;17901935",
"title": "Reversible Cerebral Vasoconstriction Syndrome Promptly Diagnosed with Magnetic Resonance Imaging Including Magnetic Resonance Angiography During Immunosuppressive Therapy in a 16-Year-Old Girl with Refractory Cytopenia of Childhood.",
"title_normalized": "reversible cerebral vasoconstriction syndrome promptly diagnosed with magnetic resonance imaging including magnetic resonance angiography during immunosuppressive therapy in a 16 year old girl with refractory cytopenia of childhood"
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"abstract": "OBJECTIVE\nBasilar artery occlusion remains one of the most devastating subtypes of ischemic stroke. The prognosis is poor if early recanalization is not achieved. The purpose of this study was to evaluate the safety and technical feasibility of self-expanding retrievable stents in the endovascular treatment of acute basilar artery occlusion.\n\n\nMETHODS\nTwenty-four patients with acute basilar artery occlusion were treated with Solitaire FR or Revive SE devices between December 2009 and May 2012. Additional treatment included intravenous and/or intra-arterial thrombolysis (21/24) and percutaneous transluminal angioplasty/permanent stent placement (7/24). Recanalization was assessed by means of the TICI score. Clinical outcome was determined at discharge (NIHSS), and at 3 months (mRS).\n\n\nRESULTS\nMedian NIHSS score on admission was 24; median duration of symptoms was 254 minutes. Successful recanalization (TICI 2b +3) by thrombectomy only was achieved in 18 patients (75%). Intracranial stent deployment after thrombectomy caused by underlying atherosclerotic stenosis was performed in 7 patients. If these patients with intracranial stent placement are included, successful recanalization was achieved in 21 of 24 patients (87.5%). NIHSS improvement ≥10 points was reached in 54% of patients (n = 13/24). Mortality during the first 3 months was 29% (7/24). After 3 months, 8 patients (33%) had a favorable clinical outcome (mRS 0-2).\n\n\nCONCLUSIONS\nIn our series, application of self-expanding retrievable stents in acute basilar artery occlusion resulted in a high recanalization rate without procedural complications and good clinical outcome in one-third of patients.",
"affiliations": "From the Departments of Neuroradiology (M.M., S.S., L.B., C.H., S.R., M.B., M.P.) markus.moehlenbruch@med.uni-heidelberg.de.;From the Departments of Neuroradiology (M.M., S.S., L.B., C.H., S.R., M.B., M.P.).;From the Departments of Neuroradiology (M.M., S.S., L.B., C.H., S.R., M.B., M.P.).;From the Departments of Neuroradiology (M.M., S.S., L.B., C.H., S.R., M.B., M.P.).;From the Departments of Neuroradiology (M.M., S.S., L.B., C.H., S.R., M.B., M.P.).;From the Departments of Neuroradiology (M.M., S.S., L.B., C.H., S.R., M.B., M.P.).;From the Departments of Neuroradiology (M.M., S.S., L.B., C.H., S.R., M.B., M.P.)Neurology (C.H., S.N., P.A.R.), University of Heidelberg Medical Center, Heidelberg, Germany.;Neurology (C.H., S.N., P.A.R.), University of Heidelberg Medical Center, Heidelberg, Germany.;Neurology (C.H., S.N., P.A.R.), University of Heidelberg Medical Center, Heidelberg, Germany.;From the Departments of Neuroradiology (M.M., S.S., L.B., C.H., S.R., M.B., M.P.).",
"authors": "Möhlenbruch|M|M|;Stampfl|S|S|;Behrens|L|L|;Herweh|C|C|;Rohde|S|S|;Bendszus|M|M|;Hametner|C|C|;Nagel|S|S|;Ringleb|P A|PA|;Pham|M|M|",
"chemical_list": null,
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"issue": "35(5)",
"journal": "AJNR. American journal of neuroradiology",
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"medline_ta": "AJNR Am J Neuroradiol",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002548:Cerebral Revascularization; D020878:Device Removal; D004867:Equipment Design; D019544:Equipment Failure Analysis; D005260:Female; D006801:Humans; D008297:Male; D061185:Mechanical Thrombolysis; D008875:Middle Aged; D011859:Radiography; D015607:Stents; D016896:Treatment Outcome; D014715:Vertebrobasilar Insufficiency",
"nlm_unique_id": "8003708",
"other_id": null,
"pages": "959-64",
"pmc": null,
"pmid": "24287087",
"pubdate": "2014-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "19577962;21493763;22851547;22932715;16439705;17110663;20947848;22759754;3363593;18499798;23536323;22723058;7678184;18617663;3176080;23124642;15956504;21597019;21596812;21971720;12869717;2389292;23463755;18323481;17261720;6410756;16339473;22014435;21817139;11847055;18346645;23645572;20538693",
"title": "Mechanical thrombectomy with stent retrievers in acute basilar artery occlusion.",
"title_normalized": "mechanical thrombectomy with stent retrievers in acute basilar artery occlusion"
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"activesubstancename": "ALTEPLASE"
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"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nApproximately 5% of patients who have undergone coronary artery stenting require noncardiac surgery within a year of their cardiac intervention. European cardiological guidelines and recommendations from the U.S. Food and Drug Administration on platelet antiaggregant therapy following coronary artery stenting are for dual treatment with acetylsalicylic acid and clopidogrel, which should be continued for at least 12 months. The aim of this study was to evaluate the clinical course in patients receiving double platelet antiaggregant therapy who underwent transurethral resection of bladder cancer.\n\n\nMETHODS\nBetween September 2007 and April 2010, twelve patients receiving double antithrombotic therapy (clopidogrel+acetylsalicylic acid) underwent transurethral resection of bladder cancer. In two cases the operation was \"urgent\". The mean age of the patients was 71.25 years (range, 52-83 years). In nine cases the bladder cancer was newly diagnosed.\n\n\nRESULTS\nThe patients' preoperative mean hemoglobin concentration was 11.4 g/dl (range=5.2-13.4 g/dl), and on the first postoperative day it was 10.2 g/dl (range=9.6-12.6 g/dl). The mean duration of the intervention was 32 min (range=20-60 min). There were no cardiac complications in either the perioperative or the postoperative period. No patient required reintervention for hemostatic purposes. Three episodes of clot-related acute urinary retention occurred after removal of the bladder catheter, all of which were resolved with replacement of the catheter without needing reintervention.\n\n\nCONCLUSIONS\nDespite the high number of complications related to cardiac problems that suspension of these drugs causes, this urological intervention, carried out during dual antithrombotic therapy, was feasible and without major complications. Given the high proportion of complications due to clot-related urinary retention, it is advisable to leave the urinary catheter in place for a longer period.",
"affiliations": "Urology Department, IRCCS Policlinico San Donato, Via Morandi 30, 20097, San Donato Milanese, Milan, Italy.",
"authors": "Carmignani|Luca|L|;Picozzi|Stefano|S|;Stubinski|Robert|R|;Casellato|Stefano|S|;Bozzini|Giorgio|G|;Lunelli|Luca|L|;Arena|Domenico|D|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00464-010-1549-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0930-2794",
"issue": "25(7)",
"journal": "Surgical endoscopy",
"keywords": null,
"medline_ta": "Surg Endosc",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin; D006348:Cardiac Surgical Procedures; D000077144:Clopidogrel; D023903:Coronary Restenosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D015607:Stents; D013988:Ticlopidine; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "8806653",
"other_id": null,
"pages": "2281-7",
"pmc": null,
"pmid": "21301885",
"pubdate": "2011-07",
"publication_types": "D016428:Journal Article",
"references": "15766834;15680728;15769784;17148711;16534015;16670113;15870416;19153328;8996289;16442208;15500897;19218260;17964710;17170397;18565395;15126782;18230778;15346088;12435254;19892050;17224480;16697332;11520521;19717703;15078797",
"title": "Endoscopic resection of bladder cancer in patients receiving double platelet antiaggregant therapy.",
"title_normalized": "endoscopic resection of bladder cancer in patients receiving double platelet antiaggregant therapy"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1090350",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Two patients are reported who developed palinopsia while taking topiramate for migraine prevention which resolved or decreased in frequency or duration on lower doses, but recurred or increased in frequency or duration on higher doses. Both patients had complete resolution of palinopsia when topiramate was discontinued. A third patient is described who developed the \"Alice in Wonderland\" syndrome about 1 week after starting topiramate for migraine prevention with complete resolution of symptoms about 1 month after stopping. Topiramate use may cause palinopsia and may be associated with the Alice in Wonderland syndrome through an unknown mechanism.",
"affiliations": "Weill Medical College of Cornell University and The Methodist Hospital, Neurology, Houston, TX 77004, USA.",
"authors": "Evans|Randolph W|RW|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1526-4610.2006.00458_1.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8748",
"issue": "46(5)",
"journal": "Headache",
"keywords": null,
"medline_ta": "Headache",
"mesh_terms": "D000328:Adult; D000360:Afterimage; D000927:Anticonvulsants; D001828:Body Image; D005260:Female; D005632:Fructose; D006801:Humans; D008875:Middle Aged; D008881:Migraine Disorders; D010469:Perceptual Distortion; D000077236:Topiramate",
"nlm_unique_id": "2985091R",
"other_id": null,
"pages": "815-8",
"pmc": null,
"pmid": "16643588",
"pubdate": "2006-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Reversible palinopsia and the Alice in Wonderland syndrome associated with topiramate use in migraineurs.",
"title_normalized": "reversible palinopsia and the alice in wonderland syndrome associated with topiramate use in migraineurs"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US04330",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "The differential diagnosis of the patient with encephalopathy is broad and remains a common yet challenging problem for critical care physicians. A case is presented of contrast-induced encephalopathy in an 81-year-old man undergoing a left heart catheterisation after receiving iopamidol, a low-osmolar contrast agent. Immediately after receiving contrast, our patient experienced severe headache, agitation, altered mentation and significant skin hypersensitivity. This rare, acute and reversible neurological disturbance can be associated with administration of intra-arterial, osmotic, iodinated contrast. Although uncommon, it is important to recognise the various presentations, risk factors and treatment of this condition.",
"affiliations": "Department of Internal Medicine, UF Health Shands, Gainesville, Florida, USA.;Department of Internal Medicine, University of Florida, Gainesville, Florida, USA.",
"authors": "Neilan|Patrick|P|;Urbine|Daniel|D|",
"chemical_list": "D003287:Contrast Media; D007479:Iopamidol",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229717",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(11)",
"journal": "BMJ case reports",
"keywords": "adult intensive care; headache (including migraines); intensive care; neurology; neurology (drugs And Medicines)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000369:Aged, 80 and over; D001927:Brain Diseases; D006328:Cardiac Catheterization; D003287:Contrast Media; D003937:Diagnosis, Differential; D006801:Humans; D007479:Iopamidol; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31791981",
"pubdate": "2019-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27122717;21861746;8793235;28621151;29402812;22440599;6712182;21927883;20435835;10227646;20936928;29686712;19504154;8282504;17943057;30459910;28201864;21861745;11357968;8448799;29159151",
"title": "A case of contrast-induced encephalopathy.",
"title_normalized": "a case of contrast induced encephalopathy"
} | [
{
"companynumb": "US-BRACCO-2019US06578",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IOPAMIDOL"
},
"drugadditional": null,
"... |
{
"abstract": "Although recent Food and Drug Administration warnings have noted proarrhythmic effects of droperidol, other antiemetic drugs may have similar effects. We report a case of cardiac arrest after uncomplicated regional anesthesia in a patient with scleroderma who received labetalol and metoclopramide after surgery. Metoclopramide should be used with caution when risk factors for dysrhythmia are present.",
"affiliations": "Department of Anesthesia and Critical Care, University of Chicago, Illinois 60637, USA. atung@airway.uchicago.edu",
"authors": "Tung|Avery|A|;Sweitzer|BobbieJean|B|;Cutter|Thomas|T|",
"chemical_list": "D000932:Antiemetics; D000959:Antihypertensive Agents; D008787:Metoclopramide; D007741:Labetalol",
"country": "United States",
"delete": false,
"doi": "10.1097/00000539-200212000-00035",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "95(6)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000328:Adult; D000932:Antiemetics; D000959:Antihypertensive Agents; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007741:Labetalol; D008787:Metoclopramide; D012595:Scleroderma, Systemic",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "1667-8, table of contents",
"pmc": null,
"pmid": "12456435",
"pubdate": "2002-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cardiac arrest after labetalol and metoclopramide administration in a patient with scleroderma.",
"title_normalized": "cardiac arrest after labetalol and metoclopramide administration in a patient with scleroderma"
} | [
{
"companynumb": "US-VISTAPHARM, INC.-VER201808-000806",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugadditional... |
{
"abstract": "Risks, benefits, alternatives, and appropriateness of psychotropic medications, including risks of no treatment, are discussed for antidepressants, mood-stabilizing medications, anxiolytic/sedative hypnotic medications, stimulants, and medication-assisted treatment of substance use disorders. Early screening, diagnosis, and intervention prior to and/or during pregnancy often reduce morbidity and mortality of mental health disorders for mothers and infants.",
"affiliations": "Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital Center for Women's Mental Health, Harvard Medical School, Simches Research Building, 185 Cambridge Street, Suite 2200, Boston, MA 02114, USA. Electronic address: eraffi@mgh.harvard.edu.;Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital Center for Women's Mental Health, Harvard Medical School, Simches Research Building, 185 Cambridge Street, Suite 2200, Boston, MA 02114, USA.;Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital Center for Women's Mental Health, Harvard Medical School, Simches Research Building, 185 Cambridge Street, Suite 2200, Boston, MA 02114, USA.",
"authors": "Raffi|Edwin R|ER|;Nonacs|Ruta|R|;Cohen|Lee S|LS|",
"chemical_list": "D000928:Antidepressive Agents; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clp.2019.02.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-5108",
"issue": "46(2)",
"journal": "Clinics in perinatology",
"keywords": "Perinatal addiction; Perinatal reproductive psychiatry; Pregnancy; Psychopharmacology; Women’s mental health",
"medline_ta": "Clin Perinatol",
"mesh_terms": "D000928:Antidepressive Agents; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001714:Bipolar Disorder; D003866:Depressive Disorder; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders; D006801:Humans; D008431:Maternal-Fetal Exchange; D001523:Mental Disorders; D009293:Opioid-Related Disorders; D010547:Persistent Fetal Circulation Syndrome; D006473:Postpartum Hemorrhage; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D011618:Psychotic Disorders; D011619:Psychotropic Drugs; D012720:Severity of Illness Index; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders",
"nlm_unique_id": "7501306",
"other_id": null,
"pages": "215-234",
"pmc": null,
"pmid": "31010557",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Safety of Psychotropic Medications During Pregnancy.",
"title_normalized": "safety of psychotropic medications during pregnancy"
} | [
{
"companynumb": "US-OTSUKA-2019_029406",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BREXPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "We report a case of esophageal extranasal NK/T cell lymphoma with biphasic morphologic features revealed by a deep large piecemeal biopsy. A 40-year-old man present with pharyngalgia, dysphagia, recurrent fever, and 5-kg weight loss for 8 months. Endoscopy demonstrated progressing longitudinal ulcers and mucosal bridges along the esophagus. The first and second biopsies obtained superficial mucosa with scattered bland-looking small lymphocytes. A subsequent large piecemeal snare abscission for biopsy showed atypical lymphoid cells infiltrating into the deep lamina propria and muscularis mucosae, whereas the superficial lamina propria was highly edematous with scant small lymphocytes. Immunohistochemical studies confirmed that both underlying atypical cells and superficial small lymphocytes were neoplastic, sharing an identical immunophenotype: positive for CD2, CD3, CD43, CD8, CD56, TIA-1 and granzyme B. Epstein-Barr virus-encoded small RNAs were found in both cells. The histologic findings were diagnostic of primary esophageal extranasal NK/T cell lymphoma. However, the patient developed bone marrow depression during chemotherapy and died of massive cerebral hemorrhage after the first cycle of chemotherapy. Primary esophageal extranodal NK/T cell lymphoma nasal type is extremely rare. We show the biphasic morphology of this disease, which highlights the importance of deep biopsy for accurate diagnosis.",
"affiliations": "From the Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University (Z-YY, Q-HC, X-FL); Department of Oncology, Nanfang Hospital of Southern Medical University (FL); Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (S-RL); Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, AL, USA (C-ZL) and Department of Pathology, Guangzhou First People's Hospital, Guangzhou, China (S-HC).",
"authors": "Ye|Zi-Yin|ZY|;Cao|Qing-Hua|QH|;Liu|Fang|F|;Lu|Xiao-Fang|XF|;Li|Shu-Rong|SR|;Li|Chang-Zhao|CZ|;Chen|Shao-Hong|SH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000001151",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2618155710.1097/MD.0000000000001151011514100Research ArticleClinical Case ReportPrimary Esophageal Extranasal NK/T Cell Lymphoma With Biphasic Morphology A Case Report and Literature ReviewYe Zi-Yin MDCao Qing-Hua MDLiu Fang PhDLu Xiao-Fang MDLi Shu-Rong MDLi Chang-Zhao PhDChen Shao-Hong PhDOhsie. Steven From the Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University (Z-YY, Q-HC, X-FL); Department of Oncology, Nanfang Hospital of Southern Medical University (FL); Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (S-RL); Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, AL, USA (C-ZL) and Department of Pathology, Guangzhou First People's Hospital, Guangzhou, China (S-HC).Correspondence: Dr. Qing-Hua Cao, Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China (e-mail: caoqhua@mail.sysu.edu.cn). Dr. Shao-Hong Chen, Department of Pathology, Guangzhou First People's Hospital, Guangzhou 510080, China (e-mail: shhonghong@126.com).7 2015 17 7 2015 94 28 e115120 1 2015 9 6 2015 21 6 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nWe report a case of esophageal extranasal NK/T cell lymphoma with biphasic morphologic features revealed by a deep large piecemeal biopsy.\n\nA 40-year-old man present with pharyngalgia, dysphagia, recurrent fever, and 5-kg weight loss for 8 months. Endoscopy demonstrated progressing longitudinal ulcers and mucosal bridges along the esophagus. The first and second biopsies obtained superficial mucosa with scattered bland-looking small lymphocytes. A subsequent large piecemeal snare abscission for biopsy showed atypical lymphoid cells infiltrating into the deep lamina propria and muscularis mucosae, whereas the superficial lamina propria was highly edematous with scant small lymphocytes. Immunohistochemical studies confirmed that both underlying atypical cells and superficial small lymphocytes were neoplastic, sharing an identical immunophenotype: positive for CD2, CD3, CD43, CD8, CD56, TIA-1 and granzyme B. Epstein-Barr virus–encoded small RNAs were found in both cells. The histologic findings were diagnostic of primary esophageal extranasal NK/T cell lymphoma. However, the patient developed bone marrow depression during chemotherapy and died of massive cerebral hemorrhage after the first cycle of chemotherapy.\n\nPrimary esophageal extranodal NK/T cell lymphoma nasal type is extremely rare. We show the biphasic morphology of this disease, which highlights the importance of deep biopsy for accurate diagnosis.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nPrimary esophageal lymphoma is rare, accounting for <1% cases of gastrointestinal lymphomas. B cell lymphomas are the most common histological subtype.1,2 Our review of the medical literature revealed only 3 cases of primary esophageal extranasal NK/T cell lymphoma published so far.3,4 Extranodal NK/T-cell lymphoma is characterized by diffuse infiltration of atypical lymphoid cells, angiocentric and angiodestructive growth pattern, coagulative necrosis, and admixed apoptotic bodies.5 Here, we report a case of primary esophageal extranasal NK/T cell lymphoma showing biphasic morphology and highlight the importance of deep biopsy for accurate diagnosis of tumor arising from the deep layer of esophageal wall.\n\nCASE REPORT\nClinical Findings\nA 40-year-old man was admitted for gradually aggravated pharyngalgia and dysphagia for 8 months in addition to recurrent fever and 5-kg weight loss. Results of physical examination were unremarkable, with no palpable lymphadenopathy, ascites, or organomegaly. A complete blood count showed a white blood cell count of 6.67 × 109 cells/L, a red blood cell count of 5.47 × 1012 cells/L, a hemoglobin level of 100 g/L, and a platelet level of 216 × 109 cells/L. The serum lactate dehydrogenase (LDH) level was 226 U/L (normal range 114–240 U/L), the total serum protein level was 69 g/L (normal range 64–87 g/L), and the serum albumin level was 35 g/L (normal range 35–50 g/L). Other laboratory values were within normal limits. Endoscopy demonstrated multiple esophageal ulcers, well-demarcated, with the largest measuring approximately 2.0 × 0.6 cm in cross-section. A biopsy was taken for pathologic examination and a diagnosis of chronic esophagitis was made. However, this patient showed no response to antibiotics administration.\n\nThree months later, he was admitted again for recurrent pharyngalgia, sharpened retrosternal pain, and continuous fever. Laboratory tests, including blood counts and hepatic and renal function tests, remained stable. Chest computer tomography (CT) scan showed that the esophagus wall was rigid and incrassated. The inner wall was rough and uneven on the surface. After contrast administration, the CT scan showed multiple mucosal interruptions with enhancement occupying more than half of the esophageal wall (Figure 1). No enlarged lymph nodes were detected. CT scans of the head, neck, abdomen, and pelvis did not detect enlarged lymph nodes. The liver and spleen were of normal size and shape. Endoscopy revealed multiple deep ulcers along middle and distal portion of esophagus, with 3 deep longitudinal ulcers measuring 2 × 10 cm. A biopsy was taken and the pathologic diagnosis was chronic nonspecific esophagitis. No lesions appeared in the nasal cavities on nasal endoscopic examination.\n\nFIGURE 1 Computed tomography (CT) scan of an esophageal lesion. CT showed the esophagus wall was rigid and demonstrated rugosity (arrows) in the sagittal view (A) and transverse section (B).\n\nThe patient had severe worsening of his original symptoms, and decreasing ability to swallow in the following 2 months. Of note, he had lost 7 kg since the first admission. Blood test showed his red blood cell count and hemoglobin level dropped to 3.50 × 1012 cells/L and 75 g/L, respectively. His LDH level was elevated to 370 U/L (normal range 114–240 U/L), his total serum protein level was decreased to 38.2 g/L (normal range 64–87 g/L), and his serum albumin level was 20.8 g/L (normal range 35–50 g/L). Repeated endoscopy showed mucosal erosion along the esophagus, approximately 17 to 40 cm from incisors. There were multiple polypoid lesions and longitudinal mucosal bridges with ulcers. A shallow longitudinal ulcer in the posterior wall was observed (Figure 2A–C). Following a large piecemeal snare abscission, a large portion of tissue was obtained for biopsy (Figure 2D). The final diagnosis was primary esophageal extranasal NK/T cell lymphoma. A bone marrow biopsy was subsequently performed and was negative for tumor involvement. In accordance with the Ann Arbor classification system, this case was classified as a stage IE disease.\n\nFIGURE 2 Endoscopy examination of esophageal lesion. Endoscopy demonstrated longitudinal ulcer (A), polypoid lesions (B), and longitudinal mucosal bridges (C). A large piecemeal snare abscission was performed to obtain sufficient tissue for diagnosis (D).\n\nOne month after diagnosis, this patient was treated with chemotherapy using CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). However, he developed bone marrow depression with fever and interspersed cutaneous petechia on the 10th day of the first cycle of chemotherapy. Consistently, blood tests showed a WBC count of 0.5 × 109 cells/L, a neutrophil count of 0.2 × 109 cells/L, a hemoglobin level of 90 g/L, and a platelet level of 15 × 109 cells/L. Three days later, he died of massive cerebral hemorrhage suddenly.\n\nMATERIALS AND METHODS\nThe specimen was fixed in a 10% neutral formalin solution and embedded in paraffin. Four-micromoles per liter sections were prepared for hematoxylin and eosin (H&E) staining or immunohistochemical (IHC) staining. An Envision 2-step assay was used for the IHC staining. Primary antibodies CD20, CD79a, CD2, CD3ε, CD5, CD4, CD8, CD43, CD56, TIA-1, Granzyme B, Ki-67, and horseradish peroxidase-conjugated secondary antibodies were obtained from DAKO Inc, Glostrup, Copenhagen, Denmark.\n\nIn situ hybridization (ISH) was performed to test for the presence of Epstein-Barr virus–encoded small RNA (EBER) in formalin-fixed, paraffin-embedded sections using a hybridization kit (DAKO).\n\nFor cytogenetic analysis, the paraffin tissue DNA was prepared with a tissue DNA extraction and purification kit (Dneasy TM Tissue Kit, Qiagene, CA). T-cell receptor rearrangement studies were performed.\n\nThis study was approved by the Human Ethics Committee of The First Affiliated Hospital, Sun Yat-sen University. Written informed consent was obtained from the patient's direct relative for publication of this Case Report and any accompanying images.\n\nPathologic Findings\nThe first biopsy obtained showed only ulceration with an inflammatory exudate and fragments of squamous epithelium (Figure 3A). Pathologic diagnosis was rendered as chronic nonspecific esophagitis without performance of IHC.\n\nFIGURE 3 Pathological features of the first (A, B, C) and second (D, E, F) biopsies. The first biopsy obtained demonstrated ulceration with inflammatory exudate (A, H&E). Immmunohistochemical (IHC) staining (B) and in situ hybridization (ISH) for EBER (C) highlighted scattered positive lymphocytes. The second biopsy obtained fragments of squamous epithelium and superficial lamina propria with scattered small lymphocytes (D, H&E), which were positive for CD3 (E) and EBER by ISH (F).\n\nThe second biopsy obtained fragments of squamous epithelium and superficial lamina propria with ulceration. Scattered small lymphocytes without atypical features were found in lamina propria (Figure 3D). IHC staining was not performed. The working pathologic diagnosis remained as chronic nonspecific esophagitis.\n\nThe last biopsy was taken with a large piecemeal snare abscission. Therefore, a large fragment of tissue was obtained. Histopathologic examination showed a biphasic population of lymphocytes in the superficial and deep lamina propria. The superficial lamina propria was highly edematous with scant small lymphocytes. These lymphocytes showed round condensed nuclei and rare mitotic figures were noted, practically identical to the lymphoid cells seen in the previous biopsies (Figure 4A, B). Focal ulceration was observed. However, numerous atypical lymphoid cells diffusely infiltrated into the deep lamina propria and muscularis mucosae, dispersing muscular bundles. The cells were small to medium-sized, with round hyperchromatic nuclei with inconspicuous nucleoli (Figure 4C, D). Neither an angiocentric infiltration pattern and nor an angiodestructive growth pattern was identified in the biopsy. Coagulative necrosis and admixed apoptotic bodies were not seen either. Immunohistochemical staining indicated tumor cells were positive for CD2, CD3 (Figure 4E), CD43, CD8, CD56 (Figure 4F), granzyme B (Figure 4G), and TIA-1(Figure 4H). A small portion of cells were positive for CD5. The proliferation index was approximately 60% as assessed by Ki-67 staining (Figure 4I). ISH for EBER showed strong positive signals in tumor cells (Figure 4J). The superficial small lymphocytes without atypical morphology were confirmed to be neoplastic because they also showed positive staining for EBER and shared the same immunophenotype with the atypical lymphoid cells beneath. No clonal rearrangement of T cell receptor genes was found by polymerase chain reaction heteroduplex analysis and polyacrylamide gel electrophoresis.\n\nFIGURE 4 Pathological features of the third biopsy. The superficial lamina propria was highly edematous with scant small lymphoid cells (A and B, H&E). Atypical lymphoid cells infiltrated the muscularis mucosae (C and D, H&E). Tumor cells were positive for CD3 (E), CD56 (F), Granzyme B (G), TIA-1 (H), Ki67 (I), and Epstein-Barr virus–encoded small RNAs (J).\n\nAfter the diagnosis of primary esophageal extranasal NK/T cell lymphoma based on the third biopsy, supplemental immunohistochemical staining and EBER ISH have been performed on tissues of the first 2 biopsies. Scattered lymphocytes were positive for CD2, CD3 (Figure 1B, E), TIA1, and EBER ISH (Figure 1C, F), suggesting the bland appearing lymphocytes, which were originally interpreted as benign were in fact neoplastic.\n\nDISCUSSION\nPrimary esophageal lymphoma is very rare, with only 40 cases reported in the English literature. The diagnosis of primary esophageal lymphoma should meet the following 5 criteria: no concomitant palpable superficial lymph nodes, no mediastinal lymphadenopathy, normal white blood cell count, no hepatic or splenic involvement, and the presence of an esophageal lesion.6 The most common subtypes of primary esophageal lymphomas reported are extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)1,7–11 and diffuse large B-cell lymphoma.12–14 Aside from B cell lymphomas, there were also 10 cases of T or NK-cell lymphoma15–18 and 3 cases of Hodgkin lymphoma19,20 reported. Most primary esophageal lymphomas arose in patients older than 50 years. The present symptoms, such as dysphagia epigastric pain and weight loss, were nonspecific. Endoscopic findings were variable and included submucosal tumor infiltration, polypoid growth, and ulceration. MALT lymphomas commonly presented as submucosal tumors with stage I disease. The most common treatment was endoscopic mucosal resection or endoscopic submucosal dissection with or without chemotherapy and radiotherapy. Most patients showed no evidence of recurrence on follow-up (1–3 years). Aggressive lymphomas, such as T-cell lymphomas and diffuse large B-cell lymphomas, commonly presented as tumor masses with obstruction and ulceration on endoscopy. Treatment included chemotherapy, with or without surgery, and radiotherapy. Prognosis is variable and advanced stage disease shows a poor outcome.\n\nPrimary esophageal NK/T cell lymphoma is extremely rare, with only 3 cases reported previously (Table 1).3,4 The present case is the fourth primary esophageal NK/T cell lymphoma reported so far. The age range of the reported cases was 40 to 54 years. Endoscopy showed ulceration with or without masses. Initial treatments were chemotherapy with or without radiotherapy. All the patients died within 2 to 32 months. The previous reports simply focused on endoscopy appearance. In the present case, we highlighted the biphasic histopathologic features of the tumor with emphasis on the bland morphologic characteristic of tumor cells, which may be seen in superficial mucosal biopsies. We emphasized the necessity of obtaining deep mucosal tissue for biopsy to avoid a benign misclassification in these cases.\n\nTABLE 1 Clinical Profile of Reported Cases of Primary Esophageal Extranodal NK/T Cell Lymphoma, Nasal Type\n\nExtranodal NK/T-cell lymphoma is much more prevalent in the Asian population as compared with the overall population.21 Nasal NK/T-cell lymphoma, referring to cases with primary tumor sites locating in the upper airway regions, including the nasal cavity, nasopharynx, paranasal sinuses, tonsils, hypopharynx, and larynx, has been reported to account for 60% to 90% of all extranodal NK/T-cell lymphomas.22,22 Extranasal NK/T-cell lymphoma is defined as the presence of primary tumor at all other sites in the absence of nasal disease, most often arising from the gastrointestinal tract, skin, lungs, or liver.23 Patients with extranasal NK/T-cell lymphoma had more adverse clinical features (eg, a higher stage, elevated LDH, more bulky disease, and poor performance status) and poorer survival rate compared with nasal cases, even in cases with apparently localized disease.23–25 However, there are no significant differences in the immunophenotypic or genotypic profiles between the nasal and extranasal cases.26\n\nThe most common feature of extranasal NK/T-cell lymphoma of gastrointestinal tract detected with endoscopy is an ulceroinfiltrative lesion. However, there are no pathognomonic signs to distinguish lymphoma from other malignancies or benign lesions, including Behçet disease or inflammatory bowel disease. Primary endoscopy detects malignant lesions in approximately 65% of gastrointestinal (GI) tract lymphomas later confirmed by biopsy.26 Endoscopic ultrasonography (EUS) has proven to be much more effective than general endoscopy in detecting GI lymphomas. This method is superior because of its high resolution and its ability to provide more accurate information as to the involvement of the deeper layers of the esophageal wall.27 Lymphomas arising from deep lamina propria or submucosa are beyond the reach of usual endoscopic biopsy, and may lead to misdiagnosis. EUS help reveal the exact location of tumor and guide precise biopsy. If EUS had been performed in this case prior to the first biopsy, it might have helped reveal that the main lesion present deep within the esophageal well and provided guidance to obtain a deeper and larger portion of tissue for biopsy. This may have avoided the initial pathologic misdiagnosis and the necessity for subsequent multiple biopsies. In addition, new endoscopic instruments, including magnifying endoscopy with narrow band images, autofluorescence imaging, and confocal laser endomicroscopy, will help increase diagnostic accuracy in the future.28,29\n\nFor those cases with masses arising from the superficial mucosa, general endoscopy is usually able to obtain diagnostic tissue with rare complications. However, for those tumors arising more deeply, general endoscopy biopsy may fail to get sufficient diagnostic tissue, which may lead to delayed treatment or misdiagnosis. In that case, a repeated biopsy for a deeper and larger portion of tissue is needed to reach an accurate diagnosis. Nevertheless, clinicians may be concerned with performing a deeper biopsy because deeper biopsies increase the risk for hemorrhage or perforation. As a result, a balance between obtaining sufficient tissue for diagnosis while minimizing the risk of iatrogenic complications should be achieved. Gastroenterologists should try to obtain a deeper and larger portion of tissue for accurate diagnosis while attempting to reduce the incidence of complications with close patient monitoring. For these purposes, EUS can aid during the procedure to avoid large blood vessels and damage to serosa during the biopsy procedure.\n\nThere are no significant differences in histopathologic features between nasal NK/T-cell lymphoma and extranasal NK/T-cell lymphoma. Medium to large-size atypical lymphoid cells diffusely infiltrate the tissue and usually demonstrate irregular hyperchromatic nuclei. Angiocentric and angiodestructive growth pattern, coagulative necrosis, and admixed apoptotic bodies are characteristic but not universal features.5 For example, the absence of an angiocentric or angiodestructive pattern is found in approximately 30% cases.25 In addition, the presence of angiocentric/angioinvasive pattern may be dependent on the size of biopsy specimen, with larger specimens more likely to show these findings. In the present case, biphasic morphology was seen in the esophageal biopsy. Scattered bland-appearing neoplastic cells resembling small lymphocytes infiltrated into superficial lamina propria with edema and were not recognizable as tumor cells by H&E staining alone. Immunohistochemical staining and EBER ISH were necessary to highlight the small tumor cells.25 Tumor cells with obviously atypical features were diffusely infiltrated into the deep lamina propria and muscularis mucosae, which were not seen on the initial biopsy. In these circumstances, superficial biopsies may lead to misdiagnosis as chronic inflammation. Diagnosis of esophageal extranasal NK/T-cell lymphoma will be difficult in some cases without a larger and deeper biopsy than that normally taken in routine endoscopy procedures.\n\nThe clinical differential diagnosis for esophageal extranasal NK/T-cell lymphoma includes Behçet disease, Crohn disease, and tuberculosis (TB). Behçet disease is characterized by the triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis. It also involves visceral organs such as the gastrointestinal tract, lung, cardiovascular, and neurological systems. Esophageal involvement was found in 4.7% of cases.30 Endoscopy shows single or multiple punched-out ulcers with well-demarcated edges and relatively flat bottoms. Microscopic features include chronic active inflammation with ulceration.31 Although vasculitis had been listed as one of the diagnostic features, it is rarely found on biopsy. Crohn disease is a chronic relapsing and remitting inflammatory disease with multifocal involvement along the gastrointestinal tract. Esophageal involvement accounts for 6% of Crohn disease,32 characterized by aphthous ulcers, longitudinal ulcers, and strictures. Morphologic features include focal or patchy chronic inflammation and noncaseating granulomas. Esophageal TB is the most common secondary site of TB developed in the lymph node or lung, but it is a rare primary site for TB. Endoscopy of esophageal TB often shows ulceration or infiltrative growth in the lumen.33 However, microscopic features of TB include multiple granulomas, often characterized by their large-sized and coalescent architectural pattern. Caseation necrosis can be found in the center of large granulomas. Mycobacterial organisms can be identified with acid-fast stains.\n\nThe strategy for management of extranodal NK/T-cell lymphoma remains controversial. The current suggestion for management of extranodal NK/T-cell lymphoma is systemic chemotherapy and radiotherapy targeting the involved field if applicable.34 For patients with clinically localized nasal disease, radiotherapy has been regarded of paramount importance because about 70% of patients achieve complete remission after treatment.35–37 However, extranasal disease appears to be less amenable to conventional radiotherapy. Currently, chemotherapy is the primary treatment for patients with systemic disseminated disease. In this regard, CHOP is a very common regimen, but the prognosis is far from satisfactory.38 The 5-year overall survival was around 40% following CHOP regimen in combination with radiotherapy. Moreover, anthracycline-containing chemotherapy has a poor response in extranodal NK/T cell lymphoma. One study showed 71% of patients with extranodal NK/T cell lymphoma failed to achieve remission with CHOP therapy.39 Other nonanthracycline drugs (eg, methotrexate, L-asparaginase) have shown some promising effects on treating relapsed or refractory patients.40,41 Autologous or allogeneic stem cell therapy may provide a survival benefit for patients with extranasal or advance nasal diseases.42,43\n\nCONCLUSION\nPrimary esophageal extranasal NK/T cell lymphoma is extremely rare. We reported a case with unique biphasic morphology. The neoplastic cells present within the superficial mucosa had a bland morphological appearance and resembled small lymphocytes, which in these cases may easily be misdiagnosed as benign. A deeper biopsy is often necessary to reveal the underlying diagnostic morphologic features of this entity.\n\nAcknowledgments\nNone.\n\nAbbreviations: CT = computerized tomography, EUS = endoscopic ultrasonography, GI = gastrointestinal, ISH = in situ hybridization, LDH = lactate dehydrogenase, TB = tuberclosis.\n\nZ-YY, Q-HC, and FL contributed equally to this study and they are co-first authors.\n\nThe authors report no conflicts of interest.\n==== Refs\nREFERENCES\n1. Bardisi ES Alghanmi N Merdad AA \nPrimary mucosa-associated lymphoid tissue lymphoma of the esophagus masquerading as a benign tumor . Ann Med Surg (Lond) \n2014 ; 3 :39 –42 .25568784 \n2. Malik AO Baig Z Ahmed A \nExtremely rare case of primary esophageal mucous associated lymphoid tissue lymphoma . World J Gastrointest Endosc \n2013 ; 5 :446 –449 .24044044 \n3. Kim JH Lee JH Lee J \nPrimary NK-/T-cell lymphoma of the gastrointestinal tract: clinical characteristics and endoscopic findings . Endoscopy \n2007 ; 39 :156 –160 .17657701 \n4. Fujihara S Mori H Kobara H \nEsophageal natural killer (NK)/T cell lymphoma of true natural killer cell origin . Endoscopy \n2014 ; 46 \n(Suppl 1 UCTN) :E77 –E78 .24676825 \n5. World Health Organization , Swerdlow S Campo E Harris NL \nWHO Classification of Tumours of Haematopoietic and Lymphoid Tissue . 4th ed. 2008 .\n6. Orvidas LJ McCaffrey TV Lewis JE \nLymphoma involving the esophagus . Ann Otol Rhinol Laryngol \n1994 ; 103 :843 –848 .7978996 \n7. O’Malley DP Goldstein NS Banks PM \nThe recognition and classification of lymphoproliferative disorders of the gut . Hum Pathol \n2014 ; 45 :899 –916 .24613566 \n8. Kudo K Ota M Narumiya K \nPrimary esophageal mucosa-associated lymphoid tissue lymphoma treated by endoscopic submucosal dissection . Dig Endosc \n2014 ; 26 :478 –481 .23772967 \n9. Hosaka S Nakamura N Akamatsu T \nA case of primary low grade mucosa associated lymphoid tissue (MALT) lymphoma of the oesophagus . Gut \n2002 ; 51 :281 –284 .12117895 \n10. Shim CS Lee JS Kim JO \nA case of primary esophageal B-cell lymphoma of MALT type, presenting as a submucosal tumor . J Korean Med Sci \n2003 ; 18 :120 –124 .12589101 \n11. Kitamoto Y Hasegawa M Ishikawa H \nMucosa-associated lymphoid tissue lymphoma of the esophagus: a case report . J Clin Gastroenterol \n2003 ; 36 :414 –416 .12702984 \n12. Ghimire P Wu GY Zhu L \nPrimary esophageal lymphoma in immunocompetent patients: Two case reports and literature review . World J Radiol \n2010 ; 2 :334 –338 .21160688 \n13. Sabljak P Stojakov D Bjelovic M \nPrimary esophageal diffuse large B-cell lymphoma: report of a case . Surg Today \n2008 ; 38 :647 –650 .18612792 \n14. Chadha KS Hernandez-Ilizaliturri FJ Javle M \nPrimary esophageal lymphoma: case series and review of the literature . Dig Dis Sci \n2006 ; 51 :77 –83 .16416216 \n15. Wagner PL Tam W Lau PY \nPrimary esophageal large T-cell lymphoma mimicking esophageal carcinoma: a case report and literature review . J Thorac Cardiovasc Surg \n2008 ; 135 :957 –958 .958.e1 .18374793 \n16. Fujisawa S Motomura S Fujimaki K \nPrimary esophageal T cell lymphoma . Leuk Lymphoma \n1999 ; 33 :199 –202 .10194139 \n17. Wu N Pang L Chen Z \nPrimary esophageal CD30-positive ALK-positive anaplastic large cell lymphoma: a case report and literature review . J Gastrointest Cancer \n2011 ; 42 :57 –60 .20524084 \n18. Yaakup H Sagap I Fadilah SA \nPrimary oesophageal Ki (CD30)-positive ALK+ anaplastic large cell lymphoma of T-cell phenotype . Singapore Med J \n2008 ; 49 :e289 –e292 .18946602 \n19. Jones K Pacella J Wasty F \nHodgkin's disease of the oesophagus: a literature review . Australas Radiol \n2007 ; 51 :489 –491 .17803804 \n20. Coppens E El NI Nagy N \nPrimary Hodgkin's lymphoma of the esophagus . AJR Am J Roentgenol \n2003 ; 180 :1335 –1337 .12704047 \n21. Lee J Suh C Park YH \nExtranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study . J Clin Oncol \n2006 ; 24 :612 –618 .16380410 \n22. Pagano L Gallamini A Trape G \nNK/T-cell lymphomas ’nasal type’: an Italian multicentric retrospective survey . Ann Oncol \n2006 ; 17 :794 –800 .16497823 \n23. Jo JC Yoon DH Kim S \nClinical features and prognostic model for extranasal NK/T-cell lymphoma . Eur J Haematol \n2012 ; 89 :103 –110 .22553935 \n24. Au WY Weisenburger DD Intragumtornchai T \nClinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project . Blood \n2009 ; 113 :3931 –3937 .19029440 \n25. Li S Feng X Li T \nExtranodal NK/T-cell lymphoma, nasal type: a report of 73 cases at MD Anderson Cancer Center . Am J Surg Pathol \n2013 ; 37 :14 –23 .23232851 \n26. Kim DH Lee D Kim JW \nEndoscopic and clinical analysis of primary T-cell lymphoma of the gastrointestinal tract according to pathological subtype . J Gastroenterol Hepatol \n2014 ; 29 :934 –943 .24325295 \n27. Zhu Q Xu B Xu K \nPrimary non-Hodgkin's lymphoma in the esophagus . J Dig Dis \n2008 ; 9 :241 –244 .18959598 \n28. Hirata I Nakagawa Y Ohkubo M \nUsefulness of magnifying narrow-band imaging endoscopy for the diagnosis of gastric and colorectal lesions . Digestion \n2012 ; 85 :74 –79 .22269282 \n29. Neumann H Kiesslich R Wallace MB \nConfocal laser endomicroscopy: technical advances and clinical applications . Gastroenterology \n2010 ; 139 :388 –392 .392.e1-2. .20561523 \n30. Yi SW Cheon JH Kim JH \nThe prevalence and clinical characteristics of esophageal involvement in patients with Behcet's disease: a single center experience in Korea . J Korean Med Sci \n2009 ; 24 :52 –56 .19270813 \n31. Wolters Kluwer , Riddell R Jain D \nLewin, Weinstein, and Riddell's Gastrointestinal Pathology and Its Clinical Implications . 2nd ed. 2014 .\n32. Lenaerts C Roy CC Vaillancourt M \nHigh incidence of upper gastrointestinal tract involvement in children with Crohn disease . Pediatrics \n1989 ; 83 :777 –781 .2717294 \n33. Park JH Kim SU Sohn JW \nEndoscopic findings and clinical features of esophageal tuberculosis . Scand J Gastroenterol \n2010 ; 45 :1269 –1272 .20568972 \n34. Tse E Kwong YL \nHow I treat NK/T-cell lymphomas . Blood \n2013 ; 121 :4997 –5005 .23652805 \n35. Li YX Yao B Jin J \nRadiotherapy as primary treatment for stage IE and IIE nasal natural killer/T-cell lymphoma . J Clin Oncol \n2006 ; 24 :181 –189 .16382127 \n36. Isobe K Uno T Tamaru J \nExtranodal natural killer/T-cell lymphoma, nasal type: the significance of radiotherapeutic parameters . Cancer \n2006 ; 106 :609 –615 .16369986 \n37. Cheung MM Chan JK Wong KF \nNatural killer cell neoplasms: a distinctive group of highly aggressive lymphomas/leukemias . Semin Hematol \n2003 ; 40 :221 –232 .12876671 \n38. Suzuki R Takeuchi K Ohshima K \nExtranodal NK/T-cell lymphoma: diagnosis and treatment cues . Hematol Oncol \n2008 ; 26 :66 –72 .18283711 \n39. Yong W Zheng W Zhu J \nMidline NK/T-cell lymphoma nasal-type: treatment outcome, the effect of L-asparaginase based regimen, and prognostic factors . Hematol Oncol \n2006 ; 24 :28 –32 .16323259 \n40. Yong W Zheng W Zhang Y \nL-asparaginase-based regimen in the treatment of refractory midline nasal/nasal-type T/NK-cell lymphoma . Int J Hematol \n2003 ; 78 :163 –167 .12953813 \n41. Yamaguchi M Suzuki R Kwong YL \nPhase I study of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy for advanced-stage, relapsed or refractory extranodal natural killer (NK)/T-cell lymphoma and leukemia . Cancer Sci \n2008 ; 99 :1016 –1020 .18294294 \n42. Kim HJ Bang SM Lee J \nHigh-dose chemotherapy with autologous stem cell transplantation in extranodal NK/T-cell lymphoma: a retrospective comparison with non-transplantation cases . Bone Marrow Transplant \n2006 ; 37 :819 –824 .16547486 \n43. Murashige N Kami M Kishi Y \nAllogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms . Br J Haematol \n2005 ; 130 :561 –567 .16098071\n\n",
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"title": "Primary Esophageal Extranasal NK/T Cell Lymphoma With Biphasic Morphology: A Case Report and Literature Review.",
"title_normalized": "primary esophageal extranasal nk t cell lymphoma with biphasic morphology a case report and literature review"
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"abstract": "We present a 76-year old man who developed papulopustular rosacea after receiving nivolumab treatment for his esophageal carcinoma, metastatic to the lungs. Nivolumab is an emerging cancer therapy whose immune-related adverse events are still not fully recognized and likely underreported. The treatment has been reported to cause a myriad of cutaneous immune-related adverse events. However, nivolumab-induced-papulopustular rosacea has been scarcely reported. Thus, this case presents a clinically important finding that physicians should be aware of when seeing patients on nivolumab therapy.",
"affiliations": "Pacific Skin Institute, Sacramento, CA Zen Dermatology, Sacramento, CA Department of Dermatology, University of California Davis, Sacramento, CA College of Medicine, California Northstate University, Sacramento, CA Department of Biological Sciences, California State University, Sacramento, CA. raja.sivamani.md@gmail.com.",
"authors": "Gahoonia|Nimrit K|NK|;Carrington|Alexis E|AE|;Chambers|Cindy J|CJ|;Sivamani|Raja K|RK|",
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"pubdate": "2021-09-15",
"publication_types": "D016428:Journal Article",
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"title": "Papulopustular rosacea during nivolumab therapy of metastatic squamous cell esophageal carcinoma.",
"title_normalized": "papulopustular rosacea during nivolumab therapy of metastatic squamous cell esophageal carcinoma"
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"abstract": "Intracranial hypertension (idiopathic-IIH and secondary) is a potentially treatable condition. Although various factors such as female gender and obesity, certain drugs have been implicated as risk factors for IIH, there remains a lack of clarity in the exact causal-effect relationship. In India, self-medication by obtaining drugs over the counter due to lack of adequate drug regulation and ignorance of the public is a very common practice with a potential for severe adverse effects. We present a case of a young lady who has developed intracranial hypertension possibly due to self-medication with steroids and cyproheptadine, obtained over the counter.",
"affiliations": "Advanced Neurosciences Institute, BGS Global Hospital, Bangalore, Karnataka, India.;Advanced Neurosciences Institute, BGS Global Hospital, Bangalore, Karnataka, India.;Advanced Neurosciences Institute, BGS Global Hospital, Bangalore, Karnataka, India.;Advanced Neurosciences Institute, BGS Global Hospital, Bangalore, Karnataka, India.;Advanced Neurosciences Institute, BGS Global Hospital, Bangalore, Karnataka, India.",
"authors": "Ramana Reddy|A M|AM|;Prashanth|L K|LK|;Sharat Kumar|G G|GG|;Chandana|G|G|;Jadav|Rakesh|R|",
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"doi": "10.4103/0976-3147.139991",
"fulltext": "\n==== Front\nJ Neurosci Rural PractJ Neurosci Rural PractJNRPJournal of Neurosciences in Rural Practice0976-31470976-3155Medknow Publications & Media Pvt Ltd India JNRP-5-38410.4103/0976-3147.139991Case ReportOver-the-counter self-medication leading to intracranial hypertension in a young lady Ramana Reddy A. M. Prashanth L. K. Sharat Kumar G. G. Chandana G. Jadav Rakesh Advanced Neurosciences Institute, BGS Global Hospital, Bangalore, Karnataka, IndiaAddress for correspondence: Dr. A. M. Ramana Reddy, Consultant Neurologist, BGS Global Hospital, 67, Uttarahalli Road, Kengeri, Bangalore - 560 060, Karnataka, India. E-mail: drramana_am@yahoo.comOct-Dec 2014 5 4 384 386 Copyright: © Journal of Neurosciences in Rural Practice2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Intracranial hypertension (idiopathic-IIH and secondary) is a potentially treatable condition. Although various factors such as female gender and obesity, certain drugs have been implicated as risk factors for IIH, there remains a lack of clarity in the exact causal–effect relationship. In India, self-medication by obtaining drugs over the counter due to lack of adequate drug regulation and ignorance of the public is a very common practice with a potential for severe adverse effects. We present a case of a young lady who has developed intracranial hypertension possibly due to self-medication with steroids and cyproheptadine, obtained over the counter.\n\nCyproheptadinedexamethasoneidiopathic intracranial hypertension (IIH)intracranial hypertensionsteroid withdrawal\n==== Body\nIntroduction\nHeadache is the one of the most common complaint in the neurology outpatient practice. Headache presenting with red flags like persistent vomiting, diplopia, blurring of vision, etc should raise suspicion of serious secondary causes of headache like raised intracranial pressure (ICP) prompting appropriate investigations. Idiopathic intracranial hypertension (IIH) is one such cause of raised ICP. The identification of IIH and work up for secondary causes of IIH will hep in deciding the most appropriate treatment for the patient. We present one such case of IIH with a rather surprising cause.\n\nCase Report\nA 26-year-old lady presented with chief complaint of headache of 4 months duration. It was off and on initially and then became continuous with increase in severity. One week, prior to presentation, the headache worsened in severity associated with transient blurring of vision. She had no other focal neurological or systemic symptoms. Past history revealed consuming dexamethasone (0.5 mg/day) and cyproheptadine (4 mg/day) tablets for intentional weight gain, obtained over the counter without any prescription. She used the tablets for a period of 1 year and stopped abruptly 6 months back. However, she has not developed any acute symptoms of steroid withdrawal. The headache had started around 2 months after she stopped the medications.\n\nAt the time of evaluation, she weighed 53 kg. Her height was 143 cm, body mass index (BMI) was 25.9 (18.5-25: Normal; 25-29.9: Overweight; >30: Obese). Her ideal body weight (Devine formula) was 45.9 kg.[1] Her blood pressure was 110/80 mmHg. Rest of the systemic examination was unremarkable. Examination revealed visual acuity of 6/6 in both eyes with normal intraocular pressure. Fundus showed bilateral optic disc edema with splinter hemorrhage in the left eye [Figure 1]. There were no cotton wool spots/macular edema. Visual field charting by Humphrey perimeter showed enlarged blind spot bilaterally with superior and inferior areas of depression in the right eye. Rest of the neurological examination was normal. In view of the gradually progressive headache and bilateral optic disc edema, raised intracranial pressure was considered and evaluated for the same.\n\nFigure 1 (a) Right fundus showing papilledema, (b) left fundus showing papilledema with splinter hemorrhage, (c) right eye showing enlargement of blind spot with superior and inferior areas of depression, (d) left eye enlargement of blind spot\n\nComplete blood counts, erythrocyte sedimentation rate, blood sugar, renal and liver function tests, serum electrolytes, HIV, Venereal disease research laboratory test (VDRL), thyroid function tests were within normal limits. Brain magnetic resonance imaging (MRI) showed tortuosity of the bilateral optic nerves with prominence of the subarachnoid space around the optic nerves, flattening of the posterior sclera, partial empty sella [Figure 2]. There was no intracranial mass lesion. The lateral ventricles were small and symmetrical. MR venography did not show any occlusion/thrombosis. After brain MRI, diagnosis of idiopathic intracranial hypertension was considered. Lumbar puncture revealed a high opening pressure of 280 mm H2O and normal cerebrospinal fluid (CSF) (clear, colorless, white blood cell count 2, red blood cell 0, protein 14.5 mg/dL, glucose 76 mg/dL, chloride 114 meq/dL, India ink-negative). Following drainage of 20 mL of CSF, there was a significant reduction in the severity of headache lasting 2-3 days. A diagnosis of intracranial hypertension was made based on modified Dandy criteria.[2] She was started on acetazolamide 250 mg TID and advised 5%-10% weight loss. She has attained a weight loss of 8 kg (15%) over 6 months by dietary control and is completely asymptomatic now. Patient's prior approval was obtained for academic publication.\n\nFigure 2 (a) T2-axial brain showing tortuosity of bilateral optic nerves along with prominent optic nerve sheath, (b) T2-coronal brain showing enlarged subarachnoid space around the optic nerve, (c) T1 sagittal showing empty sella\n\nDiscussion\nQuinke first described the syndrome of increased intracranial pressure without ventriculomegaly or mass lesion in 1893.[3] The earlier terms such as pseudotumorcerebri, benign intracranial hypertension have now been abandoned. The nomenclature, pathophysiology, clinical features, diagnostic criteria, and investigations have been extensively reviewed elsewhere and briefly discussed here.[2456789] The current favored nomenclature for “idiopathic” variety is idiopathic intracranial hypertension (IIH) and cases with an identifiable cause are labeled as “Intracranial hypertension secondary to (cause)”.[2] Although the disease can occur in all ages and both sexes, young obese women of childbearing age is the typical patient for IIH.[2] The role of obesity in Asian population in causing IIH has been debated recently.[10] Young nonobese women (BMI < 30) have also a risk of developing IIH if there is a 5%-15% recent weight gain.[11] Patients with intracranial hypertension present with headache, visual symptoms, nausea, vomiting, tinnitus and evidence of papilledema, constricted fields, or sixth nerve palsy on examination.[4] Progressive permanent vision loss is the dreaded complication of IIH.[2412] Although various medications such as vitamin A over dosage, tetracyclines, and sudden withdrawal of steroids have been described to trigger intracranial hypertension, a consistent relationship is only seen with tetracyclines.[489131415] Cyproheptadine has not been reported to cause intracranial hypertension. Its contribution in our case is debated. The MRI features of IIH include “empty sella,” slit-like ventricles, posterior globe flattening, intraocular protrusion, optic nerve sheath enlargement, optic nerve tortuosity, and transverse sinus narrowing.[6] The treatment of IIH begins with a lumbar puncture followed by weight loss and medical management, acetazolamide being the most commonly used drug.[25] Weight loss of 5%-10% is a critical part of treatment of IIH.[51617] Other therapeutic options include venous sinus stenting, CSF diversion procedures, and surgery.[1218]\n\nIn spite of the presence of all the above risk factors in our patient, their individual contribution to the clinical picture is not clear. Our patient had a borderline BMI of 25.9 (normal 18.5-24.9) and weighed 2.1 kg more than her ideal body weight. She had a weight gain of 10.4% over 1 year. Patients with this body profile are seen very often in general population, but rarely have IIH. What had caused IIH-like picture in our patient? Although the role of various mechanisms contributing to the development of IIH is debated, the most likely causative factor in this case is the recent weight gain in a young female of childbearing age. The individual contribution of cyproheptadine, prolonged steroid usage, and abrupt withdrawal remains rather unclear at this time.\n\nThis case raises two important concerns. There is still lack of clarity in the causal-effect relationship in IIH with reference to the role of obesity, weight gain, steroid usage, steroid withdrawal, and their individual contribution to the causation of IIH, which needs to be studied.\n\nAnother concern of utmost public health importance is the practice of self-medication and unregulated drug dispensing by the pharmacies. Self-medication is a very fairly common practice in India owing its roots to prevailing socioeconomic and cultural factors. However, the knowledge about the harmful effects of self-medication is very limited. The easy availability of potentially toxic drugs such as steroids over the counter is really alarming. Doctors and hospitals should educate the patients about harmful effects of self-medication. Effective use of mass media should be done to take the message to the masses. Drug regulatory authorities should strictly enforce laws pertaining to drug dispensing. Multipronged approach utilizing the media, government organizations, nongovernment organizations, doctors, pharmaceutical industry targeting the general population, as well as the pharmacy distributors should be used to increase the awareness about harmful effects of self-medication and control unregulated drug dispensing.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Pai MP Paloucek FP The origin of the “ideal” body weight equations Ann Pharmacother 2000 34 1066 9 10981254 \n2 Friedman DI Jacobson DM Idiopathic intracranial hypertension J Neuroophthalmol 2004 24 138 45 15179068 \n3 Grant DN Benign intracranial hypertension. A review of 79 cases in infancy and childhood Arch Dis Child 1971 46 651 5 5315767 \n4 Ball AK Clarke CE Idiopathic intracranial hypertension Lancet Neurol 2006 5 433 42 16632314 \n5 Biousse V Bruce BB Newman NJ Update on the pathophysiology and management of idiopathic intracranial hypertension J Neurol Neurosurg Psychiatry 2012 83 488 94 22423118 \n6 Degnan AJ Levy LM Pseudotumor cerebri: Brief review of clinical syndrome and imaging findings AJNR Am J Neuroradiol 2011 32 1986 93 21680652 \n7 Friedman DI Jacobson DM Diagnostic criteria for idiopathic intracranial hypertension Neurology 2002 59 1492 5 12455560 \n8 Friedman DI Medication-induced intracranial hypertension in dermatology Am J Clin Dermatol 2005 6 29 37 15675888 \n9 Wall M Idiopathic intracranial hypertension Neurol Clin 2010 28 593 617 20637991 \n10 Kim TW Choung HK Khwarg SI Hwang JM Yang HJ Obesity may not be a risk factor for idiopathic intracranial hypertension in Asians Eur J Neurol 2008 15 876 9 18684312 \n11 Daniels AB Liu GT Volpe NJ Galetta SL Moster ML Newman NJ Profiles of obesity, weight gain, and quality of life in idiopathic intracranial hypertension (pseudotumor cerebri) Am J Ophthalmol 2007 143 635 41 17386271 \n12 Thambisetty M Lavin PJ Newman NJ Biousse V Fulminant idiopathic intracranial hypertension Neurology 2007 68 229 32 17224579 \n13 Ang ER Zimmerman JC Malkin E Pseudotumor cerebri secondary to minocycline intake J Am Board Fam Pract 2002 15 229 33 12038730 \n14 Chiu AM Chuenkongkaew WL Cornblath WT Trobe JD Digre KB Dotan SA Minocycline treatment and pseudotumor cerebri syndrome Am J Ophthalmol 1998 126 116 21 9683157 \n15 Kesler A Goldhammer Y Hadayer A Pianka P The outcome of pseudotumor cerebri induced by tetracycline therapy Acta Neurol Scand 2004 110 408 11 15527455 \n16 Ko MW Idiopathic intracranial hypertension Curr Treat Options Neurol 2011 13 101 8 21063921 \n17 Wong R Madill SA Pandey P Riordan-Eva P Idiopathic intracranial hypertension: The association between weight loss and the requirement for systemic treatment BMC Ophthalmol 2007 7 15 17888152 \n18 Higgins JN Cousins C Owler BK Sarkies N Pickard JD Idiopathic intracranial hypertension: 12 cases treated by venous sinus stenting J Neurol Neurosurg Psychiatry 2003 74 1662 6 14638886\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0976-3155",
"issue": "5(4)",
"journal": "Journal of neurosciences in rural practice",
"keywords": "Cyproheptadine; dexamethasone; idiopathic intracranial hypertension (IIH); intracranial hypertension; steroid withdrawal",
"medline_ta": "J Neurosci Rural Pract",
"mesh_terms": null,
"nlm_unique_id": "101533710",
"other_id": null,
"pages": "384-6",
"pmc": null,
"pmid": "25288841",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports",
"references": "10981254;15527455;18684312;12455560;20637991;16632314;12038730;21063921;22423118;14638886;21680652;17224579;9683157;15179068;17386271;15675888;17888152;5315767",
"title": "Over-the-counter self-medication leading to intracranial hypertension in a young lady.",
"title_normalized": "over the counter self medication leading to intracranial hypertension in a young lady"
} | [
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"companynumb": "PHHY2014IN127533",
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"abstract": "A 56-year-old lady was admitted with complaint of involuntary muscle twitching around the eyes, face and neck for two days. She had a history of low grade non-hodgkin lymphoma with completion of the first cycle of chemotherapy. Her medication on presenting consisted of Ondansetron 8 mg two times a day and Metoclopramide 10 mg three times a day (TDS). She started taking these medications 24 hours before having the above symptoms. She was clinically diagnosed with acute dystonic reactions and was also secondarily treated with anti-emetic medications. She was given IV procyclidine 10 mg stat followed by per oral (PO) procyclidine 2.5 mg TDS. Within an hour of administering IV procyclidine her symptoms began to gradually settle down. Acute dystonic reactions are not a very rare clinical presentation in the daily practice. The above case is a good example for the clinicians dealing with acute medical admissions.",
"affiliations": "Royal Shrewsbury Hospital, Shrewsbury, SY3 8XQ UK. drmoeoo@gmail.com",
"authors": "Oo|Moe Thaw|MT|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1757-1626-2-186",
"fulltext": "\n==== Front\nCases JCases Journal1757-1626BioMed Central 1757-1626-2-1861994649610.1186/1757-1626-2-186Case ReportAcute dystonic reactions in a lady presenting with repetitive involuntary muscle twitching: a case report Oo Moe Thaw 1drmoeoo@gmail.com1 Specialist Registrar, Geriatric and Stroke Medicine, Royal Shrewsbury Hospital, Shrewsbury, SY3 8XQ UK2009 9 11 2009 2 186 186 23 10 2009 9 11 2009 Copyright ©2009 Oo; licensee BioMed Central Ltd.2009Oo; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 56-year-old lady was admitted with complaint of involuntary muscle twitching around the eyes, face and neck for two days. She had a history of low grade non-hodgkin lymphoma with completion of the first cycle of chemotherapy. Her medication on presenting consisted of Ondansetron 8 mg two times a day and Metoclopramide 10 mg three times a day (TDS). She started taking these medications 24 hours before having the above symptoms. She was clinically diagnosed with acute dystonic reactions and was also secondarily treated with anti-emetic medications. She was given IV procyclidine 10 mg stat followed by per oral (PO) procyclidine 2.5 mg TDS. Within an hour of administering IV procyclidine her symptoms began to gradually settle down.\n\nAcute dystonic reactions are not a very rare clinical presentation in the daily practice. The above case is a good example for the clinicians dealing with acute medical admissions.\n==== Body\nCase presentation\nA 56 year old lady was admitted with complaint of involuntary muscle twitching around eyes, face and neck. She presented with acute onset of repetitive muscle twitch and nausea within 48 hours after completing the first cycle of chemotherapy for low grade non-hodgkin lymphoma. She was taking Ondansetron 8 mg BD and Metoclopramide 10 mg TDS. She started taking these medications 24 hours prior to appearance of above symptoms.\n\nOn admission she was anxious and worried for having stroke or seizures. There was no history suggestive of similar symptoms in past. No other significant medical illness was also noted.\n\nPhysical examination revealed transient non-specific facial muscles twitchings. Rest of the general and systemic examination was unremarkable. All baseline blood tests results (Full Blood Count, Urea and Electrolytes, Liver Function Tests), CXR and ECG findings were normal. She was clinically diagnosed as acute dystonic reactions secondary to anti-emetic medications. All the medications were discontinued and she was treated with IV procyclidine 10 mg stat followed by PO procyclidine 2.5 mg TDS. She was also commenced on PO domperidone 10 mg PRN/QDS for her nauseous feelings. Within an hour of receiving IV procyclidine her symptoms gradually improved and disappeared. She was discharged with complete recovery within 24 hour hospital admission.\n\nDiscussion\nAcute dystonic reactions have different manifestations (Table 1)). These reactions are usually occured as a side effect of neuroleptic and anti-emetic medications. The clinical spectrum is poorly understood and frequently led to misdiagnosis.\n\nCauses or triggering factors include: neuroleptics, amantadine, benzodiazepines, carbamazepine, chloroquine, cisplatin, diazoxide, influenza vaccine, levodopa, lithium, metoclopramide, nifedipine, pemoline, phencyclidine, reserpine, tricyclics, postencephalitic Parkinson's, Tourette's syndrome, multiple sclerosis, neurosyphilis, head trauma, bilateral thalamic infarction, lesions of the fourth ventricle, cystic glioma of the 3rd ventricle, herpes encephalitis, juvenile Parkinson's. It is often not realized that in addition to the acute presentation, it can develop as a recurrent syndrome, triggered by stress, and exposure to the above drugs [1].\n\nTable 1 Manifestations of acute dystonia [2]\n\nOcculogyric crisis (OGC)\tSpasm of extraorbital muscles, facial muscles, involvement of upward and outward deviation of eyes\t\nTorticollis\tHead held turn to one side\t\n\t\nOpisthotonus\tPainful forced extension of the neck\t\n\t\nMacroglossia\tProtrusion of tongue and seemed to be swollen\t\n\t\nBuccolingual crisis\tTrismus, Dysarthria and Grimacing\t\n\t\nLaryngospasm\tUncommon but frightening\t\n\t\nSpasticity\tTrunk muscles and less commonly limbs can be affected\t\nTransient ischaemic attacks (TIA), focal seizures or other involuntary muscle tics and spasms should be considered in differential diagnosis. The detailed history taking and thorough neurology examination help in reaching the correct diagnosis. Imaging studies of brain should be conducted to exclude other intracranial pathology and structural abnormalities leading to the above mentioned manifestations, especially if these symptoms persist.\n\nTreatment in the acute phase of dystonic reactions involves reassurance and treatment with Procyclidine and/or Benztropine and/or Diazepam or lorazepam. Maintenance therapy with oral forms of the above medications or amantadine are indicated in more chronic recurrent cases [1].\n\nConclusion\nIt is a distressing complication of antiemtic and antipsychotic drugs. In the acute clinical settings these unpleasant symptoms can make the patients anxious and the diagnosis can be confused with other acute medical conditions such as transient ischaemic attacks. The prompt therapeutic action is essential in its management. It is not a very rare case in the daily practice. The above case is a good example for physicians dealing with acute medical admissions during on-calls.\n\nList of abbreviations\nBD: Two times a day; CXR: Chest X'Ray; ECG: Electrocardiogram; IV: Intravenous injection; PO: Per oral; PRN: As required; QDS: Four times a day; TDS: Three times a day.\n\nCompeting interests\nThe author declares that they have no competing interests.\n\nAuthors' contributions\nMTO is the only one and main author. No other author was contributed in this report.\n\nConsent\nThe valid informed consent was taken from the patient for this case report and publication.\n==== Refs\nThe Canadian Movement Disorder Group http://www.cmdg.org/Movement_/drug/Oculogyric_Crisis/oculogyric_crisis.htm\nAustralian Prescriber; the management of acute dystonic reactions by Diane Campbell, Emergency Physician, Emergency Department, Bendigo Hospital, Bendigo, Victoria Aust Prescr 2001 24 19 20\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1757-1626",
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"keywords": null,
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"nlm_unique_id": "101474272",
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"pages": "186",
"pmc": null,
"pmid": "19946496",
"pubdate": "2009-11-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute dystonic reactions in a lady presenting with repetitive involuntary muscle twitching: a case report.",
"title_normalized": "acute dystonic reactions in a lady presenting with repetitive involuntary muscle twitching a case report"
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"companynumb": "GB-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-111128",
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"activesubstancename": "METOCLOPRAMIDE"
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"... |
{
"abstract": "We report a very unusual case of a composite high-grade glioma and rhabdoid tumor in an adult. A 22-year-old woman presented with scintillating scotoma due to a solid tumor with surrounding brain edema in the right occipital lobe. The tumor was grossly resected. Histological examinations showed that the tumor was mainly composed of INI1-positive high-grade glioma tissue containing an INI1-negative rhabdoid component. She received radiation therapy and chemotherapy. Three months after the surgery, she again complained of visual disturbances, and tumor recurrence within the resection cavity was noted. A second operation was performed. The findings of histological examinations of the surgical specimen obtained during the second surgery were completely different from those of the specimen obtained during the initial surgery. Only the rhabdoid component showed remarkable proliferation and did not express INI1. Diffuse dissemination along the craniospinal axis eventually progressed, and she died 5 months after the initial diagnosis. We suggest that the inactivation of the INI1 gene affects potent proliferation activity and resistance to both chemotherapy and radiation therapy.",
"affiliations": "Department of Neurosurgery, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Fukuoka, Japan. yama9218@med.uoeh-u.ac.jp",
"authors": "Yamamoto|Junkoh|J|;Takahashi|Mayu|M|;Nakano|Yoshiteru|Y|;Soejima|Yoshiteru|Y|;Saito|Takeshi|T|;Akiba|Daisuke|D|;Hirato|Junko|J|;Nakazato|Yoichi|Y|;Nishizawa|Shigeru|S|",
"chemical_list": "D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10014-011-0069-6",
"fulltext": null,
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"issn_linking": "1433-7398",
"issue": "29(2)",
"journal": "Brain tumor pathology",
"keywords": null,
"medline_ta": "Brain Tumor Pathol",
"mesh_terms": "D014408:Biomarkers, Tumor; D001932:Brain Neoplasms; D059248:Chemoradiotherapy; D002868:Chromosomal Proteins, Non-Histone; D003131:Combined Modality Therapy; D004268:DNA-Binding Proteins; D017809:Fatal Outcome; D005260:Female; D005910:Glioma; D006801:Humans; D007150:Immunohistochemistry; D009364:Neoplasm Recurrence, Local; D018193:Neoplasms, Complex and Mixed; D019635:Neurosurgical Procedures; D009778:Occipital Lobe; D018335:Rhabdoid Tumor; D000071796:SMARCB1 Protein; D014157:Transcription Factors; D055815:Young Adult",
"nlm_unique_id": "9716507",
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"pages": "113-20",
"pmc": null,
"pmid": "22045501",
"pubdate": "2012-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rapid progression of rhabdoid components of a composite high-grade glioma and rhabdoid tumor in the occipital lobe of an adult.",
"title_normalized": "rapid progression of rhabdoid components of a composite high grade glioma and rhabdoid tumor in the occipital lobe of an adult"
} | [
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"companynumb": "JP-MYLANLABS-2018M1008969",
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"activesubstancename": "RANIMUSTINE"
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{
"abstract": "A 46-year-old man with a history of ulcerative colitis (UC) for over 25 years was treated with infliximab for 7 years. He noticed gradually spreading erythema on his right lower abdomen, femur, and buttocks. Skin biopsy from the right lower abdomen revealed massive invasion of lymphocytes in the papillary dermis and epidermal layer. In conjunction with the findings of immunohistochemistry, the skin lesion was diagnosed as mycosis fungoides (MF) at infiltration stage. Infliximab was discontinued, and narrow-band ultraviolet light B therapy was initiated to treat the skin lesion. The patient achieved remission for MF following treatment and UC has not relapsed for more than 1 year with 5-aminosalicylic acid treatment alone. This is the first case of MF in a UC patient treated with anti-tumor necrosis factor-alpha (anti-TNFα). Lymphoma occurrence is a complication of treatment with anti-TNFα agent or thiopurine. However, there is no evidence regarding the relationship between MF and UC. Hence, these immunomodulatory agents may have triggered the occurrence of MF in this case. When treating UC patients with immunomodulatory agents, the possibility of MF or other types of lymphoma as rare complications must be considered.",
"affiliations": "Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.;Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. takatomo@koto.kpu-m.ac.jp.;Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Surgical Pathology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Surgical Pathology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.;Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.;Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.",
"authors": "Yasuda|Takeshi|T|;Takagi|Tomohisa|T|;Asai|Jun|J|;Katoh|Norito|N|;Kuroda|Junya|J|;Kuwahara|Yasumichi|Y|;Morinaga|Yukiko|Y|;Konishi|Eiichi|E|;Uchiyama|Kazuhiko|K|;Naito|Yuji|Y|;Itoh|Yoshito|Y|",
"chemical_list": "D000069285:Infliximab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-020-01277-3",
"fulltext": null,
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"issn_linking": "1865-7265",
"issue": "14(1)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Anti TNFα agent; Mycosis fungoides; Thiopurine; Ulcerative colitis",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D003093:Colitis, Ulcerative; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides; D012867:Skin; D012878:Skin Neoplasms",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "170-175",
"pmc": null,
"pmid": "33219936",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "31542070",
"title": "Mycosis fungoides in a patient with ulcerative colitis on anti-tumor necrosis factor-alpha therapy.",
"title_normalized": "mycosis fungoides in a patient with ulcerative colitis on anti tumor necrosis factor alpha therapy"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1892935",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "3",
... |
{
"abstract": "Denosumab is a monoclonal antibody commonly used for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Hypocalcemia is a known adverse effect with denosumab, and we present an unusual case where 2 hypocalcemic events occurred after 1 denosumab treatment.\nA 76-year-old man recently diagnosed with prostate cancer with bone metastasis was given 120 mg denosumab subcutaneously due to extensive bone disease.\nThe patient experienced denosumab-induced hypocalcemia induced by a single denosumab dose which was resolved after 14 days of multiple doses of intravenous calcium gluconate and oral calcium and vitamin D replacement. However, the patient returned with acute kidney injury and severe hypocalcemia (corrected calcium of 6.9 mg/dL) without any additional dose of denosumab. The recovery following the second episode of hypocalcemia was much longer than the initial episode in this patient.\nTo our knowledge, this is the first reported case of an additional episode of hypocalcemia following a single denosumab dose. This case highlights the importance of close monitoring of renal function and serum electrolytes following the resolution of denosumab-induced hypocalcemia.",
"affiliations": null,
"authors": "McCaleb|Rachael V|RV|;Johnson|Jill T|JT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/ACCR-2018-0295",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2376-0605",
"issue": "5(1)",
"journal": "AACE clinical case reports",
"keywords": null,
"medline_ta": "AACE Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101670593",
"other_id": null,
"pages": "e82-e85",
"pmc": null,
"pmid": "31967007",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "26181529;25559408;23745518;26093811;20108337;23265605;25054070;26830549;20704155;22898302;18045781;24237647;25182228;22975218;29123990",
"title": "SEVERE, PROLONGED, DENOSUMAB-INDUCED HYPOCALCEMIA WITH RECOVERY AFTER 111 DAYS OF HIGH-DOSE CALCIUM SUPPLEMENTATION.",
"title_normalized": "severe prolonged denosumab induced hypocalcemia with recovery after 111 days of high dose calcium supplementation"
} | [
{
"companynumb": "US-AMGEN-USASP2020016143",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A 67-year-old woman with hypertension, hypothyroidism, and glaucoma was referred for jaundice and elevated liver function tests. She was treated for streptococcal endophthalmitis with 2 weeks of intravenous (IV) levofloxacin followed by 2 months of oral levofloxacin. The patient had no prior history of liver disease and denied alcohol intake. Her physical exam was remarkable for jaundice and scleral icterus without any stigmata of liver disease. Viral hepatitis serologies and antibodies, including myeloperoxidase, proteinase 3, and antinuclear, antimitochondrial, antiliver kidney microsome, antismooth muscle antibodies, were all within normal limits. The liver biopsy revealed severe cholestasis, extensive bile duct loss, and fibrosis. The patient had no known exposure to any other systemic medications or inciting factors other than levofloxacin. Although there are a few reported cases of drug-induced liver disease (DILI) related to levofloxacin, this case is believed to be the first reported case of ductopenia or vanishing bile duct syndrome (VBDS) associated with levofloxacin. Although fluoroquinolones, such as levofloxacin, are generally considered safe antibiotics, health practitioners must be aware of their association with DILI, as the diagnosis of DILI is one of exclusion and requires a high index of suspicion.",
"affiliations": "Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.;The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.;The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.",
"authors": "Levine|Calley|C|;Trivedi|Anshu|A|;Thung|Swan N|SN|;Perumalswami|Ponni V|PV|",
"chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0034-1375964",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-8087",
"issue": "34(2)",
"journal": "Seminars in liver disease",
"keywords": null,
"medline_ta": "Semin Liver Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001652:Bile Ducts; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D005260:Female; D006801:Humans; D064704:Levofloxacin; D008103:Liver Cirrhosis",
"nlm_unique_id": "8110297",
"other_id": null,
"pages": "246-51",
"pmc": null,
"pmid": "24879988",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Severe ductopenia and cholestasis from levofloxacin drug-induced liver injury: a case report and review.",
"title_normalized": "severe ductopenia and cholestasis from levofloxacin drug induced liver injury a case report and review"
} | [
{
"companynumb": "US-ACTAVIS-2015-07124",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by acute thunderclap headache, evidence of vasoconstriction in conventional angiography or magnetic resonance angiography and reversibility of these phenomena within 12 weeks. Some triggering factors, for example drugs such as selective serotonin reuptake inhibitors, sumatriptan, tacrolimus, cyclophosphamide and cocaine, or states such as pregnancy, puerperium or migraine have been described. We describe the case of a 29-year-old woman with RCVS associated with fingolimod three months after childbirth. This case represents the first report of RCVS in fingolimod treatment.",
"affiliations": "Department of Neurology, Alfried Krupp Hospital, Essen, Germany markus.kraemer@krupp-krankenhaus.de.;Department of Neurology, Alfried Krupp Hospital, Essen, Germany.;Department of Neurology, Alfried Krupp Hospital, Essen, Germany.;Department of Neurology, Alfried Krupp Hospital, Essen, Germany.",
"authors": "Kraemer|Markus|M|;Weber|Ralph|R|;Herold|Michèle|M|;Berlit|Peter|P|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "England",
"delete": false,
"doi": "10.1177/1352458515600249",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "21(11)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Reversible cerebral vasoconstriction syndrome; fingolimod; trigger",
"medline_ta": "Mult Scler",
"mesh_terms": "D000328:Adult; D002561:Cerebrovascular Disorders; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D020529:Multiple Sclerosis, Relapsing-Remitting; D036801:Parturition; D011247:Pregnancy; D013577:Syndrome; D014661:Vasoconstriction",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "1473-5",
"pmc": null,
"pmid": "26283695",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible cerebral vasoconstriction syndrome associated with fingolimod treatment in relapsing-remitting multiple sclerosis three months after childbirth.",
"title_normalized": "reversible cerebral vasoconstriction syndrome associated with fingolimod treatment in relapsing remitting multiple sclerosis three months after childbirth"
} | [
{
"companynumb": "DE-DRREDDYS-GER/GER/19/0116722",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FINGOLIMOD HYDROCHLORIDE"
},
"drugadditi... |
{
"abstract": "Sustained benzodiazepine use during pregnancy can induce neonatal abstinence syndrome (NAS). In this study, the association between NAS and plasma alprazolam concentration was examined using the measured neonatal concentrations in the time series as well as simulated plasma concentrations of pregnant woman and neonate by physiologically based pharmacokinetic (PBPK) modeling. A neonate born to a mother taking alprazolam daily throughout pregnancy exhibited symptoms such as apnea and vomiting from 9 h to 4 days after birth. Finnegan score was 7 at birth and decreased to 0 by day 4. Apnea improved by 24 h post-delivery and gastrointestinal symptoms disappeared by day 4. The plasma alprazolam concentration in the neonate was 15.2 ng/mL immediately after birth and gradually decreased over 3 days. Measured neonate and estimated maternal plasma alprazolam concentrations were within the 90% prediction intervals of each concentration by PBPK simulation using \"pregnancy\" and \"pediatrics\" population parameters including in Simcyp population-based ADME simulator. In conclusion, NAS symptoms such as apnea and digestive events disappeared in parallel with the decrease of the neonate's plasma alprazolam concentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data.",
"affiliations": "Department of Pharmacy, Kobe University Hospital, Kobe, Japan. Electronic address: yamakz@med.kobe-u.ac.jp.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Pharmacy, Kobe University Hospital, Kobe, Japan.;Department of Pharmacy, Kobe University Hospital, Kobe, Japan.;Department of Pharmacy, Kobe University Hospital, Kobe, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.;Department of Pharmacy, Kobe University Hospital, Kobe, Japan.",
"authors": "Yamamoto|Kazuhiro|K|;Fukushima|Sachiyo|S|;Mishima|Yui|Y|;Hashimoto|Mari|M|;Yamakawa|Kei|K|;Fujioka|Kazumichi|K|;Iijima|Kazumoto|K|;Yano|Ikuko|I|",
"chemical_list": "D006993:Hypnotics and Sedatives; D000525:Alprazolam",
"country": "England",
"delete": false,
"doi": "10.1016/j.dmpk.2019.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1347-4367",
"issue": "34(6)",
"journal": "Drug metabolism and pharmacokinetics",
"keywords": "Alprazolam; Neonatal abstinence syndrome; PBPK; Plasma concentration; Simulation",
"medline_ta": "Drug Metab Pharmacokinet",
"mesh_terms": "D000525:Alprazolam; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008954:Models, Biological; D009357:Neonatal Abstinence Syndrome; D011247:Pregnancy",
"nlm_unique_id": "101164773",
"other_id": null,
"pages": "400-402",
"pmc": null,
"pmid": "31699653",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pharmacokinetic assessment of alprazolam-induced neonatal abstinence syndrome using physiologically based pharmacokinetic model.",
"title_normalized": "pharmacokinetic assessment of alprazolam induced neonatal abstinence syndrome using physiologically based pharmacokinetic model"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-231422",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drug... |
{
"abstract": "BACKGROUND\nCapecitabine is a tumor-activated oral fluoropyrimidine used in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature.\n\n\nMETHODS\nTwo patients with colorectal carcinoma who developed capecitabine-induced hypertriglyceridemia (including a patient who developed hyperglycemia concurrently) were described, treatment modalities were discussed, and the literatures were reviewed.\n\n\nRESULTS\nThe first patient, a 43-year-old man, developed hyperlipidemia and hyperglycemia after two cycles of XELOX regimen chemotherapy for colorectal cancer. His triglyceride was 2.47 mmol/L (normal range 0.34-1.7 mmol/L) and total cholesterol was 6.93 mmol/L (normal range 3.12-5.9 mmol/L), while blood glucose was abnormal (fasting blood glucose was 10.58-11.9 mmol/L and 2 h postprandial glucose was 14.5-17.2 mmol/L) and glucose was positive in the urine(3+). The second patient, a 47-year-old woman, developed abnormalities in the lipid profile after the sixth cycle of XELOX regimen chemotherapy for colorectal cancer. Her serum triglyceride was 2.41 mmol/L (normal range 0.34-1.7 mmol/L), while the cholesterol level was 7.73 mmol/L (normal range 3.12-5.9 mmol/L). The profile of lipid improved gradually with reduced doses of capecitabine and was well restored after chemotherapy without any lipid-lowering agents. The Naranjo score for capecitabine-induced hypertriglyceridemia was 9 (definite). An analysis of the underlying pathogenic mechanisms was provided.\n\n\nCONCLUSIONS\nIt is important of physicians and pharmacists to be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia induced by capecitabine.",
"affiliations": "Department of Oncology, The People's Hospital of Taizhou, Taizhou Medical School, Jiangsu and Nantong University, Jiangsu, China.;Department of Oncology, The People's Hospital of Taizhou, Taizhou Medical School, Jiangsu and Nantong University, Jiangsu, China hjxtz@sina.cn.",
"authors": "Han|Gao-Hua|GH|;Huang|Jun-Xing|JX|",
"chemical_list": "D001786:Blood Glucose; D010071:Oxaloacetates; D014280:Triglycerides; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1177/1078155214532508",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "21(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Hypertriglyceridemia; capecitabine; colorectal carcinoma; hyperglycemia",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001786:Blood Glucose; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D003841:Deoxycytidine; D005260:Female; D005472:Fluorouracil; D006801:Humans; D006943:Hyperglycemia; D015228:Hypertriglyceridemia; D008297:Male; D008875:Middle Aged; D010071:Oxaloacetates; D014280:Triglycerides",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "380-3",
"pmc": null,
"pmid": "24781450",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hypertriglyceridemia and hyperglycemia induced by capecitabine: a report of two cases and review of the literature.",
"title_normalized": "hypertriglyceridemia and hyperglycemia induced by capecitabine a report of two cases and review of the literature"
} | [
{
"companynumb": "CN-MYLANLABS-2015M1031646",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nIgA nephropathy (IgAN) is not always benign, and some patients at high risk of end-stage renal disease (ESRD) experience a rapid decline in renal function. This study retrospectively examined the beneficial effects of cytotoxic therapy.\n\n\nMETHODS\nWe identified 102 patients with progressive IgAN despite optimal conservative management. Of these, 31 who received cytotoxic therapy and 55 who were managed conservatively were included.\n\n\nRESULTS\nMedian eGFR and urinary protein-to-creatinine ratio (uPCR) at baseline did not differ between the groups (p = 0.475 and 0.259, respectively). Median GFR slope was also similar (p = 0.896). Cumulative renal survival was better in the cytotoxic therapy group than in the control group (p = 0.009). Cytotoxic therapy was associated with lower risk of progression to ESRD, independent of eGFR, uPCR, GFR slope and kidney histologic findings (HR 0.13, 95% CI 0.03-0.66). In the cytotoxic therapy group, the median GFR slope decreased from -7.8 (-10.5, -5.0) mL/min/1.73 m(2) per year to -3.4 (-5.1, -1.8) mL/min/1.73 m(2) per year after treatment (p < 0.001). Mortality was not observed, but infection requiring hospitalization occurred at similar rates in both groups (p = 0.886).\n\n\nCONCLUSIONS\nCytotoxic therapy attenuated the rate of GFR decline and was associated with a favorable renal outcome in patients with progressive IgAN.",
"affiliations": "a Division of Nephrology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;a Division of Nephrology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;a Division of Nephrology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;b Department of Pathology, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;a Division of Nephrology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;b Department of Pathology, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;a Division of Nephrology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;c Biostatistics and Clinical Epidemiology Center, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea.;a Division of Nephrology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;a Division of Nephrology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;;a Division of Nephrology, Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea ;",
"authors": "Shin|Jung-ho|JH|;Lee|Jung Eun|JE|;Park|Ji Hyeon|JH|;Lim|Sharon|S|;Jang|Hye Ryoun|HR|;Kwon|Ghee Young|GY|;Huh|Wooseong|W|;Jung|Sin-Ho|SH|;Kim|Yoon-Goo|YG|;Oh|Ha Young|HY|;Kim|Dae Joong|DJ|",
"chemical_list": "D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D003603:Cytotoxins; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D003404:Creatinine",
"country": "England",
"delete": false,
"doi": "10.3109/07853890.2016.1153805",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0785-3890",
"issue": "48(3)",
"journal": "Annals of medicine",
"keywords": "Cytotoxic therapy; IgA nephropathy; end-stage renal disease",
"medline_ta": "Ann Med",
"mesh_terms": "D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001706:Biopsy; D003404:Creatinine; D003520:Cyclophosphamide; D003603:Cytotoxins; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D007676:Kidney Failure, Chronic; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D011507:Proteinuria; D056910:Republic of Korea; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "8906388",
"other_id": null,
"pages": "171-81",
"pmc": null,
"pmid": "27031662",
"pubdate": "2016",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The effects of cytotoxic therapy in progressive IgA nephropathy.",
"title_normalized": "the effects of cytotoxic therapy in progressive iga nephropathy"
} | [
{
"companynumb": "KR-ROCHE-1755677",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAnticoagulation is the mainstay of treatment for pulmonary embolism. However, if bleeding unfortunately occurs, the risks and benefits of anticoagulation present a challenge. Management of one hemorrhagic complication, retroperitoneal hematoma, is rare, difficult, and controversial.\n\n\nMETHODS\nA 73-year-old white man presented with left lower extremity swelling and dyspnea. He was tachycardic, hypertensive, and demonstrated poor oxygen saturation of 81% on ambient air. A computed tomography angiogram revealed a saddle pulmonary embolus. Tissue plasminogen activator was administered and he was started on a heparin infusion. He was eventually transitioned to enoxaparin. On the day of discharge, however, he had sudden onset of right leg numbness and weakness below his hip. A computed tomography of his head was not concerning for stroke, and neurology was consulted. Neurology was concerned for spinal cord infarction versus hematoma and recommended magnetic resonance imaging of his thoracic and lumbar spine. The magnetic resonance imaging revealed a left psoas hematoma. A computed tomography scan of his pelvis also showed a right psoas and iliacus hematoma. He was transitioned to a low intensity heparin infusion. The following day his left leg exhibited similar symptoms. There was concern of progressive and irreversible nerve damage due to compression if the hematomas were not drained. Interventional radiology was consulted for drainage. The heparin infusion was paused, drainage was performed, and the heparin infusion was reinitiated 6 hours following the procedure by interventional radiology. His blood counts and neurologic examination stabilized and eventually improved. He was discharged home on a novel anticoagulant.\n\n\nCONCLUSIONS\nManagement of a retroperitoneal hematoma can commence with recognition of the warning signs of bleeding and neurological impairment, and consulting the appropriate services in case the need for intervention arises. A conservative approach of volume resuscitation and blood transfusion can be used initially, with the need for pausing or reversing anticoagulation being assessed on an individual basis with expert consultation. If intervention becomes necessary, other interventional radiology-based modalities can be used to identify and stop the bleeding source, and interventional radiology-guided drainage can be performed to decrease the hematoma burden and relieve neurological symptoms.",
"affiliations": "University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL, 32610, USA.;University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL, 32610, USA.;University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL, 32610, USA. Ashleigh.wright@medicine.ufl.edu.",
"authors": "Cua|Girard|G|;Holland|Neal|N|;Wright|Ashleigh|A|",
"chemical_list": "D000925:Anticoagulants; D017984:Enoxaparin; D006493:Heparin; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-018-1688-x",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 168810.1186/s13256-018-1688-xCase ReportA difficult situation – balancing critical anticoagulation versus the risk of permanent neurologic deficit: a case report Cua Girard Girard.cua@medicine.ufl.edu Holland Neal Neal.holland@medicine.ufl.edu Wright Ashleigh Ashleigh.wright@medicine.ufl.edu 0000 0004 1936 8091grid.15276.37University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL 32610 USA 22 6 2018 22 6 2018 2018 12 18017 11 2017 12 4 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\nAnticoagulation is the mainstay of treatment for pulmonary embolism. However, if bleeding unfortunately occurs, the risks and benefits of anticoagulation present a challenge. Management of one hemorrhagic complication, retroperitoneal hematoma, is rare, difficult, and controversial.\n\nCase presentation\nA 73-year-old white man presented with left lower extremity swelling and dyspnea. He was tachycardic, hypertensive, and demonstrated poor oxygen saturation of 81% on ambient air. A computed tomography angiogram revealed a saddle pulmonary embolus. Tissue plasminogen activator was administered and he was started on a heparin infusion. He was eventually transitioned to enoxaparin. On the day of discharge, however, he had sudden onset of right leg numbness and weakness below his hip. A computed tomography of his head was not concerning for stroke, and neurology was consulted. Neurology was concerned for spinal cord infarction versus hematoma and recommended magnetic resonance imaging of his thoracic and lumbar spine. The magnetic resonance imaging revealed a left psoas hematoma. A computed tomography scan of his pelvis also showed a right psoas and iliacus hematoma. He was transitioned to a low intensity heparin infusion. The following day his left leg exhibited similar symptoms. There was concern of progressive and irreversible nerve damage due to compression if the hematomas were not drained. Interventional radiology was consulted for drainage. The heparin infusion was paused, drainage was performed, and the heparin infusion was reinitiated 6 hours following the procedure by interventional radiology. His blood counts and neurologic examination stabilized and eventually improved. He was discharged home on a novel anticoagulant.\n\nConclusions\nManagement of a retroperitoneal hematoma can commence with recognition of the warning signs of bleeding and neurological impairment, and consulting the appropriate services in case the need for intervention arises. A conservative approach of volume resuscitation and blood transfusion can be used initially, with the need for pausing or reversing anticoagulation being assessed on an individual basis with expert consultation. If intervention becomes necessary, other interventional radiology-based modalities can be used to identify and stop the bleeding source, and interventional radiology-guided drainage can be performed to decrease the hematoma burden and relieve neurological symptoms.\n\nKeywords\nPulmonary embolismRetroperitoneal hematomaAnticoagulationNeurologic deficitissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThe management of retroperitoneal hematomas in the setting of critical anticoagulation is rare, difficult, and controversial. There exists the need to strike a delicate balance. Management can commence with early recognition of the warning signs of occult bleeding and neurological impairment, and consulting the appropriate services in case an imminent need for intervention arises. A conservative approach of volume resuscitation and blood transfusion can be used initially, with the need for pausing or reversing anticoagulation being assessed on a case-by-case basis with expert consultation. If intervention becomes necessary, modalities such as transarterial embolization (TAE) can be used to identify and stop the bleeding source, and interventional radiology (IR)-guided drainage can be performed to decrease the hematoma burden and relieve neurological symptoms. Finally, as with all clinically complex cases, patient awareness and informed consent play a major role in how the plan is implemented. We describe a case in which a patient was admitted to our hospital after sustaining a saddle pulmonary embolus (PE), received appropriate anticoagulation, and subsequently developed bilateral retroperitoneal hematomas as a complication of therapy. This case highlights an unexpected complication of a commonly treated condition, as retroperitoneal hematomas in the setting of anticoagulation are rarely reported in the literature [1]. In addition, our publication review yielded very few case reports in which retroperitoneal hematomas occurred as a complication of pulmonary embolism treatment specifically.\n\nCase presentation\nA 73-year-old white man presented to our emergency department with a 3-day history of left lower extremity swelling and acute-onset shortness of breath. On evaluation, he was tachycardic with a pulse of 113, hypertensive with a systolic blood pressure of 130-170 mmHg, and demonstrated poor oxygen saturation of 81% on room air. He was supported with continuous positive airway pressure (CPAP) and supplemental oxygen while a computed tomography angiogram (CTA) was obtained, which revealed a saddle PE (Fig. 1).Fig. 1 Computed tomography showing the saddle pulmonary embolus\n\n\n\nTissue plasminogen activator (tPA) was administered and he was started on a heparin infusion and admitted to our intensive care unit (ICU) for management. He remained on the heparin infusion for 3 days, during which he continuously improved and was eventually weaned to 3 L oxygen via nasal cannula. On hospital day 2, he was transferred to intermediate level of care. Per hematology recommendations, he would have to be on indefinite anticoagulation due to the massive PE he had sustained, the source of which was a left lower extremity popliteal deep vein thrombosis (DVT). The plan was to transition him from the heparin infusion to enoxaparin twice per day with hematology follow-up in 1 month.\n\nClinical findings\nOn the day of discharge, however, he had sudden onset of right leg numbness and weakness below the level of his hip. He had previously been working with physical therapy and had been able to walk 200 feet with the assistance of a walker during each session. A physical examination revealed decreased sensation to light touch, 2/5 strength in right hip flexion and right knee extension and flexion, and loss of right patellar reflex. Left leg physical examination was normal at that time.\n\nDiagnostic assessment\nAn emergent head computed tomography (CT) scan was ordered due to concern for a possible stroke, and neurology was consulted. The head CT was negative for infarction or hemorrhage. Neurology was concerned for spinal cord infarction versus hematoma and recommended emergent magnetic resonance imaging (MRI) of his thoracic and lumbar spine. The MRI revealed a left psoas hematoma (Fig. 2). A CT of his pelvis performed the same day also showed a right psoas and iliacus hematoma. Due to these findings, hematology recommended discontinuing enoxaparin and reverting to a low intensity heparin infusion, as well as placement of an inferior vena cava (IVC) filter. The following day his left leg began exhibiting the same symptoms as his right leg. There was concern regarding the risk of progressive and irreversible nerve damage due to compression if the hematomas were not promptly drained. IR was consulted and advised that if the drainage were to occur while our patient was on anticoagulation, the risk of rebleeding into the retroperitoneum would be high and potentially nullify any benefit from drainage. Our patient would also be at risk of hemodynamic instability if the current hematomas were acting as tamponades against further bleeding. An additional complicating factor was the risk of further thrombosis due to the presenting saddle PE. Hematology was consulted for recommendations on pausing anticoagulation, but they were hesitant to offer a timeframe as there was no established safe period to enable this type of procedure to take place. Eventually, a window period of pausing the heparin infusion for 3 hours pre-procedure and up to 6 hours post-procedure was decided upon in the event that our patient agreed to have the drainage performed.Fig. 2 Magnetic resonance imaging showing the left psoas hematoma\n\n\n\nThroughout this sequence of events, our patient and his wife were aware of the plans and considerations on how to proceed. They were informed of the recommendations and concerns made by neurology, hematology, and IR, as well as the risks and benefits of intervention versus non-intervention.\n\nTherapeutic intervention\nAfter speaking with his wife, our patient decided to undergo the procedure. The low intensity heparin infusion was stopped 3 hours beforehand and the IR team then performed drainage of the right retroperitoneal hematoma, placing two pigtail catheters in our patient’s right flank (Fig. 3). In total, the hematoma was drained of 215 milliliters of blood, 10 milliliters of which were drained during the procedure itself. The left psoas hematoma was not found to be amenable to drainage.Fig. 3 Computed tomography showing interventional radiology-guided drainage of the right retroperitoneal hematoma\n\n\n\nFollow-up and outcomes\nOur patient tolerated the procedure well, and the heparin infusion was restarted 6 hours after it was completed. A repeat neurological examination demonstrated improved lower extremity strength bilaterally as well as the return of sensation to light touch. Hip flexion improved to 3/5 bilaterally, and knee flexion and extension improved to 4/5 bilaterally. Deep tendon reflexes remained absent. Four days later, the pigtail catheters were removed. His recovery was complicated by anemia requiring blood transfusions totaling 4 units of packed red blood cells (PRBC). Other sources of potential bleeding were evaluated and not found. A repeat CT on hospital day 10 (Fig. 4) showed a stable right-sided hematoma, and our patient did not experience any further neurologic deficits. He was transitioned again from the heparin infusion to enoxaparin after 3 more days. His hemoglobin and hematocrit remained stable. During this time, he worked with physical therapy, who recommended discharge to a skilled nursing facility where his strength began to improve somewhat. Follow-up was scheduled with neurology and hematology. On hospital day 18, he was safely discharged.Fig. 4 Repeat abdomen and pelvis computed tomography performed on hospital day 10. The implanted inferior vena cava filter can also be seen\n\n\n\nDiscussion\nThe complexity of this case far exceeded initial expectations, bringing with it several valuable learning points. Parenteral anticoagulation should be given to patients with confirmed acute PE. The risk of major bleeding with anticoagulation therapy is less than 3% [2]. Bleeding is classified as “major” if it is intracranial, retroperitoneal, leads to hospitalization, the need for blood transfusion, or death [3]. In terms of retroperitoneal hematomas, the occurrence rate approaches 0.5–1% in patients on systemic anticoagulation [3, 4], with retroperitoneal bleeds almost exclusively seen in states of anticoagulation, coagulopathies, and hemodialysis [5]. In general, risk factors for bleeding are: age > 65 years, previous bleeding, thrombocytopenia, antiplatelet therapy, poor anticoagulant control, recent surgery, frequent falls, reduced functional capacity, previous stroke, diabetes, anemia, cancer, renal failure, liver failure, and alcohol abuse [2]. In transitioning from unfractionated heparin to low molecular weight heparin, the major bleeding risk appears to decrease from 2% to 1.2%, respectively [2]. In our case, the patient’s risk factors included his age, recent administration of tPA, and ongoing anticoagulation therapy with enoxaparin due to his PE.\n\nPatients with retroperitoneal hemorrhage can present in a variety of ways. One third of patients will present with Lenk’s triad: severe flank pain, hemodynamic shock, and palpable mass [6]. The remainder of patients can have symptoms consisting of: nausea, vomiting, abdominal distension, intestinal obstruction, hypovolemia, anemia, limb swelling, paresthesia, femoral nerve compression causing paralysis of a lower limb, muscle weakness, reduced knee or thigh reflex, increased intra-abdominal pressure, and/or abdominal compartment syndrome [7]. It is therefore important to be aware of these potential complications when starting patients on anticoagulation. Proposed mechanisms that may precipitate retroperitoneal hemorrhage are: forceful muscle strain, diffuse small vessel arteriosclerosis, heparin-induced immune microangiopathy, and unrecognized minor trauma [6].\n\nTreatment of spontaneous retroperitoneal hematomas in the setting of anticoagulation is difficult. There is lack of Level I evidence for the best management plans, with most evidence based on case reports [8]. Upon review of selected case reports, there always exists the risk of stopping anticoagulation versus continued bleeding. The general pattern found in the case reports initially begins conservatively, with increasing invasiveness as chronicity and severity increases. In addition, CT imaging of the abdomen and pelvis should be performed in order to document the type, site, and extent of the suspected hematoma [8]. In a case report by Gurbuz et al., a 41-year-old patient developed femoral nerve palsy due to a retroperitoneal hematoma caused by recent addition of aspirin to his already existing warfarin therapy for a mitral valve prosthesis [3]. His international normalized ratio (INR) was supratherapeutic at 4.1. He was successfully treated by reversing warfarin with 10 mg of vitamin K and 2 units of fresh frozen plasma (FFP), along with right leg elevation above his heart. His neurologic function recovered and the hematoma remained stable, gradually reabsorbing by 3-week follow-up. Our case differs from theirs as the bleed appears to have been caused by a supratherapeutic INR as well as addition of an antiplatelet medication.\n\nAnother modality which could have been considered in our case was the use of TAE in order to target and stop the bleeding source. A case report by Wada et al. described bilateral iliopsoas hematomas that developed in an 85-year-old patient undergoing anticoagulation for transient ischemic attack (TIA) [9]. Her symptoms consisted of: pain, weakness, and decreased sensation in the groin bilaterally [9]. She underwent aortography and, although no contrast extravasation was seen, underwent TAE in the third and fourth lumbar artery trunk due to the suspected origin at that location. Her symptoms progressively improved by the third week. In another case, Won et al. employed both TAE as well as surgical decompression of a spontaneous retroperitoneal hematoma in a 48-year-old woman undergoing warfarin and aspirin anticoagulation for an artificial aortic valve [6]. She presented with hemodynamic instability and an INR of 4.6. Angiography showed right internal iliac artery extravasation, which was embolized with TAE. However, her neurologic symptoms continued to worsen with the development of anuria and abdominal compartment syndrome that necessitated exploratory laparotomy.\n\nOther therapeutic options for our patient included a TAE before the IR-guided drainage in order to stop the bleeding source. This would have reassured us that a repeat bleed would be less likely to occur. However, while TAE may stop the source of the bleed, it does not reduce the hematoma burden on the nerves and, therefore, would not have reversed the neuropathy. In addition, our patient had already developed an acute kidney injury (AKI) and did have a history of kidney transplant in 2006. A contrasted study at that point in time would not have been advisable. There is also the risk of failing to identify the bleed source even with angiography, as was seen in the case presented by Wada et al. [9].\n\nIn all reported cases where intervention was necessary, anticoagulation was either discontinued or reversed, introducing the risk of thrombosis. However, none of the cases mentioned thrombosis as a complication of their treatment. With our patient, we did not feel comfortable reversing or discontinuing the anticoagulation as, in our case, the patient was recovering from an acute thrombotic event. It would be difficult to predict the risk of hematoma recurrence after drainage, as retroperitoneal hematomas are rare. However, it is logical that, if the source of bleeding were contained with a procedure such as TAE, the risk of rebleeding would be decreased.\n\nThe management of retroperitoneal hematomas in the setting of critical anticoagulation is rare, difficult, and controversial. There exists the need to strike a delicate balance. Management can commence with early recognition of the warning signs of occult bleeding and neurological impairment, and consulting the appropriate services in case an imminent need for intervention arises. A conservative approach of volume resuscitation and blood transfusion can be used initially, with the need for pausing or reversing anticoagulation being assessed on a case-by-case basis with expert consultation. If intervention becomes necessary, modalities such as TAE can be used to identify and stop the bleeding source, and IR-guided drainage can be performed to decrease the hematoma burden and relieve neurological symptoms. Finally, as with all clinically complex cases, patient awareness and informed consent play a major role in how the plan is implemented.\n\nConclusions\n\nPatients with confirmed PE should be given parenteral anticoagulation, with the risk of major bleeding being less than 3%. There are several risk factors that predispose patients to bleeding.\n\nSpontaneous retroperitoneal hematoma is a rare clinical entity seen almost exclusively during anticoagulation, coagulopathies, or dialysis. Early recognition of signs of bleeding is important and advised in the management of patients in this population because it is a serious and potentially lethal complication.\n\nIntervention has generally consisted of conservative measures first, then progressing to more invasive modalities as the chronicity or severity of the patient’s condition manifests itself. The need for continuing anticoagulation should be reassessed, and risks and benefits should be explained to the patient before proceeding with any plan of action.\n\n\n\n\nAbbreviations\nAKIAcute kidney injury\n\nCPAPContinuous positive airway pressure\n\nCTComputed tomography\n\nCTAComputed tomography angiogram\n\nDVTDeep vein thrombosis\n\nFFPFresh frozen plasma\n\nICUIntensive care unit\n\nINRInternational normalized ratio\n\nIRInterventional radiology\n\nIVCInferior vena cava\n\nMRIMagnetic resonance Imaging\n\nPEPulmonary embolus\n\nPRBCPacked red blood cells\n\nTAETransarterial embolization\n\nTIATransient ischemic attack\n\ntPATissue plasminogen activator\n\nAuthors’ contributions\nAll authors made a significant contribution to this study. NH admitted the patient to the hospital and initiated his care. AW was the attending physician who managed the patient’s care while hospitalized. GC was the resident physician who managed the patient’s care while hospitalized and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNo approval was sought as this was a retrospective case report and the patient was at no risk from this case report.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. P. Sun, C. Lee, and K. Chiu, “Retroperitoneal hemorrhage caused by enoxaparin-induced spontaneous lumbar artery bleeding and treated by transcatheter arterial embolization: a case report,” Cases J., 2:9375. doi: 10.1186/1757-1626-2-9375\n2. Hull RD Post TW Anticoagulation in acute pulmonary embolism UpToDate 2015 Waltham UpToDate \n3. Gurbuz O Ercan A Kumtepe G Karal IH Velioglu Y Ener S Femoral Nerve Palsy due to Anticoagulant Induced Retroperitoneal Hematoma Case Rep Med 2014 2014 450750 10.1155/2014/450750 25386195 \n4. Shah RD Nagar S Shanley CJ Janczyk RJ Factors affecting the severity of spontaneous retroperitoneal hemorrhage in anticoagulated patients Am J Surg 2008 195 3 410 413 10.1016/j.amjsurg.2007.12.003 18241833 \n5. Daliakopoulos SI Bairaktaris A Papadimitriou D Pappas P Gigantic retroperitoneal hematoma as a complication of anticoagulation therapy in with heparin in therapeutic doses: a case report J Med Case Rep 2008 2 1 162 10.1186/1752-1947-2-162 18485233 \n6. Won DY Kim SD Park SC Moon IS Kim JI Abdominal compartment syndrome due to spontaneous retroperitoneal hemorrhage in a patient undergoing anticoagulation Yonsei Med J 2011 52 2 358 361 10.3349/ymj.2011.52.2.358 21319359 \n7. Fan WX Deng ZX Liu F Liu RB He L Amrit B Zang L Li JW Liu XR Huang SM Fu P Spontaneous retroperitoneal hemorrhage after hemodialysis involving anticoagulant agents J Zhejiang Univ Sci B 2012 13 5 408 412 10.1631/jzus.B1100357 22556180 \n8. Chan YC Morales JP Reidy JF Taylor PR Management of spontaneous and iatrogenic retroperitoneal haemorrhage: conservative management, endovascular intervention or open surgery? Int J Clin Pract 2008 62 10 1604 1613 10.1111/j.1742-1241.2007.01494.x 17949429 \n9. Wada Y Yanagihara C Nishimura Y Bilateral iliopsoas hematomas complicating anticoagulant therapy Intern Med 2005 44 6 641 643 10.2169/internalmedicine.44.641 16020897\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "12(1)",
"journal": "Journal of medical case reports",
"keywords": "Anticoagulation; Neurologic deficit; Pulmonary embolism; Retroperitoneal hematoma",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D017984:Enoxaparin; D006406:Hematoma; D006493:Heparin; D006801:Humans; D008297:Male; D009422:Nervous System Diseases; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "180",
"pmc": null,
"pmid": "29929554",
"pubdate": "2018-06-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22556180;25386195;18485233;17949429;18241833;21319359;16020897;20072679",
"title": "A difficult situation - balancing critical anticoagulation versus the risk of permanent neurologic deficit: a case report.",
"title_normalized": "a difficult situation balancing critical anticoagulation versus the risk of permanent neurologic deficit a case report"
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"companynumb": "US-FRESENIUS KABI-FK201807973",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
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