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"abstract": "Pancreatitis is rare in pancreatic insufficient cystic fibrosis patients. While pancreatic insufficiency has been considered irreversible until now, in the current era of new therapies with modulators of the Cystic Fibrosis Transmembrane Regulator CFTR channel, there are reports of improvement of pancreatic exocrine function. We describe the case of an adolescent with cystic fibrosis who developed pancreatitis after the partial recovery of pancreatic function while taking ivacaftor. This case adds to the limited body of evidence that CFTR modulators lead to the improvement of pancreatic exocrine function in cystic fibrosis.",
"affiliations": "Cystic fibrosis Department, Agia Sophia Children's Hospital, 115 27 Athens, Greece.;Division of Pediatric Pulmonology, First Department of Pediatrics, National and Kapodistrian University of Athens School of Medicine and Aghia Sophia Children's Hospital, 115 27 Athens, Greece.;Cystic fibrosis Department, Agia Sophia Children's Hospital, 115 27 Athens, Greece.",
"authors": "Petrocheilou|Argyri|A|0000-0003-1450-6638;Kaditis|Athanasios G|AG|;Loukou|Ioanna|I|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3390/children7010006",
"fulltext": "\n==== Front\nChildren (Basel)Children (Basel)childrenChildren2227-9067MDPI 10.3390/children7010006children-07-00006Case ReportPancreatitis in A Patient with Cystic Fibrosis Taking Ivacaftor https://orcid.org/0000-0003-1450-6638Petrocheilou Argyri 1*Kaditis Athanasios G. 2Loukou Ioanna 11 Cystic fibrosis Department, Agia Sophia Children’s Hospital, 115 27 Athens, Greece; ioannaloukou@gmail.com2 Division of Pediatric Pulmonology, First Department of Pediatrics, National and Kapodistrian University of Athens School of Medicine and Aghia Sophia Children’s Hospital, 115 27 Athens, Greece; kaditia@hotmail.com* Correspondence: apetroch@gmail.com; Tel.: +30-210-746775712 1 2020 1 2020 7 1 626 11 2019 20 12 2019 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Pancreatitis is rare in pancreatic insufficient cystic fibrosis patients. While pancreatic insufficiency has been considered irreversible until now, in the current era of new therapies with modulators of the Cystic Fibrosis Transmembrane Regulator CFTR channel, there are reports of improvement of pancreatic exocrine function. We describe the case of an adolescent with cystic fibrosis who developed pancreatitis after the partial recovery of pancreatic function while taking ivacaftor. This case adds to the limited body of evidence that CFTR modulators lead to the improvement of pancreatic exocrine function in cystic fibrosis.\n\npancreatitiscystic fibrosisivacaftorCFTR\n==== Body\n1. Introduction\nPancreatitis in cystic fibrosis (CF) was first described in patients with cystic fibrosis who were pancreatic sufficient [1]. Pancreatitis has also been described in pancreatic insufficient patients, although that is very rare and, in many cases, the patients have only become insufficient after the pancreatitis episode [2].\n\nRecently therapies in CF, such as Cystic Fibrosis Transmembrane Regulator (CFTR) potentiators, have been used in patients with specific genotypes with good results, resulting in at least partial recovery of CFTR function. In the recent report by Megalaa et al., a case of pancreatitis in a patient taking ivacaftor was described [3]. A second case of a CF patient with history of PI who developed pancreatitis while on treatment with ivacaftor is described below. This case adds to the body of evidence that at least partial restoration of pancreatic function is feasible with ivacaftor, and this is clinically significant.\n\n2. Case\nThe adolescent and her parents were informed and parents consented for the publication of this case.\n\nA 14-year old girl with CF was admitted to the hospital with a history of progressively increasing epigastric pain and nausea. She was otherwise well, reporting only mild cough secondary to recent respiratory infection that was improving. The patient’s medical history was remarkable for CF diagnosis with the genotype F508del/G551D. Patient’s oral medications included ivacaftor 150mg twice daily that was started four years prior to hospital admission. The adolescent had almost discontinued pancreatic enzyme replacement therapy (PERT) and was using PERT only with very fatty meals since about 2 years after starting ivacaftor as PI symptoms were absent and BMI had increased from 21 to 27 kg/m2. The patient’s diet was rich in meals with a high fat content, such as fast food restaurant meals and fried food items.\n\nThe patient was afebrile and physical examination of the chest revealed few crackles at the lung bases while the abdomen was diffusely tender on palpation and bowel sounds were present. Further, no hepatosplenomegaly was noted. The laboratory values on admission were notable for an amylase of 197 U/L (normal range: 28-100U/L) and a lipase of 647 (normal range: <190 U/L). Thus, the diagnosis of pancreatitis was entertained based on the history of epigastric pain, findings from examination of the abdomen and laboratory results.\n\nThe adolescent was treated with intravenous fluids and was discharged in good condition after four days later. No recurrence of pancreatitis symptoms has been noted up to more than two years after the episode. Ivacaftor was restarted shortly after discharge and was well tolerated. Stool elastase was measured almost two years after the episode and was 159 μgE/g, indicating moderate pancreatic insufficiency (normal >200 μgE/g, moderate pancreatic insufficiency 100–200 μgE/g, severe pancreatic insufficiency <100 μgE/g). Stool elastase was not measured on diagnosis or before starting ivacaftor. The patient to date denies PI symptoms and continues to use PERT only with very fatty meals.\n\n3. Discussion\nThis case further underlines the importance of the point made by Megalaa et al. that clinicians should consider measuring stool elastase on patients taking ivacaftor to determine if pancreatic function has recovered [3], especially in light of safety and efficacy studies of ivacafor, (KIWI and ARRIVAL) results [4,5] which also suggest that ivacaftor leads to recovery of pancreatic function. Unlike the patient described by Megalaa et al. that had a normal stool elastase, over 500 mcg/g right after the pancreatitis episode and 376 mcg/g shortly after the pancreatitis episode, [3] the patient described here had a stool elastase that was in the moderate pancreatic insufficiency range.\n\nStool elastase in our patient was measured much later than the pancreatitis episode, but based on the clinical symptoms it can be presumed that stool elastase value was similar at the time of the pancreatitis as well. Despite moderate pancreatic insufficiency, the patient still experienced an acute pancreatitis episode that led to hospitalization. Therefore, pancreatitis in this PI patient could be explained by the improvement of CFTR function with ivacaftor, by a similar mechanism to the one proposed by Carrion et al. for the reduction of pancreatitis frequency and recurrence risk [6].\n\nIn the current era of CFTR modulators, the question raised by the CF community, especially by patients and parents, concerns whether CFTR modulators will reduce the treatment burden. Consequently, data suggesting the restoration of pancreatic function that could lead to discontinuation of PERT are particularly important. Furthermore, pancreatitis is generally uncommon in PI patients, so the description of pancreatitis in previously PI patients on ivacaftor implies at least partial restoration of pancreatic function. Therefore, clinicians and patients should be alert to development of pancreatitis symptoms in patients treated with ivacaftor. Patient and parent education preemptively, during clinic visits, should be considered in order to prevent delays in appropriate treatment.\n\nAuthor Contributions\nA.P. prepared the first draft of the paper, A.G.K. and I.L. revised and approved the final version and all authors contributed in the conceptualization of this case presentation. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nIoanna Loukou has received advisory board reimbursements from Vertex Pharmaceuticals. The rest of the authors declare no conflict of interest.\n==== Refs\nReferences\n1. Shwachman H. Lebenthal E. Khaw K.T. Recurrent acute pancreatitis in patients with cystic fibrosis with normal pancreatic enzymes Pediatrics 1975 55 86 95 1110867 \n2. De Boeck K. Weren M. Proesmans M. Kerem E. Pancreatitis among patients with cystic fibrosis: Correlation with pancreatic status and genotype Pediatrics 2005 115 e463 e469 10.1542/peds.2004-1764 15772171 \n3. Megalaa R. Gopalareddy V. Champion E. Goralski J.L. Time for a gut check: Pancreatic sufficiency resulting from CFTR modulator use Pediatr. Pulmonol. 2019 54 E16 E18 10.1002/ppul.24353 31066218 \n4. Davies J.C. Cunningham S. Harris W.T. Lapey A. Regelmann W.E. Sawicki G.S. Southern K.W. Robertson S. Green Y. Cooke J. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): An open-label, single-arm study Lancet Respir. Med. 2016 4 107 115 10.1016/S2213-2600(15)00545-7 26803277 \n5. Rosenfeld M. Wainwright C.E. Higgins M. Wang L.T. McKee C. Campbell D. Tian S. Schneider J. Cunningham S. Davies J.C. Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): A phase 3 single-arm study Lancet Respir. Med. 2018 6 545 553 29886024 \n6. Carrion A. Borowitz D.S. Freedman S.D. Siracusa C.M. Goralski J.L. Hadjiliadis D. Srinivasan S. Stokes D.C. Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis with Ivacaftor: Case Series J. Pediatr. Gastroenterol. Nutr. 2018 66 451 454 10.1097/MPG.0000000000001788 29045347\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2227-9067",
"issue": "7(1)",
"journal": "Children (Basel, Switzerland)",
"keywords": "CFTR; cystic fibrosis; ivacaftor; pancreatitis",
"medline_ta": "Children (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101648936",
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"pages": null,
"pmc": null,
"pmid": "31940891",
"pubdate": "2020-01-12",
"publication_types": "D002363:Case Reports",
"references": "1110867;31066218;26803277;29045347;15772171;29886024",
"title": "Pancreatitis in A Patient with Cystic Fibrosis Taking Ivacaftor.",
"title_normalized": "pancreatitis in a patient with cystic fibrosis taking ivacaftor"
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"companynumb": "GR-VERTEX PHARMACEUTICALS-2020-001804",
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"abstract": "Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown.Experimental Design: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified.Results:EGFR G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC50) of osimertinib in vitro, among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these EGFR mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as MET, KRAS, and PIK3CA were also discovered, potentially contributing to the osimertinib-resistance in patients without EGFR secondary mutations.Conclusions: We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of EGFR L718 and L792 residues confer osimertinib resistance, both in vitro and in vivo, and are of great clinical and pharmaceutical relevance. Clin Cancer Res; 24(13); 3097-107. ©2018 AACR.",
"affiliations": "Tumor Research and Therapy Centre, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.;Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, China.;Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada.;Pulmonary and Critical Care Medicine, Rui Jin Hospital, School of Medicine of Shanghai Jiao Tong University, Shanghai, China.;Shanghai Pulmonary Hospital, Cancer Institute of Tongji University Medical School, Shanghai, China.;Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada.;Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada.;Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada.;Nanjing Geneseeq Technology Inc., Nanjing, China.;Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Canada.;Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Heping District, Shenyang, China.;National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. caicunzhou_dr@163.com wangyanyifu@126.com.;Shanghai Pulmonary Hospital, Cancer Institute of Tongji University Medical School, Shanghai, China. caicunzhou_dr@163.com wangyanyifu@126.com.",
"authors": "Yang|Zhe|Z|;Yang|Nong|N|;Ou|Qiuxiang|Q|;Xiang|Yi|Y|0000-0002-0724-6359;Jiang|Tao|T|;Wu|Xue|X|0000-0002-5567-1325;Bao|Hua|H|;Tong|Xiaoling|X|;Wang|Xiaonan|X|;Shao|Yang W|YW|;Liu|Yunpeng|Y|;Wang|Yan|Y|;Zhou|Caicun|C|",
"chemical_list": "D000178:Acrylamides; D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "United States",
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"doi": "10.1158/1078-0432.CCR-17-2310",
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"issn_linking": "1078-0432",
"issue": "24(13)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
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"medline_ta": "Clin Cancer Res",
"mesh_terms": "D000178:Acrylamides; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "9502500",
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"pubdate": "2018-07-01",
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"references": null,
"title": "Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small Cell Lung Cancer Patients.",
"title_normalized": "investigating novel resistance mechanisms to third generation egfr tyrosine kinase inhibitor osimertinib in non small cell lung cancer patients"
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"abstract": "Neurological infection by herpes simplex virus type 2 (HSV-2) is the cause of significant morbidity and mortality; and should be diagnosed and treated as soon as possible. Typically, it is characterized by fever, headache and behavioral changes. Symptoms association, laboratory tests results and diagnostic imaging are essential for early diagnosis and treatment of this disease, in order to prevent its fatal progression. We present the case of a 45-year-old male patient diagnosed with HSV-2 encephalitis due to chronic steroid use. In previously healthy adult patients, neurological HSV-2 infection due to chronic steroid use is extremely rare; and the association has not been previously described.",
"affiliations": "Universidad Católica de Pernambuco (UNICAP), Recife, Brasil.;Universidad de Uberaba (UNIUBE), Minas Gerais, Brasil.;Universidad Peruana Cayetano Heredia, Lima, Perú.;Universidad Peruana Cayetano Heredia, Lima, Perú.",
"authors": "Farias|Laryssa Alves-de|LA|http://orcid.org/0000-0002-2910-5194;Galvão-Silva|Daiana|D|http://orcid.org/0000-0002-5421-4659;Reyes-Cancino|Cecilia|C|http://orcid.org/0000-0003-3946-4454;Málaga|Germán|G|http://orcid.org/0000-0002-7828-300X",
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"issue": "37(3)",
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"mesh_terms": "D020803:Encephalitis, Herpes Simplex; D018258:Herpesvirus 2, Human; D006801:Humans; D008297:Male; D008875:Middle Aged",
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"pubdate": "2020-12-02",
"publication_types": "D002363:Case Reports",
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"title": "Herpes simplex virus type 2 encephalitis in a healthy adult patient: an unusual case.",
"title_normalized": "herpes simplex virus type 2 encephalitis in a healthy adult patient an unusual case"
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"abstract": "Objective assessment of fluid status is of utmost significance in the management of patients with complex disorders involving hemodynamics and multi-organ crosstalk such as cardiorenal or hepatorenal syndrome. The role of volume expansion using intravenous albumin in the setting of hepatorenal syndrome has been an everlasting debate among clinicians. With the accumulating evidence on the deleterious consequences of iatrogenic fluid overload, empiric albumin administration in these patients has been the focus of much attention, and the findings of recent studies suggest a higher incidence of pulmonary complications with albumin. Poor sensitivity of conventional physical examination has led to an interest in the utility of novel noninvasive bedside tools such as point-of-care ultrasonography (POCUS) to evaluate hemodynamics more precisely. Once confined to specialties such as obstetrics and emergency medicine, the scope of diagnostic POCUS is rapidly expanding in other fields including internal medicine and nephrology. Herein, we offer our perspective on the emerging role of POCUS for objective evaluation of patients with suspected hepatorenal physiology based on our experience. We propose that future clinical trials consider incorporating this strategy and explore the impact of POCUS-guided therapy on the outcomes.",
"affiliations": "Division of Nephrology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Nephrology, San Bortolo Hospital and International Renal Research Institute of Vicenza (IRRIV), Vicenza, Italy.;Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, Florida, USA.",
"authors": "Koratala|Abhilash|A|;Ronco|Claudio|C|;Kazory|Amir|A|",
"chemical_list": "D000418:Albumins",
"country": "Switzerland",
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"doi": "10.1159/000517363",
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"issn_linking": "1664-5502",
"issue": "11(4)",
"journal": "Cardiorenal medicine",
"keywords": "Albumin; Cirrhosis; Hepatorenal syndrome; Nephrology; Physical examination; Point-of-care ultrasound",
"medline_ta": "Cardiorenal Med",
"mesh_terms": "D000418:Albumins; D006801:Humans; D008103:Liver Cirrhosis; D010808:Physical Examination; D019095:Point-of-Care Systems; D014463:Ultrasonography",
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"pubdate": "2021",
"publication_types": "D016421:Editorial",
"references": null,
"title": "Albumin Infusion in Patients with Cirrhosis: Time for POCUS-Enhanced Physical Examination.",
"title_normalized": "albumin infusion in patients with cirrhosis time for pocus enhanced physical examination"
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"companynumb": "US-OCTA-LIT03321US",
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"abstract": "A 32-year-old male developed neuropsychiatric symptoms 2 weeks after starting mefloquine 250 mg/week for malaria prophylaxis. He continued to take the medication for the next 4 months. Initial symptoms included vivid dreams and anxiety, as well as balance problems. These symptoms persisted and progressed over the next 4 years to include vertigo, emotional lability, and poor short-term memory, which have greatly affected his personal and professional life. An extensive evaluation revealed objective evidence supporting a central vestibulopathy. These symptoms have been unresponsive to pharmacologic therapy and psychotherapy. A Naranjo assessment score of 6 was obtained for his initial symptoms, indicating a probable adverse drug reaction to mefloquine given the relationship between the clinical picture and drug exposure.",
"affiliations": "Department of Clinical Pharmacology, Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA. Jeffrey.r.livezey.mil@mail.mil.;Division of Clinical Pharmacology and Medical Toxicology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.;Division of Clinical Pharmacology and Medical Toxicology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.",
"authors": "Livezey|Jeffrey|J|;Oliver|Thomas|T|;Cantilena|Louis|L|",
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"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 277476873010.1007/s40800-016-0030-zCase ReportProlonged Neuropsychiatric Symptoms in a Military Service Member Exposed to Mefloquine Livezey Jeffrey 301-319-9872Jeffrey.r.livezey.mil@mail.mil 1Oliver Thomas 2Cantilena Louis 21 Department of Clinical Pharmacology, Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD 20910 USA 2 Division of Clinical Pharmacology and Medical Toxicology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA 8 6 2016 8 6 2016 12 2016 3 7© The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.A 32-year-old male developed neuropsychiatric symptoms 2 weeks after starting mefloquine 250 mg/week for malaria prophylaxis. He continued to take the medication for the next 4 months. Initial symptoms included vivid dreams and anxiety, as well as balance problems. These symptoms persisted and progressed over the next 4 years to include vertigo, emotional lability, and poor short-term memory, which have greatly affected his personal and professional life. An extensive evaluation revealed objective evidence supporting a central vestibulopathy. These symptoms have been unresponsive to pharmacologic therapy and psychotherapy. A Naranjo assessment score of 6 was obtained for his initial symptoms, indicating a probable adverse drug reaction to mefloquine given the relationship between the clinical picture and drug exposure.\n\nissue-copyright-statement© The Author(s) 2016\n==== Body\nKey Points\n\nMelfoquine-induced neuropsychiatric symptoms can be severely life debilitating.\t\nGiven the overlapping symptoms of post-traumatic stress disorder and mefloquine toxicity, it can be challenging to distinguish between the two diagnoses.\t\nMelfoquine toxicity can persist for several years after exposure has been discontinued, with little to no abatement in symptoms over time.\t\n\n\n\nCase Description\nA 32-year-old male United States military service member was referred to the Walter Reed National Military Medical Center (WRNMMC) Toxicology and Clinical Pharmacology Clinic for further evaluation of chronic neuropsychiatric symptoms. The patient was in his usual state of health until 2 weeks after the initiation of mefloquine 250 mg/week for malaria prophylaxis at the start of a 6- month deployment to East Africa at the end of 2009. Compliance with prophylaxis was ensured by the medical corpsmen who witnessed the weekly medication administration as directed by the ship’s Commanding Officer. The patient did not receive the Medication Guide or Information Wallet Card, and his initial symptoms included anxiety and vivid dreams. Within 2 months of the deployment the patient developed a sense of disequilibrium, as well as episodes of confusion. He continued to take mefloquine for the 4-month duration of the deployment, as prescribed. Aside from a 4-day-long febrile illness, for which he tested negative for malaria, he had no other medical problems during the deployment. He discussed the vivid dreams with his medic and was instructed to continue taking the mefloquine. He attributed the disequilibrium to being onboard a ship and felt that the heightened anxiety was a byproduct of being deployed. Neither symptom was discussed with his medic. He primarily stayed on a ship the entire deployment and did not partake of any local food or water and denies any significant environmental exposures during this time. However, during port stops he did report drinking alcohol while taking mefloquine. Four months into the deployment, the patient experienced a traumatic event (enemy gun fire). The patient reported that his symptoms remained constant after the traumatic event and did not change until he came home from deployment 2 months later.\n\nAs soon as he returned home from deployment, 6 months after starting mefloquine, the patient and his wife noted increased emotional lability, typically manifesting as anger and irritability. He also endorsed difficulty concentrating, a decreased interest in most activities, persistent short-term memory problems and word-finding difficulties. In addition, right after disembarking from his ship, he had persistent ‘sea legs’ that became more episodic over the course of a few months. At the time of his visit to WRNMMC, the episodes of vertigo occurred four to five times per day and lasted approximately 20–30 min. He described the sensation as “everything in front of me is moving”. Closing his eyes improved these vertiginous symptoms. The patient reported knowing when symptoms were coming but denied any accompanying sweating, heart rate change, chest pain or nausea. He also reported having a constant dizziness that he described as “inside my head is spinning”. This symptom worsens when changing position or when running. He routinely stumbles when walking and has fallen down the stairs once. Prior to his deployment, the patient was a marathon runner but is now unable to run due to disequilibrium and vertigo.\n\nThese symptoms have led to significant marital problems, as well as self-reported concerns over his parenting abilities. The patient has needed significant support from his surrounding staff to function at his job due to his continued poor short-term memory. At the time of his clinic visit, the vivid dreams persisted, as well as nightmares and recurrent insomnia. His nightmares are rarely related to his deployment experiences. Aside from three visits to a mental health clinic for anger-coping strategies, the patient has not sought medical attention for these symptoms over the previous 4 years.\n\nFive months prior to his visit to WRNMMC, during a visit with a provider for a febrile illness, the patient mentioned the neuropsychiatric symptoms and was referred to the mental health clinic for further evaluation. He was initially diagnosed with anxiety disorder and was started on prazosin, which was stopped due to ineffectiveness. He was also tried on clonazepam and lorazepam, which were discontinued due to an increase in vertiginous symptoms and ineffectiveness, respectively. He underwent extensive neuropsychiatric testing; however, due to a perceived lack of effort and inability to focus, he failed the performance-based validity tests, making interpretation of the results difficult. After 3 months of psychotherapy and pharmacotherapy, his psychiatrist also diagnosed him with post-traumatic stress disorder (PTSD). This was primarily due to two episodes of heightened anxiety after being in close proximity to people believed to be from Somalia, which was one of the areas of operations from his previous deployment. At the time of this clinic visit, the patient was regularly seeing a psychiatrist and psychologist and had just started cognitive behavioral therapy. His medications included meclizine, venlafaxine, diazepam and clonidine. Aside from an improvement in his depressive symptoms, the patient reported no improvement in his recurrent balance or nightmare episodes since starting pharmacotherapy.\n\nReview of symptoms was positive for daily parietal headaches that sometimes refer occipitally, typically last a few hours, and resolve without pharmacotherapy. The patient denied any accompanying photophobia, phonophobia, nausea, blurry vision or proceeding aura, and also reported having recurrent febrile episodes that lasted for 2–3 days, every 3–4 months, since his deployment. These episodes resolved without medical intervention. The patient denied any associated symptoms with the fever, including pharyngitis or aphthous ulcers. He has also had enlarged, painless cervical lymph nodes for the past year, and has denied any weight loss, skin infections, sore throats, and exposure to cats or other animals. He previously had an extensive negative workup for these, including a complete blood count (CBC), chest x-ray, mononucleosis screen and malaria smear. Two neck ultrasounds, 6 months apart, suggested reactive lymphadenopathy. Additionally, antinuclear antibodies (ANA), folate, vitamin B12, brain magnetic resonance imaging (MRI) and internal auditory canal MRI were all normal.\n\nAdditional past medical history is significant for recurrent corneal abrasions of unknown etiology occurring approximately two to three times per year since 2009. The patient denied use of any other medications, dietary supplements or herbal remedies at the time the symptoms started or since. He reported no history of head trauma or mental health disorders.\n\nThe patient denied any significant family medical history, including mental health disorders or a history of periodic fevers.\n\nThe patient has lived in three different, recently built homes since returning from deployment. His only hobby is fishing; he does eat the fish that he catches. The patient denied any work or home activities that involved chemical fumes or vapors or use of industrial chemicals. He reported heavy alcohol use upon returning from deployment as a means of coping with his behavioral changes. However, after a few months, the patient was able to self-limit his intake and now drinks socially. He denied a history of alcohol withdrawal symptoms and use of any illicit drugs or nicotine products.\n\nOn examination, the patient was a well-dressed, articulate man who responded appropriately to all questions. He did appear jittery and frequently had to check his smartphone for answers to several medical history questions. Significant positive findings on his physical examination included head and neck flushing and mildly enlarged right posterior cervical and submandibular chain lymph nodes, with one smooth, mobile, non-tender node on the cervical chain measuring approximately 1 cm in diameter. His neurological examination was normal except for loss of balance while getting up from a seated position and during the tandem walk.\n\nThe patient underwent evaluations by the Infectious Diseases, Otolaryngology, Audiology and Neurology services. His initial workup included negative urine and blood heavy metal screens (copper, arsenic, mercury, lead, cadmium), and illicit drug urine screen, normal inflammatory markers, and CBC, thyroid, parathyroid, liver and kidney function labs. He also had a normal 24-h holter monitor. Additional laboratory examination revealed normal values for human chorionic gonadotropin (hCG), carcinoembryonic antigen (CEA), vasoactive intestinal polypeptide (VIP), catecholamines and α-fetoprotein (AFP). His infectious disease workup included negative labs for malaria, histoplasmosis, blastomycosis, HIV, tuberculosis, bartonella, Epstein–Barr Virus (EBV), syphilis, Lyme disease, cytomegalovirus (CMV), babesiosis, and chronic Q fever, and microscopy was without evidence of parasites in his blood. He also underwent a fine needle aspiration of the enlarged cervical lymph node, and the pathology was consistent with benign lymphoid tissue. It was the opinion of both the infectious diseases and otolaryngology consultants that the lymphadenopathy was likely reactive and benign, and no clear infectious etiology could be identified to explain the febrile episodes.\n\nPositive findings in the patient’s initial laboratory evaluation included an elevated histamine level of 4.75 ng/mL (normal <1.00), and low serotonin (9 ng/mL [21–321 ng/mL]) and thiamine levels (42.6 nmol/L [66.5–200 nmol/L]). As a result of the elevated histamine and flushing seen on examination, a subsequent workup to rule out a carcinoid tumor demonstrated normal 5-hydroxyindoleacetic acid (5-HIAA), chromogranin A, gastrin, adrenocorticotropic hormone (ACTH) and calcitonin levels. A repeat histamine level was also normal, as was an octreotide scan. Due to the elevated histamine and decreased serotonin, the patient’s methylenetetrahydrofolate (MTHFR) gene was tested and showed a single C677T mutation. The patient also had a normal homocysteine level. He was started on oral thiamine replacement (50 mg twice daily), with no improvement in his symptoms.\n\nVestibular testing by audiology showed no evidence of peripheral vestibulopathy. An MRI of the internal auditory canals was unremarkable. Rotary chair testing results showed rare findings of hyperactive vestibulo-ocular reflex (VOR) gains and an abnormally low VOR phase. These findings were reported to be consistent with migraines, motion sickness or a central vestibulopathy. The patient was referred for vestibular rehabilitation therapy.\n\nIn follow-up, the patient has been medically discharged from the military. Four and a half years after initial mefloquine exposure, he is still experiencing significant short-term memory problems and is seeing a speech therapist to aid with techniques to improve his memory and assist in activities of daily living. As a result of his short-term memory deficiency, the patient is only able to work part-time. He sleeps approximately 3–4 h per night and still regularly has vivid dreams and nightmares. He has multiple episodes of vertigo per week that force him to lie down and close his eyes. His constant dizziness has also persisted and he has reported several more falls while walking. His behavioral and psychological issues continue, with depressed mood, lack of motivation, restlessness, anxiety and emotional lability. He sees a behavioral therapist weekly and has discontinued all prescribed medications. He currently takes only vitamins and fish oil.\n\nDiscussion\nMefloquine was first discovered at the Walter Reed Army Institute of Research in the 1970s and was approved by the US FDA in 1989, under the tradename Lariam [1]. Although the original product insert alluded to the potential for neuropsychiatric side effects, it would be another 10–15 years before the full scope of toxicity, when used for malaria prophylaxis, was demonstrated in randomized control trials [1, 2]. In 2003, the FDA mandated that all patients prescribed mefloquine also receive a patient medication guide. In 2013, the FDA approved an updated and more stringent mefloquine drug label that included a boxed warning which, along with the patient medication guide, included information that neurologic and psychologic side effects of mefloquine may persist long after the drug has been discontinued, and may become permanent [3, 4]. Due to the increasing awareness of these neuropsychiatric side effects, the United States military relegated mefloquine to a third-line medication behind doxycycline and Malarone (atovaquone-proguanil) for prophylaxis in areas of chloroquine-resistant malaria, such as Afghanistan [5]. Consequently, from 2008 to 2013, the use of mefloquine in the military has decreased dramatically [6].\n\nMefloquine is an antimalarial that can be taken as treatment or as a prophylactic medication. Due to its long half-life, it is prescribed for once weekly administration for prophylactic use against malaria. Neuropsychiatric side effects attributed to mefloquine use range from common mild symptoms of insomnia, anxiety, mood changes, headaches, dizziness or vertigo to more severe and rare psychoses, violent behaviors, seizures, neuropathies and even suicide. Case reports describe a wide range of these and other symptoms, including symptoms of bipolar disorder, peripheral polyneuropathy, paranoid psychosis and suicide [7–11]. Rates of neuropsychiatric symptoms from prospective studies have ranged anywhere from 8 to 77 % [12–15].\n\nKnown risk factors for these neuropsychiatric side effects include a history of neuropsychiatric disorders, female sex, no previous mefloquine exposure and low body mass index [16]. This patient, aside from this being his first exposure to mefloquine, had none of the purported risk factors for neuropsychiatric adverse drug effects.\n\nAlthough case reports describing the mefloquine-induced neuropsychiatric side effects are well documented, the present case is unusual in that it documents symptoms potentially associated with mefloquine greater than 4 years after discontinuing the medication. Given the timing of the patient’s initial symptoms relative to mefloquine exposure, the type of symptoms, and lack of any other plausible cause, a Naranjo assessment score of 6 was given to this patient’s initial symptoms, indicating a probable relationship with mefloquine exposure. The true etiology of his progression of symptoms over the course of 4 years is more difficult to ascertain. While it is probable he suffered from mefloquine-induced toxicity during his deployment, the contribution of the traumatic event to his post-deployment behavioral changes, and the presence of other symptoms (i.e. nightmares and insomnia), serve to confound the diagnosis. The differential diagnosis includes persistent PTSD and mal de debarquement syndrome. The significant overlap in symptoms associated with mefloquine toxicity and PTSD obscures the distinction between these diagnoses. This patient exhibited behavioral symptoms in all four PTSD diagnostic clusters used in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V): re-experiencing, avoidance, negative cognitions and mood, and arousal [17]. However, as reported in the literature, the documented history of significant vestibular dysfunction as evidence by the abnormal findings on vestibular testing are more consistent with mefloquine toxicity rather than PTSD or somatoform disorders such as chronic subjective dizziness [18, 19]. A previous case report of similar vertiginous symptoms after taking mefloquine for prophylaxis also had objective evidence of a central vestibulopathy [20]. An FDA investigation of their Adverse Event Reporting System (FAERS), as well as additional case reports, describe suspected mefloquine-induced neuropsychiatric symptoms persisting and changing over time, even after mefloquine has been discontinued [21, 22]. A retrospective study examining mefloquine-related neuropsychiatric adverse events reported to a Danish national register showed 30 and 48 % of subjects reported experiencing nightmares and some form of cognitive dysfunction respectively, for at least 9 months [22]. This supports the apparent finding in this case that mefloquine toxicity symptoms can evolve and extend well beyond the end of medication administration.\n\nIn addition to the overlap in symptoms, there exists some contrasting biochemical links between mefloquine-induced changes in the central nervous system (CNS) and the development of PTSD [23]. It has been postulated that three biochemical events (increase in markers of oxidative stress, chronic inflammation, and excitotoxicity) play roles in developing PTSD [23]. Mefloquine has also been shown to increase levels of oxidative stress markers in the CNS [24–26]. As a contrast, one of the proposed mechanisms behind mefloquine-induced neurotoxicity is gap junction, specifically connexin 36, blockade. Connexin 36 forms the primary neuronal gap junction responsible for intercellular communication, including glutamate transmission [27]. Studies have shown that excessive glutamate release and receptor overactivation can lead to secondary neuronal death as well as PTSD [23, 28]. Pharmacologic blockade of connexin 36 can inhibit this over-activation and subsequent neuronal death [29]. In a mouse traumatic brain injury model, administration of a single dose of mefloquine 10 min after trauma showed a reduction in neuronal death compared with control mice [30]. However, mefloquine by itself has also been linked to neuronal cell death [31].\n\nSome reports suggest that concomitant ethanol consumption with mefloquine may have additive toxicity [32]. This patient reported alcohol intake while on shore leave during the period he was taking mefloquine. Ethanol has also been shown to inhibit connexin 36 gap junctions connecting γ-aminobutyric acid (GABA) neurons [33]. Although plausible, it is still unclear whether concomitant use of ethanol increases the risk, or severity, of mefloquine-induced neuropsychiatric symptoms.\n\nAnother consideration in this case is the MTHFR heterozygous C677T mutation. The MTHFR enzyme is responsible for many functions, including folate metabolism and DNA methylation, in addition to reducing oxidative stress. Although some studies show a possible link between this mutation and psychological disorders, the literature is conflicting and no studies were found regarding mefloquine or PTSD and MTHFR mutations [34, 35].\n\nIt is well known that thiamine deficiency can also cause neurological signs and symptoms, both reversible and irreversible; however, after weeks of thiamine replacement, no improvement in symptomatology was observed in this patient. In addition, although symptoms can be varied, the patient did not exhibit the classic peripheral neuropathy or Wernicke’s encephalopathy seen in dry beriberi. Interestingly, it has been shown in vitro that mefloquine completely inhibits thiamine transport [36]. How, if at all, the thiamine transport inhibition impacts mefloquine toxicity is unclear.\n\nIn light of the extensive negative workup and lack of reports linking mefloquine or PTSD with recurrent fevers, it is difficult to link the febrile episodes to the patient’s current symptomatology, and these may represent repeated viral infections.\n\nConclusion\nThis case documents the potential long-term and varied mefloquine-induced neuropsychiatric side effects, ranging from a central vestibulopathy to significant behavioral changes and sleep disorders. Especially pertinent to the military population, it demonstrates the difficulty in distinguishing from possible mefloquine-induced toxicity versus PTSD, and raises some questions regarding possible linkages between the two diagnoses.\n\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent may be requested for review from the corresponding author. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting the true views of the Department of the Army or the Department of Defense.\n\nCompliance with Ethical stndards\nConflict of interest\nJeffrey Livezey, Thomas Oliver and Louis Cantilena declare that they have no conflicts of interest.\n\nFunding\nNo financial support was received for the conduct of this study or the preparation of this article.\n==== Refs\nReferences\n1. Croft A A lesson learnt: the rise and fall of Lariam and Halfan J R Soc Med 2007 100 170 174 10.1258/jrsm.100.4.170 17404338 \n2. Nevin R Idiosyncratic quinoline central nervous system toxicity: historical insights into the chronic neurological sequelae of mefloquine Int J Parasitol Drugs Drug Resist. 2014 4 118 125 10.1016/j.ijpddr.2014.03.002 25057461 \n3. US FDA. FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects. 2013. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm362227.htm. Accessed 4 May 2016.\n4. Mefloquine hydrochloride [package insert]. Teva Pharmaceuticals. 2013. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09716a24-d7da-42b2-af29-c03a1b6670bd. Accessed 3 May 2016.\n5. Woodson J. Guidance on medications for prophylaxis of malaria. Washington, DC: Department of Defense Health Affairs; 2013.\n6. Kersgard CM Hickey PW Adult malaria chemoprophylaxis prescribing patterns in the military health system from 2007–2011 Am J Trop Med Hyg 2013 89 2 317 325 10.4269/ajtmh.13-0013 23817331 \n7. Brumbaugh M Price P Fagan N Hsieh H Psychotic mania associated with mefloquine in a bipolar patient South Med J 2008 101 550 551 10.1097/SMJ.0b013e318167a9e2 18414180 \n8. Chester AC Sandroni P Case report: peripheral neuropathy and mefloquine prophylaxis Am J Trop Med Hyg 2011 85 1008 1009 10.4269/ajtmh.2011.11-0412 22144435 \n9. Fuller SJ Naraqi S Gilessi G Paranoid psychosis related to mefloquine antimalarial prophylaxis P N G Med J 2002 45 219 221 12968793 \n10. Tran TM Browning J Dell ML Psychosis with paranoid delusions after a therapeutic dose of mefloquine: a case report Malaria J. 2006 5 74 10.1186/1475-2875-5-74 \n11. Jousset N Rouge-Maillart C Turcant A Suicide by skull stab wounds Am J Foren Med Path. 2010 31 378 381 10.1097/PAF.0b013e3181f9443c \n12. Nasveld P Edstein M Reid M Randomized, double-blind study of the safety, tolerability and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects Antimicrob Agents Chemother 2010 54 792 798 10.1128/AAC.00354-09 19995933 \n13. Schlagenhauf P Steffen R Lobel H Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance Trop Med Int Health. 1996 1 485 494 10.1046/j.1365-3156.1996.d01-85.x 8765456 \n14. van Riemsdijk M Sturkenboom M Ditters J Low body mass index is associated with an increased risk of neuropsychiatric adverse events and concentration impairment in women on mefloquine Br J Clin Pharmacol 2003 57 506 512 10.1046/j.1365-2125.2003.02035.x 15025750 \n15. Schlagenhauf P Tschopp A Johnson R Tolerability of malaria chemoprophylaxis in non-immune travelers to sub-Saharan Africa: multicenter, randomised, double blind, four arm study BMJ 2003 327 1 6 10.1136/bmj.327.7423.1078 12842922 \n16. Toovey S Mefloquine neurotoxicity: a literature review Travel Med Infect Dis. 2009 7 2 6 10.1016/j.tmaid.2008.12.004 19174293 \n17. American Psychiatric Association Diagnostic and statistical manual of mental disorders 2013 5 Washington DC American Psychiatric Association \n18. Nevin RL Ritchie EC Metzgar M Wise D Redding J Mefloquine and post traumatic stress disorder Forensic and ethical issues in military behavioral health 2014 Houston Borden Institute 275 296 \n19. Staab JP Chronic dizziness: the interface between psychiatry and neuro-otology Curr Opin Neurol 2006 19 41 48 10.1097/01.wco.0000198102.95294.1f 16415676 \n20. Nevin RL Limbic encephalopathy and central vestibulopathy caused by mefloquine: a case report Travel Med Infect Dis. 2012 10 144 151 10.1016/j.tmaid.2012.03.006 22494697 \n21. FDA Safety Alert for Human Medical Products. Lariam (mefloquine hydrochloride). FDA; 2003. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm153319.htm. Accessed 4 May 2016.\n22. Ringqvist A Bech P Glenthoj B Petersen E Acute and long-term psychiatric side effects of mefloquine: a follow-up on Danish adverse event reports Travel Med Infect Dis. 2015 13 80 88 10.1016/j.tmaid.2014.10.021 25435322 \n23. Prasad KN Bondy SC Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI Brain Res 2015 1599 103 114 10.1016/j.brainres.2014.12.038 25553619 \n24. Ding D Qi W Yu D Addition of exogenous NAD+ prevents mefloquine induced neuroaxonal and hair cell degeneration through reduction of caspase-3-mediated apoptosis in cochlear organotypic cultures PLoS One 2013 8 11 e79817 10.1371/journal.pone.0079817 24223197 \n25. Milatovic D Jenkins JW Hood JE Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase Neurotoxicology. 2011 32 578 585 10.1016/j.neuro.2011.01.001 21241737 \n26. Hood JE Jenkins JW Milatovic D Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons Neurotoxicology. 2010 31 518 523 10.1016/j.neuro.2010.05.005 20562019 \n27. Bellurdo N Trovato-Salinaro A Mudo G Structure, chromosomal location, and brain expression of human Cx36 gene J Neurosci Res 1999 57 740 752 10.1002/(SICI)1097-4547(19990901)57:5<740::AID-JNR16>3.0.CO;2-Z 10462698 \n28. Yi JH Hazell AS Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury Neurochem Int 2006 48 394 403 10.1016/j.neuint.2005.12.001 16473439 \n29. Wang Y Song JH Denisova JV Neuronal gap junction coupling is regulated by glutamate and plays critical role in cell death during neuronal death J Neurosci 2012 32 713 725 10.1523/JNEUROSCI.3872-11.2012 22238107 \n30. Belousov AB Wang Y Song JH Neuronal gap junctions play a role in the secondary neuronal death following controlled cortical impact Neurosci Lett 2012 524 16 19 10.1016/j.neulet.2012.06.065 22781494 \n31. Nevin RL Epileptogenic potential of mefloquine chemoprophylaxis: a pathogenic hypothesis Malaria J. 2009 8 188 10.1186/1475-2875-8-188 \n32. Wittes RC Saguinar R Adverse reaction to mefloquine associated with ethanol ingestion Can Med Assoc J 1995 152 515 517 7859199 \n33. Steffenson SC Bradley KD Hansen DM The role of connexin-36 junctions in alcohol intoxication and consumption Synapse 2011 65 695 707 10.1002/syn.20885 21638336 \n34. El-Hadidy MA, Abdeen HM, El-Aziz SM, Al-Harrass M. MTHFR gene polymorphism and age of onset of schizophrenia and bipolar disorder. Biomed Res Int. 2014;2014:318483.\n35. Lok A Bockting CH Koeter MW Interaction between the MTHFR C677T polymorphism and traumatic childhood events predicts depression Transl Psychiatry. 2013 3 e288 10.1038/tp.2013.60 23900311 \n36. Huang Z Srinivasan S Zhang J Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy PLoS Genet 2012 8 11 e1003083 10.1371/journal.pgen.1003083 23209439\n\n",
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"title": "Prolonged Neuropsychiatric Symptoms in a Military Service Member Exposed to Mefloquine.",
"title_normalized": "prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine"
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"abstract": "To compare the safety, efficacy, and outcome measures of a single-site, mitomycin C (MMC)-augmented trabeculectomy combined with phacoemulsification (PT) versus manual small-incision cataract surgery (MSICS) with the posterior chamber intraocular lens (PCIOL) implantation as a primary surgery in the patients with primary glaucoma coexistent with cataract.\nFrom April 2015 to August 2017, medical records of all the patients who underwent combined cataract surgery with PCIOL and MMC augmented trabeculectomy were reviewed. One hundred and thirty-seven eyes met the inclusion criteria. Ninety-seven eyes which underwent PT with MMC were compared with forty eyes that underwent MSICS combined with trabeculectomy (MSICST) MMC. Outcome measures were best corrected visual acuity (BCVA), intraocular pressure (IOP), and number of anti-glaucoma medications (AGM). Complications, if any, were noted in both the groups.\nThe mean follow-up period after surgery was 18.6 ± 7.7 months (range, 12-40 months). At the last follow-up visit, there was no statistically significant difference between the groups, in terms of mean logMAR BCVA (PT: 0.22 ± 0.31, MSICST: 0.21 ± 0.33, P = 0.8), mean IOP reduction (PT: 13.9 ± 2.98 mmHg, MSICST: 14.1 ± 4.12 mmHg, P = 0.8), and mean number of AGM (PT: 0.03 ± 0.8, MSICST: 0.025 ± 0.7, P = 0.8). Complications were few and transient. One eye in the PT group was considered as a failure and had to undergo needling, repeat trabeculectomy, and later, cyclodestructive procedure. None of the eyes in the MSICST group required an additional procedure for IOP reduction.\nThere was no difference in the mean IOP reduction, BCVA, and mean number of AGM between the two procedures, and both appeared to be safe and effective techniques as a primary surgery in the patients with coexistent cataract and glaucoma.",
"affiliations": "Department of Glaucoma, Sita Lakshmi Glaucoma Center, Anand Eye Institute, Hyderabad, Telangana, India.;Department of Statistics, Apollo Institute of Medical Sciences and Research, Hyderabad, Telangana, India.",
"authors": "Mansoori|Tarannum|T|;Balakrishna|Nagalla|N|",
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"doi": "10.4103/JOCO.JOCO_4_20",
"fulltext": "\n==== Front\nJ Curr Ophthalmol\nJ Curr Ophthalmol\nJCO\nJournal of Current Ophthalmology\n2452-2325 Wolters Kluwer - Medknow India \n\nJCO-32-329\n10.4103/JOCO.JOCO_4_20\nOriginal Article\nComparison of the Surgical Outcomes of Single-Site, Mitomycin C-Augmented Trabeculectomy Combined with Phacoemulsification versus Manual Small-Incision Cataract Surgery\nMansoori Tarannum 1 Balakrishna Nagalla 2 1 Department of Glaucoma, Sita Lakshmi Glaucoma Center, Anand Eye Institute, Hyderabad, Telangana, India\n2 Department of Statistics, Apollo Institute of Medical Sciences and Research, Hyderabad, Telangana, India\nAddress for correspondence: Tarannum Mansoori, Sita Lakshmi Glaucoma Center, Anand Eye Institute, 7-147/1, Nagendra Nagar, Habsiguda, Hyderabad, Telangana, India. E-mail: tarannummansoori@yahoo.com\nOct-Dec 2020 \n12 12 2020 \n32 4 329 334\n09 1 2020 14 5 2020 04 6 2020 Copyright: © 2020 Journal of Current Ophthalmology2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Purpose:\nTo compare the safety, efficacy, and outcome measures of a single-site, mitomycin C (MMC)-augmented trabeculectomy combined with phacoemulsification (PT) versus manual small-incision cataract surgery (MSICS) with the posterior chamber intraocular lens (PCIOL) implantation as a primary surgery in the patients with primary glaucoma coexistent with cataract.\n\nMethods:\nFrom April 2015 to August 2017, medical records of all the patients who underwent combined cataract surgery with PCIOL and MMC augmented trabeculectomy were reviewed. One hundred and thirty-seven eyes met the inclusion criteria. Ninety-seven eyes which underwent PT with MMC were compared with forty eyes that underwent MSICS combined with trabeculectomy (MSICST) MMC. Outcome measures were best corrected visual acuity (BCVA), intraocular pressure (IOP), and number of anti-glaucoma medications (AGM). Complications, if any, were noted in both the groups.\n\nResults:\nThe mean follow-up period after surgery was 18.6 ± 7.7 months (range, 12–40 months). At the last follow-up visit, there was no statistically significant difference between the groups, in terms of mean logMAR BCVA (PT: 0.22 ± 0.31, MSICST: 0.21 ± 0.33, P = 0.8), mean IOP reduction (PT: 13.9 ± 2.98 mmHg, MSICST: 14.1 ± 4.12 mmHg, P = 0.8), and mean number of AGM (PT: 0.03 ± 0.8, MSICST: 0.025 ± 0.7, P = 0.8). Complications were few and transient. One eye in the PT group was considered as a failure and had to undergo needling, repeat trabeculectomy, and later, cyclodestructive procedure. None of the eyes in the MSICST group required an additional procedure for IOP reduction.\n\nConclusion:\nThere was no difference in the mean IOP reduction, BCVA, and mean number of AGM between the two procedures, and both appeared to be safe and effective techniques as a primary surgery in the patients with coexistent cataract and glaucoma.\n\nManual small-incision cataract surgeryPhacoemulsificationTrabeculectomy with mitomycin C\n==== Body\nINTRODUCTION\nTrabeculectomy augmented with mitomycin C (MMC) is often performed as a primary surgical procedure for the patients with glaucoma, along with cataract extraction and posterior chamber intraocular lens (PCIOL) implantation, as it is considered safe and effective in terms of lowering intraocular pressure (IOP) with less or no dependency on anti-glaucoma medications (AGM).1 However, it requires a longer surgical time and has the risk of complications, associated with cataract surgery (posterior capsule [PC] dehiscence, zonular dialysis, etc.) as well as trabeculectomy (postoperative hypotony, bleb leak, endophthalmitis, and failure of the bleb).123\n\nIn our urban setup, majority of the times, glaucoma is diagnosed during a routine eye examination, when the patient seeks advice for cataract surgery. Previous studies in Asian Indian eyes have shown that trabeculectomy combined with manual small-incision cataract surgery (MSICS) or phacoemulsification is effective in lowering the IOP with minimum complications.45 Both these studies looked at surgical outcomes in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), but did not include any patients with acute primary angle closure (APAC).\n\nWe evaluated the results of single-site trabeculectomy augmented with MMC, combined with phacoemulsification versus MSICS with PCIOL in the patients with primary glaucoma coexistent with cataract as a primary procedure.\n\nMETHODS\nWe retrospectively analyzed the medical records, from April 2015 to August 2017, of all the patients who underwent cataract extraction (phacoemulsification or MSICS) with MMC-augmented trabeculectomy at our institute in South India. One hundred and thirty-seven eyes met the inclusion criteria. All surgeries were performed by a single surgeon (T.M.). All procedures were performed in accordance with the 1964 Declaration of Helsinki and its later amendments, and the study was approved by the internal institute review board.\n\nThe data collected were age of the patient, gender, medical and ocular history, laterality of the eye, diagnosis, pre and postoperative number of AGM, best corrected visual acuity (BCVA), anterior and posterior segment examination, IOP measured with Goldmann applanation tonometry, gonioscopy with Sussman goniolens, optic disc and retina evaluation with +90 Diopter (D) lens, Humphrey visual field (HVF 24-2 and/or 10-2, Swedish interactive threshold algorithm standard, Carl-Zeiss Meditec, Inc, Dublin, CA), central corneal thickness (CCT), date of the surgery, intraoperative or postoperative complications, IOP at the different follow-up periods (baseline, postoperative day 1, 1 week, 1 month, 3 months, 1 year, 2 years, and 3 years), postoperative intervention (if any), and duration of follow-up after the surgery.\n\nThe choice of phacoemulsification or MSCIS was based on the socio-economic status of the patients and grading of nuclear sclerosis (patients with Brunescent or black nucleus had undergone MSICS). Patients with secondary glaucoma, such as lens-induced, neovascular, or uveitic glaucoma; previous failed trabeculectomy, or other intraocular surgery; postoperative follow-up <1 year, were excluded from the study. For a few patients, HVF 24-2 could not be performed because of poor visual acuity due to dense cataract or advanced glaucoma. For others, if the visual fields were unreliable despite repeating on two occasions, they were not included in the analysis for the visual field.\n\nAll the surgeries were performed under peribulbar anesthesia (5 cc of 2% xylocaine hydrochloride, mixed with hyaluronidase 1500 IU/ml and 2 cc of 0.5% bupivacaine hydrochloride). With 4-0 silk, superior rectus traction suture was taken, and a fornix-based conjunctival flap of 6–7 mm, without relaxing incision, was dissected at the superior limbus and backward for 8–10 mm. Tenon's capsule was separated. Three Weck Cel® MMC (0.4 mg/ml) soaked sponges were applied to the episclera posteriorly for 3 min, and after removal of the sponges, the area was irrigated thoroughly with 40 cc of Ringer lactate solution.\n\nFor MSICS trabeculectomy (MSICST), a triangular, partial-thickness, 3 mm × 3 mm, limbus-based scleral flap was made, 1.5 mm posterior to the limbus with a 11 number blade. The dissection was performed with a crescent blade till 1–1.5 mm from the limbus, and on the same plane, the corneo-scleral tunnel was fashioned for 2–2.5 mm on either side of the triangular flap (depending on the nucleus sclerosis), keeping the sides of the triangular flap intact, till 1.5–2 mm into the clear cornea. The anterior chamber (AC) was entered with a 3.2-mm keratome under the scleral flap. Continuous curvilinear capsulorrhexis (CCC, 6–7 mm) was performed with the cystitome. The inner lip of the tunnel was enlarged to approximately 8–9 mm. With the hydrodissection, the upper pole of the nucleus was prolapsed out of the capsular bag, and with the same hydro cannula, the nucleus was rotated and prolapsed into the AC. Viscoelastic (Viscomet-PF, Sun Pharmaceuticals Industries Ltd., Mumbai, Maharashtra, India) was injected both above and below the nucleus, and with the help of wire vectis, the nucleus was delivered out. The remaining epinucleus was removed with the viscoelastic, and the cortex was aspirated using a classical simcoe irrigation–aspiration cannula. A single-piece, rigid, polymethyl methacrylate PCIOL of optic diameter 5.5 or 6 mm was implanted in the bag.\n\nFor phacotrabeculectomy (PT), a triangular, partial-thickness, 3.5 mm × 3.5 mm scleral flap was made superiorly with a 11 number blade. Three Weck Cel MMC (0.4 mg/ml) soaked sponges were applied to the episclera posteriorly for 3 min, and after removal of the sponges, the area was irrigated thoroughly with 40 cc of Ringer lactate solution. The dissection was performed with a crescent blade till 1–1.5 mm into the clear cornea. AC was entered with a 3.2 mm keratome, and CCC (5–6 mm) was done. Phacoemulsification was performed using the stop and chop technique. Cortex was aspirated, and an acrylic hydrophilic or hydrophobic foldable PCIOL was inserted into the bag with the use of a disposable cartridge and injector.\n\nAfter the implantation of PCIOL, viscoelastic was aspirated. Under the triangular scleral flap, trabeculectomy was performed by excising a block of 1 × 1 tissue from the posterior lip of the scleral tunnel, using a Kelly's Descemet's membrane punch. Peripheral iridectomy was performed with a Vannas scissor. Scleral flap was closed with the 10-0 monofilament nylon sutures, one on the either side of the triangular flap, close to the base, and one at the apex of the flap. The conjunctiva was closed with 2-wing 8-0 Vicryl suture, near the limbus, in a watertight manner. Ringer's lactate was injected through the side port into the AC to observe the formation of diffuse conjunctival bleb and any possible leak. At the end of the surgery, a drop of topical 5% povidone-iodine was instilled, and the eye was patched.\n\nPostoperatively, the patients were treated with topical 1% prednisolone acetate eight times daily for a week, tapered over 5 weeks (depending on the inflammation), 0.5% moxifloxacin eight times daily for a week, and 1% cyclopentolate three times daily for a week. Patients were evaluated on postoperative day 1, 1 week, 1 month, 3 months, and every 3 months thereafter with additional visits, as and when required.\n\nBased on the level of IOP and to facilitate bleb formation, digital massage of the bleb or addition of AGM or selective Argon laser suture lysis or needling was performed, whenever required.\n\nStatistical analysis was performed with SPSS version 16 (SPSS, Inc., Chicago, IL, USA) statistical software. The t-test was used for comparison of variables with normal distribution and Mann–Whitney U-test for variables with non-normal distribution. Paired t-test and Chi-square tests were used to compare the pre and postoperative parameters. Chi-square test was used to compare categorical variables. Snellen visual acuity was converted to the logMAR acuity by the standard conversion table. Kaplan–Meier survival analysis was used to measure cumulative survival probability. Mantel–Cox log rank test was used to compare cumulative survival between the groups. P < 0.05 was considered statistically significant.\n\nPrimary outcome measures were mean IOP reduction compared to the baseline IOP, BCVA, and number of AGM at the last follow-up visit. Complete success was defined as IOP <21 mmHg without additional AGM or surgery and qualified success as IOP <21 mmHg with a single AGM. Failure was defined as IOP >21 mmHg, despite on more than one AGM or whether additional procedures such as cyclodestructive procedures, trabeculectomy, or valve surgery were required to control the IOP. Secondary outcome measure was any noted complications.\n\nRESULTS\nOne hundred and sixty-five eyes underwent combined surgery: 28 eyes were excluded as 20 patients had a follow-up of <1 year, 1 eye had subluxated lens and underwent combined surgery with iris claw lens, 4 eyes had preexisting trabeculectomy, and in 3 eyes, the surgery was combined with anti-vascular endothelial growth factor injection.\n\nDemographic data of all the study participants is shown in Table 1. There was no difference in the age, gender, baseline IOP, IOP at the last visit, number of AGM (pre and postoperatively) HVF mean deviation, pattern standard deviation, and CCT between the two groups. All the parameters were comparable between the groups except that the preoperative BCVA was worse in the MSICST group compared to the PT group. Both the groups had more number of PACG patients than the POAG. APAC was present in six eyes in the PT group and five eyes in the MSICST group. The mean cup–disc ratio was 0.717 ± 0.169 in the PT group and 0.702 ± 0.217 in the MSICST group.\n\nTable 1 Baseline characteristics of the study participants (n=137)\n\nVariables\tPhacoemulsification - trabeculectomy with MMC (n=97), n (%)\tSmall-incision cataract surgery - trabeculectomy with MMC (n=40), n (%)\tP\t\nMean age (years)\t66.18±8.16\t64.47±13.68\t0.37\t\nMale:female*\t50:47\t16:24\t0.15*\t\nRight eye/left eye*\t49/48\t24/16\t0.20*\t\nDiagnosis\t\t\t\t\n Primary open-angle glaucoma\t38 (39.2)\t13 (32.5)\t0.46\t\n Primary angle-closure glaucoma\t53 (54.6)\t22 (55)\t0.97\t\n Acute primary angle closure\t6 (6.2)\t5 (12.5)\t0.22\t\n BCVA preoperative (logMAR)\t0.68±0.4\t1.0±0.43\t<0.0001\t\n Central corneal thickness (microns)\t515.87±37.35\t509.69±34.81\t0.42\t\n Mean deviation (dB)\t−17.85±9.18\t−18.92±8.75\t0.57\t\n Pattern standard deviation (dB)\t5.97±3.14\t6.91±2.44\t0.13\t\n Intraocular pressure at baseline (mmHg)\t23.79±9.79\t22.28±8.94\t0.40\t\n Number of preoperative anti-glaucoma medications\t1.84±1.0\t1.95±0. 96\t0.56\t\nSystemic diseases\t\t\t\t\n Diabetes mellitus\t31 (32)\t9 (22.5)\t0.27\t\n Systemic hypertension\t49 (50.5)\t15 (37.5)\t0.46\t\n Coronary artery disease\t5 (5.15)\t1 (2.5)\t0.49\t\n*Chi square test, MMC: Mitomycin C, dB: Decibel, BCVA: Best corrected visual acuity\n\nThe mean follow-up period after surgery was 18.6 ± 7.7 months (range, 12–40 months). Three eyes in the PT group and one in the MSICST group required Argon laser suture lysis within 2–3 weeks after the surgery. The mean IOP at all the follow-up visits were similar in both groups [Table 2]. There was no significant difference in the IOP between the two surgical procedures at any of the follow-up visits. There was a significant reduction in IOP at all the follow-up visits when compared to the baseline IOP in both groups [Table 3]. At the last follow-up visit, there was no significant difference between the groups in terms of mean logMAR BCVA (PT: 0.22 ± 0.31, MSICST: 0.21 ± 0.33, P = 0.8), mean IOP reduction (PT: 13.9 ± 2.98 mmHg, MSICST: 14.1 ± 4.12 mmHg, P = 0.8), and mean number of AGM (PT: 0.03 ± 0.8, MSICST: 0.025 ± 0.7, P = 0.8) [Table 4].\n\nTable 2 Mean intraocular pressure at the various time periods after combined surgery\n\nIOP\tIOP in eyes with phacoemulsification - trabeculectomy with MMC\tIOP in eyes with small-incision cataract surgery - trabeculectomy with MMC\tMean IOP difference\tP\t\nBaseline\t23.79±9.79 (n=97)\t22.28±8.94 (n=40)\t1.52\t0.4\t\n1 day\t18.67±7.83 (n=97)\t18.68±9.02 (n=40)\t−0.005\t0.997\t\n1 week\t14.77±6.11 (n=97)\t15.03±7. 4 (n=39)\t−0.25\t0.84\t\n1 month\t14.74±5.12 (n=86)\t13.26±3.95 (n=34)\t1.48\t0.13\t\n3 months\t13.59±3.47 (n=70)\t14.08±4.39 (n=26)\t−0.49\t0.57\t\n6 months\t13.55±3.24 (n=49)\t13.35±3.1 (n=20)\t0.20\t0.81\t\n1 year\t14.93±4.45 (n=73)\t13.73±2.79 (n=26)\t1.2\t0.2\t\n2 year\t14±3.2 (n=46)\t13.3±2.41 (n=20)\t0.7\t0.38\t\n3 year\t14.18±3.6 (n=11)\t15±1.15 (n=4)\t−0.82\t0.67\t\nLast follow-up visit\t13.93±2.98 (n=97)\t14.08±4.12 (n=40)\t−0.15\t0.81\t\nIOP: Intraocular pressure, MMC: Mitomycin C, n = Number of eyes at the follow-up visit\n\nTable 3 Mean difference in the intraocular pressure at various time points when compared to the preoperative intraocular pressure\n\nIOP from baseline till the follow-up visit (number of patients at the follow-up visit)\tMean difference of IOP (mmHg)\tP\t95% confidence interval for difference\t\n\t\nLower bound\tUpper bound\t\nPhacotrabeculectomy with MMC\t\t\t\t\t\n 1 day (n=97)\t6.121\t0.006\t1.911\t10.331\t\n 1 week (n=97)\t9.182\t<0.0001\t5.535\t12.829\t\n 1 month (n=86)\t6.455\t0.002\t2.511\t10.398\t\n 3 months (n=70)\t8.273\t<0.0001\t4.539\t12.007\t\n 6 months (n=49)\t10.788\t<0.0001\t7.437\t14.139\t\n 1 year (n=73)\t11.303\t<0.0001\t8.168\t14.438\t\n 2 years (n=46)\t8.727\t<0.0001\t5.299\t12.155\t\n 3 years (n=11)\t10.273\t<0.0001\t6.788\t13.757\t\nManual small-incision cataract surgery with MMC-augmented trabeculectomy\t\t\t\t\t\n 1 day (n=40)\t6.364\t0.07\t−0.555\t13.282\t\n 1 week (n=39)\t11.636\t0.01\t3.512\t19.761\t\n 1 month (n=34)\t11.364\t0.015\t2.707\t20.021\t\n 3 months (n=26)\t12.00\t0.004\t4.789\t19.211\t\n 6 months (n=20)\t11.182\t0.01\t3.331\t19.033\t\n 1 year (n=26)\t10.00\t0.02\t1.582\t18.418\t\n 2 years (n=20)\t11.273\t0.007\t3.779\t18.766\t\n 3 years (n=4)\t10.727\t0.01\t3.186\t18.269\t\nIOP: Intraocular pressure, MMC: Mitomycin C\n\nTable 4 Comparison of the postoperative primary outcome variables between the two surgical groups\n\nVariables\tPhacoemulsification - trabeculectomy with MMC (n=97)\tSmall-incision cataract surgery - trabeculectomy with MMC (n=40)\tP\t\nBest corrected visual acuity (logMAR)\t0.22±0.31\t0.21±0.33\t0.82\t\nIOP at the last follow-up (mmHg)\t13.93±2.98\t14.08±4.12\t0.81\t\nNumber of anti-glaucoma medications\t0.28±0.85\t0.25±0.67\t0.85\t\nIOP: Intraocular pressure, MMC: Mitomycin C\n\nComplete success at the last follow-up was achieved in 88.7% of the eyes in the PT group and 87.5% of the eyes in the MSICST group. Qualified success at the last follow-up was seen in 99% in the PT group and 100% in the MSICST group. The difference in qualified success between the groups was not statistically significant (Mantel–Cox log rank test, P = 0.164). One eye in the PT group was considered as a failure and had to undergo needling, repeat trabeculectomy, and later, cyclodestructive procedure. None of the eyes in the MSICST group required an additional procedure for IOP reduction. Two eyes in each group had IOP of 21 mmHg at the last follow-up visit and were lost for follow-up after a year.\n\nComplications noted were overfiltering bleb with shallow AC and serous choroidal detachment in one eye of the PT group and two eyes of the MSICST group, which were managed conservatively and had good visual outcome. The eyes did not have hypotony after 2 weeks of medical management. Intraoperatively, one eye had partial flap dehiscence near the limbus in the PT group, and one eye in the MSICST group had conjunctival button hole, both of which were managed successfully. In the PT group, 1 eye had hyphema on the 3rd postoperative day as the patient had accidentally rubbed his operated eye, and 1 eye operated for APAC had decompression retinopathy after Argon laser suture lysis. None of the patients had bleb leak, blebitis, thin-walled bleb, zonular dialysis, or PC dehiscence. One eye in the PT group had endophthalmitis on the 4th postoperative day, which required intravitreal antibiotics, and had good visual recovery of 20/30 with IOP of 12 mmHg without AGM at 2 weeks and at the last follow-up visit.\n\nCauses for the decrease in vision or non-improvement in vision after the surgery in the overall cohort were age-related macular degeneration (six eyes), advanced glaucoma (six eyes), macular hole (two eyes), clinically significant macular edema (four eyes), and decompression retinopathy with clinically significant macular edema in one eye.\n\nDISCUSSION\nThe aim of combined surgery in the patients with glaucoma with coexisting cataract is to reduce IOP, improve visual acuity, and reduce dependency on the AGM with a single procedure. In our study, we compared the safety and efficacy of single-site PT with MMC and MSICST with MMC, in the eyes with PACG, APAC, and POAG and found that the survival probability was similar between the two surgeries. There was no significant difference in the mean BCVA, IOP reduction, and the number of AGM at the last follow-up visit between the two groups. The number of patients with PACG was more when compared with POAG in both the groups; however, there was no difference in the glaucoma subtypes between the groups.\n\nIn my practice, I use MMC for all the patients undergoing trabeculectomy, with safe surgical system, with wide application of MMC-soaked sponges applied posteriorly, to allow diffuse, non-cystic bleb.6 In addition, the base of scleral flap incision is not extended up to the limbus, and scleral flap sutures are applied to the base of triangular flap near the limbus to allow for a posterior directed aqueous flow. The observations of our study are relevant in the context of improvements in the safe surgical technique of trabeculectomy with the adjuvant use of MMC. In our patients, majority of the blebs were diffuse and mildly elevated with normal vascularity. Furthermore, an advantage of a single-site surgery is that the trabeculectomy can be performed through the same scleral tunnel used for MSICS or phacoemulsification.\n\nIn our series, with the criteria of complete success, 86 eyes (88.7%) maintained an IOP of ≤21 mmHg with no medications in the PT group and 87.5% in the MSICST group. With the criteria of qualified success, 96/97 eyes (98.96%) in the PT group and all the eyes in the MSICST group had an IOP of ≤21 mmHg. Ten eyes (10.3%) maintained an IOP of <21 mmHg with AGM in the PT group and five eyes (12.5%) in the MSICST group. Overall, we had excluded 28 eyes, however at the last follow-up, all of these eyes had an IOP of <21 mmHg without any AGM. The surgical success of single-site cataract surgery with trabeculectomy with MMC in terms of survival probability did not show a statistically significant difference between the two groups (P = 0.164).\n\nSurgical failure, as defined by the study protocol, was observed in 1/97 eyes in the PT (1.03%) group and none of the eyes in the MSICST group. The mean IOP at all follow-up visits was similar in both groups. Ninety-nine percent of the eyes in the PT group and 100% of the eyes in the MSICS group achieved an IOP control at 21 mmHg or lower with or without medication over a mean follow-up of 18.6 ± 7.7 months.\n\nJin et al.7 in a study of sixty eyes (43 patients who underwent PT with MMC) reported a failure rate of 5%. Rockwood et al.8 in a series of PT with antimetabolites in 456 patients found a failure rate of 9% and reported that a diagnosis other than the primary glaucoma was significantly associated with repeat surgery for glaucoma. Rao et al.9 reported an overall failure rate of 6.3% in 143 eyes of 120 patients who underwent PT without antimetabolite and found that the younger age at the time of surgery has significant association with the surgical failure.\n\nIn our study, postoperative improvement in the BCVA was similar in both groups. In all the eyes, the cause for non-improvement of vision was either preexisting retinal pathology or advanced glaucoma, and none had a decrease in the vision related to the surgery. There was a significant reduction in the number of preoperative and postoperative use of AGM in both the groups. Preoperatively, seven patients were on oral acetazolamide in the PT group and two in the MSICS group. Postoperatively, none of the patients required acetazolamide for IOP reduction.\n\nChen et al.10 reported that the most common complications after PT with MMC were hypotony, hyphema, and shallow AC. In our study, complications in both groups were few, transient, and managed without any surgical intervention. None of the patients lost light perception or had a significant reduction in the vision due to the surgery.\n\nConsidering the non-compliance for medical therapy, missed follow-up visits, and delayed time period of first presentation of the patients with advanced cataract and glaucoma, the surgical option for managing cataract and glaucoma in a single sitting is cost-effective11 (especially MSICST) in the developing countries.\n\nIn a retrospective analysis of 72 MSICST and 33 PT with MMC (mean follow-up, 13.73 months), IOP <18 mmHg without AGM was observed in 62.3% of the MSICST and 50% in the PT group.4 The surgical outcome and complications were not significantly different for both the techniques. In another retrospective study from South India, 87 eyes (follow-up range, 6–30 months) that underwent PT with MMC were compared with 86 eyes that underwent Blumenthal technique of MSICST with MMC.5 At the last follow-up visit, the mean reduction in the IOP was 17.7 ± 9.3 mmHg in the PT group and 17.1 ± 10 mmHg in the MSICST group.\n\nOur study has the limitations of a retrospective study design. The number of eyes in the MSICST group was less than that of the PT group. The distribution of cataract was also unequal, with more eyes with advanced and complicated cataract in the MSICST group, though the glaucoma staging and follow-up regimen were similar between the groups. We could not compare preoperative and postoperative visual fields in most of the patients. The reason was the inability of patients to perform the visual fields due to advanced cataract or due to unreliable HVF, which were excluded from the analysis. For these patients, visual fields were repeated at a month after the surgery when the visual acuity improved after the cataract extraction.\n\nCombined surgery provides an early visual rehabilitation and long-term reduction of the IOP with less dependency on AGM. MSICST is a cost-effective, good surgical technique, especially in patients with advanced cataract and coexisting glaucoma.\n\nIn conclusion, our retrospective study did not demonstrate any significant difference in the mean IOP reduction, BCVA, and mean number of AGM between the two procedures, and both appear to be a safe and effective technique as a primary surgery in the patients with coexistent cataract and glaucoma.\n\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgments\nThe authors would like to thank Ms. Sabera Banu, L V Prasad Eye Institute, Hyderabad, for providing research-related articles for the study.\n==== Refs\nREFERENCES\n1 Friedman DS Jampel HD Lubomski LH Kempen JH Quigley H Congdon N Surgical strategies for coexisting glaucoma and cataract: An evidence-based update Ophthalmology 2002 109 1902 13 12359612 \n2 Jampel HD Solus JF Tracey PA Gilbert DL Loyd TL Jefferys JL Outcomes and bleb-related complications of trabeculectomy Ophthalmology 2012 119 712 22 22244944 \n3 Jampel HD Friedman DS Lubomski LH Kempen JH Quigley H Congdon N Effect of technique on intraocular pressure after combined cataract and glaucoma surgery: An evidence-based review Ophthalmology 2002 109 2215 24 12466161 \n4 Khandelwal RR Raje D Rathi A Agashe A Majumdar M Khandelwal R Surgical outcome of safe surgery system trabeculectomy combined with cataract extraction Eye (Lond) 2015 29 363 70 25502867 \n5 Thomas R Parikh R Muliyil J Comparison between phacoemulsification and the Blumenthal technique of manual small-incision cataract surgery combined with trabeculectomy J Glaucoma 2003 12 333 9 12897578 \n6 Khaw PT Chiang M Shah P Sii F Lockwood A Khalili A Enhanced trabeculectomy: The Moorfields safer surgery system Dev Ophthalmol 2012 50 1 28 22517170 \n7 Jin GJ Crandall AS Jones JJ Phacotrabeculectomy: Assessment of outcomes and surgical improvements J Cataract Refract Surg 2007 33 1201 8 17586376 \n8 Rockwood EJ Larive B Hahn J Outcomes of combined cataract extraction, lens implantation, and trabeculectomy surgeries Am J Ophthalmol 2000 130 704 11 11124287 \n9 Rao HL Maheshwari R Senthil S Prasad KK Garudadri CS Phacotrabeculectomy without mitomycin C in primary angle-closure and open-angle glaucoma J Glaucoma 2011 20 57 62 20051881 \n10 Chen DZ Koh V Sng C Aquino MC Chew P Complications and outcomes of primary phacotrabeculectomy with mitomycin C in a multi-ethnic Asian population PLoS One 2015 10 e0118852 25775362 \n11 Chan PP Li EY Tsoi KK Kwong YY Tham CC Cost-effectiveness of phacoemulsification versus combined phacotrabeculectomy for treating primary angle closure glaucoma J Glaucoma 2017 26 911 22 28858162\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2452-2325",
"issue": "32(4)",
"journal": "Journal of current ophthalmology",
"keywords": "Manual small-incision cataract surgery; Phacoemulsification; Trabeculectomy with mitomycin C",
"medline_ta": "J Curr Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101678509",
"other_id": null,
"pages": "329-334",
"pmc": null,
"pmid": "33553833",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "11124287;12359612;20051881;22517170;22244944;17586376;12466161;28858162;12897578;25502867;25775362",
"title": "Comparison of the Surgical Outcomes of Single-Site, Mitomycin C-Augmented Trabeculectomy Combined with Phacoemulsification versus Manual Small-Incision Cataract Surgery.",
"title_normalized": "comparison of the surgical outcomes of single site mitomycin c augmented trabeculectomy combined with phacoemulsification versus manual small incision cataract surgery"
} | [
{
"companynumb": "IN-ACCORD-218348",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MITOMYCIN"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "A 19-year-old woman underwent multiple attempts at orogastric lavage before success 5 h after ingesting approximately 24 grams of ibuprofen in a suicide attempt. Activated charcoal was administered via the lavage tube. She vomited charcoal shortly after administration and began experiencing difficulty breathing and an increase in the pitch of her voice. A chest X-ray study showed a widened mediastinum, pneumopericardium, and subcutaneous emphysema consistent with esophageal perforation that was confirmed by computed tomography scan. Surgical exploration revealed a tear in the proximal posterior esophagus with charcoal in the posterior mediastinum. She remained intubated for 7 days and was discharged 14 days after admission. This is a report of esophageal perforation with activated charcoal contamination of the mediastinum after gastric lavage. The risks and benefits of this procedure should be carefully considered in each patient prior to its use. Awake patients should be cooperative with the procedure to minimize any risk of trauma to the oropharynx or esophagus.",
"affiliations": "Division of Emergency Medicine, University of Utah, Salt Lake City, Utah 84132, USA.",
"authors": "Caravati|E M|EM|;Knight|H H|HH|;Linscott|M S|MS|;Stringham|J C|JC|",
"chemical_list": "D002606:Charcoal",
"country": "United States",
"delete": false,
"doi": "10.1016/s0736-4679(01)00282-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "20(3)",
"journal": "The Journal of emergency medicine",
"keywords": null,
"medline_ta": "J Emerg Med",
"mesh_terms": "D000328:Adult; D002606:Charcoal; D004939:Esophageal Perforation; D004947:Esophagus; D005260:Female; D005751:Gastric Lavage; D006801:Humans; D022125:Lacerations; D008477:Mediastinal Diseases; D013406:Suicide, Attempted",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "273-6",
"pmc": null,
"pmid": "11267816",
"pubdate": "2001-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Esophageal laceration and charcoal mediastinum complicating gastric lavage.",
"title_normalized": "esophageal laceration and charcoal mediastinum complicating gastric lavage"
} | [
{
"companynumb": "US-RANBAXY-2014US-91513",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "Asymptomatic minimal pericardial effusion may be frequently found in patients with hypothyroidism. Cardiac tamponade secondary to hypothyroidism is rarely referenced in medical literature. Hypothyroidism as an adverse effect of pazopanib (tyrosine kinase inhibitor) treatment leading to cardiac tamponade is an even rarer occurrence. Here, we report an unusual case of a 71-year-old male, with a case of renal cell carcinoma on pazopanib treatment presenting with shortness of breath who was found to have hypothyroidism with a large pericardial effusion leading to cardiac tamponade. The patient did not have any prior reports of thyroid-stimulating hormone (TSH) or thyroid hormone levels at presentation. No such case of cardiac tamponade due to hypothyroidism as an adverse effect of pazopanib tablet treatment has been reported to our knowledge.",
"affiliations": "Department of Medical Oncology, HealthCare Global Enterprises Ltd., Bangalore, India.;Department of Medical Oncology, HealthCare Global Enterprises Ltd., Bangalore, India.;Department of Medical Oncology, HealthCare Global Enterprises Ltd., Bangalore, India.;Department of Medical Oncology, HealthCare Global Enterprises Ltd., Bangalore, India.",
"authors": "Sarathy|Vinu|V|https://orcid.org/0000-0002-4593-0995;Jayappa|Sriniivas Belagutty|SB|;Waran|Thianesh|T|;Naik|Radheshyam|R|https://orcid.org/0000-0003-1325-7705",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2020/9268923",
"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706 2090-6714 Hindawi \n\n10.1155/2020/9268923\nCase Report\nA Case of Cardiac Tamponade in a Patient with Metastatic Renal Cell Carcinoma on Pazopanib Treatment\nhttps://orcid.org/0000-0002-4593-0995Sarathy Vinu sarathy.vinu.88@gmail.com Jayappa Sriniivas Belagutty Waran Thianesh https://orcid.org/0000-0003-1325-7705Naik Radheshyam Department of Medical Oncology, HealthCare Global Enterprises Ltd., Bangalore, India\nAcademic Editor: Raffaele Palmirotta\n\n\n2020 \n9 4 2020 \n2020 926892324 9 2019 5 3 2020 19 3 2020 Copyright © 2020 Vinu Sarathy et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Asymptomatic minimal pericardial effusion may be frequently found in patients with hypothyroidism. Cardiac tamponade secondary to hypothyroidism is rarely referenced in medical literature. Hypothyroidism as an adverse effect of pazopanib (tyrosine kinase inhibitor) treatment leading to cardiac tamponade is an even rarer occurrence. Here, we report an unusual case of a 71-year-old male, with a case of renal cell carcinoma on pazopanib treatment presenting with shortness of breath who was found to have hypothyroidism with a large pericardial effusion leading to cardiac tamponade. The patient did not have any prior reports of thyroid-stimulating hormone (TSH) or thyroid hormone levels at presentation. No such case of cardiac tamponade due to hypothyroidism as an adverse effect of pazopanib tablet treatment has been reported to our knowledge.\n==== Body\n1. Introduction\nPericardial effusion and cardiac tamponade are caused due to a variety of etiological factors which include acute pericarditis, tumor, uremia hypothyroidism, trauma, cardiac surgery, or other inflammatory/noninflammatory conditions.\n\nRecent studies have shown that pericardial effusions are extremely rare in hypothyroidism with an incidence of 3 to 6 percent [1].\n\nPatients who are on pazopanib have been reported to develop hypothyroidism at an incidence of less than 10% [2].\n\nA small pericardial effusion can cause significant cardiac tamponade when it accumulates rapidly, and hence, it is important to suspect cardiac tamponade in patients with sudden hemodynamic compromise [3].\n\nHere, we report an uncommon case of hypothyroidism with cardiac tamponade.\n\n2. Case Report\nA 71-year-old male patient who was a known case of metastatic renal cell carcinoma on treatment with the tablet pazopanib 800 mg OD since 5 years presented to us for the first time in ER on 19.06.2018 with complaints of shortness of breath and easy fatigability.\n\nOn examination, the patient was breathless and had a sallow complexion with dry skin and peripheral edema with prominent visible neck veins.\n\nThe patient's blood pressure was 100/70 mmHg with tachycardia and oxygen saturation of 92% at room air. The patient had demonstrable pulsus paradoxus with an inspiratory drop in a blood pressure of more than 16 mmHg.\n\nBedsides, a 2D echocardiogram showed a large pericardial effusion with right atrial right ventricular diastolic collapse suggestive of cardiac tamponade as shown in Figure 1.\n\nA primary working diagnosis of suspected disease progression with pericardial/cardiac metastases was made.\n\nThe patient was immediately shifted to the Intensive Care Unit and underwent pericardiocentesis. About 350 ml of yellowish golden colour fluid was aspirated which was sent for cytological and biochemical investigation.\n\nImmediately post procedure, the patient showed significant improvement in cardiopulmonary status. His tachypnea and tachycardia subsided, and the patient maintained adequate oxygen saturation on room air. Post pericardiocentesis, the 2D echocardiogram revealed minimal pericardial fluid with no evidence of cardiac tamponade.\n\nPericardial fluid analysis showed degenerate and mesothelial cells and no evidence of any malignancy or acid fast bacilli.\n\nHowever, to rule out disease progression, the patient had an 18-fluorodeoxyglucose (FDG) PET-CT scan (Figure 2) which showed regression of the necrotic mass of the left kidney, stable proximal left renal tumor thrombosis, stable lesion adjacent to tumor thrombosis in the anterior calyx, stable metastatic right lung nodule, and interval development of bilateral pleural effusions and mild to moderate pericardial effusion with pericardial catheter drainage tube in situ.\n\nConsidering his history and findings, we did a thyroid function test which was suggestive of severe hypothyroidism with high TSH levels (TSH > 100 mIU/L) and low T3 T4 levels.\n\nThe patient did not have any prior reports of TSH or thyroid hormone levels. Antithyroid peroxidase antibody testing was done which was negative.\n\nThe patient was treated with the tablet levothyroxine 50 micrograms daily which was later gradually increased to 125 mcg daily. The patient's condition improved significantly and was discharged in a stable condition 1 week post removal of the pericardial drainage tube.\n\nFollow-up echocardiogram after a period of 2 months showed near total resolution of pericardial effusion. Within a few weeks, all his signs and symptoms completely resolved and the patient is currently continuing treatment on pazopanib tablet as part of his renal cell carcinoma treatment.\n\nThe patient is on regular follow-up, and his latest 2D Echo on 10.10.2018 showed minimal pericardial effusion with good systolic left ventricular function. The patient is currently hale and hearty on thyroid replacement and pazopanib tablet treatment with a normalized TSH value of 0.97 mIU/L.\n\n3. Discussion\nCardiac tamponade as a complication of hypothyroidism is very rare with few cases described in world literature [4].\n\nHypothyroidism may commonly cause asymptomatic pericardial effusions, but rarely leads to symptomatic tamponade. The mechanism of this myxomatous pericardial effusion is postulated to be due to the increased permeability of capillaries causing leakage of fluid rich in protein into the interstitial space and impaired lymphatic drainage leading to salt and water retention [5].\n\nAlthough the definitive mechanism of tyrosine kinase inhibitor- (TKI-) induced hypothyroidism is debatable, several theories have been proposed.\n\nVascular endothelial growth factor (VEGF) is a signal protein allowing formation of new blood vessels as well as formation of collateral circulation. TKIs like pazopanib reduce blood supply to the tumor leading to tumor regression; however, capillary regression is also noted in normal organs like the thyroid considering that the thyroid is an organ with the highest blood flow per unit weight [6].\n\nOther mechanisms proposed include alterations in thyroxine/triiodothyronine metabolism [7], induction of type 3 deiodinase activity [8], blockage of iodine uptake [9], and autoimmunity where antithyroid peroxidase antibodies are detectable [10].\n\nHowever, the latter seems highly unlikely in our patient as antithyroid peroxidase antibodies were not detected.\n\nAnother interesting extrapolation which our patient may have raised is whether adverse effects of treatment (severe hypothyroidism in our patient) translate into increased clinical benefit.\n\nPazopanib treatment in advanced renal cell carcinoma has been known to provide an average of 9 months of progression-free survival and 23 months of overall survival. Our patient has shown a progression-free survival of 5 years till date which is remarkable considering the much lower average.\n\nThe above has been demonstrated in previous studies showing hypothyroidism and other adverse effects of TKIs improved tumor response rates and survival time of kidney cancer patients treated with targeted therapy [11].\n\nDuring pazopanib therapy, monitoring the thyroid function must be necessary.\n\nOur case also highlights further the importance of stringent follow-up and monitoring to pick up adverse effects at the earliest time and prevent potentially life-threatening events.\n\n4. Conclusion\nAtypical symptoms arising in cancer patients on treatment should provoke other more easily treatable differential diagnoses like treatment-related adverse events rather than just disease progression.\n\nTreatment-related adverse events may translate into a better response and survival rate for the patient.\n\nConsent\nThe article was initiated and written after informed consent from the patient was obtained.\n\nConflicts of Interest\nAll authors declare no conflict of interest.\n\nFigure 1 2D ECHO showing a large pericardial effusion with right atrial diastolic collapse suggestive of cardiac tamponade.\n\nFigure 2 18-FDG whole body PET CT showing stable disease and metabolic activity.\n==== Refs\n1 Saito Y. Donohue A. Attai S. The syndrome of cardiac tamponade with “small” pericardial effusion Echocardiography 2008 25 3 321 327 10.1111/j.1540-8175.2007.00567.x 2-s2.0-40149089572 18307446 \n2 Sternberg C. N. Davis I. D. Mardiak J. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial Journal of Clinical Oncology 2010 28 6 1061 1068 10.1200/JCO.2009.23.9764 2-s2.0-77949890945 20100962 \n3 Retnam V. J. Chichgar J. A. Parkar L. A. Chikhalikar A. A. Golwalla A. F. Myxedema and pericardial effusion with cardiac tamponade (a case report) Journal of Postgraduate Medicine 1983 29 3 188 190B 6655610 \n4 Jiménez-Nácher J. J. de Alonso N. Vega B. Cardiac tamponade as a presentation of primary hypothyroidism in a young woman Revista Clínica Española 1993 193 6 290 292 8259451 \n5 Al Mahroos H. Al Bannay R. Massive pericardial effusion as a sole manifestation of hypothyroidism- a case report Bahrain Medical Bulletin 2000 22 4 \n6 Wang J. F. Milosveski V. Schramek C. Fong G. H. Becks G. P. Hill D. J. Presence and possible role of vascular endothelial growth factor in thyroid cell growth and function The Journal of Endocrinology 1998 157 1 5 12 10.1677/joe.0.1570005 2-s2.0-0031967581 9614352 \n7 Kappers M. H. van Esch J. H. Smedts F. M. Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression The Journal of Clinical Endocrinology and Metabolism 2011 96 10 3087 3094 10.1210/jc.2011-1172 2-s2.0-80053470531 21816788 \n8 Abdulrahman R. M. Verloop H. Hoftijzer H. Sorafenib induced hypothyroidism is associated with increased type 3 deiodination The Journal of Clinical Endocrinology and Metabolism 2010 95 8 3758 3762 10.1210/jc.2009-2507 2-s2.0-77955374095 20484486 \n9 Mannavola D. Coco P. Vannucchi G. A novel tyrosine kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake The Journal of Clinical Endocrinology and Metabolism 2007 92 9 3531 3534 10.1210/jc.2007-0586 2-s2.0-34548764576 17595247 \n10 Pani F. Atzori F. Baghino G. Thyroid dysfunction in patients with metastatic carcinoma treated with sunitinib: is thyroid autoimmunity involved? Thyroid 2015 25 11 1255 1261 10.1089/thy.2015.0170 2-s2.0-84946811554 26414109 \n11 Schmidinger M. Vogl U. M. Bojic M. Hypothyroidism in patients with renal cell carcinoma: blessing or curse? Cancer 2011 117 3 534 544 10.1002/cncr.25422 2-s2.0-78651361788 20845482\n\n",
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"pmid": "32328329",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "A Case of Cardiac Tamponade in a Patient with Metastatic Renal Cell Carcinoma on Pazopanib Treatment.",
"title_normalized": "a case of cardiac tamponade in a patient with metastatic renal cell carcinoma on pazopanib treatment"
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"abstract": "OBJECTIVE\nHepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR-dependent expression of genes involved in biotransformation and secretion in vitro.\n\n\nMETHODS\nThirteen patients (age 18-81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1-10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 μmol/L).\n\n\nRESULTS\nSerum bilirubin of patients with PHSF ranged from 264 to 755 μmol/L. Normal γGT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 μmol/L after 1-10 weeks of rifampicin treatment. In vitro, rifampicin PXR-dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OSTβ.\n\n\nCONCLUSIONS\nPersistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR-dependent induction of CYP3A4, UGT1A1, MRP2 and OSTβ could contribute to the anticholestatic effect of rifampicin in PHSF.",
"affiliations": "Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.",
"authors": "van Dijk|Remco|R|;Kremer|Andreas E|AE|;Smit|Wouter|W|;van den Elzen|Bram|B|;van Gulik|Thomas|T|;Gouma|Dirk|D|;Lameris|Johan S|JS|;Bikker|Hennie|H|;Enemuo|Valentine|V|;Stokkers|Pieter C F|PC|;Feist|Mark|M|;Bosma|Piter|P|;Jansen|Peter L M|PL|;Beuers|Ulrich|U|",
"chemical_list": "C093491:ABCB11 protein, human; C000715087:ABCC2 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D065701:Cytochrome P-450 CYP3A Inducers; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:Multidrug Resistance-Associated Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C476577:organic solute transporter beta, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C418331:UGT1A1 enzyme; D014453:Glucuronosyltransferase; D000251:Adenosine Triphosphatases; C111067:ATP8B1 protein, human; D001663:Bilirubin; D012293:Rifampin",
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"issue": "35(4)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "ABCB11; ATP8B1; cholestasis; pregnane X receptor; rifampicin",
"medline_ta": "Liver Int",
"mesh_terms": "D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001663:Bilirubin; D056486:Chemical and Drug Induced Liver Injury; D002779:Cholestasis; D051544:Cytochrome P-450 CYP3A; D065701:Cytochrome P-450 CYP3A Inducers; D005260:Female; D020022:Genetic Predisposition to Disease; D014453:Glucuronosyltransferase; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver; D017093:Liver Failure; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:Multidrug Resistance-Associated Proteins; D009154:Mutation; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012293:Rifampin; D012307:Risk Factors; D012720:Severity of Illness Index; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "1478-88",
"pmc": null,
"pmid": "24905729",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Characterization and treatment of persistent hepatocellular secretory failure.",
"title_normalized": "characterization and treatment of persistent hepatocellular secretory failure"
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"abstract": "Intellectual disability (intellectual developmental disorder) (ID/IDD) is both a psychiatric disorder and a risk factor for co-occurring psychiatric disorders in children and adolescents. DSM-5 introduced important changes in the conceptualization and diagnosis of ID/IDD, and current research studies clarify assessment and treatment of co-occurring psychiatric disorders in this population. Optimal assessment and treatment of psychiatric illness in children and adolescents with ID/IDD includes modifications in diagnostic and treatment techniques, appreciation of variations in the clinical presentation of psychiatric disorders, an understanding of the spectrum of etiologies of behavioral disturbance, and knowledge of psychosocial and medical interventions.",
"affiliations": null,
"authors": "Siegel|Matthew|M|;McGuire|Kelly|K|;Veenstra-VanderWeele|Jeremy|J|;Stratigos|Katharine|K|;King|Bryan|B|;|||;Bellonci|Christopher|C|;Hayek|Munya|M|;Keable|Helene|H|;Rockhill|Carol|C|;Bukstein|Oscar G|OG|;Walter|Heather J|HJ|",
"chemical_list": null,
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"doi": "10.1016/j.jaac.2019.11.018",
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"issue": "59(4)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": "assessment; child psychiatry; intellectual disability; practice parameter; treatment",
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D000293:Adolescent; D002648:Child; D015897:Comorbidity; D002658:Developmental Disabilities; D039721:Diagnostic and Statistical Manual of Mental Disorders; D006801:Humans; D008607:Intellectual Disability; D001523:Mental Disorders; D012307:Risk Factors",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "468-496",
"pmc": null,
"pmid": "33928910",
"pubdate": "2020-04",
"publication_types": "D017065:Practice Guideline",
"references": null,
"title": "Practice Parameter for the Assessment and Treatment of Psychiatric Disorders in Children and Adolescents With Intellectual Disability (Intellectual Developmental Disorder).",
"title_normalized": "practice parameter for the assessment and treatment of psychiatric disorders in children and adolescents with intellectual disability intellectual developmental disorder"
} | [
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"companynumb": "US-OTSUKA-2020_015562",
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{
"abstract": "A 67-year-old male had prostate adenocarcinoma with liver, bone metastases, iliac lymph nodes invasion ever receive hormone and chemotherapy. He was presented to our emergency department with acute onset of mild dizziness and shortness of breath. Elevated CK (1477 U/L) and elevated CK-MB (1602 U/L) was noticed. Electrocardiogram was unremarkable for myocardial ischemia. CK-isoenzyme lab test (electrophoresis) was obtained, which revealed macro CK type 2 accounting for 6.2% of total CK. Type 2 macro CK syndrome was impressed. The falsely elevated CK-MB and macro CK type 2 in serum may be associated with the patient's worsening metastatic disease.",
"affiliations": "Department of Education, Taichung Veterans General Hospital, Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.;Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.",
"authors": "Lin|Yu-Ju|YJ|;Chang|Li-Wen|LW|;Hung|Sheng-Chun|SC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2021.101805",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420\nElsevier\n\nS2214-4420(21)00245-X\n10.1016/j.eucr.2021.101805\n101805\nOncology\nMacro-Ck type 2 syndrome in prostate adenocarcinoma: Case report and review article\nLin Yu-Ju nps798@gmail.com\nabc\nChang Li-Wen cd\nHung Sheng-Chun weshong1118@vghtc.gov.tw\ncd∗\na Department of Education, Taichung Veterans General Hospital, Taichung, Taiwan\nb Department of Family Medicine, Taichung Veterans General Hospital, Taichung, Taiwan\nc Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan\nd Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan\n∗ Corresponding author. Division of Urology, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan, 40705, ROC. Tel.: +886423592525x5121. weshong1118@vghtc.gov.tw\n09 8 2021\n11 2021\n09 8 2021\n39 10180512 7 2021\n4 8 2021\n9 8 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 67-year-old male had prostate adenocarcinoma with liver, bone metastases, iliac lymph nodes invasion ever receive hormone and chemotherapy. He was presented to our emergency department with acute onset of mild dizziness and shortness of breath. Elevated CK (1477 U/L) and elevated CK-MB (1602 U/L) was noticed. Electrocardiogram was unremarkable for myocardial ischemia. CK-isoenzyme lab test (electrophoresis) was obtained, which revealed macro CK type 2 accounting for 6.2% of total CK. Type 2 macro CK syndrome was impressed. The falsely elevated CK-MB and macro CK type 2 in serum may be associated with the patient's worsening metastatic disease.\n\nKeywords\n\nMacro CK syndrome\nProstate cancer\n==== Body\n1 Introduction\n\nElevated serum levels of creatine kinase (CK) is most often linked with the diagnosis of acute coronary syndrome (ACS); while other differential diagnoses, such as hyperthyroidism, connective tissue disorders, and acute kidney injury should also be taken into consideration.1 One lesser known phenomenon is the macro-CK syndrome, in which the serum CK would be falsely elevated due to the increase of CK macroenzymes.2 From the biochemical point of view, the macroenzymes are referred to as complexes formed by their corresponding enzymes with abnormally high molecular masses. It takes more time to remove these macroenzymes from human bodies than usual enzymes. The clinical importance of macroenzymes is that they could lead to laboratory errors of enzyme activity in blood samples.2 Here, we present a case of metastatic castration-resistant prostate cancer (mCRPC) with macro-CK syndrome.\n\n2 Case presentation\n\nThis 67-year-old male patient with past history of hypertension, first came to our hospital due to difficult in voiding for 3 months. He underwent transurethral resection of the prostate (TURP) and the pathologic report revealed prostate adenocarcinoma Gleason score 4 + 5 (Grade Group 5). Liver, bone and lymph node metastases and rectal invasion was confirmed by abdominal computed tomography (CT) (Fig. 1) and bone scan (Fig. 2). Meanwhile, his Prostate-Specific Antigen (PSA) was 2.43 and hormone therapy (Leuprorelin Acetate subcutaneous injection) and upfront chemotherapy (Docetaxel Dose 75 mg/m2, Total 130mg, three weekly) were initiated after diagnosis. CT revealed progression of liver metastases together with worsening bone pain despite PSA rised only from 0.039 ng/ml to 0.200 ng/ml at 9 months from primary treatment. mCRPC was impressed and Enzalutamide was added for cancer control. PSA level soon decreased to 0.059 ng/ml one month later but increased to 0.349 soon. He came to our emergency department for sudden onset of dizziness and mild respiratory distress 6 months later. 12-lead Electrocardiogram (ECG) showed no evidence of myocardial ischemia (no ST-segment elevation, no ST-segment depression, no T-wave inversion). Laboratory test showed elevated CK (1477 U/L), elevated CK-MB (1602 U/L) but only mild elevation of Troponin-T (17 ng/L, on the reference range of 2012 New Zeeland Guideline for Troponin-T). No evidence of myocardial ischemia on repeated ECG 5 hours later and the patient's symptoms resolved. Repeated lab test, however, revealed marked elevation of CK (2136 U/L) and elevated CK-MB (2296 U/L). Cardiologist was consulted. CK-isoenzyme lab test (electrophoresis) was obtained and the report (SPIFE Touch - Helena Laboratories) showed macro CK type 2 accounting for 6.2% of total CK (CK-Total 2136 U/L, CK-BB 87.2%, CK-MB 0%, CK-MM 6.6%) (Fig. 3). Subsequent follow up in cardiovascular ward revealed no typical chest pain or dynamic ECG changes despite elevated CK. Color doppler echocardiography showed normal left ventricle systolic wall motion and 54% left ventricle ejection fraction. Macro-CK secondary to prostate cancer was impressed. The patient still expired three months later due to progression of liver metastases causing hepatic failure.Fig. 1 CT axial view showed several low attenuation lesions at liver, up to 2.5cm with irregular margin, biopsy proved liver metastases (arrow).\n\nFig. 1\n\nFig. 2 Bone scan revealed multiple bone metastases at pelvic, sacrum and spin.\n\nFig. 2\n\nFig. 3 CK-isoenzyme lab test (electrophoresis): macro CK type 2 accounting for 6.2% of total CK (CK-Total 2136 U/L, CK-BB 87.2%, CK-MB 0%, CK-MM 6.6%).\n\nFig. 3\n\n3 Discussion\n\nCreatine kinase is an important muscle enzymes being released by several tissues and cells, such as striated muscle, heart tissue, brain, smooth muscle of gastrointestinal tract and urinary bladder. Creatine kinase may exist in the form of dimer, octamer, or macromolecule complex. Dimers of creatine kinase inside the cytoplasm include the well-known CK-BB, CK-MB and CK-MM. Another isoenzyme, CK-Mt, exists within the intermembrane space of mitochondria and can be observed as dimers or octamers.1\n\nOccasionally, CK can be found in a macromolecular form (macro-CK) with two different types. Macro-CK type 1 consists of immunoglobulin and CK dimer, usually IgG and CK-BB; while macro-CK type 2 consists of oligomeric mitochondrial CK. Both types of macro-CKs are rare in prevalence.\n\nThe current measurement of CK is mostly based on its catalytic function converting creatine phosphate (CrP) to creatine (Cr).3 As for CK isoenzyme detection, the most commonly used method is immunoinhibition.3 This technique utilizes the anti-CK-M antibody, which selectively inhibits the M component of CK dimers in CK-MB and CK-MM. The remaining activities are all from B component. Considering no CK-BB or macro-CK in serum, the total activity of CK-MB can be calculated by multiplying the remaining activity by 2.4 In our patient, a series of lab tests all showed higher levels of CK-MB than total CK, which indicated calculating errors with CK-MB measurement. The possible explanation of this was the presence of macro-CK molecules. These high-molecular complexes have reduced clearance and could not be inhibited by the anti-CK-M antibodies.4 Since the assumption of CK-MB measurement (non-existence of CK-BB or marco-CK in the serum) was not met, the calculated CK-MB activity would be falsely elevated, causing diagnostic pitfalls.\n\nOther methods can be used to avoid this situation. Electrophoresis appeared to be a preferred technique for detecting macro-CK existence (Fig. 3). With electrophoresis, we can separate the CK family into different bands on the agarose gel.4 From the anode side, the first band found is CK-BB, followed by CK-MB and CK-MM. With the presence of macro-CK, type 1 complex will lie between CK-MB and CK-MM, whereas type 2 complex will be cathodal to MM.2\n\nIn previous studies, the prevalence of macro CK type 2 has been reported to be from 0.5 to 3.7% and cancer and liver disease.1 Three case reports discussing about macro CK type 2 in metastatic prostate cancer were record.3, 4, 5 The pathophysiology of marco CK type-2 existence in these conditions was not fully studied. One hypothesis is that the rich content of mitochondrial CK in liver will be released by dying and regenerating cells in liver disease and metastatic liver tumor.\n\nIn conclusion, creatine kinase level higher than normal limit is not always an indicator of coronary artery disease or connective tissue disease. Also, electrophoresis is the method of choice for detecting the composition of CK isoenzymes on account of false elevation of CK-MB level in the existence of macro CK with the immunoinhibition method. In the scenario of macro CK type 2, associated comorbidities such as liver cirrhosis and metastases should be included in clinical decision making.\n\nDeclaration of competing interest\n\nNo competing financial interests exist.\n==== Refs\nReferences\n\n1 Silvestri N.J. Wolfe G.I. Asymptomatic/pauci-symptomatic creatine kinase elevations (hyperckemia) Muscle Nerve 47 6 2013 805 815 10.1002/mus.23755 23625835\n2 Liu C.Y. Lai Y.C. Wu Y.C. Tzeng C.H. Lee S.D. Macroenzyme creatine kinase in the era of Modern laboratory medicine J Chin Med Assoc 73 1 2010 35 39 10.1016/S1726-4901(10)70019-8 20103489\n3 Tsai S.J. Wang T.E. Lin S.C. Lo C.I. Lo C.I. Tseng C.Y. Extremely high CK-MB levels exceeding total CK levels in A patient with chest pain: a case report J Intern Med Taiwan 14 5 2003 243 247\n4 Eidizadeh A. von Ahsen N. Friedewald S. Binder L. Macro-CK type 2 in metastatic prostate cancer Diagnosis 6 3 2018 307 309 10.1515/dx-2018-0039\n5 Arenas J. Bronstein B. Mayor J.J. Santos I. Leiva O. Martinez A. Macro creatine kinase type 2 in a patient with prostatic carcinoma Clin Chim Acta 200 1 1991 53 56 10.1016/0009-8981(91)90334-9 1934512\n\n",
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"journal": "Urology case reports",
"keywords": "Macro CK syndrome; Prostate cancer",
"medline_ta": "Urol Case Rep",
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"title": "Macro-Ck type 2 syndrome in prostate adenocarcinoma: Case report and review article.",
"title_normalized": "macro ck type 2 syndrome in prostate adenocarcinoma case report and review article"
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"abstract": "Neuroleptics are a group of drugs widely used in the treatment of psychotic symptoms. Among their adverse effects is the ability to trigger a neuroleptic malignant syndrome (NMS). The diagnosis of NMS is determined by exclusion, and its initial therapeutic management should be the withdrawal of neuroleptics, the administration of benzodiazepines, and electroconvulsive therapy (ECT). ECT is an effective treatment in these patients, and in those cases with a poor response to treatment with antipsychotic drugs. A review is presented on the treatment options and anaesthetic implications of ECT used to handle a patient diagnosed with paranoid schizophrenia in the context of NMS.",
"affiliations": "Servicio de Anestesiología, Reanimación y Terapéutica del Dolor, Hospital Abente y Lago, Complexo Hospitalario Universitario A Coruña, A Coruña, España. Electronic address: pablocasasreza@gmail.com.;Servicio de Anestesiología, Reanimación y Terapéutica del Dolor, Hospital Abente y Lago, Complexo Hospitalario Universitario A Coruña, A Coruña, España.;Servicio de Anestesiología, Reanimación y Terapéutica del Dolor, Hospital Abente y Lago, Complexo Hospitalario Universitario A Coruña, A Coruña, España.;Servicio de Anestesiología, Reanimación y Terapéutica del Dolor, Hospital Abente y Lago, Complexo Hospitalario Universitario A Coruña, A Coruña, España.;Servicio de Anestesiología, Reanimación y Terapéutica del Dolor, Hospital Abente y Lago, Complexo Hospitalario Universitario A Coruña, A Coruña, España.",
"authors": "Casas Reza|P|P|;Gestal Vázquez|M|M|;Outeiro Rosato|Á|Á|;López Álvarez|S|S|;Diéguez García|P|P|",
"chemical_list": "D000732:Androstanols; D018686:Anesthetics, Intravenous; D014150:Antipsychotic Agents; D003473:Neuromuscular Nondepolarizing Agents; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D003024:Clozapine; D000077123:Rocuronium; D015742:Propofol",
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"issue": "64(2)",
"journal": "Revista espanola de anestesiologia y reanimacion",
"keywords": "Electroconvulsive therapy; Esquizofrenia paranoide; Neuroleptic malignant syndrome; Neuroleptics; Neurolépticos; Paranoid schizophrenia; Rocuronio; Rocuronium; Succinilcolina; Succinylcholine; Síndrome neuroléptico maligno; Terapia electroconvulsiva",
"medline_ta": "Rev Esp Anestesiol Reanim",
"mesh_terms": "D000732:Androstanols; D018686:Anesthetics, Intravenous; D014150:Antipsychotic Agents; D003024:Clozapine; D004565:Electroconvulsive Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009459:Neuroleptic Malignant Syndrome; D061886:Neuromuscular Monitoring; D003473:Neuromuscular Nondepolarizing Agents; D015742:Propofol; D000077123:Rocuronium; D012563:Schizophrenia, Paranoid; D000077122:Sugammadex; D047408:gamma-Cyclodextrins",
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"pages": "105-107",
"pmc": null,
"pmid": "27424873",
"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rocuronium-sugammadex for electroconvulsive therapy management in neuroleptic malignant syndrome: A case report.",
"title_normalized": "rocuronium sugammadex for electroconvulsive therapy management in neuroleptic malignant syndrome a case report"
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"abstract": "Hemorrhagic diathesis due to anti-factor XIII (FXIII) autoantibody is a rare but severe disorder. Challenges of the diagnosis and treatment is demonstrated by the case of a 67-year-old female without previous bleeding history, who suffered a huge muscular hematoma. Without blank subtraction 18% plasma FXIII activity was measured; however, after correction for blank the activity was below the limit of detection and the lack of fibrin cross-linking in the patient's plasma confirmed the latter result. FXIII-A2 antigen was not detectable by enzyme-linked immunosorbent assay (ELISA); however, it was well detected by western blotting. The autoantibody showed high affinity toward FXIII-A2 . Its considerable inhibitory activity was demonstrated by high titer in Bethesda units and the low immunoglobulin G concentration required for inhibition. The main biochemical effect was the inhibition of Ca2+ -induced activation. Eradication therapy was only partially successful. Four months after the last hemorrhagic event the patient suffered deep vein thrombosis complicated by pulmonary embolism.",
"affiliations": "Hemophilia Care Center University Hospital of Dijon, Dijon, France.;Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.;Hemophilia Care Center University Hospital of Dijon, Dijon, France.;Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.;Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.;Division of Clinical Laboratory Science, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.",
"authors": "Bovet|Julien|J|;Hurják|Boglárka|B|;De Maistre|Emmanuel|E|;Katona|Éva|É|;Pénzes|Krisztina|K|;Muszbek|László|L|0000-0002-3798-9962",
"chemical_list": "D005176:Factor XIII; D026122:Factor XIIIa",
"country": "England",
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"doi": "10.1111/jth.14811",
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"issue": "18(6)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "autoimmune disease; blood coagulation; factor XIII; factor XIII deficiency; hemorrhagic disorder",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D000368:Aged; D005176:Factor XIII; D005177:Factor XIII Deficiency; D026122:Factor XIIIa; D005260:Female; D006801:Humans; D007753:Laboratories; D010641:Phenotype",
"nlm_unique_id": "101170508",
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"pages": "1330-1334",
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"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Autoimmune factor XIII deficiency with unusual laboratory and clinical phenotype.",
"title_normalized": "autoimmune factor xiii deficiency with unusual laboratory and clinical phenotype"
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"abstract": "We report a challenging case of recurrent flat anterior chamber without hypotony after trabeculectomy in a 54-year-old Black male with a remote history of steroid-treated polymyositis, cataract surgery, and uncontrolled open angle glaucoma. The patient presented with a flat chamber on postoperative day 11, but had a normal fundus exam and intraocular pressure (IOP). Flat chamber persisted despite treatment with cycloplegics, steroids, and a Healon injection into the anterior chamber. A transverse B-scan of the peripheral fundus revealed a shallow annular peripheral choroidal detachment. The suprachoroidal fluid was drained. The patient presented 3 days later with a recurrent flat chamber and an annular peripheral choroidal effusion. The fluid was removed and reinforcement of the scleral flap was performed with the resolution of the flat anterior chamber. A large corneal epithelial defect developed after the second drainage. The oral prednisone was tapered quickly and the topical steroid was decreased. One week later, his vision decreased to count fingers with severe corneal stromal edema and Descemet's membrane folds that improved to 20/50 within 24 h of resumption of the oral steroid and frequent topical steroid. The patient's visual acuity improved to 20/20 following a slow withdrawal of the oral and topical steroid. Eight months after surgery, the IOP was 15 mm Hg without glaucoma medication. The detection of a shallow anterior choroidal detachment by transverse B-scan is critical to making the correct diagnosis. Severe cornea edema can occur if the steroid is withdrawn too quickly. Thus, steroids should be tapered cautiously in steroid-dependent patients.",
"affiliations": "Department of Ophthalmology, Louisiana State University Health Science Center-Shreveport, Shreveport, La., USA.;Department of Ophthalmology, Louisiana State University Health Science Center-Shreveport, Shreveport, La., USA.;Department of Ophthalmology, Louisiana State University Health Science Center-Shreveport, Shreveport, La., USA.;Department of Ophthalmology, Louisiana State University Health Science Center-Shreveport, Shreveport, La., USA.;Department of Ophthalmology, Louisiana State University Health Science Center-Shreveport, Shreveport, La., USA.",
"authors": "Liu|Shaohui|S|;Sun|Lisa L|LL|;Kavanaugh|A Scott|AS|;Langford|Marlyn P|MP|;Liang|Chanping|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000356166",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. 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 10.1159/000356166cop-0004-0192Published online: October, 2013Recurrent Annular Peripheral Choroidal Detachment after Trabeculectomy Liu Shaohui Sun Lisa L. Kavanaugh A. Scott Langford Marlyn P. Liang Chanping *Department of Ophthalmology, Louisiana State University Health Science Center-Shreveport, Shreveport, La., USA*Chanping Liang, MD, MS, Department of Ophthalmology, Louisiana State University Health Science Center-Shreveport, P.O. Box 33932/1501 Kings Hwy., Shreveport, LA 71130 (USA), E-Mail CLiang@lsuhsc.eduSep-Dec 2013 24 10 2013 24 10 2013 4 3 192 198 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.We report a challenging case of recurrent flat anterior chamber without hypotony after trabeculectomy in a 54-year-old Black male with a remote history of steroid-treated polymyositis, cataract surgery, and uncontrolled open angle glaucoma. The patient presented with a flat chamber on postoperative day 11, but had a normal fundus exam and intraocular pressure (IOP). Flat chamber persisted despite treatment with cycloplegics, steroids, and a Healon injection into the anterior chamber. A transverse B-scan of the peripheral fundus revealed a shallow annular peripheral choroidal detachment. The suprachoroidal fluid was drained. The patient presented 3 days later with a recurrent flat chamber and an annular peripheral choroidal effusion. The fluid was removed and reinforcement of the scleral flap was performed with the resolution of the flat anterior chamber. A large corneal epithelial defect developed after the second drainage. The oral prednisone was tapered quickly and the topical steroid was decreased. One week later, his vision decreased to count fingers with severe corneal stromal edema and Descemet's membrane folds that improved to 20/50 within 24 h of resumption of the oral steroid and frequent topical steroid. The patient's visual acuity improved to 20/20 following a slow withdrawal of the oral and topical steroid. Eight months after surgery, the IOP was 15 mm Hg without glaucoma medication. The detection of a shallow anterior choroidal detachment by transverse B-scan is critical to making the correct diagnosis. Severe cornea edema can occur if the steroid is withdrawn too quickly. Thus, steroids should be tapered cautiously in steroid-dependent patients.\n\nKey words\nAnnular peripheral choroidal detachmentTrabeculectomySteroid withdrawalUltrasonographyGlaucoma\n==== Body\nIntroduction\nShallow or flat anterior chamber occurs as an early postoperative complication in about 10% of glaucoma filtration surgery patients [1, 2, 3]. Failure to reform the normal chamber can cause vision-threatening problems such as cataract and corneal decompensation [4]. Identifying the cause as soon as possible is crucial to avoiding severe complications [5, 6, 7]. Treatment for flat anterior chamber is directed at eliminating the cause(s). The differential diagnosis for flat anterior chamber with increased intraocular pressure (IOP) includes suprachoroidal hemorrhage, aqueous misdirection glaucoma or pupillary block, while the causes of flat anterior chamber with low IOP include over-filtration, wound leak, cyclodialysis or serous choroidal detachment [5, 6, 7, 8, 9, 10]. In some cases, the underlying cause of the flat chamber can be difficult to treat and identify. Here we report the case of recurrent flat anterior chamber with normal IOP after trabeculectomy due to annular peripheral choroidal detachment. This case reinforces the awareness of this complication as one of the differential diagnoses of flat anterior chamber after glaucoma surgery, the importance of ultrasonography in making the diagnosis, and the need for accommodating therapeutic modification to treat complications arising in cases with underlying inflammatory disease.\n\nCase Report\nA 54-year-old African-American male with a remote history of prednisone treated polymyositis developed bilateral open angle glaucoma. His past ocular history included trabeculectomy in the right eye, bilateral cataract surgery and the maintenance of topical steroid drops to manage his rebound iritis. On the day of surgery, he reported some mild cold symptoms, but he insisted on having the surgery done. He had an uneventful trabeculectomy with mitomycin C performed on his left eye and did well during the first postoperative week with deep anterior chamber and an IOP in the 7–9 mm Hg range. He was on Vigamox 0.5% (Alcon, Fort Worth, Tex., USA) and prednisolone acetate 1% 4 times a day. He returned for a follow-up on postoperative day 11 with a complaint of persistent left eye pain for the last 3 days. On examination, his visual acuity was 20/80, pin holed (PH) to 20/30, and IOP was 10 mm Hg. His anterior chamber was flat with a complete iris-cornea touch except a 1/5 cornea thickness space between the cornea and the intraocular lens (IOL). The superior fornix-based bleb was slightly elevated without leakage and the peripheral iridectomy was patent. There were severe fibrin exudates in the anterior chamber with a 360° posterior synechiae of the pupil. The retina was flat on fundus exam without scleral depression. The initial differential diagnosis included: overfiltration, pupillary block, aqueous misdirection, choroidal effusion or choroidal hemorrhage. Inflammation was considered to play a role because of his history of steroid dependency, eye pain and copious fibrin in the anterior chamber. He was given oral prednisone 60 mg daily, topical Atropine 1% (Falcon Pharmaceuticals, Ltd., Fort Worth, Tex., USA) and phenylephrine 2.5% (Akorn, Inc., Lake Forest, Ill., USA) to dilate the pupil. Prednisolone was discontinued and Durezol (Difluprednate Ophthalmic Emulsion 0.05%; Alcon) was given one drop every hour [11]. In addition, he was given a 2-mg dexamethasone subconjunctival injection. Following the application of dilating drops in the clinic, the anterior chamber began reforming and posterior synechiae began to break down. He was sent home with Atropine 1% and phenylephrine 2.5% 4 times a day as well as Durezol every hour. The next morning, his visual acuity was 20/200 (PH 20/60), IOP was 7 mm Hg, and his anterior chamber was flat with cornea-IOL touch. His fundus exam revealed no choroidal detachment or hemorrhage. Healon (Abbott Medical Optics Inc., Santa Ana, Calif., USA) was injected to reform the anterior chamber [12]. His oral prednisone and topical drops were continued.\n\nDespite this treatment, the patient returned to the clinic 2 days later. He had a totally flat anterior chamber with a normal fundus and an IOP of 10 mm Hg. Aqueous misdirection was suspected, but peripheral choroidal effusion could not be ruled out. Transverse B-scan using a temporal approach identified a shallow annular anterior choroidal effusion (fig. 1). He was taken to the operating room the same day and the suprachoroidal effusion was drained from infero-nasal and infero-temporal sclerotomies [5]. A moderate amount of light yellow clear fluid was retrieved. The anterior chamber was reformed with Healon (Abbott Medical Optics Inc.) at the end of the surgery aiming at a high IOP to prevent choroidal effusion from recurring. He was continued on oral prednisone 60 mg daily and Durezol every 2 h and dilating drops 4 times a day.\n\nHis anterior chamber remained deep for 2 days with IOP in the mid-teens. However, on the third day after drainage of the choroidal effusion, the anterior chamber was flat with an IOP of 10 mm Hg. Aqueous misdirection was suspected, but repeat transverse B-scans showed recurrent peripheral choroidal effusion. The patient was taken to the operating room. One sclerotomy wound was reopened and a smaller amount of suprachoroidal fluid aspirated. The conjunctival incision for trabeculectomy was opened and additional 10–0 nylon sutures were placed on the sclera flap. Also, a half-thickness 3 × 3 mm donor scleral patch was placed to reinforce a thin area on the scleral flap. Postoperatively, his anterior chamber was deep with an IOP in the 40's. The IOP was lowered to the 30's over the next 2 days with paracentesis and ocular massage. Suture lysis was performed on the third postoperative day and his IOP decreased to the mid 20's. The patient developed a large corneal epithelial defect postoperatively. The oral prednisone was decreased by 20 mg every 2 days from the initial 60 mg/day, and topical Durezol was decreased from one drop every 2 h to 4 times a day to promote corneal healing.\n\nThe patient presented 7 days later with counting fingers vision due to diffuse corneal stromal edema and Descemet's membrane folds. The epithelial defect was completely healed and the IOP was 18 mm Hg with a deep anterior chamber. The corneal edema was thought to be due to the rapid steroid tapering. Oral prednisone 60 mg/day was resumed. The first dose of prednisone was given in the clinic and topical Durezol was increased to one drop every 2 h. The patient's corneal edema and Descemet's membrane folds cleared with vision improving to 20/50 the next morning. Oral prednisone was slowly tapered by 10 mg/week, while topical Durezol was continued at one drop every 2 h for 5 weeks, followed by a very slow taper. At this point, his anterior chamber depth stabilized and cornea remained clear. Suture lysis was performed cautiously and as needed. Visual acuity in the eye returned to 20/20 and IOP was 15 mm Hg, 8 months after the initial surgery, without glaucoma drops.\n\nDiscussion\nExtremely high or low IOP can be of great assistance when trying to sort out the cause of a flat chamber following glaucoma surgery. However, a flat anterior chamber with normal IOP creates a more puzzling situation. The differential diagnosis usually includes conditions from both ends of the spectrum, including overfiltration, pupillary block, suprachoroidal hemorrhage, choroidal detachment, aqueous misdirection, and annular peripheral choroidal detachment.\n\nIn our case, overfiltration was not a significant factor. The bleb never became highly elevated and the eye never hypotensive. Based on the presence of a patent peripheral iridectomy, pupillary block was ruled out. Suprachoroidal hemorrhages are usually located posterior to the equator and associated with severe pain, but neither were present. In typical cases of choroidal detachment, IOP is low with choroidal detachment being easily recognized on the fundus exam. However, not all cases of choroidal detachment are associated with a low IOP [3]. Aqueous misdirection, a diagnosis of exclusion, is characterized by flattening of the anterior chamber, increased IOP despite a patent iridectomy, the absence of choroidal detachment, and suprachoroidal hemorrhage or bleb overfiltration. IOP is usually, but not always, elevated [1]. The pathophysiology of aqueous misdirection glaucoma is not fully understood. A key mechanism is believed to be abnormal aqueous dynamics leading to vitreous expansion. The expanding vitreous then pushes the iris-lens diaphragm forward, causing secondary angle closure [10]. In addition, an inherent permeability defect in the anterior vitreous body as well as choroidal expansion may also play a role in the pathophysiological process [7].\n\nOur case of annular peripheral choroidal detachment was difficult to diagnose because it presented with clinical characteristics similar to aqueous misdirection. Dugel et al. [8] reported 18 patients diagnosed initially as aqueous misdirection, but were found to subsequently have annular peripheral choroidal detachment. Annular peripheral choroidal detachment is usually not recognized by fundus examination because it typically does not extend posterior to the equator [8]. A peripheral retinal exam with sclera depression was not feasible for fear of wound dehiscence or leak in the early postoperative stage. It is easy to misdiagnose annular peripheral choroidal detachment as aqueous misdirection if the choroidal detachment is not detected. The important point is that annular peripheral choroidal detachment can be identified with standard echography, with a transverse approach as a smooth, or scallop-shaped thick membrane in the periphery with little aftermovement [8, 13]. Ultrasound biomicroscopy (UBM) is helpful to illustrate the anatomical changes associated with annular peripheral choroidal detachment. However, it is not available to every practice and requires an emersion technique that may unduly stress the postoperative eye, especially those with a flat anterior chamber and a weak bleb wound. Supraciliary fluid has been detected in patients by UBM and associated with aqueous misdirection glaucoma [1]. As the correct diagnosis, an alternative view to this finding could be that supraciliary fluid found on the ultrasound exam lends itself to annular choroidal detachment. If supraciliary fluid is detected by either ultrasound or UBM, the proper diagnosis should be annular peripheral choroidal detachment.\n\nIOP is less helpful in diagnosing annular peripheral choroidal detachment as it can be high, low, or normal. In our case, IOP was always in the normal range. However, low IOP readings could be caused by enhanced aqueous outflow from the suprachoroidal space in the areas of detachment [14]. On the other hand, if the flat chamber is caused by anterior rotation of the ciliary body-iris-lens diaphragm, it may lead to secondary angle closure glaucoma and IOP might be normal or high [8]. Another hypothesis for normal IOP in our case is the possibility of an error in IOP measurement. Because the chamber was totally flat, there was direct contact between the cornea and the iris/IOL, a false high IOP may have been obtained.\n\nLittle is known about the pathogenesis of annular peripheral choroidal detachment. It is not clear why some cases have large choroidal effusion located posterior to the equator, and some cases develop annular peripheral choroidal detachment in which only a small amount of fluid is needed to create a flat anterior chamber. Usually, choroidal effusion is a consequence of hypotony from overfiltration in the immediate postoperative period, which can be followed by a vicious cycle of hypotony and choroidal effusion. In our case, the patient did not have overfiltration within the first postoperative week. We believe that inflammation played a major role in his disease process. The patient had a history of steroid dependence and mild cold symptoms on the day of surgery and that may have made him prone to more postoperative inflammation, perhaps necessitating more frequent topical steroid use with or without oral prednisone. Although his bleb was never highly elevated to suggest true overfiltration, there could have been some relative overfiltration as he required bleb revision to resolve the choroidal detachment.\n\nIt is controversial whether annular peripheral choroidal detachment should be considered as a separate diagnosis [3, 8]. We deem it worthwhile to list it as a distinct entity to reinforce awareness of this condition. Once the diagnosis of annular peripheral choroidal detachment is confirmed by ultrasonography, the management should aim at resolving the choroidal detachment.\n\nSome cases of annular peripheral choroidal detachment have responded well to treatment with topical cycloplegics and corticosteroids, but our case did not. Dugel et al. [8] reported that 10 out of 18 patients with annular peripheral choroidal detachment treated only medically had complete resolution of detachment with a mean time to resolution of 19.6 days. The authors hypothesized that this treatment tightens the zonules, rotates the ciliary body-iris-lens diaphragm backward and relieves the secondary angle closure.\n\nSurgical treatment of annular peripheral choroidal detachment by drainage of the suprachoroidal effusion has been employed successfully by others [1, 8]. Dugel et al. [8] reported surgical drainage of suprachoroidal fluid, which resulted in the immediate resolution of 8 cases concerning annular peripheral choroidal detachment. However, they did not mention recurrent cases. In our case, the annular peripheral choroidal detachment recurred 3 days after the first drainage and the patient underwent repeat effusion drainage due to total flat anterior chamber. The scleral flap was reinforced with a scleral patch during the second suprachoroidal drainage, in case overfiltration played a role in the causes of his flat anterior chamber. The revision of the scleral flap helped to resolve the choroidal effusion. Trope et al. [10] treated a similar case of flat anterior chamber with normal IOP by using pars plana vitrectomy to resolve the supraciliary effusion. However, we believe that the surgical procedure of choice should be drainage of suprachoroidal fluid, not vitrectomy, if the presence of fluid is proven. Bleb revision is generally not required for choroidal detachment surgery. The decision whether to repair the bleb is made based upon clinical judgment during surgery. If a significant elevation of the bleb is observed while using a balanced salt solution to form the chamber during surgery, it is probably wise to reinforce the bleb. The surgeon for this case was debating whether to place a trans-conjunctival suture over the bleb during the first drainage, but decided against it because the thick conjunctiva made it difficult.\n\nSevere corneal edema developed after the second drainage of choroidal effusion when the patient's oral and topical steroids were tapered. When the dosage of both, oral and topical steroid, was resumed, his cornea cleared up dramatically. The reason for the corneal edema is most likely due to the patient's steroid dependence and postoperative inflammation.\n\nConclusion\nAnnular peripheral choroidal effusion can cause a flat chamber without an obvious visible choroidal effusion on a clinical exam. It should be emphasized that annular peripheral choroidal effusion can easily be misdiagnosed as an aqueous misdirection when the IOP is normal or high. A transverse B-scan can detect the presence of shallow anterior choroidal detachment, which is critical for the diagnosis. We strongly recommend transverse B-scans for all patients with flat chamber when the diagnosis is not straight-forward. It is essential to differentiate annular peripheral choroidal effusion from aqueous misdirection. The appropriate surgical procedure is drainage of the suprachoroidal fluid, once it is confirmed by B-scan. Rapid steroid withdrawal in steroid dependent patients can cause severe corneal edema, which can be a challenge to treat and diagnose. Thus, steroids should be tapered very slowly in those patients.\n\nAcknowledgements\nThe research was supported in part by an unrestricted grant from Alcon for the LSU Medical School Ophthalmology Resident Continuing Medical Education.\n\nFig. 1 Transverse B-scan from the temporal approach (probe placed on globe temporally and oriented vertically), showing an annular peripheral choroidal effusion [ring-shaped fluid accumulation between the choroid (arrow) and sclera (*)].\n==== Refs\nReferences\n1 Gedde SJ Herndon LW Brandt JD Budenz DL Feuer WJ Schiffman JC Tube Versus Trabeculectomy Study Group. Postoperative complications in the tube versus trabeculectomy (TVT) study during five years of follow-up Am J Ophthalmol 2012 153 804 814 22244522 \n2 Jampel HD Musch DC Gillespie BW Lichter PR Wright MM Guire KE Collaborative Initial Glaucoma Treatment Study Group. Perioperative complications of trabeculectomy in the collaborative initial glaucoma treatment study (CIGTS) Am J Ophthalmol 2005 140 16 22 15939389 \n3 Pavlin CJ Buys Y Pathmanathan T Trope G Annular peripheral choroidal detachment after glaucoma surgery Ophthalmology 1997 104 1983 1984 9400754 \n4 AGIS (Advanced Glaucoma Intervention Study) Investigators The Advanced Glaucoma Intervention Study: Risk of cataract formation after trabeculectomy Arch Ophthalmol 2001 119 1771 1779 11735786 \n5 de Barros DS Navarro JB Mantravadi AV Siam GA Gheith ME Tittler EH Baez KA Martinez SM Spaeth GL The early flat anterior chamber after trabeculectomy: a randomized, prospective study of 3 methods of management J Glaucoma 2009 18 13 20 19142129 \n6 Kim YY Jung HR The effect of flat anterior chamber on the success of trabeculectomy Acta Ophthalmol Scand 1995 73 268 272 7493243 \n7 Quigley HA Friedman DS Congdon NG Possible mechanisms of primary angle-closure and malignant glaucoma J Glaucoma 2003 12 167 180 12671473 \n8 Dugel PU Heuer DK Thach AB Baerveldt G Lee PP Lloyd MA Minckler DS Green RL Annular peripheral choroidal detachment simulating aqueous misdirection after glaucoma surgery Ophthalmology 1997 104 439 444 9082270 \n9 Luntz MH Rosenblatt M Malignant glaucoma Surv Ophthalmol 1987 32 73 93 3317956 \n10 Trope GE Pavlin CJ Bau A Baumal CR Foster FS Malignant glaucoma. Clinical and ultrasound biomicroscopic features Ophthalmology 1994 101 1030 1035 8008343 \n11 Wand M Viscoelastic agent and the prevention of post-filtration flat anterior chamber Ophthalmic Surg 1988 19 523 524 3412765 \n12 Foster CS Davanzo R Flynn TE McLeod K Vogel R Crockett RS Durezol (difluprednate ophthalmic emulsion 0.05%) compared with Pred Forte 1% ophthalmic suspension in the treatment of endogenous anterior uveitis J Ocul Pharmacol Ther 2010 26 475 483 20809807 \n13 Grigera D Moreno C Fava O Girado SG Ultrasound biomicroscopy in eyes with anterior chamber flattening after trabeculectomy Can J Ophthalmol 2002 37 27 32 11865955 \n14 Pederson JE Outflow facility in acute experimental ciliochoroidal detachment Invest Ophthalmol Vis Sci 1984 25 1231 1232 6480299\n\n",
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"keywords": "Annular peripheral choroidal detachment; Glaucoma; Steroid withdrawal; Trabeculectomy; Ultrasonography",
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"abstract": "Primary dural marginal zone lymphomas (MZLs) are exceptionally rare, with fewer than 100 cases reported to date. While the association between hepatitis C virus (HCV) infection and lymphoma is well established, it is unclear if this association extends to all anatomic sites. Here we report a case of dural MZL in a 61-year-old woman with an HCV infection. To our knowledge, this is the first report of a dural MZL associated with an HCV infection in an immunocompetent patient and was successfully treated with radiotherapy and rituximab. As such, future cases of primary MZL found in the dura should prompt consideration of co-infection with microbials such as HCV and upfront treatment with anti-virals should be considered.",
"affiliations": "Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Hematology and Bone Marrow Transplant, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.;Vanderbilt University School of Medicine, Nashville, TN, USA.;Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.",
"authors": "Villaume|Matthew T|MT|;Patel|Dilan|D|;Lopez|Christine|C|;Patel|Vivek|V|;Diggs|Pauleatha|P|;Harmsen|Hannah|H|;Thompson|Mary Ann|MA|;Morgan|David|D|",
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"fulltext": "\n==== Front\nWorld J Oncol\nWorld J Oncol\nElmer Press\nWorld Journal of Oncology\n1920-4531 1920-454X Elmer Press \n\n10.14740/wjon1285\nCase Report\nDural Marginal Zone Lymphoma in a Patient With a Hepatitis C Virus Infection\nMZL in HCV PatientVillaume Matthew T. ae Patel Dilan b Lopez Christine a Patel Vivek a Diggs Pauleatha c Harmsen Hannah d Thompson Mary Ann d Morgan David ab a Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA\nb Department of Hematology and Bone Marrow Transplant, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA\nc Vanderbilt University School of Medicine, Nashville, TN, USA\nd Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA\ne Corresponding Author: Matthew T. Villaume, Department of Medicine, Vanderbilt University Medical Center, 2100 Pierce Avenue, PRB 518, Nashville, TN 37232, USA. Email: matthew.t.villaume@vanderbilt.edu\n6 2020 \n14 5 2020 \n11 3 122 125\n14 4 2020 21 4 2020 Copyright 2020, Villaume et al.2020This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Primary dural marginal zone lymphomas (MZLs) are exceptionally rare, with fewer than 100 cases reported to date. While the association between hepatitis C virus (HCV) infection and lymphoma is well established, it is unclear if this association extends to all anatomic sites. Here we report a case of dural MZL in a 61-year-old woman with an HCV infection. To our knowledge, this is the first report of a dural MZL associated with an HCV infection in an immunocompetent patient and was successfully treated with radiotherapy and rituximab. As such, future cases of primary MZL found in the dura should prompt consideration of co-infection with microbials such as HCV and upfront treatment with anti-virals should be considered.\n\nHepatitis C virusMarginal zone lymphomaDura\n==== Body\nIntroduction\nMarginal zone B-cell lymphoma (MZL) is an uncommon, indolent form of non-Hodgkin lymphoma (NHL) that accounts for 5-17% of cases [1]. The subtypes of MZL are splenic, nodal, and extranodal (EMZL). EMZL is the most common entity, accounting for 67% of cases, and is characterized by occurrence at sites that typically lack discrete nodal lymphoid tissue but have mucosa-associated lymphoid tissue (MALT) [1]. The most common sites include the stomach (21%), adnexa of the eye (8%), skin (5%), and salivary glands (5%) [2]. A number of reports have linked specific infectious agents and inflammatory conditions to particular sites of EMZL, including MZL in the stomach with Helicobacter pylori, in the ocular adnexa with Chlamydia psittaci, and in the skin with Borrelia species [3-5]. Hepatitis C virus (HCV) has a known association with NHL, and with MZL in particular, and there are reports of the elimination of an infectious agent leading to complete remission of the lymphoma [6].\n\nNHL of the central nervous system (CNS) represents less than 1% of NHL cases, and dural lymphomas have generally been included in this group [7]. CNS NHL is usually intraparenchymal and has a poor prognosis [7]. Intracranial EMZL is an extremely rare entity, with only 69 reported cases as of 2018 [7]. It typically has an indolent course and is found as a dural-based mass mimicking a meningioma or subdural hematoma [8, 9]. A case report of dural EMZL in a liver transplant recipient with prolonged immunosuppression and chronic HCV infection is the only reported case of the co-occurrence of HCV and EMZL [10]. Given the rarity of the condition, no randomized trials have been conducted to evaluate treatment options, and reported regimens have included a combination of surgery, radiotherapy, chemotherapy or a combination of each [7].\n\nHere we report a case of dural EMZL in a patient with a chronic HCV infection. A combination of chemotherapy and radiotherapy was used to treat the lymphoma with anti-viral treatment being initiated after discharge. To our knowledge, this is the first report of a dural EMZL associated with an HCV infection in an immunocompetent patient.\n\nCase Report\nA 61-year-old woman with no past medical history presented to the emergency room with altered mental status (AMS). She reported a 3-month history of worsening cognitive and physical function. At the time of evaluation she had an inability to dress herself, loss of urinary continence, personality change, and memory loss. On exam, she was ill-appearing, but speaking fluently. Intermittent inattention to the interviewer was noted. Her vital signs were normal. She was alert and oriented to person, place, and time. Cranial nerves function was intact, and no other motor or sensory deficits were noted. The Romberg sign was negative. She had a normal complete blood count, basic metabolic panel, and urinalysis upon admission.\n\nNon-contrasted computed tomography (CT) scan showed a prominent bifrontal white matter hypodensity involving the periventricular regions along with a poorly marginated region of hyperdensity along the anterior cranial vault (Fig. 1a). Magnetic resonance imaging (MRI) showed a plaque-like extra-axial, T1/T2 isointense mass over the bifrontal convexity which exerted a mass effect. There was no evidence on gradient sequences to suggest hemorrhage or diffusion restriction to suggest infection (Fig. 1b). The initial differential diagnosis included meningioma, dural metastases, hypertrophic pachymeningitis, and lymphoma. The patient underwent frontal craniotomy for biopsy of the abnormally thickened dura. Histopathology of the mass revealed a dense infiltrate of small lymphocytes, composed predominantly of CD20 positive B cells aberrantly expressing CD43 by immunohistochemistry (Fig. 2). Flow cytometry demonstrated that the B cells were lambda-restricted and were negative for CD5, CD10, and CD200. The immunophenotype was most consistent with MZL [11]. CT of the chest, abdomen, and pelvis showed no other abnormalities. Lumbar puncture was initially deferred due to concerns regarding intracranial mass effect. She was treated with dexamethasone 4 mg twice daily and discharged after cognitive improvement.\n\nFigure 1 Brain imaging at presentation. (a) Initial non-contrasted computed tomography scan of the brain. Marked bifrontal white matter hypodensity extends across the corpus callosum with mass effect on the frontal horns of the lateral ventricles. In addition, there is a large poorly marginated region of hyperdensity along the anterior falx and anterior cranial vault which appears extra-axial. (b) T1/2-weighted brain MRI. Bifrontal extra-axial mass with extensive dural tail with invasion into both frontal lobes and extensive edema extending across the corpus callosum. MRI: magnetic resonance imaging.\n\nFigure 2 Histopathology of dural biopsy. Microscopic examination shows sheets of small lymphoid cells with clumped chromatin and monocytoid morphology (hematoxylin and eosin, × 400) (a). The lymphoid population is composed predominantly of CD20-positive B cells (b) which aberrantly express CD43 (c) (CD20 and CD43 IHC, × 400). Frequent interspersed small CD3-positive T cells are also present (CD3 IHC, × 400) (d). IHC: immunohistochemistry.\n\nThe patient was subsequently admitted for seizure along with AMS and generalized weakness. She was started on levetiracetam 750 mg and dexamethasone 4 mg twice daily. Repeat brain MRI showed an increase in mass effect on the bifrontal cortices. The hospital course was characterized by steroid-induced psychosis, which included a loss of orientation to person, place and time as well as physical aggression toward staff. The mental status improved, but did not completely normalize after discontinuation of steroids as she continued to be disoriented and hypersomnolent. An extensive evaluation for infection showed no cause for the AMS, but revealed antibodies to HCV genotype 1a and a viral load of 807,015 IU/mL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were mildly elevated at 83 U/L and 45 U/L, respectively. Liver fibrosis assessment via biomarker analysis (α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase) yielded a stage of F3, indicating advanced fibrosis (FibroTest, scale F0 - F4). A lumbar puncture was performed and showed that the cerebrospinal fluid was negative for lymphoma involvement.\n\nStereotactic radiosurgery (SRS) was initiated along with concurrent rituximab (375 mg/m2 weekly for four doses), which was given without anti-viral prophylaxis. The radiotherapy included low dose whole brain radiation (24 Gy) followed by intensity modulated radiotherapy (IMRT) boost (34 Gy) to areas of gross disease. During the first 2 weeks after beginning treatment, her mental status and personality returned to normal. There were no subsequent seizures. She was discharged home to her family.\n\nAt her next oncology follow-up, she was found to be fully recovered mentally and physically. Brain MRI showed a moderate decrease in dural enhancement and vasogenic edema with interval enlargement of the lateral ventricles likely demonstrating reduced mass effect. She was started on Mavyret (glecaprevir/pibrentsavir) 100 mg/40 mg for 8 weeks to treat her chronic HCV infection. Follow-up MRI scans over the next year did not detect any growth of the lymphoma and showed only post-treatment changes.\n\nDiscussion\nPrimary dural MZLs are exceptionally rare, with fewer than 100 cases reported to date. Women are more likely to be affected than men (77%) and the median age at diagnosis is 55 years [7]. Patients typically present with headache, seizure, or vision changes [8, 9]. Our report recapitulates these typical presenting characteristics and reinforces the challenge of diagnosis.\n\nThe tissue of origin in EMZL is thought to be lymphoid tissue, analogous to Peyer patches in the small intestine [12]. However, no prototypical intracranial lymphoid tissue exists to explain examples of MZL of the dura. Kumar et al proposed that meningothelial cells can play the role of MALT based on their observation that these intracranial MZLs arise at dural sites where meningothelial cells are concentrated [13]. The putative pathogenic mechanism is chronic antigen stimulation by an infectious or inflammatory condition leading to polyclonal proliferation of unidentified lymphoid tissue, analogous to MALT lymphomas at other sites [14].\n\nThe association between HCV and NHL has long been established, with studies showing a 20-100% increased incidence of NHL in HCV-infected subjects as compared to that of HCV-negative controls [15].The strongest evidence of a causal relationship is reports showing complete remissions of lymphoma with anti-viral regimens [16]. The mechanism of this relationship has not been definitively demonstrated but likely involves chronic antigen stimulation by HCV-E2 [17]. Other proposed mechanisms include direct infection of B cells by HCV as well as a unique HCV-induced mutator phenotype [18, 19].\n\nThe only example to date in the literature of a dural MZL associated with an HCV infection was also complicated by immunosuppression, which is itself associated with NHL [10, 20]. Given the unique immune environment surrounding the dura, it is a significant finding that such a case exists in an immunocompetent person. Growing evidence shows that MZLs of different anatomic sites have different pathogeneses and may therefore be susceptible to different treatments. Perhaps future attempts to treat HCV-associated dural EMZLs with anti-microbial therapy alone will be successful as it has been with other anatomic sites, although the acuity of our patient’s condition did not allow for such a consideration. We hope that our report of this association could prompt the use of such a low-toxicity treatment regimen by future providers.\n\nA 2018 systematic review of existing reports of dural EMZL showed that treatment modalities are heavily skewed towards localized therapy, including radiotherapy (27%), surgery alone (15%), with chemotherapy rarely used alone (4%), or some combination of the three (53%) [7]. Of these, only one case reported the use of radiotherapy and rituximab, as was used in our case [18]. No reports of anti-viral therapy treatment exist in cases of dural EMZL, as the single case of HCV-associated dural EMZL in the literature was treated with radiotherapy alone [12]. Anti-viral treatment was started only after initial response of the tumor to rituximab and radiotherapy. The continued tumor size decrease over the next 12 months cannot be attributed to its inclusion.\n\nConclusions\nWe report a case of EMZL in a patient with active HCV infection. To date, it is not known whether the association between infectious agents and NHL extends to intracranial lymphomas. Our case shows an association, though we cannot prove any causal link, between NHL and HCV infection. However, it is provocative, as HCV is known to be causative in other types of lymphomas. This may provide an avenue for additional treatments in dural EMZL. Our example of such a case should prompt future providers to consider evaluating infectious sources when presented with intracranial lymphomas.\n\nNone to declare.\n\nFinancial Disclosure\nNone to declare.\n\nConflict of Interest\nNone to declare.\n\nInformed Consent\nWritten informed consent was obtained from the patient for publication of this manuscript and any accompanying images.\n\nAuthor Contributions\nMTV wrote the manuscript. HH and MAT diagnosed the patient and edited the manuscript. MTV, DP, CL, VP, PD, and DM treated the patient and edited the manuscript.\n\nData Availability\nThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nReferences\n1 Thieblemont C Clinical presentation and management of marginal zone lymphomas Hematology Am Soc Hematol Educ Program 2005 2005 307 313 10.1182/asheducation-2005.1.307 16304396 \n2 Khalil MO Morton LM Devesa SS Check DP Curtis RE Weisenburger DD Dores GM Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus on primary anatomic site Br J Haematol 2014 165 1 67 77 10.1111/bjh.12730 24417667 \n3 Farinha P Gascoyne RD Helicobacter pylori and MALT lymphoma Gastroenterology 2005 128 6 1579 1605 10.1053/j.gastro.2005.03.083 15887153 \n4 Ferreri AJ Guidoboni M Ponzoni M De Conciliis C Dell'Oro S Fleischhauer K Caggiari L et al Evidence for an association between Chlamydia psittaci and ocular adnexal lymphomas J Natl Cancer Inst 2004 96 8 586 594 10.1093/jnci/djh102 15100336 \n5 Roggero E Zucca E Mainetti C Bertoni F Valsangiacomo C Pedrinis E Borisch B et al Eradication of Borrelia burgdorferi infection in primary marginal zone B-cell lymphoma of the skin Hum Pathol 2000 31 2 263 268 10.1016/S0046-8177(00)80233-6 10685647 \n6 Gisbert JP Garcia-Buey L Pajares JM Moreno-Otero R Prevalence of hepatitis C virus infection in B-cell non-Hodgkin's lymphoma: systematic review and meta-analysis Gastroenterology 2003 125 6 1723 1732 10.1053/j.gastro.2003.09.025 14724825 \n7 Arcaini L Vallisa D Rattotti S Ferretti VV Ferreri AJ Bernuzzi P Merli M et al Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi Ann Oncol 2014 25 7 1404 1410 10.1093/annonc/mdu166 24799461 \n8 Vora M Ghildyal A Wei E et al Primary dural marginal zone lymphoma presenting as a meningioma: a case report and review of the literature Am J Clin Pathol 2018 149 S81 10.1093/ajcp/aqx121.190 \n9 Gocmen S Gamsizkan M Onguru O Sefali M Erdogan E Primary dural lymphoma mimicking a subdural hematoma J Clin Neurosci 2010 17 3 380 382 10.1016/j.jocn.2009.02.014 20079653 \n10 Estevez M Chu C Pless M Small B-cell lymphoma presenting as diffuse dural thickening with cranial neuropathies J Neurooncol 2002 59 3 243 247 10.1023/A:1019913611512 12241122 \n11 Boyd SD Natkunam Y Allen JR Warnke RA Selective immunophenotyping for diagnosis of B-cell neoplasms: immunohistochemistry and flow cytometry strategies and results Appl Immunohistochem Mol Morphol 2013 21 2 116 131 22820658 \n12 Zucca E Bertoni F Roggero E Cavalli F The gastric marginal zone B-cell lymphoma of MALT type Blood 2000 96 2 410 419 10.1182/blood.V96.2.410 10887100 \n13 Kumar S Kumar D Kaldjian EP Bauserman S Raffeld M Jaffe ES Primary low-grade B-cell lymphoma of the dura: a mucosa associated lymphoid tissue-type lymphoma Am J Surg Pathol 1997 21 1 81 87 10.1097/00000478-199701000-00009 8990144 \n14 Suarez F Lortholary O Hermine O Lecuit M Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation Blood 2006 107 8 3034 3044 10.1182/blood-2005-09-3679 16397126 \n15 Giordano TP Henderson L Landgren O Chiao EY Kramer JR El-Serag H Engels EA Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus JAMA 2007 297 18 2010 2017 10.1001/jama.297.18.2010 17488966 \n16 Sultanik P Klotz C Brault P Pol S Mallet V Regression of an HCV-associated disseminated marginal zone lymphoma under IFN-free antiviral treatment Blood 2015 125 15 2446 2447 10.1182/blood-2014-12-618652 25858892 \n17 Lesniewski R Okasinski G Carrick R Van Sant C Desai S Johnson R Scheffel J et al Antibody to hepatitis C virus second envelope (HCV-E2) glycoprotein: a new marker of HCV infection closely associated with viremia J Med Virol 1995 45 4 415 422 10.1002/jmv.1890450411 7545212 \n18 Inokuchi M Ito T Uchikoshi M Shimozuma Y Morikawa K Nozawa H Shimazaki T et al Infection of B cells with hepatitis C virus for the development of lymphoproliferative disorders in patients with chronic hepatitis C J Med Virol 2009 81 4 619 627 10.1002/jmv.21388 19235854 \n19 Machida K Cheng KT Pavio N Sung VM Lai MM Hepatitis C virus E2-CD81 interaction induces hypermutation of the immunoglobulin gene in B cells J Virol 2005 79 13 8079 8089 10.1128/JVI.79.13.8079-8089.2005 15956553 \n20 van Leeuwen MT Grulich AE Webster AC McCredie MR Stewart JH McDonald SP Amin J et al Immunosuppression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation Blood 2009 114 3 630 637 10.1182/blood-2009-02-202507 19443660\n\n",
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"abstract": "BACKGROUND\nPost-transplant lymphoproliferative disease (PTLD) is one of the major complications of organ transplantation, especially in children with Epstein-Barr virus (EBV) viremia (EV). We performed a retrospective study to evaluate risk factors for PTLD in children with EV.\n\n\nMETHODS\nAmong 199 pediatric kidney transplantation (KT) recipients at our center from January 2001 to October 2015, records of those with EBV viral loads of > 1,000 copies/mL and/or PTLD were reviewed.\n\n\nRESULTS\nDiagnosis of PTLD was made in seven patients (PTLD group), and 39 patients had EV only (EV only group). The median time from KT to EV and PTLD diagnosis was 6.7 (range 0.4-47.8) months and 8.2 (range, 2.8-98.9) months, respectively. There were no significant differences between the groups in terms of sex, age at transplantation, donor type, EBV viral load, or EV-free duration after KT. Higher tacrolimus level before EV (hazard ratio, 44.5; P = 0.003) was an independent risk factor for PTLD in multivariate Cox regression analysis. Six patients with a high EBV load (median 171,639 copies/mL) were treated with preemptive rituximab (RTX) therapy, resulting in transient reduction of EBV load. None of these patients developed PTLD (median follow-up 51.5 months); however, two had neutropenia and two developed infection requiring hospital admission.\n\n\nCONCLUSIONS\nIn pediatric KT recipients, higher tacrolimus levels were associated with a higher incidence of PTLD. Conversely, those who received preemptive RTX for EV did not develop PTLD.",
"affiliations": "Department of Pediatrics, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.;Department of Pediatrics, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.;Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.;Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea. kanghg@snu.ac.kr.;Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea. yhahn@snub.org.",
"authors": "Hyun|Hyesun|H|https://orcid.org/0000-0001-8525-1471;Park|Eujin|E|https://orcid.org/0000-0002-4413-468X;Cho|Myunghyun|M|https://orcid.org/0000-0002-3237-3173;Min|Sang Il|SI|https://orcid.org/0000-0002-0688-0278;Ha|Jongwon|J|https://orcid.org/0000-0003-2285-3517;Kang|Hyoung Jin|HJ|https://orcid.org/0000-0003-1009-6002;Shin|Hee Young|HY|https://orcid.org/0000-0003-2091-1947;Ha|Il Soo|IS|https://orcid.org/0000-0001-5428-6209;Cheong|Hae Il|HI|https://orcid.org/0000-0001-7556-1265;Ahn|Yo Han|YH|https://orcid.org/0000-0002-8185-4408;Kang|Hee Gyung|HG|https://orcid.org/0000-0001-8323-5320",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000069283:Rituximab",
"country": "Korea (South)",
"delete": false,
"doi": "10.3346/jkms.2019.34.e203",
"fulltext": "\n==== Front\nJ Korean Med SciJ. Korean Med. SciJKMSJournal of Korean Medical Science1011-89341598-6357The Korean Academy of Medical Sciences 10.3346/jkms.2019.34.e203Original ArticlePediatricsPost-Transplant Lymphoproliferative Diseases in Pediatric Kidney Allograft Recipients with Epstein-Barr Virus Viremia https://orcid.org/0000-0001-8525-1471Hyun Hyesun 1https://orcid.org/0000-0002-4413-468XPark Eujin 2https://orcid.org/0000-0002-3237-3173Cho Myunghyun 3https://orcid.org/0000-0002-0688-0278Min Sang-Il 4https://orcid.org/0000-0003-2285-3517Ha Jongwon 45https://orcid.org/0000-0003-1009-6002Kang Hyoung Jin 6https://orcid.org/0000-0003-2091-1947Shin Hee Young 6https://orcid.org/0000-0001-5428-6209Ha Il-Soo 3https://orcid.org/0000-0001-7556-1265Cheong Hae Il 3https://orcid.org/0000-0002-8185-4408Ahn Yo Han 7https://orcid.org/0000-0001-8323-5320Kang Hee Gyung 31 Department of Pediatrics, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.2 Department of Pediatrics, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.3 Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.4 Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.5 Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea.6 Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea.7 Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.Address for Correspondence: Hee Gyung Kang, MD, PhD. Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. kanghg@snu.ac.krAddress for Correspondence: Yo Han Ahn, MD. Department of Pediatrics, Seoul National University Bundang Hospital, 82 Gumi-ro 173-beon-gil, Bundang-gu, Seongnam 13620, Korea. yhahn@snub.org24 7 2019 05 8 2019 34 30 e20307 11 2018 07 7 2019 © 2019 The Korean Academy of Medical Sciences.2019The Korean Academy of Medical SciencesThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nPost-transplant lymphoproliferative disease (PTLD) is one of the major complications of organ transplantation, especially in children with Epstein-Barr virus (EBV) viremia (EV). We performed a retrospective study to evaluate risk factors for PTLD in children with EV.\n\nMethods\nAmong 199 pediatric kidney transplantation (KT) recipients at our center from January 2001 to October 2015, records of those with EBV viral loads of > 1,000 copies/mL and/or PTLD were reviewed.\n\nResults\nDiagnosis of PTLD was made in seven patients (PTLD group), and 39 patients had EV only (EV only group). The median time from KT to EV and PTLD diagnosis was 6.7 (range 0.4–47.8) months and 8.2 (range, 2.8–98.9) months, respectively. There were no significant differences between the groups in terms of sex, age at transplantation, donor type, EBV viral load, or EV-free duration after KT. Higher tacrolimus level before EV (hazard ratio, 44.5; P = 0.003) was an independent risk factor for PTLD in multivariate Cox regression analysis. Six patients with a high EBV load (median 171,639 copies/mL) were treated with preemptive rituximab (RTX) therapy, resulting in transient reduction of EBV load. None of these patients developed PTLD (median follow-up 51.5 months); however, two had neutropenia and two developed infection requiring hospital admission.\n\nConclusion\nIn pediatric KT recipients, higher tacrolimus levels were associated with a higher incidence of PTLD. Conversely, those who received preemptive RTX for EV did not develop PTLD.\n\nGraphical Abstract\n\n\nPost-Transplant Lymphoproliferative DiseaseKidney TransplantationEpstein-Barr VirusRituximabMinistry of Health and Welfarehttps://doi.org/10.13039/501100003625HI12C0014\n==== Body\nINTRODUCTION\nPost-transplant lymphoproliferative disease (PTLD) is one of the major complications of organ transplantation, with an incidence ranging from 1% to 16% depending on the allograft organ.1 This incidence is 0.2%–2.5% in liver and kidney transplantation cases, which is relatively lower than that in other organ transplant cases.23 Incidence rates of PTLD are higher in pediatric kidney transplant recipients than in adult kidney transplant recipients, ranging from 1.2% to 10%.456 More than 90% of pediatric PTLDs are due to Epstein-Barr virus (EBV)-positive B-cell proliferation. Previously reported risk factors for EBV-associated PTLD include recipient EBV seronegativity, degree of immunosuppression, acute rejection episode, use of OKT3 or tacrolimus, recipient age and race, allograft type, host genetic variations, and especially Epstein-Barr virus viremia (EV).789101112 While adult allograft recipients usually have acquired-immunity to EBV at the time of transplantation, pediatric allograft recipients often experience primary EBV infection after transplantation. Although EBV-infected transformed B cells are highly immunogenic and rapidly eliminated by EBV-specific T cells in healthy hosts, if immunosuppressed pediatric patients have primary EBV infection, then an inadequate immune response may result in massive infection of B cells. Primary EBV infection increases the chance of developing PTLD 6–76 fold.13141516\n\nEBV infection and/or reactivation, which can be detected as increasing copy numbers of EBV DNA in the peripheral blood, usually precede PTLD. Therefore, it is recommended that EBV titer be regularly monitored after solid-organ transplantation in patients at a higher risk for PTLD. The Kidney Disease Improving Global Outcomes clinical practice guideline for the care of kidney transplant recipients recommended the following monitoring regimen for EBV viral load monitoring in EBV-seronegative patients who received an allograft from a seropositive donor: every 1 week in the first 3 months after transplantation, at least monthly for 3–6 months, and then every 3 months for the rest of the first year.17 Once EBV infection and/or reactivation is noted, transplantation physicians reduce immunosuppression to prevent EBV-associated PTLD. However, EBV infection often persists and progresses despite reduction in immunosuppressive drug regimen, and there is no anti-viral agent with proven efficacy against EBV.8 In contrast, during stem cell transplantation, pre-emptive treatment with rituximab is often used to eradicate B lymphocytes, the reservoir of EBV, thereby to prevent PTLD.1819 A similar approach has been attempted in solid organ transplantation in patients at high-risk for EBV-associated PTLD.20\n\nIn this study, the risk factors for PTLD were assessed in pediatric kidney allograft recipients with EV, including the effect of pre-emptive rituximab treatment to prevent PTLD.\n\nMETHODS\nPatients and data collection\nWe performed a retrospective study that included all patients aged 0–19 years who underwent kidney transplantation in Seoul National University Children's Hospital from January 2001 to October 2015. Patients were enrolled if their EBV load in whole blood was greater than 1,000 copies/mL for 2 consecutive tests. The EBV Q-PCR Alert kit (ELITech Group, Puteaux, France) was used to quantify the amount of Epstein-Barr virus nuclear antigen (EBNA)-1 in whole blood. The diagnosis of PTLD was made histologically after biopsy, and the association with EBV was assessed in tissue specimens by in-situ hybridization of Epstein-Barr virus-encoded RNA (EBER). Patients who received another solid organ transplantation before or after kidney transplantation were excluded. Data were obtained from electronic medical records. Data reviewed included underlying disease, sex, age at transplantation, EBV serologic status of the donor and the recipient at transplantation, donor source, type of induction therapy, maintenance immunosuppressive medication, rejection episodes, and tacrolimus level at EV onset and median levels before and after onset of EV. The median levels of tacrolimus before the onset of EV were calculated using all values measured from transplantation to the appearance of EV. EBV serostatus at the time of transplant was determined by viral capsid antigen (VCA)-IgM, VCA-IgG, and EBNA. Cytomegalovirus (CMV) viremia was defined as positive antigenemia or detection of CMV DNA determined by whole-blood PCR.\n\nImmunosuppression\nIn our center, induction immunosuppression therapy for kidney transplantation consisted of methylprednisolone with or without basiliximab or antithymocyte globulin. Steroids, tacrolimus, and mycophenolate mofetil were started perioperatively and continued as maintenance therapy. Methylprednisolone was administered as 10 mg/kg intravenous bolus dose at the time of surgery and was tapered gradually to a maintenance dose of prednisolone 0.3 mg/kg by 1 month after transplantation. The target tacrolimus trough level was 8–12 ng/mL for up to 3 months, 6–8 ng/mL between 3 and 6 months, and 4–6 ng/mL thereafter. Tacrolimus levels were monitored weekly for a month after discharge from operation, biweekly for the next 3 months, and monthly thereafter. From 2001 to 2008, basiliximab was used as induction therapy for high-risk patients with deceased-donor kidney transplant or higher number of human leukocyte antigen (HLA) mismatches. After 2008, most patients received basiliximab induction therapy.\n\nEV monitoring\nPrincipally, EBV was monitored every month for the first three months following transplant, then every 3 months for the rest of the first year, and then yearly. For recipients who were positive for EBV VCA IgG, EBV was monitored every three months. When EV was detected, EBV was monitored again in 2 weeks, and if the titer was still high, immunosuppression was reduced, usually by reducing antimetabolites and then tacrolimus according to the judgment of the physicians.\n\nPre-emptive rituximab therapy\nSome of the patients who exhibited persistent high titers of EV (more than 1 × 104 copies/mL in whole blood for two consecutive weeks) despite immunosuppression reduction were treated with rituximab (RTX). These patients had prolonged high viremia over 1 year, a 3-fold or greater increase in EBV titer, or higher risk of malignancy (WT1 mutation). After confirming that the patients did not have active infection or neutropenia, a single dose of RTX therapy of 375 mg/m2 body surface area was administered.\n\nStatistical analysis\nTo determine statistical differences between groups, we used the chi-square test or Fischer's exact test for categorical variables and the t-test or Mann-Whitney test for continuous variables. Cox regression analysis was performed to identify risk factors for PTLD following EV. We performed the univariate Cox regression test to identify significant independent variables, and used independent variables with a univariate P value < 0.2 for multivariate Cox regression analysis. A P value < 0.05 was considered statistically significant. The statistical analysis was performed using IBM SPSS Statistics version 22.0 (IBM cooperation, Armonk, NY, USA).\n\nEthics statement\nThe study was approved by the Institutional Review Board (IRB) of our center (IRB No. H-1312-068-541). The informed consent requirement was waived by the board.\n\nRESULTS\nDuring the study period, 199 children underwent kidney transplantation in our center. Of these, 46 (23.1%) had viremia defined as an EBV load greater than 1,000 copies/mL in whole blood for 2 consecutive tests during a median follow-up period of 5.3 years (Fig. 1). Viremia of all patients (EBV > 1,000 copies/mL) was first detected at a median of 6.7 months (range, 0.4–47.8 months) after kidney transplantation. The diagnosis of PTLD was made in seven patients (PTLD group) at a median of 8.2 months (2.8–98.9 months) after transplantation. The other 39 patients had EV only (EV only group).\n\nFig. 1 Distribution of patients with kidney transplantation by EBV status and PTLD.\nEBV = Epstein-Barr virus, PTLD = post-transplant lymphoproliferative disease, RTX = rituximab.\n\nClinical course of PTLD\nPatients with PTLD presented with fever, lymph node enlargement, or gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea (Table 1). Any gastrointestinal symptoms and/or lymph node enlargement raised suspicion for PTLD and prompted the clinician to perform further work-up to rule out PTLD. The majority of patients (n = 4) had gastrointestinal organ involvement, including small bowel and intraperitoneal lymph nodes. There was no extranodal PTLD. Pathologic diagnosis of PTLD revealed one case of early lesion, two cases of polymorphic PTLD, one case of Burkitt lymphoma, and three cases of diffuse large B-cell lymphoma. Upon diagnosis of PTLD, immunosuppressive medications were reduced, and RTX and/or chemotherapy were administered as appropriate. All patients achieved complete remission of PTLD after treatments. While one patient lost her allograft kidney due to complications of chemotherapy, six patients retained renal function after follow-up for 2.5–10.5 years.\n\nTable 1 Characteristics of patients with post-transplant lymphoproliferative disease\nCase No.\tSex/age at time of PTLD, yr\tPrimary disease\tTime from KT to PTLD, mon\tPresentation\tInvolved sitea\tHistologic diagnosis\tEBV serostatus\tTreatment\tEBV titer, copies/mL\tOutcome\t\nPeak\tMedian\tPTLD\tGraft\t\n1\tF/5\tFSGS\t10\tFever, cervical LNE\tNeck mass, jugular LNs, portocaval LN\tDiffuse large B-cell lymphomab\tDUK/RUK\tRTX, chemotherapy\t81,700\t1,385\tRemission\tFunction\t\n2\tF/7\tFSGS\t6\tVomiting, abdominal pain\tCervical, axillary, inguinal LNs, stomach, small bowel, umbilicus, vagina\tDiffuse large B-cell lymphomab\tDUK/R−\tRTX, chemotherapy\t166,571\t587\tRemission\tFunction\t\n3\tF/14\tFSGS\t5\tEpigastric pain, poor oral intake\tStomach, duodenum, mesenteric nodules\tDiffuse large B-cell lymphomab\tD+/R−\tRTX, chemotherapy\t152,987\t1,133\tRemission\tLost\t\n4\tM/18\tFSGS\t3\tHead and neck LNE\tCervical LNs\tPolymorphic typeb\tDUK/R−\tRTX\t555\t555\tRemission\tFunction\t\n5\tF/7\tCongenital NS\t8\tTonsillar hypertrophy\tBilateral tonsils, cervical LNs\tEarly lesionb\tDUK/R−\tRTX\t52,135\t6,081\tRemission\tFunction\t\n6\tM/4\tBilateral MCDK\t10\tFever, cervical LNE\tCervical LNs\tPolymorphic typeb\tD+/R−\tRTX\t134,159\t208,947\tRemission\tFunction\t\n7\tF/15\tFraiser syndromec\t99\tDiarrhea, abdominal mass with tenderness\tPerigastric, mesenteric LNs, stomach, small bowel\tBurkitt lymphomab\tDUK/R−\tRTX, chemotherapy\t315,080\t86,642\tRemission\tFunction\t\nPTLD = post-transplant lymphoproliferative disease, KT = kidney transplantation, EBV = Epstein-Barr virus, F = female, FSGS = focal segmental glomerulosclerosis, LNE = lymph node enlargement, LN = lymph node, D/R = donor/recipient, UK = unknown, RTX = rituximab, M = male, NS = nephrotic syndrome, MCDK = multicystic dysplastic kidney.\n\naLesion detected by imaging study (computed tomography or positron emission tomography); bEBV in-situ hybridization positive; cGenetic disorder caused by WT1 mutation.\n\nRisk factors for PTLD\nTable 2 shows the comparison of clinical variables between the PTLD and EV only group by univariate analysis. There were no significant differences between the two groups in terms of sex, age at transplantation, donor type, interval between transplantation, and first appearance of EV. Although the peak median EBV titer was higher in the PTLD group (152,987 EBV copies/mL whole blood) than the EV only group (17,305 copies/mL whole blood), there was no statistical significance. There were also no significant differences between groups in terms of median EBV viral load and EV-free duration after kidney transplant. At the time of transplantation, six patients (85.7%) in the PTLD group and 14 patients (35.9%) in the EV only group were seronegative for EBV (P = 0.009). Data of donor EBV status before transplantation were available only in a few cases, with no statistically significant difference observed between the groups.\n\nTable 2 Characteristics of patients\nCharacteristics\tPTLD (n = 7)\tEV only (n = 39)\tP value\t\nSex, M:F\t2:5\t18:21\t0.446\t\nAge at transplantation, yr\t6 (3–18)\t7 (1–16)\t0.811\t\nDonor type\t\t\t1.000\t\n\tDeceased\t4 (57.1)\t21 (53.8)\t\n\tLiving related\t3 (42.9)\t18 (46.2)\t\nEBV recipient serostatus\t\t\t0.009\t\n\tPositive\t0\t23 (59.0)\t\n\tNegative\t6 (85.7)\t14 (35.9)\t\n\tUnknown\t1 (14.3)\t2 (5.1)\t\nEBV donor serostatus\t\t\t1.000\t\n\tPositive\t2 (28.6)\t10 (25.6)\t\n\tNegative\t0\t3 (7.7)\t\n\tUnknown\t5 (71.4)\t26 (66.7)\t\nTime to EV, mon\t5 (1–48)\t8 (0–47)\t0.946\t\nPeak EBV level, copies/mL\t152,987 (555–1,341,159)\t17,305 (1,198–1,279,841)\t0.278\t\nMedian EBV level, copies/mL\t6,081 (555–208,947)\t4,250 (485–326,880)\t0.834\t\nCMV viremia\t2 (28.6)\t12 (30.8)\t1.000\t\nInduction therapy\t\t\t\t\n\tBasiliximab\t6 (85.7)\t22 (56.4)\t0.220\t\n\tThymoglobulin\t0\t2 (5)\t1.000\t\nMaintenance medication\t\t\t0.496\t\n\tSteroid + tacrolimus + MMF\t6 (85.7)\t36 (92.3)\t\n\tSteroid + tacrolimus + AZA\t1 (14.3)\t1 (2.6)\t\n\tSteroid + tacrolimus\t0\t2 (5.1)\t\nImmunosuppressant after EV\t\t\t0.423\t\n\tMonotherapy\t2 (28.6)\t5 (12.8)\t\n\tDouble immunotherapy\t3 (42.9)\t26 (66.7)\t\n\tTriple immunotherapy\t2 (28.6)\t8 (20.5)\t\nTacrolimus level, ng/mL\t\t\t\t\n\tPre EV diagnosis\t9.5 (6.2–10.3)\t7.7 (5.4–12.7)\t0.039\t\n\tAt EV diagnosis\t6.5 (2.5–9.6)\t5.9 (2.2–14.3)\t0.549\t\n\tPost EV diagnosis\t4.1 (0–5.8)\t4.5 (2.4–7.2)\t0.278\t\nRejection history\t5 (71.4)\t15 (38.5)\t0.213\t\nPreemptive RTX\t0\t6 (15.4)\t0.266\t\nValues are expressed as numbers (%) and median (range).\n\nPTLD = post-transplant lymphoproliferative disease, EV = Epstein-Barr virus viremia, EBV = Epstein-Barr virus, CMV = cytomegalovirus, MMF = mycophenolate, AZA = azathioprine, RTX = rituximab.\n\nTacrolimus levels before EV tended to be higher in the PTLD group (9.5 ng/mL) than in the EV only group (7.7 ng/mL, P = 0.039). Maintenance immunosuppression regimen or history of rejection was not significantly different between the two groups. Six patients were treated with pre-emptive RTX, none of whom developed PTLD, while the number of RTX-treated patients was too small to be statistically significant.\n\nThe Cox proportional-hazard model was used to identify factors associated with an increased risk of developing PTLD after EV (Table 3). Values of 8.9 ng/mL for tacrolimus level and 35,900 copies/μL for peak EBV titer were determined as cutoff values based on the receiver operating characteristic curve analysis. The areas under curve of tacrolimus and peak EBV titer were 0.745 (95% confidence interval [CI] 0.522–0.969, sensitivity 85.7%, and specificity 79.5%) and 0.634 (95% CI 0.399–0.869, sensitivity 85.7%, and specificity 59.0%), respectively. A higher tacrolimus level (hazard ratio [HR], 13.7; 95% CI, 1.6–117.9; P = 0.017) was associated with PTLD. Basiliximab induction therapy, higher EBV titer, EBV seronegativity of recipients, and rejection history were not significant in multivariate Cox regression analysis.\n\nTable 3 Risk factors for post-transplant lymphoproliferative disease in patients with EV\nVariables\tUnivariate\tMultivariatea\t\nHR\t95% CI\tP value\tHR\t95% CI\tP value\t\nTacrolimus level ≥ 8.9 ng/mL before EV\t16.783\t2.013–139.950\t0.009\t13.737\t1.601–117.892\t0.017\t\nBasiliximab induction therapy\t4.480\t0.537–37.374\t0.166\t-\t-\t0.438\t\nPeak EBV titer ≥ 35,900 copies/µL\t7.304\t0.877–60.832\t0.066\t-\t-\t0.149\t\nRecipient EBV serostatus negative\t87.887\t0.112–69,135.034\t0.188\t-\t-\t0.054\t\nRejection history\t3.651\t0.707–18.852\t0.122\t-\t-\t0.285\t\nAge, yr\t\t\t\t\t\t\t\n\t< 5\tReference\t\t\t\t\t\t\n\t6 to < 12\t0.580\t0.097–3.471\t0.550\t-\t-\t-\t\n\t≥ 12\t1.518\t0.213–10.788\t0.677\t-\t-\t-\t\nHR = hazard ratio, CI = confidence interval, EV = Epstein-Barr virus viremia, EBV = Epstein-Barr virus.\n\naFactors with a value of P < 0.2 in the univariate Cox regression analysis were included in the multivariate analysis.\n\nEfficacy and safety of pre-emptive rituximab treatment in pediatric kidney transplant\nSix patients in the EV only group (male: female, 2:4) who had a high EBV load received preemptive RTX therapy. Their median age at transplant was 4 years (1–14 years), and EBV infection was first detected at 4.3 months (3.9–9.9 months) after kidney transplantation. Administration of RTX was carried out at a median of 29.2 months (5.1–69.6 months) after transplantation. These six patients did not exhibit any symptoms such as fever, lymph node enlargement, or gastrointestinal problems; and no imaging studies were performed. Two patients were EBV seropositive and four patients were EBV seronegative (Table 4). The two EBV-seropositive patients were at low risk for the development of PTLD, but RTX was administered to these patients based on the clinician's decision; one patient had a mutation of WT1, and was therefore prone to tumor development, while the other had persistently high EBV load for 46 months despite the reduction of immunosuppression. Median EBV viral loads at the time of RTX treatment were 171,639 copies/mL (6,181–783,504 copies/mL). After a single dose of RTX therapy, a concordant decrease in EBV load and B lymphocytes was observed (Fig. 2). In five patients, EV disappeared within months; the other patient showed reduction of EBV titer but persistence of EV despite RTX treatment. Unfortunately, the patient lost the allograft due to rejection and concomitant infection within 8 months after RTX therapy, and EBV titer was not monitored after this adverse event. In the remaining five patients, EBV load rebounded along with recovery of B cells in a median 8 months. However, none of these five patients developed PTLD over a median follow-up of 51.5 months.\n\nTable 4 Description of six patients with preemptive rituximab therapy\nPatient No.\tAge at KT, yr\tSex\tUnderlying disease\tEBV serostatus\tDuration of EV before RTX, mon\tMedian EBV before RTX, copies/mL\tEBV at RTX, copies/mL\tIS at RTX\tEBV at last F/U, copies/mL\tRejection\tOutcome\t\n1\t14\tF\tLupus nephritis\tDUK/R−\t3.3\t335,728\t783,504\tTAC, steroid\t172,839\tAcute rejection\tESRD\t\n2\t1\tF\tDenys-Drash syndromea\tD+/R−\t1.2\t266,825\t266,825\tTAC\t192,321\tNo\tNormal\t\n3\t10\tM\tFrasier syndromea\tD+/R+\t18.3\t20,296\t283,074\tTAC, sirolimus\t2,050\tNo\tNormal\t\n4\t2\tF\tNephronophthisis\tDUK/R+\t46.1\t19,738\t26,464\tTAC, sirolimus\t1,122\tNo\tCKD stage 2\t\n5\t2\tF\tNephronophthisis\tD+/R−\t26.0\t195,724\t76,453\tTAC, sirolimus\t10,411\tNo\tNormal\t\n6\t6\tM\tAcute tubular necrosis\tDUK/R−\t63.6\t23,813\t6,181\tTAC, sirolimus\t981\tNo\tNormal\t\nKT = kidney transplantation, EBV = Epstein-Barr virus, EV = Epstein-Barr virus viremia, RTX = rituximab, IS = immunosuppressant, F/U = follow up, F = female, D/R = donor/recipient, UK = unknown, TAC = tacrolimus, ESRD = end stage renal disease, CKD = chronic kidney disease, M = male.\n\naGenetic disorder caused by WT1 mutation.\n\nFig. 2 EBV viral load after RTX therapy. (A) EBV viral loads in Patients 1, 2, and 3. (B) EBV viral loads in Patients 4, 5, and 6.\nEBV = Epstein-Barr virus, RTX = rituximab.\n\nRegarding the safety of RTX therapy, only one patient complained of chest discomfort during RTX infusion. Two patients experienced neutropenia at 4 months and 1 month after RTX treatment (Fig. 3). Two patients were admitted for viral or bacterial infections at 1 month and 2 months after RTX treatment. In comparison, of 8 patients with high EV (EBV > 10,000 copies/mL) but without RTX treatment, three patients experienced 6 infection episodes and one patient developed neutropenia during 12 months after the occurrence of high EV. Infectious complications included Citrobacter freundii, CMV, influenza A, adenovirus and Pneumocystis jirovecii infections. There were no significant differences in the infectious complications and neutropenia between the RTX group and the non-RTX group in patients with high EV.\n\nFig. 3 Late adverse events after rituximab treatment.\nANC = absolute neutrophil count, NF = neutropenic fever, RTX = rituximab.\n\nDISCUSSION\nDuring the last 15 years, among the almost 200 pediatric kidney transplantation recipients at our center, seven developed EBV-associated PTLD (3.5%). In our study, the risk factor for PTLD in pediatric kidney transplant recipients with EV was a high tacrolimus level before EV. Twenty (43.4%) out of 46 recipients who had viremia were EBV seronegative, which is similar to the rates reported in previous studies in North America and Europe (19%–57%).212223 Pre-transplant recipient EBV seronegativity is a well-known risk factor for PTLD. In adult transplant studies, the rate of developing PTLD is 5–12 fold higher in EBV-seronegative patients than in EBV-seropositive patients.2324 McDonald et al.6 reported that EBV-seronegative pediatric subjects have a 4.7-fold higher relative HR than EBV-positive subjects. In our study, recipient EBV seronegativity did not increase the risk of PTLD in multivariate Cox regression analysis. While transplant from an EBV-seropositive donor to a seronegative recipient has been associated with the development of PTLD,25 there was no statistically significant difference in EBV serostatus (donor/recipient) in the present study. This finding was attributed mainly to the fact that there were no EBV seropositive recipients in PTLD group and we did not have serostatus information for the majority of donors (67.3%).\n\nThe majority of kidney allograft recipients in this study were given tacrolimus, and mycophenolate was used in more than 80% of patients instead of azathioprine.26 By the late 2000s, monoclonal interleukin-2 receptor antibodies were used as induction therapy in up to 80% of patients. Basiliximab, a monoclonal antibody which targets activated T lymphocytes, was not related to PTLD risk in our study, as previously reported.427 Several studies have suggested that higher tacrolimus levels are associated with higher risk for PTLD, and others have reported that the net state of immunosuppression, rather than any individual agent, increases the risk for PTLD.282930 In our study, all patients received tacrolimus for maintenance immunosuppression, and we found that a higher pre-EV tacrolimus level in the PTLD group compared with the EV only group was a risk factor for PTLD.\n\nRegular monitoring of EBV viral load and early recognition of recipients at high risk of PTLD have been identified as clinical priorities in recent years.31 Previous studies have shown that elevated levels of EBV DNA and persistent high EBV loads are risk factors for PTLD,122032 but no clear cut-off point of EBV viral load for the prediction of PTLD development has been determined. We did not find a significant relationship between EV and PTLD in this study; however, six patients with a high EBV titer were treated with preemptive RTX and they did not develop PTLD. Because they were included in analysis, this could have confounded the causality of high EBV titer and PTLD development.\n\nTreatment strategies for organ transplant recipients with EV include reduction of immunosuppression with/without antiviral agents, immunoglobulin, or RTX.33 These treatments are still undergoing clinical studies. Preemptive administration of RTX is widely used and has been demonstrated to reduce the incidence of PTLD in stem cell transplant recipients with a high EBV viral load.183435 Pre-emptive RTX therapy has been reported in 14.5% of global transplant programs, and in more than 60% of pediatric transplant patients worldwide.33 However, only one study reported the use of RTX in five pediatric renal allograft recipients,20 and there have been no prospective studies on the efficacy of pre-emptive RTX therapy in solid organ transplantation. Rituximab is a murine/human chimeric monoclonal anti-CD20 antibody and is able to deplete circulating B cells rapidly, including those infected with EBV. Although RTX was effective for reducing EBV viral load in our patients, this reduction was not permanent in line with previous reports.20 In addition, significant adverse effects, such as infection and neutropenia, accompanied RTX administration. In patients with stem cell transplant (SCT), preemptive RTX was not associated with an increase in infectious complications.1819 This is important because, while SCT recipients are able to discontinue their immunosuppressive agents within 6–9 months after SCT, recipients of solid organ transplantation have to be on immunosuppressive agents for as long as their allografts are functioning. Therefore, the long-term use of immunosuppressive agents may explain why infection and neutropenia are common clinical findings after RTX therapy in this patient population.\n\nAlthough the small sample size of the current study precludes us from drawing any definite conclusions, our observations suggest that preemptive RTX treatment may effectively reduce high EBV viral load in pediatric recipients of solid organ transplants. Because RTX therapy eradicates B-lymphocytes including transformed lymphocytes, the risk of PTLD might be reduced at least during the period of B cell depletion. However, one should take into account that this treatment significantly increases the risk of neutropenia and infection. More research into the influence of preemptive RTX therapy on PTLD development is needed.\n\nThe occurrence of PTLD in kidney transplant recipients follows a bimodal distribution, with one peak in the first year and the second in the later post-transplantation period. Early PTLD, occurring within the first year of transplantation, is associated with EBV infection and tends to occur more commonly in children than adults.123637 In this study, while six patients in the PTLD group were diagnosed with PTLD within the first year of renal transplantation, one patient with WT1 mutation developed PTLD later than 8.2 years after renal transplantation. We suspect that in this patient, the WT1 mutation of a tumor suppressor gene might have increased the risk of PTLD, and especially that of late-onset. The occurrence of PTLD in patients with WT1 mutation has been reported previously, within the first year in two cases and later than the first year in another.383940 Based on the limited availability of clinical data, the association between WT1 mutation and development of PTLD requires further investigation in future clinical studies and is beyond the scope of the current study.\n\nThere are several limitations of this study. First, this is a retrospective observational study of a single center and the number of the patients observed was therefore small. The limitations of this small sample size might have affected the outcome of multivariate analysis. In addition, data of donor EBV serology were not uniformly available in our study. Data on donor serology status was only available for 33% of participants. Therefore, our study did not show any association between PTLD and EBV-donor/recipient serostatus. Finally, the number of patients who were treated with RTX was not large enough to draw any definitive conclusions.\n\nIn summary, this study demonstrates that a higher tacrolimus level before EV is correlated with the development of PTLD. Preemptive RTX appears to be effective for reducing EBV viral load in pediatric kidney transplant recipients. However, the reduction of EBV viral load was not persistent, and adverse effects of RTX, namely infection and neutropenia, were clinically significant.\n\nFunding: This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI12C0014).\n\nDisclosure: The authors have no potential conflicts of interest to disclose.\n\nAuthor Contributions:\nConceptualization: Hyun H, Ahn YH, Kang HG.\n\nData curation: Hyun H, Park E, Cho M, Min SI, Ha J, Kang HJ, Shin HY, Ha IS, Cheong HI, Ahn YH, Kang HG.\n\nFormal analysis: Hyun H, Ahn YH.\n\nInvestigation: Hyun H, Park E, Cho M, Min SI, Ha J, Kang HJ, Shin HY, Ha IS, Cheong HI, Ahn YH, Kang HG.\n\nMethodology: Hyun H, Park E, Cho M, Ha IS, Cheong HI, Ahn YH, Kang HG.\n\nValidation: Min S, Ha J, Kang HJ, Shin HY.\n\nWriting - original draft: Hyun H, Kang HG.\n\nWriting - review & editing: Hyun H, Ahn YH, Kang HG.\n==== Refs\n1 Mucha K Foroncewicz B Ziarkiewicz-Wróblewska B Krawczyk M Lerut J Paczek L Post-transplant lymphoproliferative disorder in view of the new WHO classification: a more rational approach to a protean disease? Nephrol Dial Transplant 2010 25 7 2089 2098 20576725 \n2 Caillard S Lamy FX Quelen C Dantal J Lebranchu Y Lang P Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas Am J Transplant 2012 12 3 682 693 22226336 \n3 Sampaio MS Cho YW Qazi Y Bunnapradist S Hutchinson IV Shah T Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database Transplantation 2012 94 10 990 998 23085553 \n4 Caillard S Dharnidharka V Agodoa L Bohen E Abbott K Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression Transplantation 2005 80 9 1233 1243 16314791 \n5 Jeong HJ Ahn YH Park E Choi Y Yi NJ Ko JS Posttransplantation lymphoproliferative disorder after pediatric solid organ transplantation: experiences of 20 years in a single center Korean J Pediatr 2017 60 3 86 93 28392824 \n6 McDonald RA Smith JM Ho M Lindblad R Ikle D Grimm P Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids Am J Transplant 2008 8 5 984 989 18416737 \n7 Allen UD Preiksaitis JK AST Infectious Diseases Community of Practice Epstein-Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation Am J Transplant 2013 13 Suppl 4 107 120 23465004 \n8 Al-Mansour Z Nelson BP Evens AM Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies Curr Hematol Malig Rep 2013 8 3 173 183 23737188 \n9 Bingler MA Feingold B Miller SA Quivers E Michaels MG Green M Chronic high Epstein-Barr viral load state and risk for late-onset posttransplant lymphoproliferative disease/lymphoma in children Am J Transplant 2008 8 2 442 445 18211510 \n10 Knight JS Tsodikov A Cibrik DM Ross CW Kaminski MS Blayney DW Lymphoma after solid organ transplantation: risk, response to therapy, and survival at a transplantation center J Clin Oncol 2009 27 20 3354 3362 19451438 \n11 Kim J Lee J Kim YH Clinical utility of Epstein-Barr viral load assay to diagnose posttransplant lymphoproliferative disorders in pediatric heart transplant recipients Pediatr Infect Vaccine 2017 24 1 44 53 \n12 Le J Durand CM Agha I Brennan DC Epstein-Barr virus and renal transplantation Transplant Rev (Orlando) 2017 31 1 55 60 28089555 \n13 Pereira MS Blake JM Macrae AD EB virus antibody at different ages BMJ 1969 4 5682 526 527 4902364 \n14 Porter DD Wimberly I Benyesh-Melnick M Prevalence of antibodies to EB virus and other herpesviruses JAMA 1969 208 9 1675 1679 4305626 \n15 Green M Michaels MG Epstein-Barr virus infection and posttransplant lymphoproliferative disorder Am J Transplant 2013 13 Suppl 3 41 54 23347213 \n16 Nijland ML Kersten MJ Pals ST Bemelman FJ Ten Berge IJ Epstein-Barr virus-positive posttransplant lymphoproliferative disease after solid organ transplantation: Pathogenesis, clinical manifestations, diagnosis, and management Transplant Direct 2015 2 1 e48 27500242 \n17 Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group KDIGO clinical practice guideline for the care of kidney transplant recipients Am J Transplant 2009 9 Suppl 3 S1 S157 \n18 Worth A Conyers R Cohen J Jagani M Chiesa R Rao K Pre-emptive rituximab based on viraemia and T cell reconstitution: a highly effective strategy for the prevention of Epstein-Barr virus-associated lymphoproliferative disease following stem cell transplantation Br J Haematol 2011 155 3 377 385 21910716 \n19 van der Velden WJ Mori T Stevens WB de Haan AF Stelma FF Blijlevens NM Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab Bone Marrow Transplant 2013 48 11 1465 1471 23749107 \n20 Colombini E Guzzo I Morolli F Longo G Russo C Lombardi A Viral load of EBV DNAemia is a predictor of EBV-related post-transplant lymphoproliferative disorders in pediatric renal transplant recipients Pediatr Nephrol 2017 32 8 1433 1442 28280938 \n21 Walker RC Marshall WF Strickler JG Wiesner RH Velosa JA Habermann TM Pretransplantation assessment of the risk of lymphoproliferative disorder Clin Infect Dis 1995 20 5 1346 1353 7620022 \n22 Ellis D Jaffe R Green M Janosky JJ Lombardozzi-Lane S Shapiro R Epstein-Barr virus-related disorders in children undergoing renal transplantation with tacrolimus-based immunosuppression Transplantation 1999 68 7 997 1003 10532541 \n23 Shroff R Trompeter R Cubitt D Thaker U Rees L Epstein-Barr virus monitoring in paediatric renal transplant recipients Pediatr Nephrol 2002 17 9 770 775 12215833 \n24 Dharnidharka VR Lamb KE Gregg JA Meier-Kriesche HU Associations between EBV serostatus and organ transplant type in PTLD risk: an analysis of the SRTR National Registry Data in the United States Am J Transplant 2012 12 4 976 983 22226225 \n25 Suzuki T Ikezumi Y Okubo S Uchiyama M Takahashi K Shiraga H Epstein-Barr virus DNA load and seroconversion in pediatric renal transplantation with tacrolimus immunosuppression Pediatr Transplant 2007 11 7 749 754 17910652 \n26 Min SI Han A Choi C Kim SY Kang HG Ha IS Immunosuppression in pediatric kidney transplant patients J Korean Soc Transplant 2015 29 1 1 8 \n27 Bustami RT Ojo AO Wolfe RA Merion RM Bennett WM McDiarmid SV Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients Am J Transplant 2004 4 1 87 93 14678038 \n28 Shapiro R Nalesnik M McCauley J Fedorek S Jordan ML Scantlebury VP Posttransplant lymphoproliferative disorders in adult and pediatric renal transplant patients receiving tacrolimus-based immunosuppression Transplantation 1999 68 12 1851 1854 10628763 \n29 Opelz G Döhler B Lymphomas after solid organ transplantation: a collaborative transplant study report Am J Transplant 2004 4 2 222 230 14974943 \n30 Höcker B Fickenscher H Delecluse HJ Böhm S Küsters U Schnitzler P Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study Clin Infect Dis 2013 56 1 84 92 23042966 \n31 Dharnidharka VR Peripheral blood Epstein-Barr viral nucleic acid surveillance as a marker for posttransplant cancer risk Am J Transplant 2017 17 3 611 616 27458691 \n32 Riddler SA Breinig MC McKnight JL Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients Blood 1994 84 3 972 984 8043879 \n33 San-Juan R Manuel O Hirsch HH Fernández-Ruiz M López-Medrano F Comoli P Current preventive strategies and management of Epstein-Barr virus-related post-transplant lymphoproliferative disease in solid organ transplantation in Europe. Results of the ESGICH Questionnaire-based Cross-sectional Survey Clin Microbiol Infect 2015 21 6 604.e1 604.e9 25686696 \n34 van Esser JW Niesters HG van der Holt B Meijer E Osterhaus AD Gratama JW Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation Blood 2002 99 12 4364 4369 12036863 \n35 Omar H Hägglund H Gustafsson-Jernberg A LeBlanc K Mattsson J Remberger M Targeted monitoring of patients at high risk of post-transplant lymphoproliferative disease by quantitative Epstein-Barr virus polymerase chain reaction Transpl Infect Dis 2009 11 5 393 399 19497070 \n36 Francis A Johnson DW Teixeira-Pinto A Craig JC Wong G Incidence and predictors of post-transplant lymphoproliferative disease after kidney transplantation during adulthood and childhood: a registry study Nephrol Dial Transplant 2018 33 5 881 889 29342279 \n37 Mynarek M Hussein K Kreipe HH Maecker-Kolhoff B Malignancies after pediatric kidney transplantation: more than PTLD? Pediatr Nephrol 2014 29 9 1517 1528 24061645 \n38 Miloševic B Bogdanović R Kostić M Stojanović V Frasier syndrome diagnosed in a 4-year-old girl Cent Eur J Med 2012 7 2 142 144 \n39 Spasojević-Dimitrijeva B Peco-Antić A Paripović D Kruscić D Krstić Z Cupić M Post-transplant lymphoproliferative disorder--case reports of three children with kidney transplant Srp Arh Celok Lek 2014 142 1-2 83 88 24684038 \n40 Miyazono A Okamoto Y Nagasako H Hamasaki Y Shishido S Yoshioka T Multifocal Epstein-Barr virus-negative posttransplantation lymphoproliferative disorder treated with reduction of immunosuppression Am J Kidney Dis 2016 68 3 469 472 27178679\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1011-8934",
"issue": "34(30)",
"journal": "Journal of Korean medical science",
"keywords": "Epstein-Barr Virus; Kidney Transplantation; Post-Transplant Lymphoproliferative Disease; Rituximab",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D002675:Child, Preschool; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007223:Infant; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D009503:Neutropenia; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D014184:Transplantation, Homologous; D019562:Viral Load; D014766:Viremia",
"nlm_unique_id": "8703518",
"other_id": null,
"pages": "e203",
"pmc": null,
"pmid": "31373185",
"pubdate": "2019-08-05",
"publication_types": "D016428:Journal Article",
"references": "10532541;10628763;12036863;12215833;14678038;14974943;16314791;17910652;18211510;18416737;19451438;19497070;19845597;20576725;21910716;22226225;22226336;23042966;23085553;23347213;23465004;23737188;23749107;24061645;24684038;25686696;27178679;27458691;27500242;28089555;28280938;28392824;29342279;4305626;4902364;7620022;8043879",
"title": "Post-Transplant Lymphoproliferative Diseases in Pediatric Kidney Allograft Recipients with Epstein-Barr Virus Viremia.",
"title_normalized": "post transplant lymphoproliferative diseases in pediatric kidney allograft recipients with epstein barr virus viremia"
} | [
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"companynumb": "KR-PBT-000019",
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"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFlecainide is a commonly used IC antiarrhythmic. Clinical presentations of Flecainide toxicity are not commonly described.\n\n\nMETHODS\nA 62 year old man on dialysis presented for evaluation of outpatient bradycardia and hypotension. In the ED, patient had wide-complex rhythm with heart rates ranging from 76 to 127. The previous day, Flecainide and Metoprolol were discontinued and patient was dialyzed and discharged. The patient was treated empirically for possible hyperkalemia. No significant change in ECG was noted with administration of calcium. Sodium bicarbonate produced questionable benefit. Potassium level was 4.6 mmol/L. Cardiac rhythm fluctuated between sinus rhythm and wide complex tachycardia in the ED & ICU. Flecainide level was 2.1 μg/ml (normal <1 μg/ml). Toxicity developed despite previous discontinuation and dialysis prior to presentation because of Flecainide's large volume of distribution and lipopholicity. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although Flecainide toxicity is uncommon, it has a high mortality rate, requiring early identification and treatment. Flecainide toxicity can develop in patients with hepatic or renal insufficiency, and can manifest with ventricular tachycardia or bradycardia. If suspicion of Flecainide toxicity arises, lidocaine and procainamide should be avoided to prevent further sodium channel blockade. Absence of response to calcium for a very wide complex QRS should raise clinicians' suspicion that WCT is not due to hyperkalemia, emphasizing the importance of reviewing patients' home medications. Sodium bicarbonate should be administered early to treat widened QRS. Amiodarone, intralipid emulsion therapy and ECMO may be considered in severe cases.",
"affiliations": "Department of Emergency Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, 1000 Oakland Drive, Kalamazoo, MI 49008, United States of America.;Department of Emergency Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, 1000 Oakland Drive, Kalamazoo, MI 49008, United States of America.;Department of Emergency Medicine, Western Michigan University Homer Stryker M.D. School of Medicine, 1000 Oakland Drive, Kalamazoo, MI 49008, United States of America. Electronic address: whakmeh@yahoo.com.",
"authors": "Hoang|Kenny|K|;Pazderka|Philip|P|;Hakmeh|Wael|W|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2021.08.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": null,
"journal": "The American journal of emergency medicine",
"keywords": "Bradycardia; Flecainide; Renal failure; Tachycardia; Toxicity; Wide complex",
"medline_ta": "Am J Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "8309942",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34391584",
"pubdate": "2021-08-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Wide complex tachycardia in dialysis patients is not always hyperkalemia.",
"title_normalized": "wide complex tachycardia in dialysis patients is not always hyperkalemia"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-01078",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METOPROLOL SUCCINATE"
},
... |
{
"abstract": "A pheochromocytoma is a rare tumor that develops from adrenomedullary chromaffin cells and produce ones or more catecholamines, including adrenaline, norepinephrine, and dopamine. On rare occasions a pheochromocytoma is hormonally inactive. Cyanotic heart disease is also a relatively rare pathology. One of its least frequently occurring variants is the single ventricle of the heart. Presumably, in patients with cyanotic heart defects, the occurrence of pheochromocytes and paragangliomas will be higher due to the presence of certain germinative and somatic mutations. In cyanotic heart defects, the development of malignant arrythmias is one of the frequent causes of death. A combination of a pheochromocytoma with a single ventricle of the heart is extremely rare: only eight such cases have been described in the literature. This article describes a young patient with a unique case of a single ventricle of the heart, pheochromocytoma and sustained ventricular tachycardia. The cause of the ventricular tachycardia, in all likelihood, was inappropriate medical care - in this case, a prescription for verapamil. The surgical excision of the pheochromocytoma and the referral of the patient for cardiac surgery became possible only after correcting the antihypertensive and antiarrhythmic therapy. Verapamil was replaced with a combination of doxazosin and amiodarone, resulting in relatively satisfactory blood pressure readings and sinus rhythm.",
"affiliations": "Endocrinology Research Centre.;Endocrinology Research Centre.;Endocrinology Research Centre.;Endocrinology Research Centre.;Endocrinology Research Centre.;Endocrinology Research Centre.;Endocrinology Research Centre.",
"authors": "Melkozerov|K V|KV|0000-0002-7328-6316;Kuznetsov|A B|AB|0000-0002-9008-6893;Kalashnikov|V Y|VY|0000-0001-5573-0754;Abdulkhabirova|F М|FМ|0000-0001-8580-2421;Kuznetsov|S N|SN|0000-0001-8558-7725;Gorbacheva|A M|AM|0000-0003-2669-9457;Dedov|I I|II|0000-0002-8175-7886",
"chemical_list": "D000889:Anti-Arrhythmia Agents",
"country": "Russia (Federation)",
"delete": false,
"doi": "10.14341/probl9949",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0375-9660",
"issue": "65(2)",
"journal": "Problemy endokrinologii",
"keywords": "case report; pheochromocytoma; single ventricle of the heart; ventricular tachycardia",
"medline_ta": "Probl Endokrinol (Mosk)",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000889:Anti-Arrhythmia Agents; D006321:Heart; D006338:Heart Neoplasms; D006801:Humans; D010673:Pheochromocytoma; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "0140673",
"other_id": null,
"pages": "107-112",
"pmc": null,
"pmid": "31271713",
"pubdate": "2019-06-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sustained ventricular tachycardia in a patient with a single ventricle of the heart and a pheochromocytoma.",
"title_normalized": "sustained ventricular tachycardia in a patient with a single ventricle of the heart and a pheochromocytoma"
} | [
{
"companynumb": "RU-CPL-001102",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXAZOSIN MESYLATE"
},
"drugadditional": "3",
"... |
{
"abstract": "Ovarian dysgerminoma is the most common ovarian malignancy in young women. Conservative treatment is indicated in the reproductive-age woman who wishes to preserve childbearing capacity. This case report describes a patient with ovarian dysgerminoma who underwent chemotherapy with a cisplatin-vinblastine-bleomycin regimen that resulted in serious toxic complications--including cortical blindness and seizures--that were transient in nature. Although current chemotherapy regimens have dramatically improved the overall survival of women with germ-cell tumors, there are toxic complications such as those demonstrated in this report, and toxicity must be balanced against presumed benefit.",
"affiliations": "David Grand USAF Medical Center, Travis AFB, Calif.",
"authors": "Young|D C|DC|;Mitchell|A|A|;Kessler|J|J|;Christman|J E|JE|",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-6151",
"issue": "93(4)",
"journal": "The Journal of the American Osteopathic Association",
"keywords": null,
"medline_ta": "J Am Osteopath Assoc",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D001766:Blindness; D002945:Cisplatin; D004407:Dysgerminoma; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D012640:Seizures; D014747:Vinblastine",
"nlm_unique_id": "7503065",
"other_id": null,
"pages": "502-4, 507",
"pmc": null,
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"abstract": "Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases.",
"affiliations": "Hematology-Oncology Unit, Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Rimini 1, Haidari, 12462 Athens, Greece.;Second Radiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Haidari, 12462 Athens, Greece.;Radiotherapy Unit, Second Radiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Haidari, 12462 Athens, Greece.;Maternity-Health, 30 Papanikoli Street, Halandri, 15232 Athens, Greece.",
"authors": "Koumarianou|Anna|A|;Kontopoulou|Christina|C|;Kouloulias|Vassilis|V|;Tsionou|Christina|C|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi Publishing Corporation 10.1155/2016/5718104Case ReportDurable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain Koumarianou Anna \n1\n\n*\nKontopoulou Christina \n2\nKouloulias Vassilis \n3\nTsionou Christina \n4\n1Hematology-Oncology Unit, Fourth Department of Internal Medicine, National and Kapodistrian University of Athens, Attikon University Hospital, Rimini 1, Haidari, 12462 Athens, Greece2Second Radiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Haidari, 12462 Athens, Greece3Radiotherapy Unit, Second Radiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Haidari, 12462 Athens, Greece4Maternity-Health, 30 Papanikoli Street, Halandri, 15232 Athens, Greece*Anna Koumarianou: akoumari@yahoo.comAcademic Editor: Guido Fadda\n\n2016 18 4 2016 2016 57181048 9 2015 23 2 2016 22 3 2016 Copyright © 2016 Anna Koumarianou et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Patients with HER2-positive breast cancer and brain metastases have limited treatment options, and, as a result of their poor performance status and worse prognosis, they are underrepresented in clinical trials. Not surprisingly, these patients may not be fit enough to receive any active treatment and are offered supportive therapy. BRCA2 mutations are reported to be rarely associated with HER2-overexpressing advanced breast cancer and even more rarely with brain metastases at diagnosis. We report on a BRCA2-positive breast cancer patient with metastatic disease in multiple sites, including the brain, and poor performance status who exhibited an extraordinary clinical and imaging response to the novel anti-HER2 therapy pertuzumab after multiple lines of therapy including anti-HER2 targeting. To our knowledge, the clinicopathologic and therapeutic characteristics of this patient point to a unique case and an urgent need for further investigation of pertuzumab in patients with brain metastases.\n==== Body\n1. Introduction\nBrain involvement of metastatic breast cancer is largely dependent on the molecular subtype of the disease, and in the case of HER2-overexpressing tumors, it affects 30% of patients and is associated with devastating symptoms and quality of life [1, 2].\n\nSeveral studies confirm that the median survival from diagnosis of brain metastases is from 6 months for patients who do not receive trastuzumab to 13 months for those who receive trastuzumab [1, 3, 4]. With few exceptions, there are hardly any prospective phases II-III clinical studies interrogating the role of anti-HER2 drugs in brain involvement [5, 6]. A plausible explanation for such a serious underrepresentation of patients in clinical trials is the poor performance status of this patient subgroup due to the tumoral involvement of the central nervous system. A recent study combining trastuzumab and pertuzumab for patients with metastatic disease resulted in survival improvement of 15.7 months [7]. Because this study did not include patients with brain metastases, there is no established experience about such anti-HER2 therapy's potential administration and benefit in patients relapsing after trastuzumab and lapatinib. With regard to patients with HER2-overexpressing metastatic breast cancer who are BRCA2 carriers, there is a scarcity of information in the published literature [8], so there is not much data on their survival and responses to the available treatments. However, a recent meta-analysis including breast cancer patients who are BRCA2 mutation carriers indicated no survival differences compared to patients without BRCA2 mutations [9].\n\n2. Case Presentation\nA 34-year-old female with abdominal pain and headache presented at the emergency department in November 2009. Upon clinical examination, she had a red, hard, fixed right breast with a fixed lymph nodal mass in the right axilla. She was living in the outskirts of Sparta with her husband and two children. She was never a smoker or an alcohol drinker.\n\nHer past medical history included a pituitary adenoma; she had no brothers or sisters, but she had a remarkable family history, as her father and uncle died of metastatic breast cancer.\n\nHer imaging with computed tomography (CT) and laboratory investigations revealed a single brain and multiple lung, liver, and bone metastases. A full blood count and biochemistry were normal except for the following: hemoglobin: 9.8 g/dL (normal value; nv 12–16); aspartate aminotransferase: 78 U/L (nv 5–40); alanine aminotransferase: 96 U/L (nv 5–35); gamma-glutamyl transferase: 216 U/L (nv 7–49); alkaline phosphatase: 261 U/L (nv 25–125); lactic acid dehydrogenase: 778 U/L (<250); and tumor markers: Ca 15-3 >1000 U/mL (nv < 31) and CEA > 50 ng/mL (nv < 5).\n\nHistologic and immunohistochemical examination of a true-cut biopsy revealed an invasive ductal adenocarcinoma, grade III differentiation, estrogen receptor (ER) strong nuclear positivity in 70% of cells, progesterone receptor (PR) nuclear positivity in less than 3%, HER2 strongly positive (+3), Ki-67 nuclear positivity in 40% of cells, and p53 nuclear positivity in 60% of cells according to the histopathology.\n\nFollowing stereotactic brain radiotherapy to the single lesion, the patient was treated according to the 2009 NCCN first-line strategy recommendations, which included paclitaxel, trastuzumab, and zoledronic acid [10]. Reevaluation after four cycles revealed disease progression (PD) in the lung and liver according to the RECIST criteria of response. A second line of therapy was initiated and included pegylated doxorubicin, trastuzumab, and zoledronic acid [11]. The choice of this combination was primarily based on patient's desire to avoid further alopecia. The first reevaluation at 3 months indicated partial response (PR) at all sites, including the breast, but a second assessment at 6 months revealed a relapse in the brain and lung. Following whole brain radiation, the patient was treated with a third-line therapy consisting of combination therapy with lapatinib, capecitabine, and zoledronic acid [12]. At CT reevaluation at 6 months, there was leptomeningeal dissemination and a vertebral thoracic mass (T12). After cytologic confirmation of leptomeningeal disease by lumbar puncture, the patient was treated with three courses of intrathecal methotrexate and radiotherapy to the spine (T12 level). The reevaluation showed a negative cerebrospinal fluid cytology but PD at all other sites: brain, lung, and liver. The patient received three further lines of combination chemotherapy including carboplatin, following a positive BRCA2 test [13–16], experiencing brief responses as described in Figure 1.\n\nFollowing PD after the seventh line of therapy based on the combination of carboplatin, gemcitabine, and trastuzumab [16], the patient was physically and psychologically exhausted and willing to proceed with some form of active treatment. Thus, an eighth line of orally administered therapy at home was initiated and included lapatinib and hormonal therapy. Seven months later, the patient deteriorated clinically (PS ECOG/WHO: 3-4) and arrived at the outpatient department in a wheelchair. Total body CT scans revealed PD in all sites, including the brain. Based on new NCCN guidelines and following discussion with the patient and her family, a ninth line of therapy was initiated, including the novel combination of pertuzumab/trastuzumab, docetaxel, and denosumab [17]. The patient's performance status gradually improved with CT reevaluation at 4 months, revealing a PR at all sites, including the brain (Figure 2). The clinical and imaging response continued to improve until 12 months later when a “plateau” was achieved. The patient continued on maintenance therapy with pertuzumab/trastuzumab/denosumab without chemotherapy for further six months. During all this time, she was walking and active at home taking care of her children, but when this time elapsed the patient rapidly deteriorated and succumbed to her disease.\n\n3. Discussion\nWe report on a young patient who is a BRCA2 mutation carrier diagnosed with HER2-positive breast cancer with visceral and brain metastases. Having received nine lines of anti-HER2 treatment, including a platinum agent, and radiotherapy to the brain, there were only two available options: referral to the supportive care team or a tenth line of treatment with the recently approved pertuzumab. The CLEOPATRA trial had indicated an excellent survival benefit for patients with HER2-positive metastatic disease treated with pertuzumab but provided no data on patients with brain metastases, as these were excluded [7]. At that time, the EMILIA trial on TMD-1 had just been completed, and the treatment was shown to result in very good response rates [18], but it was not yet locally approved or readily available for the patient. A recently reported phase II trial on pertuzumab/trastuzumab combination without chemotherapy in patients who had progressed under trastuzumab based regimen indicated a 50% clinical benefit rate and a 5.5-month median progression-free survival [19]. Our patient received one cycle of pertuzumab, trastuzumab, and docetaxel and experienced rapid symptomatic relief, indicating the need for continuation.\n\nPatients with HER2-positive breast cancer are living longer due to effective treatment, and as a result, brain metastases are now most common [3]. Patients like ours are usually not involved in clinical trials due to their poor performance status that is allegedly related to bad prognosis, and the optimal therapy remains an open question. Until today, only one case with brain metastases has been reported to experience complete response under second-line combination of pertuzumab-trastuzumab and docetaxel [20]. A retrospective study including patients rechallenged with trastuzumab after second-line lapatinib therapy for CNS involvement indicated a rather poor median OS of 17.3 (3.4–32.2) months [21]. Although monoclonal antibody penetration in the CNS has been questioned [22, 23], recently, a TDM-1 study [24] and a PET imaging analysis employing a radiolabeled trastuzumab-DOTA conjugate [25] have indicated indirectly and directly that monoclonal antibody targeting of brain metastases occurs effectively.\n\nThere are only a few studies available evaluating the role of anti-HER2 treatments in patients with disease metastasized to the brain, and these include small numbers of patients. Among these is one retrospective exploratory analysis of the phase III EMILIA study including 92 patients, of whom 43 were treated with T-DM1 and had an overall survival time of 26.8 months, compared to 12.9 months in the lapatinib/capecitabine group (49 patients) [24]. Additional studies include a multicenter phase II study including 242 patients treated with lapatinib [6], one phase III study of 36 patients with brain metastases treated with trastuzumab and lapatinib [5], one retrospective analysis of 432 patients, indicating that patients treated with both trastuzumab and lapatinib after developing metastases had significantly longer survival than patients treated with either agent alone [26], and one retrospective study including 79 patients treated with trastuzumab [27]. Based on the clinical activity observed in the EGF104900, LANDSCAPE, and EMILIA studies, the most active treatment options for HER2-positive breast cancer patients with brain metastases include trastuzumab/lapatinib [28], capecitabine/lapatinib [29], and TDM-1 [24].\n\nA major challenge faced in patients with metastatic disease, including those with breast cancer, is whether metastases develop according to a linear or a metastatic cascade model, which could lead to a separate molecular profile with important therapeutic implications [30].\n\n4. Conclusions\nBrain metastases are increasingly being acknowledged as the next major step to prolong survival in HER2-positive breast cancer. Our patient, combining systemic and local therapies, lived 67 months from the diagnosis of brain disease. The effectiveness observed in our patient indicated that the combination of pertuzumab/trastuzumab deserves further investigation in the context of larger studies. Nevertheless, it is necessary to assess the optimal anti-HER2 drug sequence in conjunction with efforts to redefine the role of radiotherapy and surgery in breast cancer patients with metastatic disease in the brain.\n\nAcknowledgments\nThe costs of this paper were deducted from a donation of the Hellenic Study Group of Psychoneuroimmunology in Cancer.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nAuthors' Contributions\nAll the authors have contributed to the paper preparation.\n\nFigure 1 Timeline of patient's diagnosis and treatments.\n\nFigure 2 Brain computed tomography at baseline (a) and after 3 (b), 9 (c), and 12 (d) months of treatment with pertuzumab, trastuzumab, and taxane-based chemotherapy.\n==== Refs\n1 Bendell J. C. Domchek S. M. Burstein H. J. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma Cancer 2003 97 12 2972 2977 10.1002/cncr.11436 2-s2.0-0038010542 12784331 \n2 Lin N. U. Amiri-Kordestani L. Palmieri D. Liewehr D. J. Steeg P. S. CNS metastases in breast cancer: old challenge, new frontiers Clinical Cancer Research 2013 19 23 6404 6418 10.1158/1078-0432.ccr-13-0790 2-s2.0-84890286030 24298071 \n3 Brufsky A. M. Mayer M. Rugo H. S. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER Clinical Cancer Research 2011 17 14 4834 4843 10.1158/1078-0432.ccr-10-2962 2-s2.0-79960429096 21768129 \n4 Dawood S. Broglio K. Esteva F. J. Defining prognosis for women with breast cancer and CNS metastases by HER2 status Annals of Oncology 2008 19 7 1242 1248 10.1093/annonc/mdn036 2-s2.0-46249099391 18334512 \n5 Blackwell K. L. Burstein H. J. Storniolo A. M. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer Journal of Clinical Oncology 2010 28 7 1124 1130 10.1200/jco.2008.21.4437 2-s2.0-77949884661 20124187 \n6 Lin N. U. Diéras V. Paul D. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer Clinical Cancer Research 2009 15 4 1452 1459 10.1158/1078-0432.ccr-08-1080 2-s2.0-63149110733 19228746 \n7 Swain S. M. Baselga J. Kim S.-B. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer The New England Journal of Medicine 2015 372 8 724 734 10.1056/nejmoa1413513 2-s2.0-84923052492 25693012 \n8 Arun B. Bayraktar S. Liu D. D. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience Journal of Clinical Oncology 2011 29 28 3739 3746 10.1200/jco.2011.35.2682 2-s2.0-80053595196 21900106 \n9 Lee E.-H. Park S. K. Park B. Effect of BRCA1/2 mutation on short-term and long-term breast cancer survival: a systematic review and meta-analysis Breast Cancer Research and Treatment 2010 122 1 11 25 10.1007/s10549-010-0859-2 2-s2.0-77953538854 20376556 \n10 Slamon D. J. Leyland-Jones B. Shak S. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 The New England Journal of Medicine 2001 344 11 783 792 10.1056/nejm200103153441101 2-s2.0-0035869407 11248153 \n11 Stickeler E. Klar M. Watermann D. Pegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trial Breast Cancer Research and Treatment 2009 117 3 591 598 10.1007/s10549-008-0306-9 2-s2.0-70349567015 19156515 \n12 Geyer C. E. Forster J. Lindquist D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer The New England Journal of Medicine 2006 355 26 2733 2743 10.1056/nejmoa064320 2-s2.0-33845886440 17192538 \n13 Kriege M. Seynaeve C. Meijers-Heijboer H. Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers Journal of Clinical Oncology 2009 27 23 3764 3771 10.1200/JCO.2008.19.9067 2-s2.0-68949127264 19564533 \n14 Robert N. Leyland-Jones B. Asmar L. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer Journal of Clinical Oncology 2006 24 18 2786 2792 10.1200/jco.2005.04.1764 2-s2.0-33745530224 16782917 \n15 Valero V. Forbes J. Pegram M. D. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens Journal of Clinical Oncology 2011 29 2 149 156 10.1200/jco.2010.28.6450 2-s2.0-79951982754 21115860 \n16 Nelli F. Moscetti L. Natoli G. Gemcitabine and carboplatin for pretreated metastatic breast cancer: the predictive value of immunohistochemically defined subtypes International Journal of Clinical Oncology 2013 18 2 343 349 10.1007/s10147-012-0384-x 2-s2.0-84880923023 22350024 \n17 Baselga J. Cortés J. Kim S.-B. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer The New England Journal of Medicine 2012 366 2 109 119 10.1056/nejmoa1113216 2-s2.0-84862914692 22149875 \n18 Verma S. Miles D. Gianni L. Trastuzumab emtansine for HER2-positive advanced breast cancer New England Journal of Medicine 2012 367 19 1783 1791 10.1056/NEJMoa1209124 2-s2.0-84868520609 23020162 \n19 Baselga J. Gelmon K. A. Verma S. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy Journal of Clinical Oncology 2010 28 7 1138 1144 10.1200/JCO.2009.24.2024 2-s2.0-77949903478 20124182 \n20 Senda N. Yamaguchi A. Nishimura H. Shiozaki T. Tsuyuki S. Pertuzumab, trastuzumab and docetaxel reduced the recurrence of brain metastasis from breast cancer: a case report Breast Cancer 2016 23 2 323 328 10.1007/s12282-015-0623-x 2-s2.0-84933556506 26116144 \n21 Gori S. Montemurro F. Spazzapan S. Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer Annals of Oncology 2012 23 6 1436 1441 10.1093/annonc/mdr474 2-s2.0-84861735490 22039084 \n22 Steeg P. S. Camphausen K. A. Smith Q. R. Brain metastases as preventive and therapeutic targets Nature Reviews Cancer 2011 11 5 352 363 10.1038/nrc3053 2-s2.0-79955475531 21472002 \n23 Stemmler H.-J. Schmitt M. Willems A. Bernhard H. Harbeck N. Heinemann V. Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier Anti-Cancer Drugs 2007 18 1 23 28 10.1097/01.cad.0000236313.50833.ee 2-s2.0-33845599378 17159499 \n24 Krop I. E. Lin N. U. Blackwell K. Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA Annals of Oncology 2015 26 1 113 119 10.1093/annonc/mdu486 2-s2.0-84922507404 25355722 \n25 Kurihara H. Hamada A. Yoshida M. \n64 Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients EJNMMI Research 2015 5, article 8 10.1186/s13550-015-0082-6 2-s2.0-84938061527 \n26 Hayashi N. Niikura N. Masuda N. Prognostic factors of HER2-positive breast cancer patients who develop brain metastasis: a multicenter retrospective analysis Breast Cancer Research and Treatment 2015 149 1 277 284 10.1007/s10549-014-3237-7 2-s2.0-84925487074 25528021 \n27 Dawood S. Gonzalez-Angulo A. M. Albarracin C. Prognostic factors of survival in the trastuzumab era among women with breast cancer and brain metastases who receive whole brain radiotherapy: a single-institution review Cancer 2010 116 13 3084 3092 10.1002/cncr.25115 2-s2.0-77954251392 20564633 \n28 Blackwell K. L. Burstein H. J. Storniolo A. M. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study Journal of Clinical Oncology 2012 30 21 2585 2592 10.1200/jco.2011.35.6725 2-s2.0-84864066561 22689807 \n29 Bachelot T. Romieu G. Campone M. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study The Lancet Oncology 2013 14 1 64 71 10.1016/s1470-2045(12)70432-1 2-s2.0-84871722407 23122784 \n30 Naxerova K. Jain R. K. Using tumour phylogenetics to identify the roots of metastasis in humans Nature Reviews Clinical Oncology 2015 12 5 258 272 10.1038/nrclinonc.2014.238 2-s2.0-84928823491\n\n",
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"title": "Durable Clinical Benefit of Pertuzumab in a Young Patient with BRCA2 Mutation and HER2-Overexpressing Breast Cancer Involving the Brain.",
"title_normalized": "durable clinical benefit of pertuzumab in a young patient with brca2 mutation and her2 overexpressing breast cancer involving the brain"
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"abstract": "The authors present an atypical case of presumed stroke-like migraine attacks after radiation therapy (SMART) syndrome in the brainstem. A 29-year-old male, who had been treated with resection and subsequent craniospinal radiation for posterior fossa medulloblastoma 21 years before, presented with subacute progressive left hemiparesis evolving over 4 days. Hematological findings, cerebrospinal fluid (CSF), and electroencephalogram (EEG) were unremarkable. Magnetic resonance imaging (MRI) showed a round area of hyperintense FLAIR signal centered within the pons associated with central restricted diffusion, peripheral enhancement, and small paramagnetic low susceptibility signal foci consistent with petechial hemorrhage. Positron emission tomography (PET), perfusion MRI, and MR spectroscopy revealed no evidence of tumor recurrence. The diagnosis of SMART syndrome is presumed from the conventional and advanced imaging findings, clinical history, and clinical course.",
"affiliations": "Division of Neuroradiology, Department of Radiology, University of Michigan, 1500 E Medical Center Dr, UH B2, Ann Arbor, MI, 48109, USA. yoshiako@med.umich.edu.;Division of Neuro-oncology, Department of Neurology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA.;Division of Neuroradiology, Department of Radiology, University of Michigan, 1500 E Medical Center Dr, UH B2, Ann Arbor, MI, 48109, USA.;Division of Neuroradiology, Department of Radiology, University of Michigan, 1500 E Medical Center Dr, UH B2, Ann Arbor, MI, 48109, USA.",
"authors": "Ota|Yoshiaki|Y|http://orcid.org/0000-0001-8992-2156;Leung|Denise|D|;Moritani|Toshio|T|;Capizzano|Aristides A|AA|",
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"issue": "63(8)",
"journal": "Neuroradiology",
"keywords": "Brainstem; DSC MR perfusion; MRS; PET-CT; SMART syndrome; SWI",
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"mesh_terms": "D000328:Adult; D001933:Brain Stem; D002528:Cerebellar Neoplasms; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008881:Migraine Disorders; D009364:Neoplasm Recurrence, Local; D020521:Stroke",
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"title": "Atypical imaging findings of presumed stroke-like migraine attacks after radiation therapy syndrome in the brainstem.",
"title_normalized": "atypical imaging findings of presumed stroke like migraine attacks after radiation therapy syndrome in the brainstem"
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"abstract": "Many studies have been made on ABO-compatible kidney transplants following hematopoietic stem cell transplantation. However, there have been few reports on ABO-incompatible kidney transplantation following hematopoietic stem cell transplantation (HSCT). We report on the case of a successful ABO-incompatible kidney transplantation with high titers after bone marrow transplantation experienced no infectious episodes. The patient was a 38-year-old man with end-stage kidney disease resulting from interstitial nephritis induced by drug toxicity or graft-vs-host disease (GVHD). He had received allogeneic bone marrow transplantation from a human leukocyte antigen-identical unrelated donor to treat chronic myelogenous leukemia. The patient with high anti-B antibody titers (IgM 1:1024 IgG 1:256) received a desensitization protocol consisting of 2 doses of rituximab and 5 courses of plasmapheresis. The patient had prolonged depletion of circulating B cells 2 years after the transplant and was infected with cytomegalovirus viremia, pneumocystis jiroveci pneumonia, and adenovirus urinary tract infection at 2, 3, and 17 months post-transplant, respectively. Currently, at 6 years after his transplant, the patient has had no rejection and is in good clinical condition with only mild renal insufficiency. Our results suggest that ABO-incompatible kidney transplantation may be an effective renal replacement therapy for patients with end-stage kidney disease after HSCT, but desensitization in combination with immunosuppressants could lead to a state of over-immunosuppression, causing various infections.",
"affiliations": "Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan. Electronic address: highspeed@med.osaka-cu.ac.jp.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.;Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.",
"authors": "Kosoku|Akihiro|A|;Uchida|Junji|J|;Shimada|Hisao|H|;Kabei|Kazuya|K|;Nishide|Shunji|S|;Iwai|Tomoaki|T|;Nakatani|Tatsuya|T|",
"chemical_list": "D000017:ABO Blood-Group System; D006680:HLA Antigens; D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.01.173",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(9)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000017:ABO Blood-Group System; D000328:Adult; D001787:Blood Group Incompatibility; D016026:Bone Marrow Transplantation; D006680:HLA Antigens; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D010956:Plasmapheresis; D000069283:Rituximab",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2754-2757",
"pmc": null,
"pmid": "32586664",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "ABO-Incompatible Kidney Transplantation After Bone Marrow Transplantation: A Case Report.",
"title_normalized": "abo incompatible kidney transplantation after bone marrow transplantation a case report"
} | [
{
"companynumb": "JP-PFIZER INC-2020254167",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,... |
{
"abstract": "No controlled comparisons between dolutegravir/lamivudine or dolutegravir maintenance therapy have been done. We hypothesized that these options would have similar efficacy to triple ART.\n\n\n\nWe used an open-label non-inferiority randomized controlled trial comprising two phases: phase A was established to test that experimental arms did not have an unacceptable (≥5%) failure rate; phase B was intended to include the full number of patients followed for 48 weeks. Treated HIV-1-infected adults with viral load <50 copies/mL for ≥12 months, no prior viral failure or resistance mutations to study drugs, nadir CD4 >200 cells/mm3, and hepatitis B virus surface antigen negative were randomized 1:1:1 to maintain triple therapy (control arm), or to switch to dolutegravir/lamivudine, or to dolutegravir monotherapy stratifying by anchor drug. Premature discontinuation was considered if viral failure or therapy interruption due to adverse events, concurrent illness, protocol deviation or patient's wish occurred. Blips were registered. Planned phase A results at 24 weeks are reported here. The study is registered at EudraCT: 201500027435.\n\n\n\nNinety-one (control, n = 31; dual therapy, n = 29; monotherapy, n = 31) patients were randomized. Three patients (none previously exposed to integrase inhibitors) prematurely discontinued treatment due to viral failure: dolutegravir/lamivudine (n = 1), no resistance mutations (subject A); dolutegravir (n = 2), N155H, S147G and Q148R resistance mutations (subject B), and E138K, G140S and N155H resistance mutations (subject C). There were no discontinuations for other reasons. One patient (dolutegravir/lamivudine) experienced a blip in viral load. The Data Safety Monitoring Board recommended stopping the dolutegravir monotherapy arm.\n\n\n\nIn contrast to dolutegravir/lamivudine, a higher than expected risk of viral failure with development of cross-resistance integrase mutations occurred with dolutegravir maintenance monotherapy.",
"affiliations": "Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.;Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.;Hospital Universitari Germans Trias i Pujol, Badalona, Spain.;Hospital Universitari Germans Trias i Pujol, Badalona, Spain.;Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.;Hospital Universitari Germans Trias i Pujol, Badalona, Spain.;Hospital Universitari Germans Trias i Pujol, Badalona, Spain.;Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.;Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.;Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.",
"authors": "Blanco|Jose L|JL|;Rojas|Jhon|J|;Paredes|Roger|R|;Negredo|Eugenia|E|;Mallolas|Josep|J|;Casadella|Maria|M|;Clotet|Bonaventura|B|;Gatell|Jose M|JM|;de Lazzari|Elisa|E|;Martinez|Esteban|E|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D019259:Lamivudine; C562325:dolutegravir",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dky093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "73(7)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006679:HIV Seropositivity; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D012367:RNA, Viral; D019562:Viral Load",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "1965-1971",
"pmc": null,
"pmid": "29608685",
"pubdate": "2018-07-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial.",
"title_normalized": "dolutegravir based maintenance monotherapy versus dual therapy with lamivudine a planned 24 week analysis of the dolam randomized clinical trial"
} | [
{
"companynumb": "ES-VIIV HEALTHCARE LIMITED-ES2018GSK008926",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOLUTEGRAVIR"
},
"drugadditi... |
{
"abstract": "Taxanes are a group of cytotoxic anti-cancer agents used in the treatment of solid tumours. The neurotoxic adverse effects of docetaxel and paclitaxel, including optic neuropathy, are well known. Cabazitaxel is a new generation taxane showing lesser drug resistance when compared with previous ones. Optic atrophy due to the use of cabazitaxel has not been previously reported. Herein, we report a patient with prostate cancer who developed optic atrophy after cabazitaxel treatment.",
"affiliations": "1 Medical Doctor, Department of Neurology, Faculty of Medicine, Near East University, Nicosia, Cyprus.;2 Medical Doctor, Department of Medical Oncology, Faculty of Medicine, Near East University, Nicosia, Cyprus.",
"authors": "Diker|Sevda|S|;Diker|Ömer|Ö|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; C552428:cabazitaxel",
"country": "Scotland",
"delete": false,
"doi": "10.1177/0036933018810653",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0036-9330",
"issue": "64(2)",
"journal": "Scottish medical journal",
"keywords": "Taxanes; cabazitaxel; optic atrophy",
"medline_ta": "Scott Med J",
"mesh_terms": "D000230:Adenocarcinoma; D000970:Antineoplastic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D009896:Optic Atrophy; D064129:Prostatic Neoplasms, Castration-Resistant; D043823:Taxoids",
"nlm_unique_id": "2983335R",
"other_id": null,
"pages": "71-73",
"pmc": null,
"pmid": "30396314",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Optic atrophy after cabazitaxel treatment in a patient with castration-resistant prostate cancer: a case report.",
"title_normalized": "optic atrophy after cabazitaxel treatment in a patient with castration resistant prostate cancer a case report"
} | [
{
"companynumb": "CY-ABBVIE-20P-041-3488845-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "CY",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEUPROLIDE ACETATE"
},
"drugadditional": "... |
{
"abstract": "To provide further evidence of dependence on non-opioid analgesics (NOAs).\n\n\n\nPost-hoc-analysis of a cross-sectional study of a ≥ -65-year-old non-demented German general hospital population. Four hundred in-patients (75 ± 6.4 years; 63% females) were included and screened for current and past dependence on NOAs using a structured interview (SKID-I) based on DSM-IV-TR. The addiction section of SKID-I was expanded to the following NOAs: gabapentinoids, acetaminophen, metamizole, flupirtine, and non-steroidal anti-inflammatory drugs (NSAIDs).\n\n\n\nWe found twenty-eight seniors (7%) who fulfilled the criteria for a NOA-dependence. Of whom, twenty-four and four patients were currently dependent and in remission, respectively. According to SKID-I, twenty-one (75%) patients were mildly, five patients (17.9%) moderately, and two (7.1%) patients severely dependent on NOAs. All patients showed at least one sign of physical dependence (tolerance and/or withdrawal symptoms) and most of them reported additional behavioral dependence symptoms. Whereas there was one dependence on gabapentinoids or acetaminophen only, NSAIDs and metamizole were involved in the majority of cases (n = 25; 89.3%). Of note, ten (35.7%) seniors had a de-novo substance dependence exclusively on NOAs - including 2 females with signs of a de-novo dependence on metamizole, a NOA which yet has been not in the focus of addiction medicine.\n\n\n\nThis cross-sectional study provides further evidence of the existence of a physical and behavioral dependence on NOAs including NSAIDs. Furthermore, preliminary evidence of a de-novo dependence on metamizole is provided which needs further verification.",
"affiliations": "Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg-Essen, D-44577 Castrop-Rauxel, Germany; LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Duisburg-Essen, D-45147 Essen, Germany. Electronic address: udo.bonnet@uni-due.de.;Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg-Essen, D-44577 Castrop-Rauxel, Germany.;LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Duisburg-Essen, D-45147 Essen, Germany.",
"authors": "Bonnet|Udo|U|;Strasser|Johanna Cristina|JC|;Scherbaum|Norbert|N|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal",
"country": "England",
"delete": false,
"doi": "10.1016/j.addbeh.2018.11.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-4603",
"issue": "90()",
"journal": "Addictive behaviors",
"keywords": "Acetaminophen; Addiction; Flupirtine; Gabapentinoids; Liking; Metamizole; NSAID; Wanting",
"medline_ta": "Addict Behav",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003430:Cross-Sectional Studies; D005260:Female; D015577:Geriatric Assessment; D005858:Germany; D006801:Humans; D007297:Inpatients; D007407:Interviews as Topic; D008297:Male; D012720:Severity of Illness Index; D019966:Substance-Related Disorders",
"nlm_unique_id": "7603486",
"other_id": null,
"pages": "265-271",
"pmc": null,
"pmid": "30472534",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Screening for physical and behavioral dependence on non-opioid analgesics in a German elderly hospital population.",
"title_normalized": "screening for physical and behavioral dependence on non opioid analgesics in a german elderly hospital population"
} | [
{
"companynumb": "DE-PFIZER INC-2018519789",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "Peripheral T-cell lymphomas (PTCL) are a unique subset of lymphomas with a poor prognosis due to limited treatment options. We performed a phase 1 study of carfilzomib in patients with relapsed/refractory PTCL to determine the safety profile and the maximum tolerated dose (MTD) of this agent. The study was a classical 3 + 3 phase 1 design with intra-patient dose escalation allowed beginning on day 8 of cycle 1 and subsequently. Dose-limiting toxicity (DLT) was defined as the occurrence of any grade 3/4 adverse event. Carfilzomib was given on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Fifteen patients were enrolled from 3 centers. The median age of patients was 62. The median number of prior therapies for subjects on this trial was five. The MTD of carfilzomib was 36 mg/m2. Dose-limiting toxicities included anemia and sepsis. Serious adverse events were seen in 45% of patients. Single-agent carfilzomib leads to a complete response in one patient and a partial response in one patient. Overall, the drug was reasonably tolerated for a heavily pretreated population, but the limited response rate and short duration of response demonstrate a lack of promise for carfilzomib as a single agent in this patient population.",
"affiliations": "Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. mridula.krishnan@unmc.edu.;Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.;Department of Lymphoma/Multiple Myeloma, MD Anderson Cancer Center, Houston, TX, USA.;Department of Lymphoma/Multiple Myeloma, MD Anderson Cancer Center, Houston, TX, USA.;Department of Hematology, Emory University, Atlanta, GA, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.;Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.",
"authors": "Krishnan|Mridula|M|http://orcid.org/0000-0002-6388-5219;Bociek|R Gregory|RG|;Fanale|Michelle|M|;Iyer|Swaminathan P|SP|;Lechowicz|Mary Jo|MJ|;Bierman|Philip J|PJ|;Armitage|James O|JO|;Lunning|Matthew|M|;Kallam|Avyakta|A|;Vose|Julie M|JM|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-021-04692-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": null,
"journal": "Annals of hematology",
"keywords": "Carfilzomib; PTCL; Phase 1 trial",
"medline_ta": "Ann Hematol",
"mesh_terms": null,
"nlm_unique_id": "9107334",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34668982",
"pubdate": "2021-10-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Phase 1 trial of carfilzomib in relapsed/refractory peripheral T-cell lymphoma.",
"title_normalized": "phase 1 trial of carfilzomib in relapsed refractory peripheral t cell lymphoma"
} | [
{
"companynumb": "US-AMGEN-USASP2021167421",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARFILZOMIB"
},
"drugadditional": "4",
... |
{
"abstract": "Community-acquired Pseudomonas aeruginosa infections are rare. Most cases involve patients either with underlying immunosuppression or structural chronic lung diseases. We report here an atypical case of a severe community-acquired invasive infection due to a hypervirulent ExoU-producing strain, in an immunocompetent patient.",
"affiliations": "AP-HP, Hôpital Tenon, Service de Réanimation médico-chirurgicale, 4 rue de la Chine, 75020, Paris Cedex 20, France.;Biology of Cancer and Infection, University of Grenoble Alpes, U1036 INSERM, CEA, ERL5261 CNRS, Grenoble, France.;AP-HP, Hôpital Tenon, Service de Bactériologie-Hygiène, Groupe hospitalier des Hôpitaux Universitaires de l'Est Parisien, Paris, France.;Centre National de Référence de la résistance aux antibiotiques, CHRU Jean Minjoz, Besançon, France.;Biology of Cancer and Infection, University of Grenoble Alpes, U1036 INSERM, CEA, ERL5261 CNRS, Grenoble, France.;AP-HP, Hôpital Tenon, Service de Réanimation médico-chirurgicale, 4 rue de la Chine, 75020, Paris Cedex 20, France; Faculté de médecine Sorbonne Université, France; Groupe de Recherche Clinique CARMAS, Collégium Gallilée, UPEC, France.;AP-HP, Hôpital Tenon, Service de Réanimation médico-chirurgicale, 4 rue de la Chine, 75020, Paris Cedex 20, France; Faculté de médecine Sorbonne Université, France; Groupe de Recherche Clinique CARMAS, Collégium Gallilée, UPEC, France.;AP-HP, Hôpital Tenon, Service de Réanimation médico-chirurgicale, 4 rue de la Chine, 75020, Paris Cedex 20, France. Electronic address: michel.djibre@aphp.fr.",
"authors": "Elabbadi|Alexandre|A|;Pont|Stéphane|S|;Verdet|Charlotte|C|;Plésiat|Patrick|P|;Cretin|François|F|;Voiriot|Guillaume|G|;Fartoukh|Muriel|M|;Djibré|Michel|M|",
"chemical_list": "D001426:Bacterial Proteins; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa",
"country": "England",
"delete": false,
"doi": "10.1016/j.jmii.2019.06.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1684-1182",
"issue": "53(4)",
"journal": "Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi",
"keywords": "Invasive infection; Pseudomonas aeruginosa; Virulence",
"medline_ta": "J Microbiol Immunol Infect",
"mesh_terms": "D000072283:A549 Cells; D001426:Bacterial Proteins; D017714:Community-Acquired Infections; D006801:Humans; D007121:Immunocompetence; D008297:Male; D008875:Middle Aged; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa; D018805:Sepsis; D012772:Shock, Septic; D018746:Systemic Inflammatory Response Syndrome; D014774:Virulence",
"nlm_unique_id": "100956211",
"other_id": null,
"pages": "647-651",
"pmc": null,
"pmid": "31345686",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual community-acquired invasive and multi systemic infection due to ExoU-harboring Pseudomonas aeruginosa strain: Clinical disease and microbiological characteristics.",
"title_normalized": "an unusual community acquired invasive and multi systemic infection due to exou harboring pseudomonas aeruginosa strain clinical disease and microbiological characteristics"
} | [
{
"companynumb": "FR-PFIZER INC-2020343611",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAmoxicillin-induced aseptic meningitis (AIAM) is an extremely rare adverse reaction with only 12 reported cases. The term aseptic meningitis refers to patients who have clinical and laboratory evidence for meningeal inflammation with negative routine bacterial cultures. Since the exact pathogenesis is still unknown and clinical signs and cerebrospinalfluid (CSF) findings vary greatly, AIAM is usually a diagnosis of exclusion.\n\n\nMETHODS\nWe report a clinical case of a patient referred to the clinical pharmacology outpatient clinic for consultation on suspected recurrent AIAM and a review of published cases.\n\n\nCONCLUSIONS\nThis report adds to the evidence-base of AIAM and emphasizes the importance of taking a thorough medication history in individuals with suspected meningitis. Considering the wide utilization of amoxicillin, it is important that healthcare providers are aware of AIAM.
.",
"affiliations": null,
"authors": "Turk|Viktorija Erdeljić|VE|;Šimić|Iveta|I|;Makar-Aušperger|Ksenija|K|;Radačić-Aumiler|Matea|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000658:Amoxicillin",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP202645",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "54(9)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000328:Adult; D000658:Amoxicillin; D000900:Anti-Bacterial Agents; D005260:Female; D006801:Humans; D008582:Meningitis, Aseptic; D012008:Recurrence",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "716-8",
"pmc": null,
"pmid": "27443662",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Amoxicillin-induced aseptic meningitis: case report and review of published cases
.",
"title_normalized": "amoxicillin induced aseptic meningitis case report and review of published cases"
} | [
{
"companynumb": "HR-VERNALIS THERAPEUTICS, INC.-2016VRN00046",
"fulfillexpeditecriteria": "1",
"occurcountry": "HR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditi... |
{
"abstract": "OBJECTIVE\nPrimary and metastatic pancreatic neuroendocrine tumours (PNET) can be treated with combination of surgery, locoregional and systemic therapy. Survival benefits from individual treatments have been well reported, however, the combined outcome from multimodal treatments are not well described in the literature. We report outcomes in a cohort of PNET patients treated with proactive, multimodality therapy.\n\n\nMETHODS\n106 patients were identified from a single tertiary referral centre prospective database. Outcomes of treatment were studied, with the primary end point being death from any cause.\n\n\nRESULTS\nMedian follow-up was 71 months and overall 5-year survival of 62%. In patients with stage I-III disease (51 patients) estimated 5-year survival was 90%. Median survival in patients with stage IV disease was 51 months with an estimated 5-year survival of 40% in this group. A total of 80 patients (75%) had surgery of which 16% suffered complications requiring intervention. There was no perioperative mortality.\n\n\nCONCLUSIONS\nThis study demonstrates that proactive multimodal treatment is safe and may confer a survival benefit to patients in this cohort compared to historical data.",
"affiliations": "Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom. Electronic address: l.tanno@doctors.org.uk.;Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Oncology, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Oncology, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Interventional Radiology, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Nuclear Medicine, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.;Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Tremona Road, Southampton, SO16 6YD, United Kingdom.",
"authors": "Tanno|L|L|;Mayo|D|D|;Mills|S|S|;Takhar|A|A|;Cave|J|J|;Nolan|L|L|;Stedman|B|B|;Sundram|F X|FX|;Abu Hilal|M|M|;Connor|H|H|;Pearce|N|N|;Armstrong|T|T|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal",
"country": "Switzerland",
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"issue": "18(3)",
"journal": "Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]",
"keywords": "Multimodal treatment; Pancreatic neuroendocrine tumour; Survival",
"medline_ta": "Pancreatology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal; D015331:Cohort Studies; D003131:Combined Modality Therapy; D016208:Databases, Factual; D005260:Female; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D011446:Prospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
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"other_id": null,
"pages": "304-312",
"pmc": null,
"pmid": "29433805",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
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"title": "Proactive multi-modality treatment of Pancreatic Neuroendocrine Tumours (PNETs): Potential survival benefits.",
"title_normalized": "proactive multi modality treatment of pancreatic neuroendocrine tumours pnets potential survival benefits"
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"abstract": "BACKGROUND\nGemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy.\n\n\nMETHODS\nIn this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200mg/m(2) followed by 5-fluorouracil 2g/m(2) (24h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m(2) on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy.\n\n\nRESULTS\nAfter inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively.\n\n\nCONCLUSIONS\nAlthough stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.",
"affiliations": "Universitätsmedizin Berlin - Charité, Centrum für Tumormedizin, Augustenburger Platz 1, 13353 Berlin, Germany.",
"authors": "Pelzer|Uwe|U|;Schwaner|Ingo|I|;Stieler|Jens|J|;Adler|Mathias|M|;Seraphin|Jörg|J|;Dörken|Bernd|B|;Riess|Hanno|H|;Oettle|Helmut|H|",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil; D005858:Germany; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9005373",
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"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Best supportive care (BSC) versus oxaliplatin, folinic acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic cancer: a phase III-study from the German CONKO-study group.",
"title_normalized": "best supportive care bsc versus oxaliplatin folinic acid and 5 fluorouracil off plus bsc in patients for second line advanced pancreatic cancer a phase iii study from the german conko study group"
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"abstract": "Acquired pulmonary vein stenosis (PVS) is an infrequent complication of atrial fibrillation ablation that is often misdiagnosed due to predominant respiratory symptoms. It can result in pulmonary venous hypertension, with varying presentations, ranging from shortness of breath to haemoptysis.\nWe report two patients with a history of paroxysmal atrial fibrillation treated with radiofrequency ablation and pulmonary vein (PV) isolation, who subsequently developed PVS. Case 1 initially presented with indolent symptoms of shortness of breath and cough. He was initially diagnosed with and treated for pneumonia. In contrast, Case 2 presented with massive haemoptysis, requiring intubation and intensive care unit admission. Both patients were eventually diagnosed with PVS by computed tomography. They were treated with PV angioplasty and stenting.\nWhile previously limited to the congenital heart disease population, PVS is occurring more frequently now in adult patients as a complication of ablation procedures. It is most effectively treated with angioplasty and stent implantation but has a high rate of recurrence.",
"affiliations": "Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA.;Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA.;Department of Radiology, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA.;Leon H. Charney Division of Cardiology, Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA.",
"authors": "Talmor|Nina|N|https://orcid.org/0000-0002-4765-4250;Massera|Daniele|D|https://orcid.org/0000-0002-9499-6456;Small|Adam|A|https://orcid.org/0000-0002-7035-6331;Ramachandran|Abhinay|A|;Argilla|Michael|M|https://orcid.org/0000-0002-6968-8224;Staniloae|Cezar S|CS|;Latson|Larry A|LA|;Halpern|Dan G|DG|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab235",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n34222784\n10.1093/ehjcr/ytab235\nytab235\nCase Series\nAcademicSubjects/MED00200\nAcquired pulmonary vein stenosis resulting in haemoptysis: a case series\nhttps://orcid.org/0000-0002-4765-4250\nTalmor Nina 1\nhttps://orcid.org/0000-0002-9499-6456\nMassera Daniele 2\nhttps://orcid.org/0000-0002-7035-6331\nSmall Adam 2\nRamachandran Abhinay 1\nhttps://orcid.org/0000-0002-6968-8224\nArgilla Michael 2\nStaniloae Cezar S 2\nLatson Larry A Jr 3\nHalpern Dan G 2\n1 Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA\n2 Leon H. Charney Division of Cardiology, Department of Medicine, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA\n3 Department of Radiology, New York University Langone Medical Center, 550 First Ave, New York City, NY 10016, USA\nVanezis Andrew Peter Handling Editor\nBatty Jonathan Adam Editor\nMoreno-Ruiz Luis Antonio Editor\nTindale Alexander Editor\nMehta Vishal Shahil Editor\nCorresponding author. Tel: (212) 263-1616, Email: Nina.Talmor@nyulangone.org\n6 2021\n30 6 2021\n30 6 2021\n5 6 ytab23527 5 2021\n02 1 2021\n23 2 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nAcquired pulmonary vein stenosis (PVS) is an infrequent complication of atrial fibrillation ablation that is often misdiagnosed due to predominant respiratory symptoms. It can result in pulmonary venous hypertension, with varying presentations, ranging from shortness of breath to haemoptysis.\n\nCase summary\n\nWe report two patients with a history of paroxysmal atrial fibrillation treated with radiofrequency ablation and pulmonary vein (PV) isolation, who subsequently developed PVS. Case 1 initially presented with indolent symptoms of shortness of breath and cough. He was initially diagnosed with and treated for pneumonia. In contrast, Case 2 presented with massive haemoptysis, requiring intubation and intensive care unit admission. Both patients were eventually diagnosed with PVS by computed tomography. They were treated with PV angioplasty and stenting.\n\nDiscussion\n\nWhile previously limited to the congenital heart disease population, PVS is occurring more frequently now in adult patients as a complication of ablation procedures. It is most effectively treated with angioplasty and stent implantation but has a high rate of recurrence.\n\nCongenital heart disease\nPulmonary vein stenosis\nPulmonary vein stenting\nCase report\nAblation complication\nHaemoptysis\n==== Body\nLearning points\n\nPulmonary vein stenosis is a rare complication of atrial fibrillation ablation with varying clinical presentations, ranging from recurrent pleural effusions and pulmonary infections to life-threatening haemoptysis.\n\nBalloon angioplasty with pulmonary vein stenting is the most effective treatment.\n\nIntroduction\n\nPulmonary venous hypertension causes a myriad of pulmonary findings such as pleural effusion formation, recurrent pneumonias, and haemoptysis.1 Massive haemoptysis secondary to pulmonary vein stenosis (PVS) is a rare, but life-threatening occurrence. Progressive reduction in pulmonary vein (PV) cross-sectional area leads to an increase in pulmonary venous pressure, venous congestion, and a decrease in pulmonary perfusion.2\n\nHere, we describe two widely differing presentations of PVS secondary to radiofrequency ablation/PV isolation for atrial tachyarrhythmia. It is crucial to consider PVS in the workup of pulmonary symptoms in patients with a history of atrial fibrillation ablation.3\n\nTimeline\n\n\tCase 1\t\nMonth 0\tPatient underwent atrial fibrillation ablation with pulmonary vein isolation\t\nMonth 18\tInitial presentation with cough, fever, and shortness of breath\t\nMonth 21\tSecond presentation with cough, fever, and shortness of breath. Patient diagnosed with recurrent pneumonia; pleural effusion identified on X-ray\t\nMonth 22\tOutpatient thoracentesis\t\nMonth 22\tContrast-enhanced CT scan demonstrated pulmonary vein stenosis\t\nMonth 23\tPulmonary vein angioplasty\t\nMonth 25\tPulmonary vein angioplasty with stenting\t\n\t\n\tCase 2\t\n\t\nMonth 0\tPatient underwent atrial fibrillation ablation with pulmonary vein isolation\t\nMonth 17\tPatient underwent surgery with septal myectomy, pulmonary vein ablation, left atrial appendage clipping\t\nMonth 25 Day 1\n\n\tInitial presentation with small volume hemoptysis\t\nMonth 25 Day 8\n\n\tRepeat presentation with large volume hemoptysis. Patient emergently intubated in emergency room and admitted to ICU\t\nMonth 25 Day 9\n\n\tInitial non-contrast-enhanced CT scan demonstrated opacification in left lower lobe with unclear source of bleeding\t\nMonth 25 Day 11\n\n\tPatient transferred to our facility; pulmonary vein stenosis identified on contrast-enhanced CT scan\t\nMonth 25 Day 13\n\n\tPulmonary vein angioplasty with stenting\t\n\nCase presentations\n\nCase 1\n\nA 33-year-old man with Ebstein anomaly and atrial septal defect (latter repaired at age 4) and paroxysmal atrial fibrillation presented to the emergency room with 2 weeks cough and intermittent fever. The patient underwent radiofrequency ablation with PV isolation 21 months prior. He had visited the emergency room with similar symptoms several months previously and was treated for presumed community-acquired pneumonia.\n\nOn presentation, the patient was febrile to 38.7˚C with otherwise normal vitals. X-ray was significant for a large left-sided pleural effusion with an opacity at the left lung base. He was again prescribed a course of azithromycin and discharged home from the emergency room.\n\nAt a subsequent outpatient visit, lung ultrasound demonstrated a persistent pleural effusion for which he underwent a therapeutic thoracentesis with the removal of 1.3 L serosanguinous fluid. His symptoms of cough and shortness of breath returned within 1 week. Therefore, a thoracoscopy with pleural biopsy and tunnelled pleural catheter placement was performed. Biopsy revealed non-specific inflammation. Follow-up contrast-enhanced CT scan after the procedure revealed a small loculated left pleural effusion, volume loss at the periphery of the left lower lobe, and a new finding of marked narrowing of the left PVs.\n\nGiven these findings, a cardiac catherization was performed. Intra-procedural trans-oesophageal echocardiography revealed severe stenosis of the common trunk of the left upper and lower PVs. Balloon angioplasty of the stenotic ostium was performed with a dual kissing balloon technique. Mean pre-procedural Doppler gradient on echocardiography was 7 mmHg, which decreased to 3.8 mmHg post-procedure (Figure 1). Following the procedure, he was started on aspirin, clopidogrel, and apixaban to maintain stent patency.\n\nFigure 1: Case 1. Chest X-ray demonstrating pleural effusion at time of initial presentation, asterisk (A). Chest X-ray, following pulmonary vein stenting procedure (B). Computed tomography angiography on which pulmonary vein stenosis diagnosed, arrow. Computed tomography also notable for left pleural effusion and subsegmental atelectasis in left lower lobe. (C). Pulsed wave Doppler of pulmonary vein, mean gradient 7 mmHg pre-procedure. Systolic and diastolic components marked on slide (D). Pulsed wave Doppler, mean gradient 3.8 mmHg post-procedure. Systolic and diastolic components marked on slide (E).\n\nThe patient’s recovery was complicated by recurrence of symptoms several weeks later. Repeat catheterization demonstrated restenosis of the left pulmonary venous antrum. In the second procedure, the lesion was pre-dilated, and a 10 mm diameter by 20 mm long bare-metal stent was placed from the PV ostium to the point of bifurcation. The patient was continued on apixaban and clopidogrel to maintain stent patency and for recurrent paroxysmal atrial fibrillation. Over the following 5 years, he had two small-sized haemoptysis episodes related to PV stent restenosis (Figure 2). Symptoms were alleviated after repeat angioplasty. While the patient’s CHA2DS2VASc Score was 0 and HASBLED Score was 2, he was continued on apixaban post-procedure to maintain stent patency.\n\nFigure 2: Case 1. Computed tomography reconstruction, demonstrating restenosis of left-sided pulmonary veins following initial angioplasty.\n\nCase 2\n\nA 43-year-old male with prior history of pulmonary sarcoidosis, obstructive hypertrophic cardiomyopathy, and paroxysmal atrial fibrillation presented with haemoptysis. The patient was diagnosed with obstructive hypertrophic cardiomyopathy 15 years prior, had a single-chamber ICD placed for primary prevention, and underwent PV isolation 2 years prior to presentation. He had recurrent syncopal episodes from left ventricular outflow tract obstruction and underwent septal myectomy, mitral valvuloplasty, left atrial appendage clipping, and epicardial radiofrequency ablation 8 months prior to presentation. Myectomy pathology revealed myocyte hypertrophy and granulomas consistent with cardiac sarcoidosis.\n\nThe patient first began coughing up blood-tinged sputum 1 week prior to admission but was thought to have bronchitis at two urgent care encounters. Over the course of the week prior to admission, he developed progressive shortness of breath and increased frequency and quantity of blood in his sputum. On presentation, he was afebrile, normotensive, with normal work of breathing. In the emergency room, he had several episodes of massive haemoptysis, each over 100 mL, and was emergently intubated for airway protection. Immediate bronchoscopy demonstrated active bleeding with large clots in the left lower lobe. Prothrombin complex concentrate was administered to mitigate the effect of rivaroxaban, which he had been taking prior to admission for atrial fibrillation (CHA2DS2VASc Score 3, HAS-BLED Score 2). Initial non-contrast CT and repeated bronchoscopies suggested primarily left lung involvement without a clear source of bleeding.\n\nThe patient was transferred to our institution after several days with limited control of the haemoptysis. Repeat contrast-enhanced CT angiography did not reveal active bleeding, but the left upper and left lower PVs were poorly visualized, increasing clinical suspicion for PVS as the underlying cause of haemoptysis (Figure 3). Cardiac catheterization revealed complete obstruction of the left upper PV, with evidence of collateralization to left lower PV circulation, suggesting chronicity. Balloon angioplasty and stenting of the left lower PV was performed with a 9 mm diameter by 26 mm long bare-metal stent, reducing the PV mean pressure difference from 15 mmHg to 4 mmHg via cardiac catheterization measurements. The left upper PV was inaccessible. He was started on heparin post-procedure to maintain stent patency.\n\nFigure 3: Case 2. Chest X-ray at time of presentation to our centre, demonstrating complete collapse of left lung, asterisk (A). Chest X-ray several days after pulmonary vein stenting procedure (B). Computed tomography angiography on which pulmonary vein stenosis diagnosed, arrow (C). Pulmonary vein angiography via trans-septal access, before stent was placed. Left upper pulmonary vein is occluded, arrow (D). Pulmonary vein angiography via trans-septal access, post-stent placement. The branch veins are incompletely opacified due to brisk antegrade flow of contrast. Left upper pulmonary vein is stented, arrow (E).\n\nHe was eventually extubated 9 days post-procedure and safely transitioned to apixaban prior to discharge. Repeated chest X-rays have shown re-inflation of the left lung. Thirty-six weeks after discharge, he is doing well without recurrence of haemoptysis.\n\nDiscussion\n\nUntil recently, PVS had been most commonly described in the paediatric population. Congenital PVS is associated with anomalous PV connection, atrial and ventricular septal defects, and complex heterotaxy syndromes.1 Acquired PVS is a rare complication of atrial fibrillation ablation with PV isolation that is often missed due to predominant pulmonary symptoms.\n\nPresentation includes shortness of breath, haemoptysis, recurrent symptoms suggestive of pneumonia, and progression to right-sided heart failure. Transcatheter balloon angioplasty and stent placement is the mainstay treatment, though with high recurrence rates.4,5 Antiproliferative agents such as imatinib and bevacizumab are under investigation.\n\nThe advent of new treatment modalities for atrial fibrillation has led to an increase in the incidence of acquired PVS.3,6 A multi-centre trial conducted at 13 sites found mild or moderate PV stenosis in 8.2% of ablated PVs at 3 months post-procedure, though all patients were asymptomatic.7 It is an infrequent complication of atrial fibrillation ablation procedures, previously estimated to occur following 0.3–3.4% of cases,8 though patients typically only undergo PV imaging when symptomatic.7 Aetiology is attributed to adventitial inflammation and collagen deposition at the site of ablation.9,10\n\nPulmonary vein anatomy varies widely in the general population, with up to 20% of people having three right-sided PVs, rather than two.11 In up to 25% of patients, the left PVs drain into a common ostium.11 Prior case studies have also demonstrated an association between severity of symptoms and number of PVs involved.1 This likely occurs due to an increase in outflow obstruction of pulmonary venous flow, leading to an increase in pulmonary venous hypertension. Having only one vein occluded can lead to compensatory collateralization,12 as was seen in Case 2, with increased pulmonary venous pressures developing only when the other vessel becomes occluded as well.\n\nImaging such as an echocardiogram, cardiac CT and magnetic resonance imaging (MRI), and ventilation-perfusion scans have previously been used as diagnostic modalities. Signs of congestion can be seen on chest X-ray but are non-specific. While ventilation–perfusion scans are superior in characterizing blood flow, CT, and MRI can be used to evaluate the size and calibre of PVs, including the exact site and length of stenosis.1,13 Trans-oesophageal echocardiography can also be used to visualize PVs but often is not the initial test of choice, unless there is high clinical suspicion.\n\nManagement of PVS typically involves angioplasty to increase the calibre of the veins.14 However, the restenosis rate is high, and patients may require additional interventions for recurrent symptoms in the future.8 Stent implantation has been associated with better outcomes than balloon angioplasty, with one study estimating a relative risk reduction of 53%.5 In another study, the restenosis rate following PVS intervention was 57% for balloon angioplasty alone and 27% for balloon angioplasty with stenting.8 A different study reported restenosis rates of 72% for balloon angioplasty alone and 33% for balloon angioplasty with stenting.14 However, stent implantation also requires the initiation of antiplatelets or anticoagulants, which lead to an increased bleeding risk. Careful risk/benefit analysis is necessary. In some cases of massive haemoptysis that is not relieved by PV angioplasty, partial pneumonectomy may be necessary.15 Clinicians should maintain a high index of suspicion for PVS in cases of recurrent, unexplained pulmonary symptoms, especially in patients with a history of radiofrequency ablation procedures.3\n\nLead author biography\n\nNina (Gertsvolf) Talmor, MD, is an Internal Medicine resident physician at New York University Langone Health Center in New York, NY, USA. She will be applying to Cardiology Fellowship in 2021 and plans to pursue a career in interventional cardiology. Her research interests include complications occurring during or after angiography, sex differences in cardiovascular disease, and adult congenital heart disease management.\n\nAcknowledgements\n\nThe authors thank Samuel Maidman MD, Jonathan Lee MD, Sunil Saharan MD, and Anthony Andriotis MD for treating the patients presented in this case report and their critical reading of the manuscript.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patients in line with COPE guidelines.\n\nConflict of interest: Dr. Massera reports consulting fees from Bristol Meyers Squibb.\n\nFunding: None declared.\n==== Refs\nReferences\n\n1 Latson LA , PrietoLR. Congenital and acquired pulmonary vein stenosis. Circulation 2007;115 :103–108.17200453\n2 Pazos-López P , García-RodríguezC, Guitián-GonzálezA, Paredes-GalánE, Álvarez-MoureM, Rodríguez-ÁlvarezM et al Pulmonary vein stenosis: etiology, diagnosis and management. World J Cardiol 2016;8 :81–88.26839659\n3 Saad EB , RossilloA, SaadCP, MartinDO, BhargavaM, ErciyesD et al Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterization, evolution, and influence of the ablation strategy. Circulation 2003;108 :3102–3107.14623799\n4 Braun S , PlatzekI, ZöphelK, WeiseM, KolditzM, HalankM et al Haemoptysis due to pulmonary venous stenosis. Eur Respir Rev 2014;23 :170–179.24881072\n5 Fender EA , WidmerRJ, MahowaldMK, HodgeDO, PackerDL, HolmesDRJr. Recurrent pulmonary vein stenosis after successful intervention: prognosis and management of restenosis. Catheter Cardiovasc Interv 2020;95 :954–958.31854110\n6 Robbins IM , ColvinEV, DoyleTP, KempWE, LoydJE, McMahonWS et al Pulmonary vein stenosis after catheter ablation of atrial fibrillation. Circulation 1998;98 :1769–1775.9788832\n7 Samuel M , KhairyP, MongeonFP, AndradeJG, GomesS, GalvanZ et al Pulmonary vein stenosis after atrial fibrillation ablation: insights from the ADVICE trial. Can J Cardiol 2020;36 :1965–1974.33157186\n8 Fender EA , WidmerRJ, HodgeDO, CooperGM, MonahanKH, PetersonLA et al Severe pulmonary vein stenosis resulting from ablation for atrial fibrillation: presentation, management, and clinical outcomes. Circulation 2016;134 :1812–1821.27793993\n9 Dong J , VasamreddyCR, JayamV, DalalD, DickfeldT, EldadahZ et al Incidence and predictors of pulmonary vein stenosis following catheter ablation of atrial fibrillation using the anatomic pulmonary vein ablation approach: results from paired magnetic resonance imaging. J Cardiovasc Electrophysiol 2005;16 :845–852.16101625\n10 Ito K , KatoK, TanakaH. Experience using drug-coated balloon venoplasty for acquired pulmonary vein stenosis after radiofrequency ablation. J Cardiol Cases 2021;23 :3–5.33437330\n11 Klimek-Piotrowska W , HołdaMK, PiątekK, KoziejM, HołdaJ. Normal distal pulmonary vein anatomy. PeerJ 2016;4 :e1579.26793429\n12 Hilbert S , PaetschI, BollmannA, JahnkeC. Pulmonary vein collateral formation as a long-term result of post-interventional pulmonary vein stenosis. Eur Heart J 2016;37 :2474.26795444\n13 Widmer RJ , HolmesDRJr. Chapter 23 - Pulmonary vein stenosis: management and outcomes. In: Rihal CS, Raphael CE(eds). Handbook of Structural Heart Interventions. Elsevier; 2021:267-278.e1.\n14 Prieto LR , SchoenhagenP, ArrudaMJ, NataleA, WorleySE. Comparison of stent versus balloon angioplasty for pulmonary vein stenosis complicating pulmonary vein isolation. J Cardiovasc Electrophysiol 2008;19 :673–678.18284494\n15 Lee JY , ChonGR, ParkJH, KangBJ, ShimTS, JoKW. Massive hemoptysis due to pulmonary vein stenosis following catheter ablation for atrial fibrillation. Respir Care 2015;60 :e52–5.25316885\n\n",
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"journal": "European heart journal. Case reports",
"keywords": "Ablation complication; Case report; Congenital heart disease; Haemoptysis; Pulmonary vein stenosis; Pulmonary vein stenting",
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"title": "Acquired pulmonary vein stenosis resulting in haemoptysis: a case series.",
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{
"abstract": "Mycobacterium septicum is a rarely identified nontuberculous mycobacterium capable of causing infections in both healthy and immunocompromised individuals. Only a few cases of M. septicum infections have been reported, which makes recognizing corresponding clinical disease more challenging for clinicians. Antimicrobial susceptibility profiles for this organism are not well described, and corresponding optimal therapeutic regimens have not been established. We report a tertiary care center's experience with M. septicum from 2014 to 2020. Twelve adult patients with positive cultures for M. septicum were identified. Most cases were identified from sputum samples of individuals with underlying lung disease. Most cases involving M. septicum isolation in culture were not felt to be clinically significant. Two cases were considered possible infections, while only one case was considered a definite infection that required antimicrobial treatment. All M. septicum isolates were susceptible in vitro to amikacin, ciprofloxacin, imipenem, linezolid, moxifloxacin, and trimethoprim-sulfamethoxazole. Isolates were universally resistant to clarithromycin and doxycycline. The isolation of M. septicum in culture is uncommon and requires clinical correlation to determine its clinical relevance and need for treatment. Susceptibility testing should be performed to guide therapy.",
"affiliations": "Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA Go.john@mayo.edu.;Division of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.;Division of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota, USA.;Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota, USA.",
"authors": "Go|John Raymond|JR|0000-0002-0299-4817;Wengenack|Nancy L|NL|;Abu Saleh|Omar M|OM|;Corsini Campioli|Cristina|C|;Deml|Sharon M|SM|;Wilson|John W|JW|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.02091-20",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "58(12)",
"journal": "Journal of clinical microbiology",
"keywords": "Mycobacterium septicum\n; NTM; nontuberculous mycobacterium",
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D006801:Humans; D007753:Laboratories; D008826:Microbial Sensitivity Tests; D009159:Mycobacteriaceae; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D062606:Tertiary Care Centers",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32967896",
"pubdate": "2020-11-18",
"publication_types": "D016428:Journal Article",
"references": "13612432;10074551;17277290;25278573;25568437;21891775;32797222;8484642;29291713;32425103;17875513;28011857;22890130;28084211;10758863;16364605;31856133;27826888;20491285;18294801;23352491;29030295;26637381;9987532;30885902",
"title": "Mycobacterium septicum: a 6-Year Clinical Experience from a Tertiary Hospital and Reference Laboratory.",
"title_normalized": "mycobacterium septicum a 6 year clinical experience from a tertiary hospital and reference laboratory"
} | [
{
"companynumb": "US-MYLANLABS-2021M1018969",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo observe the frequency of complications in patients undergoing intravitreal anti-VEGF injections for different ocular diseases in a five-year period.\n\n\nMETHODS\nCharts of patients receiving intravitreal anti-VEGF were retrospectively reviewed. Out of 1173 eyes, 762 were treated with bevacizumab, 382 with ranibizumab, and 29 with pegaptanib. Data recorded included demographic information, clinical findings, total injections received, and info about the onset of adverse effects.\n\n\nRESULTS\n12.86% of the eyes treated with bevacizumab presented side-effects, while ratings in the ranibizumab and pegaptanib groups were 15.97% and 20.69%, respectively. Odds ratios calculated comparing incidences after each anti-VEGF are 0.78 (bevacizumab versus ranibizumab, p = 0.152), 0.57 (bevacizumab versus pegaptanib, p = 0.227), and 0.73 (ranibizumab versus pegaptanib, p = 0.508). A total of 185 complications were detected (62.16% after bevacizumab). Ocular side-effects registered were 40 cases of sustained intraocular pression (IOP) elevation, one infectious uveitis, one retinal detachment, and one sub-retinal hemorrhage. Other cases were related to transient IOP elevation immediately after injection. Systemic complications registered were one case of nausea, one episode of chest pain with acute vision loss, and one case of acute blood hypertension.\n\n\nCONCLUSIONS\nThe majority of significant complications occurred in patients receiving multiple bevacizumab administrations. However, results may be affected by the difference in the utilization amount for each drug. AMD patients were the most represented, probably due to greater indication to treatment.",
"affiliations": "Department of Clinical Pathophysiology, Institute of Ophthalmology, Visual System and Eye Clinic Section, University of Turin , Turin , Italy.",
"authors": "Nuzzi|Raffaele|R|;Tridico|Federico|F|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C495058:pegaptanib; D000068258:Bevacizumab; D000069579:Ranibizumab",
"country": "England",
"delete": false,
"doi": "10.3109/08820538.2013.835833",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0882-0538",
"issue": "30(2)",
"journal": "Seminars in ophthalmology",
"keywords": "Anti-VEGF; bevacizumab; complications; pegaptanib; ranibizumab",
"medline_ta": "Semin Ophthalmol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D052157:Aptamers, Nucleotide; D000068258:Bevacizumab; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007429:Intraocular Pressure; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D000069579:Ranibizumab; D012163:Retinal Detachment; D012164:Retinal Diseases; D012166:Retinal Hemorrhage; D012189:Retrospective Studies; D014605:Uveitis; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "8610759",
"other_id": null,
"pages": "129-35",
"pmc": null,
"pmid": "24171832",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Local and systemic complications after intravitreal administration of anti-vascular endothelial growth factor agents in the treatment of different ocular diseases: a five-year retrospective study.",
"title_normalized": "local and systemic complications after intravitreal administration of anti vascular endothelial growth factor agents in the treatment of different ocular diseases a five year retrospective study"
} | [
{
"companynumb": "IT-ROCHE-1556028",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "We report a case of an elderly woman with congenital rubella who presented with epithelial downgrowth (EDG) masquerading as hypopyon uveitis. We highlight the importance of endoscopy to completely identify all ingrowing epithelium with combined use of 5-fluorouracil to completely eradicate invading tissue.",
"affiliations": "a Department of Ophthalmology , Casey Eye Institute, Oregon Health & Science University , Portland , Oregon, USA.;a Department of Ophthalmology , Casey Eye Institute, Oregon Health & Science University , Portland , Oregon, USA.;a Department of Ophthalmology , Casey Eye Institute, Oregon Health & Science University , Portland , Oregon, USA.",
"authors": "Saleh|Mohamed G A|MGA|;Parikh|Mansi|M|;Lin|Phoebe|P|",
"chemical_list": "D015796:HLA-B27 Antigen; D007166:Immunosuppressive Agents; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2016.1213856",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "26(2)",
"journal": "Ocular immunology and inflammation",
"keywords": "Epithelial downgrowth; endoscopy; hypopyon",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000369:Aged, 80 and over; D000867:Anterior Chamber; D017679:Cryotherapy; D003937:Diagnosis, Differential; D019573:Epithelium, Corneal; D005128:Eye Diseases; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil; D015796:HLA-B27 Antigen; D006801:Humans; D007166:Immunosuppressive Agents; D015948:Keratoplasty, Penetrating; D013508:Ophthalmologic Surgical Procedures; D013492:Suppuration; D014606:Uveitis, Anterior",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "280-282",
"pmc": null,
"pmid": "27598054",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment of Epithelial Downgrowth Masquerading as Unilateral Hypopyon Uveitis in a HLA-B27+ Individual.",
"title_normalized": "treatment of epithelial downgrowth masquerading as unilateral hypopyon uveitis in a hla b27 individual"
} | [
{
"companynumb": "US-ACCORD-044879",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Treatment with radiotherapy (RT) is associated with an increased risk of second malignant neoplasms (SMNs) in childhood cancer survivors; it is unclear how treatment with intensity-modulated radiation therapy (IMRT) impacts this risk. We provide the first report of SMN risk in a cohort of childhood cancer survivors treated with IMRT.\n\n\n\nRetrospective review of patients ≤21 years of age treated with IMRT at Memorial Sloan Kettering Cancer Center between December 1998 and February 2009. Eligible patients survived at least 5 years from IMRT initiation. The risk of SMN was assessed via standardized incidence ratios (SIRs) and excess absolute risk (EAR). The cumulative incidence was estimated using methods for competing risks.\n\n\n\nAmong 242 patients, six developed SMNs: four developed second solid cancers (all within the radiation field), and two developed myelodysplastic syndrome. Median time from IMRT initiation to a second solid cancer was 7.2 years (range, 6.8-9.5), with a 10-year cumulative incidence of 3.3% (95% confidence interval [CI], 1.0-7.8%), SIR of 11.4 (95% CI, 3.1-29.2) and EAR of 1.8 per 1,000 person-years (95% CI, -0.1 to 3.8).\n\n\n\nLonger follow-up is required to determine how the risk of SMN after IMRT compares to other modalities of radiation treatment, such as proton therapy. This study provides a preliminary report, which will serve as a baseline for future longitudinal analyses of SMN risk after IMRT. Pediatr Blood Cancer 2015;62:311-316. © 2014 Wiley Periodicals, Inc.",
"affiliations": "Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.;Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.",
"authors": "Casey|Dana L|DL|;Friedman|Danielle N|DN|;Moskowitz|Chaya S|CS|;Hilden|Patrick D|PD|;Sklar|Charles A|CA|;Wexler|Leonard H|LH|;Wolden|Suzanne L|SL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25285",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "62(2)",
"journal": "Pediatric blood & cancer",
"keywords": "late effects of cancer treatment; radiation oncology; radiation therapy",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D016609:Neoplasms, Second Primary; D061766:Proton Therapy; D050397:Radiotherapy, Intensity-Modulated; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "311-316",
"pmc": null,
"pmid": "25328040",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Second cancer risk in childhood cancer survivors treated with intensity-modulated radiation therapy (IMRT).",
"title_normalized": "second cancer risk in childhood cancer survivors treated with intensity modulated radiation therapy imrt"
} | [
{
"companynumb": "US-009507513-2206USA002516",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Mycobacterium avium complex is a rare cause of musculoskeletal infection, usually occurring in patients with compromised immune systems. Obtaining the diagnosis requires a high index of suspicion, and treatment can be delayed because of difficulty with isolating the organism. Treatment involves prolonged, targeted combination antibiotic therapy, and it is unclear whether eradication of the infection can occur in the presence of a foreign body, such as antibiotic spacers. The authors report a case of M avium infection presenting as presumed osteonecrosis of the femoral head in a young woman with systemic lupus erythematosus. She presented with collapse of her femoral head coinciding with several months of progressive, debilitating hip pain. She had mild fevers during that time, but results from multiple infectious workups, including hip aspiration, were negative. Purulent fluid was found in the operating room, but diagnosis was delayed for 5 weeks while waiting for cultures. The patient required 3 subsequent operations, eventually being left with a resection arthroplasty. Pertinent issues concerning diagnosis, therapy, and treatment challenges in M avium infections of the musculoskeletal system are discussed in this case report. [Orthopedics. 2017; 40(3):e549-e552.].",
"affiliations": null,
"authors": "Christ|Alexander B|AB|;Zininberg|Elena V|EV|;Jules-Elysee|Kethy M|KM|;Parks|Michael L|ML|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.3928/01477447-20161229-04",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0147-7447",
"issue": "40(3)",
"journal": "Orthopedics",
"keywords": null,
"medline_ta": "Orthopedics",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001170:Arthritis, Infectious; D004359:Drug Therapy, Combination; D005260:Female; D005270:Femur Head; D005271:Femur Head Necrosis; D006801:Humans; D016867:Immunocompromised Host; D008180:Lupus Erythematosus, Systemic; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D061665:Time-to-Treatment; D055815:Young Adult",
"nlm_unique_id": "7806107",
"other_id": null,
"pages": "e549-e552",
"pmc": null,
"pmid": "28056158",
"pubdate": "2017-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mycobacterium avium Complex Septic Arthritis Presenting as Osteonecrosis of the Femoral Head in a Patient With Systemic Lupus Erythematosus.",
"title_normalized": "mycobacterium avium complex septic arthritis presenting as osteonecrosis of the femoral head in a patient with systemic lupus erythematosus"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-02265",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"... |
{
"abstract": "To report the safety and efficacy of subthreshold micropulse yellow laser of 577 nm for a complex case of refractory pseudophakic cystoid macular edema.\nA retrospective chart review of an interventional case report of three subthreshold micropulse yellow laser interventions for refractory pseudophakic cystoid macular edema.\nA 77-year-old healthy female underwent pseudoexfoliative cataract surgery complicated by posterior capsule rupture and sulcus intraocular lens implantation. After 3 months, she required a scleral fixation of the same lens, due to a lack of capsular support and decentration of the intraocular lens. One month later, she experienced a severe pseudophakic cystoid macular edema (foveal thickness of 399 µm and best-corrected visual acuity of 20/80 Snellen). The condition was refractory to conventional treatments prior to subthreshold micropulse yellow laser interventions, including non-steroidal anti-inflammatory eye drops, topical steroids, oral indomethacin and three sub-Tenon's triamcinolone injections, attempted over a 14-month period.\nSubthreshold micropulse yellow laser treatment was performed and immediate resolution was achieved and maintained for 2 months. Two cases of edema relapse were observed at 3 months from initial laser treatment and again at 4 months from the second laser treatment. Final patient's follow-up at 6 months from the third laser treatment evidenced the absence of edema, improved visual acuity (foveal thickness of 265 µm/best-corrected visual acuity of 20/30 Snellen) and the absence of complications.\nSubthreshold micropulse yellow laser seems to be a safe and effective treatment for short-term resolution of refractory pseudophakic cystoid macular edema after complicated cataract surgery and represents a useful alternative to expensive and invasive therapies. A trend towards a longer duration of edema resolution with every subthreshold micropulse yellow laser repetition was observed.",
"affiliations": "Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy.;Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy.;Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy.;Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy.;Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy.;Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy.;Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy.",
"authors": "Verdina|Tommaso|T|https://orcid.org/0000-0001-7877-4485;Ferrari|Cecilia|C|https://orcid.org/0000-0001-7793-4803;Valerio|Edoardo|E|;Brombin|Alberto|A|;Lazzerini|Andrea|A|;Mastropasqua|Rodolfo|R|;Cavallini|Gian Maria|GM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1120672120928008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "31(5)",
"journal": "European journal of ophthalmology",
"keywords": "Pseudophakic cystoid macular edema; cataract surgery; micropulse yellow laser; refractory macular edema",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "NP93-NP98",
"pmc": null,
"pmid": "32468853",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Subthreshold micropulse yellow laser for the management of refractory cystoid macular edema consequent to complicated cataract surgery.",
"title_normalized": "subthreshold micropulse yellow laser for the management of refractory cystoid macular edema consequent to complicated cataract surgery"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-249233",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INDOMETHACIN"
},
"dr... |
{
"abstract": "The aim of this study was to evaluate the frequency of transaminase elevations (TE) and total bilirubin elevations (TBE) during the first year of therapy with a single tablet regimen including RPV/FTC/TDF (EPA) in HIV/hepatitis C virus (HCV)-coinfected subjects in clinical practice.\n\n\n\nIn a retrospective analysis, HIV/HCV-coinfected subjects who started EPA at 17 centres throughout Spain were included as cases. Subjects who started an antiretroviral therapy (ART) other than EPA during the study period at the same hospitals were randomly selected as controls in a 1:2 ratio. Primary outcome variables were grade (G) 3-4 TE and G4 TBE.\n\n\n\nOf the 519 subjects included, 173 individuals started EPA. Nine (5.2%) subjects of the EPA group and 49 (14.2%) controls were naïve to ART. The median (Q1-Q3) follow-up was 11.2 (9.7-13.9) months. TE was observed in 2 [1.2%; 95% confidence interval (CI): 0.14%-4.1%] subjects receiving EPA and 11 (3.2%; 95%CI: 1.6%-5.6%) controls (p = 0.136), all events were G3. No patient discontinued ART due to TE. One (0.6%; 95%CI: 0.01%-3.1%) subject on EPA and 8 (2.3%; 95%CI: 1%-4.5%) subjects in the control group developed TBE (p = 0.141), without developing any other hepatic event during follow-up. Three (2.3%) subjects with cirrhosis versus 10 (3.1%) without cirrhosis showed G3-4 TE (p = 0.451).\n\n\n\nThe frequency of severe liver toxicity in HIV/HCV-coinfected subjects receiving EPA under real-life conditions is very low, TE were generally mild and did not lead to drug discontinuation. All these data suggest that EPA can be safely used in this particular subpopulation.",
"affiliations": "Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain.;Service of Infectious Diseases, Hospital Universitario Virgen del Rocío, Seville, Spain.;Unit of Infectious Diseases, Hospital Torrecárdenas, Almeria, Spain.;Unit of Infectious Diseases, Hospital Regional de Málaga. Malaga, Spain.;Unit of Infectious Diseases, Hospital Universitario Puerto Real, Puerto Real, Spain.;Unit of Infectious Diseases, Hospital Universitario Reina Sofía, Instituto de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain.;HIV Unit, Service of Internal Medicine, Hospital Universitario La Paz/IdiPAZ, Madrid, Spain.;Service of Internal/Infectious Medicine, Hospital Universitario de la Princesa, Madrid, Spain.;Unit of Infectious Diseases, Hospital Universitario Virgen de la Victoria, Malaga, Spain.;Unit of Infectious Diseases, Complejo Hospitalario de Huelva, Huelva, Spain.;Unit of Infectious Diseases/HIV, Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Unit of Infectious Diseases, Hospital La Línea, AGS Campo de Gibraltar, La Linea de la Concepcion, Spain.;Unit of Infectious Diseases, Hospital Virgen Macarena, Seville, Spain.;Unit of Infectious Diseases, Hospital Universitario San Cecilio, Granada, Spain.;HIV Unit. Hospital Universitario 12 de Octubre, Madrid, Spain.;Tropical Medicine Unit, Hospital Poniente, El Ejido, Spain.;Infectious Medicine Section, Hospital Universitario Santa Lucia, Cartagena, Spain.;Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain.;Unit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain.",
"authors": "Neukam|Karin|K|;Espinosa|Nuria|N|;Collado|Antonio|A|;Delgado-Fernández|Marcial|M|;Jiménez-Aguilar|Patricia|P|;Rivero-Juárez|Antonio|A|;Hontañón-Antoñana|Victor|V|;Gómez-Berrocal|Ana|A|;Ruiz-Morales|Josefa|J|;Merino|Dolores|D|;Carrero|Ana|A|;Téllez|Francisco|F|;Ríos|María José|MJ|;Hernández-Quero|José|J|;de Lagarde-Sebastián|María|M|;Pérez-Camacho|Inés|I|;Vera-Méndez|Francisco|F|;Macías|Juan|J|;Pineda|Juan A|JA|;|||",
"chemical_list": "D044966:Anti-Retroviral Agents; D000998:Antiviral Agents; D013607:Tablets; D000068698:Tenofovir; D000637:Transaminases; D000068696:Rilpivirine; D000068679:Emtricitabine; D001663:Bilirubin",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0155842",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2719579710.1371/journal.pone.0155842PONE-D-16-00719Research ArticleBiology and Life SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesImmunologyVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyMedicine and Health SciencesPublic and Occupational HealthPreventive MedicineVaccination and ImmunizationAntiviral TherapyAntiretroviral TherapyBiology and life sciencesOrganismsVirusesRNA virusesFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis C virusBiology and Life SciencesAnatomyBody FluidsBileBilirubinMedicine and Health SciencesAnatomyBody FluidsBileBilirubinBiology and Life SciencesPhysiologyBody FluidsBileBilirubinMedicine and Health SciencesPhysiologyBody FluidsBileBilirubinBiology and Life SciencesDevelopmental BiologyFibrosisBiology and Life SciencesToxicologyToxicityMedicine and Health SciencesPathology and Laboratory MedicineToxicologyToxicityMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesCirrhosisBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesViral PathogensImmunodeficiency VirusesHIVBiology and Life SciencesOrganismsVirusesImmunodeficiency VirusesHIVBiology and life sciencesOrganismsVirusesRNA virusesRetrovirusesLentivirusHIVBiology and Life SciencesMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVMedicine and Health SciencesPathology and Laboratory MedicinePathogensMicrobial PathogensViral PathogensRetrovirusesLentivirusHIVBiology and Life SciencesOrganismsVirusesViral PathogensRetrovirusesLentivirusHIVResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsHepatic Safety of Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate Fixed-Dose Single-Tablet Regimen in HIV-Infected Patients with Active Hepatitis C Virus Infection: The hEPAtic Study Liver Safety of RPV/TDF/FTC in Hepatitis C CoinfectionNeukam Karin 1*Espinosa Nuria 2Collado Antonio 3Delgado-Fernández Marcial 4Jiménez-Aguilar Patricia 5Rivero-Juárez Antonio 6Hontañón-Antoñana Victor 7Gómez-Berrocal Ana 8Ruiz-Morales Josefa 9Merino Dolores 10Carrero Ana 11Téllez Francisco 12Ríos María José 13Hernández-Quero José 14de Lagarde-Sebastián María 15Pérez-Camacho Inés 16Vera-Méndez Francisco 17Macías Juan 1Pineda Juan A. 1on behalf of the hEPAtic Study Group ¶1 \nUnit of Infectious Diseases and Microbiology, Hospital Universitario de Valme, Seville, Spain2 \nService of Infectious Diseases, Hospital Universitario Virgen del Rocío, Seville, Spain3 \nUnit of Infectious Diseases, Hospital Torrecárdenas, Almeria, Spain4 \nUnit of Infectious Diseases, Hospital Regional de Málaga. Malaga, Spain5 \nUnit of Infectious Diseases, Hospital Universitario Puerto Real, Puerto Real, Spain6 \nUnit of Infectious Diseases, Hospital Universitario Reina Sofía, Instituto de Investigación Biomédica de Córdoba (IMIBIC), Cordoba, Spain7 \nHIV Unit, Service of Internal Medicine, Hospital Universitario La Paz/IdiPAZ, Madrid, Spain8 \nService of Internal/Infectious Medicine, Hospital Universitario de la Princesa, Madrid, Spain9 \nUnit of Infectious Diseases, Hospital Universitario Virgen de la Victoria, Malaga, Spain10 \nUnit of Infectious Diseases, Complejo Hospitalario de Huelva, Huelva, Spain11 \nUnit of Infectious Diseases/HIV, Hospital General Universitario Gregorio Marañón, Madrid, Spain12 \nUnit of Infectious Diseases, Hospital La Línea, AGS Campo de Gibraltar, La Linea de la Concepcion, Spain13 \nUnit of Infectious Diseases, Hospital Virgen Macarena, Seville, Spain14 \nUnit of Infectious Diseases, Hospital Universitario San Cecilio, Granada, Spain15 \nHIV Unit. Hospital Universitario 12 de Octubre, Madrid, Spain16 \nTropical Medicine Unit, Hospital Poniente, El Ejido, Spain17 \nInfectious Medicine Section, Hospital Universitario Santa Lucia, Cartagena, SpainLin Wenyu EditorHarvard Medical School, UNITED STATESCompeting Interests: KN has received lecture fees from Janssen-Cilag, Roche, Bristol-Meyers Squibb and Merck Sharp & Dohme and has received research support from Janssen-Cilag, Bristol-Meyers Squibb, Merck Sharp & Dohme, Gilead Sciences and Abbott Pharmaceuticals. AC reports having received consultancy fees from Janssen-Cilag, Merck Sharp & Dohme, Bristol-Myers Squibb, Gilead Sciences, Pfizer and AbbVie. ARJ has received lecture fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, ViiV Healthcare and Roche. DM reports having received consultancy fees from Janssen Cilag, Merck Sharp & Dohme, Bristol-Myers Squibb, Gilead Sciences, AbbVie and ViiH Healthcare. JM has received lectures fees from Roche, Gilead Sciences, Merck Sharp & Dome, Boehringer Ingelheim, Janssen-Cilag and Bristol-Myers Squibb and consulting fees from Roche, Gilead Sciences, Boehringer Ingelheim, Bristol Myers-Squibb and Merck Sharp & Dome. JAP reports having received consulting fees from GlaxoSmithKline, Bristol-Myers Squibb, Abbott Pharmaceuticals, Gilead Sciences, Merck Sharp & Dohme, Schering-Plough, Janssen-Cilag and Boehringer Ingelheim. He has received research support from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Schering-Plough, Abbott Pharmaceuticals and Boehringer Ingelheim, and has received lecture fees from GlaxoSmithKline, Roche, Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Janssen-Cilag, Boehringer Ingelheim and Schering-Plough. All other authors: none to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.\n\nConceived and designed the experiments: KN JAP. Performed the experiments: KN NE A. Collado MD-F PJ-A AR-J VH-A AG-B JR-M DM A. Carrero FT MJR JH-Q ML-S IP-C FV-M JM JAP. Analyzed the data: KN JAP. Wrote the paper: KN JAP.\n\n¶ Membership of the hEPAtic Study Group is listed in the Acknowledgments.\n\n* E-mail: karin.neukam@gmail.com19 5 2016 2016 11 5 e01558427 1 2016 5 5 2016 © 2016 Neukam et al2016Neukam et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Objectives\nThe aim of this study was to evaluate the frequency of transaminase elevations (TE) and total bilirubin elevations (TBE) during the first year of therapy with a single tablet regimen including RPV/FTC/TDF (EPA) in HIV/hepatitis C virus (HCV)-coinfected subjects in clinical practice.\n\nMethods\nIn a retrospective analysis, HIV/HCV-coinfected subjects who started EPA at 17 centres throughout Spain were included as cases. Subjects who started an antiretroviral therapy (ART) other than EPA during the study period at the same hospitals were randomly selected as controls in a 1:2 ratio. Primary outcome variables were grade (G) 3–4 TE and G4 TBE.\n\nResults\nOf the 519 subjects included, 173 individuals started EPA. Nine (5.2%) subjects of the EPA group and 49 (14.2%) controls were naïve to ART. The median (Q1–Q3) follow-up was 11.2 (9.7–13.9) months. TE was observed in 2 [1.2%; 95% confidence interval (CI): 0.14%–4.1%] subjects receiving EPA and 11 (3.2%; 95%CI: 1.6%–5.6%) controls (p = 0.136), all events were G3. No patient discontinued ART due to TE. One (0.6%; 95%CI: 0.01%–3.1%) subject on EPA and 8 (2.3%; 95%CI: 1%–4.5%) subjects in the control group developed TBE (p = 0.141), without developing any other hepatic event during follow-up. Three (2.3%) subjects with cirrhosis versus 10 (3.1%) without cirrhosis showed G3-4 TE (p = 0.451).\n\nConclusion\nThe frequency of severe liver toxicity in HIV/HCV-coinfected subjects receiving EPA under real-life conditions is very low, TE were generally mild and did not lead to drug discontinuation. All these data suggest that EPA can be safely used in this particular subpopulation.\n\nhttp://dx.doi.org/10.13039/100005564Gilead Scienceshttp://dx.doi.org/10.13039/501100004587Instituto de Salud Carlos IIICP13/00187Neukam Karin Junta de AndalucíaRH-0024-2013Rivero-Juárez Antonio http://dx.doi.org/10.13039/501100004587Instituto de Salud Carlos IIIPrograma-I3SNSPineda Juan A. Junta de AndalucíaB-0037Macías Juan KN is the recipient of a Miguel Servet research grant from the Instituto de Salud Carlos III (grant number CP13/00187). AR-J is the recipient of a post-doctoral extension grant of the Fundación Progreso y Salud of the Junta de Andalucía (grant number RH-0024-2013). JM is the recipient of a grant from the Servicio Andaluz de Salud de la Junta de Andalucía (B-0037). JAP is the recipient of an intensification grant from the Instituto de Salud Carlos III (grant number Programa-I3SNS). This work was partially funded by Gilead Sciences SL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nAntiretroviral therapy (ART) may lead to hepatotoxic events, such as liver enzyme elevations, acute liver failure and death [1]. These events occur more frequently in HIV/HCV-coinfected subjects as compared to HIV monoinfected patients [2–6]. Liver toxicity at the beginning of the ART era was relatively common in HIV/HVC-coinfected subjects, with high risk of severe and eventually fatal hepatic events. Among non-nucleoside reverse transcriptase inhibitors (NNRTI), nevirapine demonstrated a higher risk of hepatotoxicity as compared to efavirenz (EFV) [7] and among protease inhibitors (PIs), tipranavir and higher doses of ritonavir were more toxic than other members of this drug family [8]. However, most of these drugs are not used nowadays. Conversely, newer antiretroviral drugs, such as boosted atazanavir (ATV) or darunavir (DRV), as well as integrase inhibitors, have been associated to a lower rate of toxic liver events in the clinical practice [2,6,9].\n\nRilpivirine is a newer NNRTI that is given coformulated with tenofovir and emtricitabine as a single tablet regimen (EPA) or as single drug along with other antiretroviral drugs. In a pooled analysis of the two pivotal phase III clinical trials on RPV, the hepatic safety profile in subjects with chronic viral hepatitis appeared somewhat poorer as compared to HIV-monoinfected subjects [10]. However, due to the relatively low frequency of HIV/HCV-coinfected patients in these studies, these figures need confirmation and additionally, these studies did not evaluate a single tablet regimen (STR). The STaR and SPIRIT clinical trials did evaluate these drugs in a STR, however, likely due to the low number of patients with HCV and/or HBV coinfection, no data on hepatic safety in this subpopulation is available [11,12]. Finally, no data on this topic based on routine clinical data are available. Consequently, studies on the hepatic safety of EPA, particularly those based on real-life experience, are warranted.\n\nThe aim of the present study was to evaluate the frequency of severe hepatic toxicity, defined as grade 3 or 4 transaminase elevations (TE) or grade 4 total bilirubin elevations (TBE), during the first 48 weeks of EPA in HIV-infected subject with chronic HCV infection.\n\nPatients and Methods\nStudy design and study population\nIn a retrospective case-control study, all patients consecutively seen at the Infectious Diseases Units of 17 Spanish hospitals between November 2012 and February 2014, were selected disregarding the presence or severity of hepatic toxicities if they fulfilled the following criteria: i) Older than 18 years; ii) HIV-1 infection, as diagnosed on the basis of the presence of serum HIV antibodies detected by EIA and western-blot; iii) Chronic HCV infection as confirmed by detectable plasma HCV-RNA; iv) Starting a new antiretroviral drug regimen; v) Exposure to study drugs for at least one week; vi) Clinical visits and blood tests available at baseline and, at least, after 12, 24 and 48 weeks thereafter, unless treatment was discontinued for any reason. In those patients who received therapy against HCV-infection, follow-up was stopped at the moment of anti-HCV treatment initiation. Likewise, treatment interruption due to any reason required immediate stop of follow-up resulting to drug exposure being reflected by the time of follow-up.\n\nART Regimens\nOut of the overall population included in the database, patients naïve for RPV were selected in a 1:2 (case/control) ratio according to the following regimens: i) Cases (EPA group): All patients who had started EPA during the study period and ii) Controls: Subjects who initiated any ART that did not include RPV during the study period. The control group was randomly selected out of all the patients with ART changes or initiation of one or more new antiretroviral drugs in the participant hospitals.\n\nDefinition of liver enzyme and bilirubin elevations\nGrade 3 TE were defined as elevations of alanine-aminotransferase (ALT) or aspartate-aminotransferase (AST) between 5 and 10 times above the upper level of normality (ULN) among patients who had normal baseline levels. Grade 4 TE were defined as ALT or AST increases greater than 10 times the ULN. In patients with elevated baseline ALT or AST levels, 3.5- to 5-fold increase from baseline levels were considered grade 3 TE and greater than 5-fold elevations were defined as grade 4 TE. Grade 1 and grade 2 TE was analysed in those patients with baseline ALT and AST values below the ULN and were defined as ALT or AST levels 1.25 to 2.5-fold and 2.5 to 5-fold above the ULN, respectively. Grade 4 TBE were defined as increases of total bilirubin equal or greater than 5 mg/dL. Likewise, grade 1, grade 2 and grade 3 TBE were considered when total bilirubin levels were ≥1.1 mg/dL to <1.6 mg/dL, ≥1.6 mg/dL to <2.6 mg/dL and ≥2.6 mg/dL to <5 mg/dL, respectively [13].\n\nLiver fibrosis assessment\nBaseline advanced fibrosis and cirrhosis was diagnosed when stage 3 (F3) or stage 4 (F4) according to the Scheuer index was detected in a liver biopsy [14]. If biopsy was not available, transient elastography cut-off values of ≥9.5 kPa for advanced fibrosis and ≥14.6 kPa for cirrhosis were applied [15,16]. In patients without liver biopsy or liver stiffness measurement, advanced fibrosis was excluded when baseline FIB-4 index was ≤1.45 and diagnosed when baseline FIB-4 values were ≥3.25 [17]. Both liver biopsy and transient elastography were considered valid if obtained within six months before or after ART initiation. In the case of F4, a 12 month-period before ART initiation was allowed.\n\nStatistical analysis\nThe frequency of subjects who present grade 3 or 4 TE and/or grade 4 TBE, as well as of those who discontinue ART due to adverse events, were assessed and the 95% confidence interval (CI) was calculated. Comparisons of continuous variables were carried out by means of the Student’s t-test or the Mann-Whitney U-test, when applicable. To compare categorical variables, the χ2 test or the Fisher’s exact test were used. In order to compare the CD4 cell counts and the HIV viral loads at baseline and the end of follow-up, the Wilcoxon Signed Rank test and the McNemar test were applied, respectively. A univariate analysis was carried out to identify baseline factors associated with hepatic toxicity. Subsequently, a multivariate logistic regression analysis was applied, adjusting for age, sex, as well as those factors that were associated with a p<0.2 in the univariate analysis. Statistical analysis and control randomization was performed using the SPSS statistical software package release 22.0 (IBM, Chicago, IL, USA) and R i386 3.0.1 (The R Foundation for Statistical Computing, Boston, USA).\n\nEthical aspects\nThe study was designed and performed according to the Helsinki declaration and was approved by the Autonomic Ethics Committees of Andalusia (Comité Coordinador de Ética de la Investigación Biomédica de Andalucía, CCEIBA). Patients gave their written informed consent.\n\nResults\nCharacteristics of the patients\nOne hundred and seventy-three patients who initiated EPA were included in this study. Accordingly, 346 controls were randomly selected. Median (IQR) age was 47.6 (43.7–50.8) years and 427 (82.3%) were male. The demographic and baseline characteristics of the study population are listed in Table 1. Table 2 lists the reasons for ART initiations by treatment group.\n\n10.1371/journal.pone.0155842.t001Table 1 Baseline characteristics of the study population (n = 519).\nEPA: RPV/TDF/FTC group.\n\nCharacteristic\tStudy groups\tp\t\n\tEPA group\tControl group\t\t\n\tn = 173\tn = 346\t\t\nMale gender, n (%)\t146 (84.4)\t281 (81.2)\t0.371\t\nAge*, years\t47.9 (44.5–51)\t47 (43.2–50.7)\t0.103\t\nIntravenous drug use, n (%)\t138 (79.8)\t279 (80.6)\t0.815\t\nAlcohol intake >50 g/day, n (%)\t19 (11)\t50 (14.5)\t0.273\t\nHBsAg(+), n (%)\t5 (3.1)\t4 (1.2)\t0.129\t\nCDC clinical category C, n (%)\t51 (29.5)\t127 (36.7)\t0.102\t\nHIV RNA >1000 copies/mL1, n (%)\t26 (15)\t108 (31)\t<0.001\t\nCD4 cell counts*, cells/mL\t515 (332–764)\t398 (240–589)\t<0.001\t\nPlasma HCV RNA*, log10\nIU/mL\t6.16 (5.67–6.78)\t6.19 (5.72–6.63)\t0.482\t\nHCV genotype2, n (%)\t\t\t0.849\t\n 1\t108 (62.5)\t214 (62.8)\t\t\n 2\t1 (0.6)\t2 (0.6)\t\t\n 3\t26 (15.8)\t50 (14.7)\t\t\n 4\t30 (18.2)\t74 (21.7)\t\t\n 6\t0\t1 (0.3)\t\t\nTreatment naïve for anti-HCV\t99 (57.2)\t246 (71.1)\t0.002\t\ntherapy, n (%)\t\t\t\t\nALT*, IU/mL\t48 (33–69)\t47 (31.8–75.3)\t0.795\t\nAST*, IU/mL\t48 (33–69)\t47 (31–70.3)\t0.535\t\nTotal bilirubin*, mg/dL\t0.52 (0.4–0.93)\t0.6 (0.41–0.9)\t0.146\t\nAdvanced fibrosis3, n (%)\t61 (37.9)\t145 (46.6)\t0.07\t\nCirrhosis4, n (%)\t42 (26.6)\t91 (30.2)\t0.413\t\n*Median (Q1-Q3).\n\n1: determined in those patients with detectable baseline HIV RNA (46 cases and 191 controls)\n\n2: available in 165 cases and 341 controls\n\n3: available in 161 cases and 311 controls\n\n4: available in 158 cases and 301 controls.\n\n10.1371/journal.pone.0155842.t002Table 2 Reasons for initiation of antiretroviral therapy (ART) within the RPV/TDF/FTC group (EPA) and the control group; overall p <0.001.\nReason\tEPA group\tControl group\t\n\tn = 173\tn = 346\t\nNaïve for ART\t9 (5.2)\t49 (14.2)\t\nReinitiation after therapy discontinuation\t10 (5.8)\t37 (10.7)\t\nSimplification\t49 (28.3)\t50 (14.5)\t\nVirological failure\t10 (5.8)\t49 (14.2)\t\nAdverse events\t69 (39.9)\t98 (28.3)\t\nInteractions with future anti-HCV treatment\t9 (5.2)\t28 (8.1)\t\nInteractions with other drugs\t3 (1.7)\t12 (3.5)\t\nIntensification\t0 (0)\t5 (1.4)\t\nOther\t14 (8.1)\t18 (5.2)\t\nART regimens in the control group\nTriple therapy with a NRTI backbone among the controls was mainly based on TDF/FTC, which was administered to 165 (47.7%) patients. NRTI-sparing regimens were administered to 92 (26.6%) individuals and abacavir (ABC)/ lamivudine (3TC) were provided to 59 (17.1%) subjects. A total of 475 drug initiations were registered in the control group. The newly introduced drugs are summarized in Table 3.\n\n10.1371/journal.pone.0155842.t003Table 3 Newly introduced antiretroviral therapy (ART) in the control group (n = 346).\nAntiretroviral drug\tInitiated ART,\t\n\tn (%)\t\nNucleoside analogue reverse transcriptase inhibitors\t\t\nTenofovir/emtricitabine\t75 (21.7)\t\nAbacavir/lamivudine\t43 (12.4)\t\nOther NRTI combinations\t38 (11)\t\nRitonavir(r)-boosted protease inhibitors\t\t\nLopinavir/r\t15 (4.3)\t\nAtazanavir/r\t48 (13.9)\t\nDarunavir/r\t114 (32.9)\t\nNon-nucleoside analogue reverse transcriptase inhibitors\t\t\nEfavirenz\t33 (9.5)\t\nNevirapine\t10 (2.9)\t\nEtravirine\t30 (8.7)\t\nIntegrase inhibitors\t\t\nRaltegravir\t45 (13)\t\nEntry inhibitors\t\t\nMaraviroc\t24 (6.9)\t\nFollow-up\nThe median (IQR) follow-up of the study patients was 11.2 (6.2–12.4) months for the EPA group and 11.2 (7.8–12.5) months for the control group (p = 0.856), 362 (70%) subjects reached the scheduled end of follow-up. The numbers of patients who did not reach week 12 of therapy were 8 (4.6%) for the EPA group and 27 (7.8%) for the control group (p = 0.173). Therapy against HCV infection was initiated after 4.9 (3–9.7) months in the EPA group and 3.8 (2.5–6.8) months (p = 0.269). The detailed outcome for the two study populations is shown in Fig 1. The number of patients with plasma HIV RNA below 50 copies/mL at baseline versus after 12 months of follow-up was 133 (76.9%) versus 91 (89.2%; p = 0.263) among the patients who received EPA and 170 (49.1%) versus 169 (84.5%; p<0.001) in the control group (p = 0.173), respectively. Median (IQR) CD4 cell counts at baseline versus the end of follow-up were 515 (332–764) cells/mL versus 606 (362–819) cells/mL (p = 0.092) in the EPA group and 398 (240–589) cells/mL versus 465 (295–696) cells/mL (p<0001) among the controls.\n\n10.1371/journal.pone.0155842.g001Fig 1 Patient disposition and treatment outcome according to study group.\nEPA: RPV/TDF/FTC group. None of the outcomes showed statistically significant differences between the two groups.\n\nLiver safety\nGrade 3 TE was observed in 2 (1.2%; 95%CI: 0.14%-4.1%) individuals receiving EPA and in 11 (3.2%; 95%CI: 1.6%-5.6%) patients of the control group (p = 0.136). All grades of TE according to the study group are summed up in Table 4. No episode of grade 4 TE during the study period was detected. In the EPA group, grade 3 TE episodes were observed after 24.4 and 25.6 weeks of therapy, respectively. In the control group, the time (IQR) to grade 3 TE was 16.4 (13–37.8) weeks. Among the subgroup of patients who initiated the new ART due to simplification, adverse events to prior ART or due to interactions, 2 (1.7%) patients who received EPA and 6 (3.8%) subjects of the control group showed grade 3 TE (p = 0.251).\n\n10.1371/journal.pone.0155842.t004Table 4 Frequency of different grades of transaminase elevations and total bilirubin elevations according to study group.\nEvent\tControl group\tEPA group\tp\t\n\tn = 346\tn = 173\t\t\nTransaminase elevations\t\t\t\t\n Grade 1*\t51 (34)\t28 (27.3)\t0.621\t\n Grade 2*\t20 (13.8)\t4 (6)\t0.095\t\n Grade 3\t11 (3.2)\t2 (1.2)\t0.136\t\n Grade 4\t0\t0\t-\t\nTotal bilirubin elevations\t\t\t\t\n Grade 1\t28 (9.9)\t17 (12)\t0.504\t\n Grade 2\t22 (7)\t7 (4.4)\t0.265\t\n Grade 3\t26 (7.9)\t3 (1.8)\t0.007\t\n Grade 4\t8 (2.3)\t1 (0.6)\t0.141\t\n*Determined in the subpopulation who showed AST and ALT values below the upper limit of normality at baseline.\n\nGrade 4 TBE were identified in 1 (0.6%; 95%CI: 0.01%-3.1%) patients on EPA and in 8 (2.3%; 95%CI: 1%-4.5%; p = 0.141) subjects of the control group. Of the latter, 7 patients received ritonavir-boosted atazanavir as part of their ART regimen. Other TBE grades according to study group are shown in Table 4. No patient discontinued ART due to liver toxicity and none of those individuals who developed grade 3 or 4 TE or grade 4 TBE developed other hepatic events during the follow-up.\n\nFourteen (8%; 95%CI: 4.4%-13%) of the EPA group and 18 (5.2%; 95%CI: 3.1%-8.1%) of the control group discontinued therapy due to any adverse event. Hepatic decompensations during the study period were observed in one (0.6%; 95%CI: 0.001%-3.2%) patient who received EPA and in 6 (1.7%; 95%CI: 0.6%-3.7%) subjects from the control group. The patient receiving EPA presented hepatic encephalopathy and portal hypertensive gastrointestinal bleeding. The episodes observed within the control group were: hepatic encephalopathy (5 patients), ascites (two patients) and portal hypertensive gastrointestinal bleeding (one patient). One (0.6%) patient of the EPA group and 8 (2.3%) patients of the control group died during the period of follow-up. Death due to hepatic events was observed in 1 (0.6%) patient of the EPA group and 2 (0.2%) patients of the control group (p = 0.741).\n\nA total of 3 (1.5%) subjects with advanced fibrosis (F≥3) versus 10 (3.8%) without advanced fibrosis (F<3) showed grade 3 or 4 TE (p = 0.129). The corresponding figures for subjects with and without cirrhosis were 3 (2.3%) subjects and 10 (3.1%) patients, respectively (p = 0.451). The proportions of severe TE according to liver damage and within the study groups are shown in Fig 2.\n\n10.1371/journal.pone.0155842.g002Fig 2 Grade 3 transaminase elevations (TE) according to the presence of advanced fibrosis (2A) or cirrhosis (2B) at baseline by treatment group. EPA: RPV/TDF/FTC group.\n\nPredictors of grade 3 or 4 TE and grade 4 TBE\nIn the multivariate analysis, no predictors of grade 3 or 4 TE could be identified (Table 5). The initiation of ritonavir-boosted atazanavir was the only factor independently associated with grade 4 TBE (Table 6).\n\n10.1371/journal.pone.0155842.t005Table 5 Predictors of grade 3 or 4 transaminase elevations (TE).\n\tn\tGrade 3 or 4\tp\tAOR\tp\t\n\t\tTE, n (%)\tuni-variate\t(95% confidence interval)\tmulti-variate\t\nAge*1\t\t\t\t\t\t\n <47.6 years\t259\t3 (3.1)\t0.360\t0.997\t0.949\t\n ≥47.6 years\t260\t5 (5.2)\t\t(0.913–1.088)\t\t\nSex\t\t\t\t\t\t\n Male\t427\t12 (2.8)\t0.297\t2.792\t0.33\t\n Female\t92\t1 (1.1)\t\t(0.354–22.04)\t\t\nAlcohol intake\t\t\t\t\t\t\n <50 g/day\t450\t10 (2.2)\t0.243\t\t\t\n ≥50 g/day\t69\t3 (4.3)\t\t\t\t\nALT levels*\t\t\t\t\t\t\n ≥40 IU/mL\t329\t10 (3)\t0.236\t\t\t\n <40 IU/mL\t190\t3 (1.6)\t\t\t\t\nCDC category\t\t\t\t\t\t\n C\t178\t4 (2.2)\t0.522\t\t\t\n A or B\t341\t9 (2.6)\t\t\t\t\nUndetectable HIV\t\t\t\t\t\t\nRNA\t\t\t\t\t\t\n Yes\t282\t6 (2.1)\t0.549\t\t\t\n No\t237\t7 (3)\t\t\t\t\nAdvanced fibrosis\t\t\t\t\t\t\n Yes\t206\t3 (1.5)\t0.129\t3.312\t0.087\t\n No\t266\t10 (3.8)\t\t(0.84–13.049)\t\t\nCD4 cell count*2\t\t\t\t\t\t\n <350 cells/mL\t186\t6 (1.8)\t0.148\t0.999\t0.405\t\n ≥350 cells/mL\t327\t7 (3.8)\t\t(0.997–1.001)\t\t\nEPA treatment\t\t\t\t\t\t\n Yes\t173\t2 (1.2)\t0.136\t0.337\t0.169\t\n No\t346\t11 (3.2)\t\t(0.071–1.589)\t\t\nStart of a NRTI\t\t\t\t\t\t\n Yes\t194\t6 (3.1)\t0.348\t\t\t\n No\t325\t7 (2.2)\t\t\t\t\nStart of a PI/r\t\t\t\t\t\t\n Yes\t177\t6 (3.4)\t0.258\t\t\t\n No\t342\t7 (2)\t\t\t\t\nStart of raltegravir\t\t\t\t\t\t\n Yes\t45\t1 (2.2)\t0.687\t\t\t\n No\t474\t12 (2.5)\t\t\t\t\nStart of a maraviroc\t\t\t\t\t\t\n Yes\t24\t1 (4.2)\t0.464\t\t\t\n No\t495\t12 (2.4)\t\t\t\t\n1Categorized by median\n\n2available in 513 patients\n\n*entered as continuous variable in the multivariate analysis. AOR: adjusted odd´s ratio; EPA: RPV/TDF/FTC; PI/r: ritonavir-boosted protease inhibitor; NRTI: nucleos(t)ide reverse transcriptase inhibitors.\n\n10.1371/journal.pone.0155842.t006Table 6 Predictors of grade 4 total bilirubin elevations (TBE).\n\tn\tGrade 4\tp\tAOR\tp\t\n\t\tTBE, n(%)\tuni-variate\t(95% confidence interval)\tmulti-variate\t\nAge*1\t\t\t\t\t\t\n ≥47.6 years\t260\t3 (1.2)\t0.25\t0.988\t0.832\t\n <47.6 years\t259\t6 (2.3)\t\t(0.881–1.107)\t\t\nSex\t\t\t\t\t\t\n Male\t427\t8 (1.9)\t0.506\t1.874\t0.561\t\n Female\t92\t1 (1.1)\t\t(0.223–15.75)\t\t\nAlcohol intake\t\t\t\t\t\t\n <50 g/day\t450\t9 (2)\t0.274\t\t\t\n ≥50 g/day\t69\t0 (0)\t\t\t\t\nALT levels*\t\t\t\t\t\t\n ≥40 IU/mL\t329\t7 (2.1)\t0.366\t\t\t\n <40 IU/mL\t190\t2 (1.1)\t\t\t\t\nCDC category\t\t\t\t\t\t\n C\t178\t2 (1.1)\t0.652\t\t\t\n A or B\t341\t7 (2.1)\t\t\t\t\nUndetectable HIV\t\t\t\t\t\t\nRNA\t\t\t\t\t\t\n Yes\t282\t7 (2.5)\t0.138\t\t\t\n No\t237\t2 (0.8)\t\t\t\t\nAdvanced fibrosis\t\t\t\t\t\t\n Yes\t206\t5 (2.4)\t0.346\t\t\t\n No\t266\t4 (1.5)\t\t\t\t\nCD4 cell count*2\t\t\t\t\t\t\n <350 cells/mL\t186\t3 (1.6)\t0.577\t\t\t\n ≥350 cells/mL\t327\t6 (1.8)\t\t\t\t\nEPA treatment\t\t\t\t\t\t\n Yes\t173\t1 (0.6)\t0.141\t0.432\t0.455\t\n No\t346\t8 (2.3)\t\t(0.048–3.915)\t\t\nStarting NRTIs\t\t\t\t\t\t\n Yes\t194\t4 (2.1)\t0.451\t\t\t\n No\t325\t5 (1.5)\t\t\t\t\nStarting ATV/r\t\t\t\t\t\t\n Yes\t48\t5 (10.4)\t0.001\t6.324\t0.014\t\n No\t471\t4 (0.8)\t\t(1.447–27.63)\t\t\nStart of DRV/r or\t\t\t\t\t\t\nLPV/r\t\t\t\t\t\t\n Yes\t129\t0 (0)\t0.075\t0 (0)\t0.996\t\n No\t390\t9 (2.3)\t\t\t\t\nStarting raltegravir\t\t\t\t\t\t\n Yes\t45\t0 (0)\t0.439\t\t\t\n No\t474\t9 (1.9)\t\t\t\t\nStarting maraviroc\t\t\t\t\t\t\n Yes\t24\t0 (0)\t0.651\t\t\t\n No\t495\t9 (1.8)\t\t\t\t\n1Categorized by median\n\n2available in 513 patients\n\n*entered as continuous variable in the multivariate analysis. AOR: adjusted odd´s ratio; EPA: RPV/TDF/FTC; ATV/r: ritonavir-boosted atazanavir; DRV/r: ritonavir-boosted darunavir; LPV/r: ritonavir-boosted lopinavir; NRTI: nucleos(t)ide reverse transcriptase inhibitors\n\nDiscussion\nThe present study shows that the frequency of grade 3 or 4 TE or grade 4 TBE is very low in HIV/HCV-coinfected patients who receive EPA in the clinical practice. Furthermore, all TE were grade 3 and these hepatotoxic events did not lead to treatment discontinuation.\n\nTo date, the little data available on hepatotoxic events in HIV/HCV-coinfected patients who receive RPV is derived from clinical trials. On the one hand, the rates of grade 3 or 4 ALT elevations reported herein are somewhat lower than what was reported in the TMC278-C204 phase II clinical trial, where a frequency of 6% was observed in a population that consisted mainly of patients without HCV coinfection [18]. However, the presence of elevated baseline ALT or AST levels was not taken into account for the definition of TE and therefore, comparisons of these results with those from the present study are difficult to interpret. On the other hand, in a pooled analysis of data derived from the ECHO and the THRIVE clinical trials conducted by Nelson et al [10], TE were among the most frequent adverse events in HCV or hepatitis B virus (HBV)-coinfected subjects receiving RPV in combination with TDF/FTC. In this context, 20.4% of the patients showed grade 2–4 AST elevations and 33.3% of the subjects presented grade 2–3 ALT elevations. However, as it was also the case for TMC278-C204, the number of patients with viral hepatitis was very low in these trials, with only 49 HCV and/or HBV-coinfected patients at baseline and consequently, inferential statistics comparing grade 2–4 TE between patients with and without viral hepatitis were not possible. Furthermore, ART was not applied as a single tablet regimen in these trials and no analysis to distinguish between grade 2 and 3–4 TE was conducted, therefore, the results cannot be compared with the present work. Although results of the STaR and the SPIRIT trials are available, in which EPA was given in a single-tablet regimen in combination with food, unfortunately no specific data on TE or TBE have been published for the coinfected subpopulation [11,12]. Also, over 96% of the participants in these trials did not show HCV coinfection. In contrast, the study described herein includes a high number of HIV-infected subjects with active HCV infection at baseline. Importantly, the frequencies of grade 3 or 4 TE and grade 4 TBE in patients receiving EPA were not only low, they also tended to be under to what is observed for commonly administered ART, as represented by the control group.\n\nApart from the low frequency of hepatotoxic events, it is important to underline that TE episodes in patients who were given EPA were mild. In this context, no grade 4 TE were observed. Additionally, none of the TE resulted in drug discontinuation. This is an important finding, since patients in a real-life setting may be less motivated to tolerate adverse events and regimens may be switched earlier. Of note, the rate of discontinuations due to liver adverse events or liver-related death was generally low in the EPA group. Finally, the presence of advanced fibrosis or cirrhosis was not associated with an increased risk of grade 3 or 4 TE or grade 4 TBE in patients receiving EPA, which stands in accordance with earlier findings [7,9,19,20]. All this adds up to the safety of EPA in patients with HCV coinfection and is especially important since hepatic safety in cirrhotic patients is crucial for drug selection in this population.\n\nSeveral studies [7,9,21–24] have assessed the impact of different third agents used in combination with a backbone of two NRTI in subjects with chronic viral hepatitis. These studies found that EFV [7,9] and nevirapine [7] are associated with 5.9–6.6% and 11% of grade 3–4 TE and 2.2–2.6% and 0.8% of grade 4 TBE, PI/r [7,9,21–24] with 8.1–10.5% of grade 3–4 TE and 3.7–15% of grade 4 TBE and raltegravir (RAL) [19] with 9.3% of grade 3–4 TE and 1.9% of grade 4 TBE. Although it is not possible to draw definite conclusions from comparing different studies, given that the cited studies were designed and conducted similar to the present work, EPA appears to be less hepatotoxic than the drugs examined in the other studies.\n\nThis study has limitations. First, due to the retrospective character of the study, self-limited hypertransaminasemia may have passed undetected. However, a adequate follow-up was inclusion criteria for this study and it can therefore be ruled out that an episode of severe liver toxicity has gone unnoticed. Second, drugs that were approved after the end of the inclusion period, as dolutegravir and elvitegravir/cobicistat, were not administered to the control group. Still, this study was not aimed to compare specific regimens of the control group and further studies are warranted to clarify this issue.\n\nIn conclusion, the frequency of severe liver toxicity in HIV-infected subjects with chronic hepatitis C receiving EPA is very low in the clinical practice. Taken together with the findings that TE episodes in the EPA group were generally mild and did not lead to drug discontinuation, all these data suggest that EPA can be safely used in this particular subpopulation.\n\nOther members of the hEPAtic study group were: Teresa Aldámiz-Echevarría, José Ramón Arribas López, Otilia Bisbal, Javier Borrallo Torrejón, Ignacio de los Santos-Gil, Marta Díaz Menéndez, Cristina Díez, Lourdes Domínguez, Elisa Fernández-Fuertes, Juan González-García, Juan Carlos López, Juan Macías Sánchez, María Mancebo Hernández, Onofre Martínez, Lorena Martínez Fernández, Mariano Matarranz, Pilar Miralles, María Luisa Montes Ramírez, Patricia Monje Agudo, Alberto Romero Palacios, Francisco Parras, Federico Pulido, Francisco Tejerina, Antonio Vergara de Campos.\n==== Refs\nReferences\n1 Pineda JA , Macias J , Mira JA , Merchante N , del Valle J , Neukam KI . (2010 ) HAART and the liver: friend or foe? \nEur J Med Res ; 15 : 93 –96 . 20452892 \n2 Di Biagio A , Nicolini LA , Lorenzini P , Puoti M , Antinori A , Cozzi-Lepri A , et al (2014 ) Liver enzyme elevation during darunavir-based antiretroviral treatment in HIV-1-infected patients with or without hepatitis C coinfection: data from the ICONA foundation cohort . HIV Clin Trials ; 15 : 151 –160 \n10.1310/hct1504-151 \n25143024 \n3 Ha B , Wine B , Rodriguez-Alcantra F , Shaefer M . (2012 ) Hepatic safety profile of fosamprenavir-containing regimens in HIV-1-infected patients with or without hepatitis B or C coinfection . HIV Clin Trials ; 13 : 171 –177 . 10.1310/hct1303-171 \n22592097 \n4 Van Welzen B , Mudrikova T , Arends J , Hoepelman A . (2012 ) No increased risk of hepatotoxicity in long-term use of nonnucleoside reverse transcriptase inhibitors in HIV-infected patients . HIV Med ; 13 : 448 –452 . 10.1111/j.1468-1293.2012.00995.x \n22413955 \n5 Lapadula G , Costarelli S , Chatenoud L , Castelli F , Astuti N , Di Giambenedetto S , et al (2015 ) Risk of Liver Enzyme Elevation during Treatment with Ritonavir-boosted Protease Inhibitors among HIV-monoinfected and HIV/HCV Coinfected Patients . J Acquir Immune Defic Syndr \n69 : 312 –318 . 10.1097/QAI.0000000000000585 \n25723139 \n6 Vispo E , Fernández-Montero JV , Labarga P , Barreiro P , Soriano V . (2013 ) Low risk of liver toxicity using the most recently approved antiretroviral agents but still increased in HIV-hepatitis C virus coinfected patients . AIDS ; 27 : 1187 –11888 . 10.1097/QAD.0b013e32835cb815 \n23739226 \n7 Macias J , Neukam K , Mallolas J , Lopez-Cortes LF , Carton JA , Domingo P , et al (2012 ) Liver toxicity of initial antiretroviral drug regimens including two nucleoside analogs plus one non-nucleoside analog or one ritonavir-boosted protease inhibitor in HIV/HCV-coinfected patients . HIV Clin Trials ; 13 : 61 –69 . 10.1310/hct1302-61 \n22510353 \n8 Jones M , Nunez M . (2011 ) HIV and hepatitis C co-infection: the role of HAART in HIV/hepatitis C virus management . Curr Opin HIV AIDS ; 6 : 546 –552 . 10.1097/COH.0b013e32834bcbd9 \n22001896 \n9 Neukam K , Mira JA , Ruiz-Morales J , Rivero A , Collado A , Torres-Cornejo A \net al (2011 ) Liver toxicity associated with antiretroviral therapy including efavirenz or ritonavir-boosted protease inhibitors in a cohort of HIV/hepatitis C virus co-infected patients . J Antimicrob Chemother ; 66 : 2605 –2614 . 10.1093/jac/dkr357 \n21903660 \n10 Nelson M , Amaya G , Clumeck N , Arns da Cunha C , Jayaweera D , Junod P , et al (2012 ) Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials . J Antimicrob Chemother ; 67 : 2020 –2028 . 10.1093/jac/dks130 \n22532465 \n11 Cohen C , Wohl D , Arribas JR , Henry K , Van Lunzen J , Bloch M , et al (2014 ) Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults . AIDS ; 28 : 989 –997 . 10.1097/QAD.0000000000000169 \n24508782 \n12 Palella FJ Jr, Fisher M , Tebas P , Gazzard B , Ruane P , Van Lunzen J , et al (2014 ) Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants . AIDS ; 28 : 335 –344 . 10.1097/QAD.0000000000000087 \n24670520 \n13 World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach (2010). Available at http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf. Last date accessed: 20th of December 2015.\n14 Scheuer PJ . (1991 ) Classification of chronic viral hepatitis: a need for reassessment . J Hepatol ; 13 : 372 –374 . 1808228 \n15 Castéra L , Vergniol J , Foucher J , Le Bail B , Chanteloup E , Haaser M , et al (2005 ) Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C . Gastroenterology ; 128 : 343 –350 . 15685546 \n16 Vergara S , Macias J , Rivero A , Gutiérrez-Valencia A , González-Serrano M , Merino D , et al (2007 ) The use of transient elastometry for assessing liver fibrosis in patients with HIV and hepatitis C virus coinfection . Clin Infect Dis ; 45 : 969 –974 . 17879910 \n17 Sterling RK , Lissen E , Clumeck N , Sola R , Correa MC , Montaner J , et al (2006 ) Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection . Hepatology ; 43 : 1317 –1325 . 16729309 \n18 Wilkin A , Pozniak AL , Morales-Ramirez J , Lupo SH , Santoscoy M , Grinsztejn B , et al (2012 ) Long-term efficacy, safety, and tolerability of rilpivirine (RPV, TMC278) in HIV type 1-infected antiretroviral-naive patients: week 192 results from a phase IIb randomized trial . AIDS Res Hum Retroviruses ; 28 : 437 –446 . AIDS 2014; 28: 335–344. 10.1089/AID.2011.0050 \n21902621 \n19 Macias J , Neukam K , Portilla J , Iribarren JA , de LS I , Rivero A , et al (2011 ) Liver tolerance of raltegravir-containing antiretroviral therapy in HIV-infected patients with chronic hepatitis C . J Antimicrob Chemother ; 66 : 1346 –1350 . 10.1093/jac/dkr083 \n21398295 \n20 Casado JL , Mena A , Bañón S , Moreno A , Castro A , Perez-Elías MJ , et al (2014 ) Efficacy and safety of etravirine-containing regimens in a large cohort of HIV/HCV coinfected patients according to liver fibrosis . J Int AIDS Soc ; 17 (4 Suppl 3): 19574 \n10.7448/IAS.17.4.19574 \n25394081 \n21 Macias J , Orihuela F , Rivero A , Viciana P , Marquez M , Portilla J , et al (2009 ) Hepatic safety of tipranavir plus ritonavir (TPV/r)-based antiretroviral combinations: effect of hepatitis virus co-infection and pre-existing fibrosis . J Antimicrob Chemother ; 63 : 178 –183 . 10.1093/jac/dkn429 \n18952618 \n22 Merchante N , Lopez-Cortes LF , Delgado-Fernandez M , Rios-Villegas MJ , Marquez-Solero M , Merino D , et al (2011 ) Liver toxicity of antiretroviral combinations including fosamprenavir plus ritonavir 1400/100 mg once daily in HIV/hepatitis C virus-coinfected patients . AIDS Patient Care STDS ; 25 : 395 –402 . 10.1089/apc.2011.0109 \n21688986 \n23 Mira JA , Macias J , Giron-Gonzalez JA , Merino D , Gonzalez-Serrano M , Jimenez-Mejias ME , et al (2006 ) Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C . J Antimicrob Chemother ; 58 : 140 –146 . 16720565 \n24 Pineda JA , Santos J , Rivero A , Abdel-Kader L , Palacios R , Camacho A , et al (2008 ) Liver toxicity of antiretroviral combinations including atazanavir/ritonavir in patients co-infected with HIV and hepatitis viruses: impact of pre-existing liver fibrosis . J Antimicrob Chemother ; 61 : 925 –932 . 10.1093/jac/dkn045 \n18276600\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(5)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D000998:Antiviral Agents; D001663:Bilirubin; D016022:Case-Control Studies; D060085:Coinfection; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D005355:Fibrosis; D015658:HIV Infections; D016174:Hepacivirus; D006526:Hepatitis C; D006760:Hospitalization; D006801:Humans; D008099:Liver; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000068696:Rilpivirine; D013030:Spain; D013607:Tablets; D000068698:Tenofovir; D000637:Transaminases",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0155842",
"pmc": null,
"pmid": "27195797",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "18276600;15685546;21398295;21688986;22001896;18952618;24670520;21903660;22592097;22510353;20452892;16729309;25143024;21902621;25723139;1808228;25394081;24508782;22532465;16720565;22413955;23739226;17879910",
"title": "Hepatic Safety of Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate Fixed-Dose Single-Tablet Regimen in HIV-Infected Patients with Active Hepatitis C Virus Infection: The hEPAtic Study.",
"title_normalized": "hepatic safety of rilpivirine emtricitabine tenofovir disoproxil fumarate fixed dose single tablet regimen in hiv infected patients with active hepatitis c virus infection the hepatic study"
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"companynumb": "ES-CIPLA LTD.-2016ES06033",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EMTRICITABINE"
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{
"abstract": "Global rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana.\n\n\n\nIn this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [<37 weeks' gestation], small for gestational age [SGA; less than the tenth percentile of birthweight by gestational age], or neonatal death [within 28 days of age]) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks' gestation], and very SGA [less than the third percentile of birthweight by gestational age]). We fitted log-binomial regression models, controlling for maternal age, gravidity, and education, to estimate adjusted risk ratios (aRRs).\n\n\n\nOur analysis included 1729 pregnant women who initiated dolutegravir-based ART and 4593 who initiated efavirenz-based ART. The risk for any adverse birth outcome among women on dolutegravir versus efavirenz was similar (33·2% vs 35·0%; aRR 0·95, 95% CI 0·88-1·03), as was the risk of any severe birth outcome (10·7% vs 11·3%; 0·94, 0·81-1·11). We found no significant differences by regimen in the individual outcomes of stillbirth, neonatal death, preterm birth, very preterm birth, SGA, or very SGA.\n\n\n\nAdverse birth outcomes were similar among pregnant women who initiated dolutegravir-based and efavirenz-based ART. Dolutegravir-based ART can be safely initiated in pregnancy.\n\n\n\nNational Institutes of Health.",
"affiliations": "Beth Israel Deaconess Medical Center, Division of Infectious Disease, Boston, MA, USA. Electronic address: rzash@bidmc.harvard.edu.;Center for Biostatistics in AIDS Research, Harvard TH Chan School of Public Health, Boston, MA, USA.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Botswana Ministry of Health, Gaborone, Botswana.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.;Medical Genetics Unit, MassGeneral Hospital for Children, Boston, MA, USA.;Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.;Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA.",
"authors": "Zash|Rebecca|R|;Jacobson|Denise L|DL|;Diseko|Modiegi|M|;Mayondi|Gloria|G|;Mmalane|Mompati|M|;Essex|Max|M|;Gaolethe|Tendani|T|;Petlo|Chipo|C|;Lockman|Shahin|S|;Holmes|Lewis B|LB|;Makhema|Joseph|J|;Shapiro|Roger L|RL|",
"chemical_list": "D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir; C098320:efavirenz",
"country": "England",
"delete": false,
"doi": "10.1016/S2214-109X(18)30218-3",
"fulltext": "\n==== Front\n10161366542402Lancet Glob HealthLancet Glob HealthThe Lancet. Global health2214-109X2988031010.1016/S2214-109X(18)30218-3nihpa975563ArticleComparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study Zash Rebecca MDJacobson Denise L PhDDiseko Modiegi BAMayondi Gloria BScMmalane Mompati MDEssex Max Prof.PhDGaolethe Tendani MDPetlo Chipo BALockman Shahin MDHolmes Lewis B MDMakhema Joseph MBBSShapiro Roger L MDBeth Israel Deaconess Medical Center, Division of Infectious Disease, Boston, MA, USA (R Zash MD); Center for Biostatistics in AIDS Research (D L Jacobson PhD) and Department of Immunology and Infectious Diseases (Prof M Essex PhD, R L Shapiro MD), Harvard TH Chan School of Public Health, Boston, MA, USA; Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana (M Diseko BA, G Mayondi BSc, M Mmalane MD, T Gaolethe MD, J Makhema MBBS); Botswana Ministry of Health, Gaborone, Botswana (C Petlo BA); Division of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA, USA (S Lockman MD); and Medical Genetics Unit, MassGeneral Hospital for Children, Boston, MA, USA (L B Holmes MD)Correspondence to: Dr Rebecca Zash, Beth Israel Deaconess Medical Center, Division of Infectious Disease, Boston, MA 02215, USA, rzash@bidmc.harvard.edu15 6 2018 04 6 2018 7 2018 02 8 2018 6 7 e804 e810 This is an Open Access article under the CC BY-NC-ND 4.0 license.Summary\nBackground\nGlobal rollout of dolutegravir-based antiretroviral therapy (ART) has been hampered in part by insufficient safety data in pregnancy. We compared birth outcomes among women initiating dolutegravir-based ART with those among women initiating efavirenz-based ART in pregnancy in Botswana.\n\nMethods\nIn this observational study, we captured birth outcome data at eight government hospitals throughout Botswana (~45% of all deliveries in the country) in an ongoing study that started on Aug 15, 2014. In 2016, Botswana changed first-line ART from efavirenz-tenofovir-emtricitabine to dolutegravir-tenofovir-emtricitabine, including for pregnant women. This analysis includes women starting either efavirenz-based ART or dolutegravir-based ART during singleton pregnancy (regimen started and delivery occurring between Aug 15, 2014, and Aug 15, 2016, for efavirenz-based ART and between Nov 1, 2016, and Sept 30, 2017, for dolutegravir-based ART). We excluded births to mothers who had switched regimen or stopped ART. The primary outcomes were the combined endpoints of any adverse outcome (stillbirth, preterm birth [<37 weeks’ gestation], small for gestational age [SGA; less than the tenth percentile of birthweight by gestational age], or neonatal death [within 28 days of age]) and severe adverse outcomes (stillbirth, neonatal death, very preterm birth [<32 weeks’ gestation], and very SGA [less than the third percentile of birthweight by gestational age]). We fitted log-binomial regression models, controlling for maternal age, gravidity, and education, to estimate adjusted risk ratios (aRRs).\n\nFindings\nOur analysis included 1729 pregnant women who initiated dolutegravir-based ART and 4593 who initiated efavirenz-based ART. The risk for any adverse birth outcome among women on dolutegravir versus efavirenz was similar (33·2% vs 35·0%; aRR 0·95, 95% CI 0·88–1·03), as was the risk of any severe birth outcome (10·7% vs 11·3%; 0·94, 0·81–1·11). We found no significant differences by regimen in the individual outcomes of stillbirth, neonatal death, preterm birth, very preterm birth, SGA, or very SGA.\n\nInterpretation\nAdverse birth outcomes were similar among pregnant women who initiated dolutegravir-based and efavirenz-based ART. Dolutegravir-based ART can be safely initiated in pregnancy.\n\nFunding\nNational Institutes of Health.\n==== Body\nIntroduction\nIntegrase strand inhibitor-based antiretroviral therapy (ART) with dolutegravir has become a preferred regimen for first-line HIV treatment because of its efficacy, tolerability, limited drug–drug interactions, and a high barrier to resistance.1,2 Use of dolutegravir in low-income and middle-income countries is likely to be cost-effective,3,4 particularly once low-cost generic dolutegravir becomes widely available. However, in part because of insufficient data on the safety of dolutegravir in pregnancy, WHO has refrained from recommending dolutegravir-based treatment as the preferred first-line ART regimen for use in national treatment programmes in countries where harmonisation of ART regimens for all adults (including pregnant women) is important.5\n\nTo our knowledge, no previously published studies have evaluated the safety of dolutegravir in pregnancy. Outcomes from a total of 112 pregnancies exposed to dolutegravir have been reported in the literature,5 which is an insufficient number to evaluate risks of adverse birth outcomes (the antiretroviral pregnancy registry requires 200 pregnancies before reporting).6 Additionally, more than half of these pregnancies (67 [60%]) come from post-marketing surveillance in which there is no comparator group.5 By contrast, there is now sufficient data showing that the WHO first-line recommended regimen efavirenz-tenofovir-emtricitabine is safer in pregnancy than are older ART regimens containing nevirapine, lopinavir-ritonavir, and zidovudine-lamivudine.7,8 Therefore, to justify a transition to dolutegravir-based ART, dolutegravir needs to be shown to be at least as safe as efavirenz-based ART in pregnancy.\n\nBotswana was the first country to recommend use of dolutegravir in pregnancy, and offers a unique opportunity to study the safety of in-utero exposure to dolutegravir. In June, 2016, there was a swift rollout of new guidelines by the Botswana national HIV treatment programme, recommending initiation of dolutegravir-tenofovir-emtricitabine instead of efavirenz-tenofovir-emtricitabine for all adults with HIV, including pregnant women.9 We have been conducting a large birth outcomes surveillance study at eight sites in Botswana since August, 2014, and have been able to take advantage of this unique landscape to compare birth outcomes among women initiating dolutegravir versus efavirenz with the same nucleoside reverse transcriptase inhibitor (NRTI) backbone.\n\nMethods\nStudy design and participants\nMethods from the Tsepamo study have been previously described.8 In summary, data were abstracted from obstetric records of all women who delivered liveborn or stillborn infants at 24 weeks’ gestational age or later at eight government maternity wards in Botswana, representing approximately 45% of all births in the country.10 Two sites were tertiary referral centres and the remainder were primary and district hospitals.\n\nFrom January, 2012, up to May, 2016, Botswana national HIV treatment guidelines recommended efavirenz-based ART (efavirenz-tenofovir-emtricitabine) for adults with CD4 cell count of 350 cells per mL or lower, and for all pregnant women regardless of CD4 count.11 In May, 2016, guidelines were updated and recommended dolutegravir-based ART (dolutegravir-tenofovir-emtricitabine) for all adults with HIV, regardless of CD4 cell count or pregnancy status.9 All HIV services, including testing, treatment, laboratory monitoring, and clinical care, are provided free of charge to Botswana citizens.\n\nIn this analysis, we included singleton births to women who started dolutegravir-based ART at any time during pregnancy and gave birth between Nov 1, 2016, and Sept 30, 2017, and to women who started efavirenz-based ART during pregnancy and gave birth between Aug 15, 2014, and Aug 15, 2016. Although dolutegravir-based ART was rolled out in May, 2016, births to women on this regimen before November, 2016, were not comparable to births on efavirenz-based ART because births shortly after the rollout included a high proportion of women who had started dolutegravir late in pregnancy (often associated with late presentation for antenatal care and worse birth outcomes) and women who had a preterm or very preterm birth. Inclusion of data from this period could have led to an artificially high rate of adverse birth outcomes among the dolutegravir group. Therefore, births to mothers who had switched or stopped ART were excluded from analyses.\n\nEthical approval for this study was granted by the Human Research and Development Council in Botswana and by the Office of Human Research Administration at Harvard TH Chan School of Public Health.\n\nData collection\nData were abstracted from the maternity obstetric cards (medical record throughout pregnancy) at the postnatal ward at each site. Information included maternal demographics, maternal medical history, self-reported alcohol and tobacco use, laboratory values measured in pregnancy (haemoglobin and rapid plasma reagin), maternal diagnoses and medications prescribed during pregnancy, and birth information for the infant. HIV blood test results in pregnancy were collected for all women, and for women with HIV, further information was gathered on the timing of HIV diagnosis, most recent CD4 cell count, and history of antiretroviral use (including start date, regimen, and any switch or discontinuation during pregnancy).\n\nAs in our prior analyses,8 we used the estimated gestational age documented by nurses at the time of delivery for our analysis. This was typically calculated during antenatal care on the basis of the last menstrual period documented at first antenatal care visit, and was confirmed by ultrasound when available. If the last menstrual period was unknown or suspected to be incorrect, and if no ultrasound was available, fundal height measurements were occasionally used by midwives to estimate gestational age.\n\nOutcomes\nThe primary outcomes were the combined endpoints of any adverse outcome and any severe adverse outcome. The former comprised stillbirth, preterm birth, small for gestational age (SGA), or neonatal death, and the latter comprised stillbirth, very preterm birth, very SGA, or neonatal death. Secondary endpoints were the individual outcomes for stillbirth, preterm birth, very preterm birth, SGA, very SGA, and neonatal death. Stillbirth was defined as fetal death (summed Apgar score of 0). Preterm birth was a birth at less than 37 weeks’ gestation and very preterm was a birth at less than 32 weeks’ gestation. An infant was considered SGA if less than the tenth percentile and very SGA if less than the third percentile of birthweight by gestational age using Intergrowth-21 norms (defined from 24 to 42 weeks’ gestation).12,13 Neonatal deaths comprised deaths within 28 days of age among infants who had never left the hospital. Congenital abnormalities were a further secondary outcome, and were detected by the nurse midwife during the neonatal surface examination and photographed if maternal consent was obtained. Photographs were then evaluated and classified by a specialist in Boston (LBH) who was blinded to HIV and ART status. Congenital abnormalities were considered major if they had clinical, surgical, or cosmetic significance. Positional and genetic deformities were excluded.\n\nStatistical analysis\nBirth outcomes were analysed for women with singleton pregnancy by ART regimen and among HIV-negative women. We used the exact method to estimate 95% CIs around the prevalence of each outcome. To compare the risk of each primary and secondary birth outcome between the two treatment groups, we calculated the unadjusted and adjusted risk difference for each outcome using additive binomial regression and calculated the unadjusted and adjusted risk ratio (aRR) using a log-binomial regression model. We chose covariates for adjusted analyses a priori based on our previous analyses8,9 and included maternal age (<18 years, 18–35 years, or >35 years), gravidity (1, 2–5, or >5), and low education (none or primary vs secondary or higher). The sample size needed for analyses was based on an ability to have 80% power to detect a relative risk of 1·3 for any severe birth outcomes (and therefore more power to detect this risk ratio among the most common outcomes of any adverse birth outcome, namely preterm birth and SGA). In a secondary analysis, we used the same methodology but a separate model to evaluate the risk of the primary outcomes among HIV-negative women compared with women with HIV who had initiated either dolutegravir-based ART or efavirenz-based ART. In a further secondary analysis, to assess for potential temporal changes in birth outcomes, we also included HIV-negative women who delivered during the two ART exposure periods (August, 2014–August, 2016, and November, 2016–October, 2017). We did two a-priori sensitivity analyses. The first model excluded women who started ART from 0–4 weeks’ gestation and the second model included only women who started ART after their first antenatal care visit.\n\nStatistical analyses were done using SAS, version 9.3. All reported p values are based on a two-sided test with a significance level of α=0·05.\n\nRole of the funding source\nThe funders of this study had no role in the design; collection, analysis, or interpretation of data; writing of the manuscript; or decision to submit the manuscript. 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\nResults\nBetween Aug 15, 2014, and Aug 15, 2016, 11708 women with HIV delivered singletons, of whom 4593 (39%) began efavirenz-based ART after conception. Between Nov 1, 2016, and Sept 30, 2017, 5418 women with HIV delivered singletons, of whom 1729 (32%) began dolutegravir-based ART after conception. 51167 HIV-negative women had singleton delivery during these two time periods.\n\nAge, parity, socioeconomic indicators, timing of initiation of antenatal care, and site of delivery were similar among women on dolutegravir-based ART and efavirenz-based ART (table 1). HIV-negative women were more likely to be younger, primiparous, and have higher educational attainment than women infected with HIV. HIV-positive and HIV-negative women had similar timing of initiation of antenatal care.\n\nThe time from first presentation at antenatal care to initiation of ART was shorter among those on dolutegravir compared with efavirenz, resulting in a slightly earlier median gestational age at ART initiation for women starting dolutegravir-based ART compared with women starting efavirenz-based ART (table 2). Median CD4 count was similar among women who started dolutegravir-based ART and efavirenz-based ART, although a greater proportion of women in the efavirenz group had a CD4 count test during pregnancy (2054 [44·7%] vs 247 [14·2%]; table 2).\n\nOverall, 2180 (34·5%) of all births to women infected with HIV included in this analysis resulted in any adverse birth outcome and 704 (11·1%) in a serious adverse birth outcome. The occurrence of any adverse birth outcome was similar among women initiating dolutegravir-based ART (574 women [33·2%, 95% CI 31·0–35·5]) and women initiating efavirenz-based ART (1606 women [35·0%, 95% CI 33·6–36·4]; table 3). The occurrence of any severe adverse birth outcome was also similar among women initiating dolutegravir-based ART (185 women [10·7%, 9·3–12·3]) and women initiating efavirenz-based ART (519 women [11·3%, 10·4–12·3]; table 3).\n\nWe observed no di3erence in preterm birth, very preterm birth, SGA, very SGA, stillbirth, or neonatal death among women initiating dolutegravir-based ART compared with those initiating efavirenz-based ART (table 4). In adjusted analyses, we found no increased risk of preterm birth, very preterm birth, SGA, very SGA, stillbirth, or neonatal death (table 3). Sensitivity analyses that excluded participants who had started ART from 0–4 weeks’ gestation and that limited the analysis to women who started ART after their first antenatal care visit did not change the results of the analysis (appendix).\n\nAmong 675 women with first-trimester exposure to ART (280 to dolutegravir-based ART and 395 to efavirenz-based ART), one major congenital abnormality occurred: skeletal dysplasia in an efavirenz-exposed infant. Additionally, there were six cases of postaxial polydactyly type B (two in infants exposed to dolutegravir and four in infants exposed to efavirenz), which were not considered major abnormalities because all cases were managed by tying off the extra digits after birth.\n\nAmong HIV-negative women, 14766 (28·9%) had any adverse birth outcomes, including preterm birth in 7884 (15·6%) of 50683 women, SGA in 7419 (14·8%) of 50172 women, stillbirth in 1061 (2·1%) of 51164 women, and neonatal death in 697 (1·4%) of 50055 women with livebirths (appendix). Severe adverse birth outcomes occurred in 5085 (9·9%) women, including very preterm births in 1807 (3·6%) of 50683 women and very SGA infants in 2708 (5·4%) of 50172 women. Birth outcomes did not differ by time period among HIV-negative women (appendix).\n\nIn adjusted analyses, compared with HIV-negative women, women with HIV on either dolutegravir-based or efavirenz-based ART had significantly higher risk of any adverse birth outcomes (aRR 1·23, 95% CI 1·18–1·28) and any severe adverse birth outcomes (1·16, 1·07–1·25). These women also had higher risk of preterm birth (1·18, 1·12–1·25), SGA (1·30, 1·23–1·38), and very SGA (1·28, 1·16–1·42). We found no difference in very preterm birth (1·01, 0·88–1·16), stillbirth (1·08, 0·91–1·29), or neonatal death (0·92, 0·73–1·17; appendix).\n\nDiscussion\nThe 2016 rollout of dolutegravir-tenofovir-emtricitabine in Botswana allowed us to do what, to our knowledge, is the first large study of the safety of dolutegravir-based ART in pregnancy. We found no difference in the risk of adverse birth outcomes among women initiating dolutegravir-based ART compared with women initiating efavirenz-based ART in pregnancy. Compared with HIV-negative women, both groups of women with HIV had a mildly increased risk for adverse birth outcomes and severe adverse birth outcomes.\n\nWe have previously shown that women on efavirenz-tenofovir-emtricitabine had fewer adverse birth outcomes than did those on older ART regimens containing nevirapine, lopinivir-ritonavir, or zidovudine plus lamivudine backbone.7 The finding that dolutegravir-based ART has a similar risk profile to efavirenz-based ART is highly reassuring, and two small studies14,15 of pregnant women on integrase inhibitors in Europe support these results. The first study14 found similar rates of preterm and SGA among 81 European women on dolutegravir in pregnancy compared with the general population in the UK. The second study15 found similar rates of preterm and stillbirth among 479 pregnant women in France on raltegravir compared with the general French population. Although we cannot exclude a small difference in relative risk between these two regimens—the 95% CIs in our study are 0·88–1·03 for any adverse outcome and 0·81–1·11 for any severe adverse outcome, thus non-significant—these absolute differences would be very small and unlikely to have clinical significance that would outweigh the decision to use the preferred ART regimen for maternal health. We also found no difference in relative risk for all individual birth outcomes, providing reassurance that dolutegravir is likely to be safe when started in pregnancy. Our findings similarly provide further reassurance about the safety of efavirenz in pregnancy, which is widely used throughout the world.\n\nBecause we evaluated dolutegravir started in pregnancy, we were unable to adequately evaluate whether the risk of major congenital abnormalities differs by regimen because we only had information about surface abnormalities for a small number of exposures from the first trimester. We report a substantially lower rate of total congenital abnormalities than do the antiretroviral pregnancy registry6 and IMPAACT P1026s16 and EPIIC/PANNA data17—two pharmacokinetic studies of antiretroviral drugs in pregnancy. One reason for this is that we report only major congenital abnormalities of medical, surgical, or cosmetic importance, excluding minor abnormalities, positional abnormalities, and genetic abnormalities. The other reason is that we ascertain abnormalities that are visible on the neonatal surface examination and therefore do not evaluate for internal defects such cardiac or renal, or defects that are more likely to present after the first few days of life. We do not believe the reason for the low rate of abnormalities is lack of ascertainment, because we did active surveillance on all infants and documented a 1·2% prevalence of postaxial polydactyly type B—a minor abnormality found in first-trimester exposure to dolutegravir or efavirenz—that is consistent with the reported prevalence of this abnormality in African American infants18 and also similar to the prevalence among HIV-negative women in our birth outcomes study (data not shown). Further research is needed among a larger number of women on dolutegravir from conception, with longitudinal infant follow-up, to fully evaluate congenital abnormalities.\n\nOur results show that women with HIV on either efavirenz-based or dolutegravir-based regimens had a small but significant increase in adverse birth outcomes compared with HIV-negative women. This risk was smaller than in prior studies done when most women with HIV received nevirapine, lopinavir-ritonavir, and zidovudine-lamivudine.19 However, even small differences can translate into a large number of adverse birth outcomes in a high-prevalence HIV setting, and can adversely affect child health and survival. The reasons for the difference in outcomes by maternal HIV status remain unknown. The difference might be due to chronic HIV infection, comorbidities or coinfections,20,21 or a direct effect from ART.\n\nOur study has several strengths, including a sample size large enough to evaluate severe birth outcomes, and the same NRTI backbone (tenofovir-emtricitabine) for both regimens, which enabled us to truly compare the effects of dolutegravir and efavirenz. However, our study also had several limitations, including an inability to fully evaluate CD4 cell count because of the low proportion of women on dolutegravir who had a reported CD4 count in pregnancy (14·3%), probably due to the new strategy of test and treat, which does not require a CD4 count for initiation of ART. The data we do have available suggest this is not a major confounder. The sequential switch from efavirenz to dolutegravir puts our data at risk of historical bias. However, the total interval was short (3 years) and there was no change in birth outcomes among HIV-negative women by calendar year (appendix). Given the observational study design, unmeasured confounding could bias our results. Although we can be reassured because baseline covariates were well balanced between the two groups, we controlled for potential confounders identified in prior similar studies in Botswana and sensitivity analyses with additional baseline covariates did not change our results (appendix). Additionally, we could not compare other outcomes such as early pregnancy loss (<24 weeks’ gestation); maternal viral load at the time of delivery; efficacy in prevention of mother-to-child HIV transmission; adherence, tolerability, and toxicity in pregnancy; or paediatric outcomes after birth. Finally, we are unable to assess the quality of data in the medical records or validate gestational age dating, although we feel neither should differ by ART regimen.\n\nIn conclusion, adverse birth outcomes were similar for dolutegravir-based ART and efavirenz-based ART when started during pregnancy. Although further studies are needed to determine the safety of dolutegravir exposure from conception and to confirm its efficacy for prevention of mother-to-child HIV transmission, these results should pave the way for wider use of dolutegravir in pregnancy throughout the world.\n\nSupplementary Material\nsupplement We wish to acknowledge our research assistants from the Botswana Harvard AIDS Institute Partnership: Judith Mabuta, Daphne Segobye, and Tsaone Gaonakala (Gaborone); Cynthia Dube, Edith Moseki, and Gosego Legase (Francistown); Keemenao France (Mahalapye); Mmapula Ofhentse (Selbi-Phikwe); Naledi Kamanga (Maun); Onkabetse Mokgosi (Ghanzi); Rosemary Moremi (Serowe); and Shally Morgan and Tshepang Motlotlegi (Molepolole). We also would like to thank the staff at the participating hospitals: Princess Marina Hospital, Gaborone, Scottish Livingstone Hospital, Molepolole, Sekgoma Memorial Hospital, Serowe, Letsholathebe II Memorial Hospital, Maun, Nyangabwe Hospital, Francistown, Selebi-Phikwe Hospital, Selebi-Phikwe, Mahalapye Hospital, Mahalapye and Ghanzi Primary Hospital, Ghanzi. Additionally, we would like to thank members of the Botswana Ministry of Health, in particular the department of HIV/AIDS Prevention and Care, and the department of Maternal and Child Health. This study would not have been possible without the support of the leadership the Botswana-Harvard AIDS Institute Partnership including Ria Madison, Bernadette Kgake, Tryphinah Majutah-Lungah, and Erik van Widenfeld (Gaborone). We also acknowledge the funding and support from the National Institute of Child Health and Human Development/National Institute of Allergy and Infectious Diseases. This work was funded by National Institutes of Health grants R01 HD080471-01 and K23 HD088230-01A1.\n\nContributors\n\nRZ and RLS contributed to the conception and design of the study, acquisition of data, analysis and interpretation of data, and drafting of the manuscript. DLJ contributed to the design of the study, analysis and interpretation of data, and drafting of the manuscript. GM and MD contributed to the acquisition of data and to critical revision of the manuscript. MM, ME, TG, CP, JM, and SL contributed to conception and design of the study and critical revision of the manuscript. LBH contributed to the conception and design of the study, interpretation of data, and critical revision of the manuscript.\n\nDeclaration of interests\n\nWe declare no competing interests.\n\nTable 1 Baseline maternal demographics and pregnancy history among singleton births\n\n\tHIV negative (n=51167)\tHIV positive (n=6322)\n\t\nDolutegravir-based ART (n=1729)\tEfavirenz-based ART (n=4593)\t\nMaternal age, years\t25 (21–30)\t28 (23–33)\t28 (23–32)\t\n Data missing\t30 (0·1%)\t0\t0\t\n\n\t\nMarried\t5684 (11·1%)\t114 (6·6%)\t325 (7·1%)\t\n Data missing\t1336 (2·6%)\t33 (1·9%)\t109 (2·4%)\t\n\n\t\nPrimary or no education\t3078 (6·0%)\t150 (8·7%)\t435 (9·5%)\t\n Data missing\t1192 (2·3%)\t17 (1·0%)\t102 (2·2%)\t\n\n\t\nOccupation\t\n Housewife or none\t27537 (53·8%)\t1013 (58·6%)\t2508 (54·6%)\t\n Student\t4664 (9·1%)\t61 (3·5%)\t192 (4·2%)\t\n Salaried\t16716 (32·7%)\t601 (34·8%)\t1722 (37·5%)\t\n Missing\t2250 (4·4%)\t54 (3·1%)\t171 (3·7%)\t\n\n\t\nNon-citizen\t1690 (3·3%)\t5 (0·3%)\t77 (1·7%)\t\n Data missing\t129 (0·3%)\t6 (0·3%)\t7 (0·2%)\t\n\n\t\nPrimiparous\t22125 (43·2%)\t446 (25·8%)\t1095 (23·8%)\t\n\n\t\nGrand multiparous (≥5 pregnancies)\t3570 (7·0%)\t188 (10·9%)\t551 (12·0%)\t\n Data missing\t126 (0·2%)\t0\t5 (0·1%)\t\n\n\t\nGestational age at antenatal care presentation, years\t17 (13–22)\t17 (13–22)\t17 (13–22)\t\n Data missing\t2535 (5·0%)\t39 (2·3%)\t163 (3·5%)\t\n\n\t\nReceived no prenatal care\t1254 (2·5%)\t17 (1·0%)\t32 (0·7%)\t\n Data missing\t393 (0·8%)\t0\t35 (0·8%)\t\n\n\t\nAlcohol or smoking in pregnancy\t4047 (7·9%)\t196 (11·3%)\t475 (10·3%)\t\n Data missing\t3705 (7·2%)\t121 (7·0%)\t287 (6·2%)\t\n\n\t\nBirth at a tertiary facility\t24910 (48·7%)\t862 (49·9%)\t2315 (50.4%)\t\n Data missing\t0\t0\t0\t\n\n\t\nBirth via cesarean section\t11368 (22·2%)\t406 (23·5%)\t1062 (23·1%)\t\n Data missing\t62 (0·1%)\t1 (0·1%)\t2 (<0·1%)\t\nData are n (%) or median (IQR). ART=antiretroviral treatment.\n\nTable 2 Baseline HIV-related characteristics among women on dolutegravir-based and efavirenz-based ART\n\n\tDolutegravir-based ART (n=1729)\tEfavirenz-based ART (n=4593)\t\nDiagnosed with HIV before pregnancy\t452 (26·1%)\t1558 (33·9%)\t\n Data missing\t0\t0\t\n\n\t\nDays from first antenatal care visit to initiation of ART\t9 (0–30)\t23 (7–45)\t\n Data missing\t60 (3·5%)\t232 (5·1%)\t\n\n\t\nGestational week at ART initiation\t19 (14–25)\t21 (16–27)\t\n Data missing\t100 (5·8%)\t341 (7·4%)\t\n\n\t\nNumber with CD4 result in pregnancy\t247 (14·3%)\t2054 (44·7%)\t\n\n\t\nCD4 count in pregnancy (cells per mm3)\t411 (282–549)\t402 (281–551)\t\n\n\t\nCD4 category in pregnancy\t\n <200 cells per mm3\t30/247 (12·1%)\t257/2054 (12·5%)\t\n 200–349 cells per mm3\t66/247 (26·7%)\t543/2054 (26·4%)\t\n 350–499 cells per mm3\t72/247 (29·1%)\t594/2054 (28·9%)\t\n ≥500 cells per mm3\t79/247 (32·0%)\t660/2054 (32·1%)\t\nData are n (%), n/N (%), or median (IQR). ART=antiretroviral treatment.\n\nTable 3 Birth outcomes among women initiating dolutegravir-based ART versus efavirenz-based ART in pregnancy\n\n\tDolutegravir-based ART (n=1729)\tEfavirenz-based ART (n=4593)\t\nAny adverse birth outcome\t\n\n\t\nNumber of women\t574 (33·2%, 31·0 to 35·5)\t1606 (35·0%, 33·6 to 36·4)\t\nUnadjusted relative risk\t0·95 (0·88 to 1·03)\t1 (ref)\t\nAdjusted relative risk\t0·95 (0·88 to 1·03)\t1 (ref)\t\nUnadjusted risk difference\t−1·77% (−4·38 to 0·85)\t1 (ref)\t\nAdjusted risk difference\t−1·76% (−4·39 to 0·87)\t1 (ref)\t\n\n\t\nAny severe birth outcome\t\n\n\t\nNumber of women\t185 (10·7%, 9·3 to 12·3)\t519 (11·3%, 10·4 to 12·3)\t\nUnadjusted relative risk\t0·95 (0·81 to 1·11)\t1 (ref)\t\nAdjusted relative risk\t0·94 (0·81 to 1·11)\t1 (ref)\t\nUnadjusted risk difference\t−0·60% (−2·32 to 1·12)\t1 (ref)\t\nAdjusted risk difference\t−0·51% (−2·24 to 1·23)\t1 (ref)\t\nData in parentheses are 95% CIs or %, 95% CI. ART=antiretroviral therapy.\n\nTable 4 Adverse birth outcomes among singleton births by ART exposure\n\n\tDolutegravir-based ART (n=1729)\tEfavirenz-based ART (n=4593)\tUnadjusted risk difference (95% CI)\tAdjusted risk difference (95% CI)\tUnadjusted relative risk (95% CI)\tAdjusted relative risk (95% CI)\t\nPreterm birth (<37 weeks)*\t309 (18·0%, 16·2 to 19·9)\t844 (18·5%, 17·4 to 19·6)\t−0·5% (−2·6 to 1·7)\t−0·3% (−2·5 to 1·8)\t0·97 (0·87 to 1·10)\t0·98 (0·87 to 1 to 11)\t\nVery preterm birth (<32 weeks)*\t66 (3·8%, 3·0 to 4·9)\t160 (3·5%, 3·0 to 4·1)\t0·3% (−0·7 to 1·4)\t0·4% (−0·7 to 1·4)\t1·10 (0·83 to 1·45)\t1·09 (0·82 to 1·45)\t\nSmall for gestational age (<10th percentile weight-for-gestational-age)*†\t297 (17·4%, 15·7, 19·3)\t838 (18·5%, 17·4 to 19·7)\t−1·1% (−3·2 to 1·0)\t−0·9% (−3·1 to 1·2)\t0·94 (0·83 to 1·06)\t0·94 (0·83 to 1·06)\t\nVery small for gestational age (<3rd percentile weight-for-gestational-age)*†\t104 (6·1%, 5·0 to 7·4)\t302 (6·7%, 6·0 to 7·5)\t−0·6% (−1·9 to 0·8)\t0·3% (−1·6 to 1·1)\t0·91 (0·74 to 1·13)\t0·91 (0·74 to 1·13)\t\nStillbirth‡\t39 (2·3%, 1·6 to 3·1)\t105 (2·3%, 1·9 to 2·8)\t0·03% (−0·9 to 0·8)\t0·1% (−0·9 to 0·8)\t0·99 (0·69 to 1·42)\t0·99 (0·69 to 1·42)\t\nNeonatal death (<28 days)§\t21 (1·2%, 0·8 to 1·9)\t60 (1·3%, 1·0 to 1·7)\t0·1% (−0·7 to 0·5)\t−0·1% (−0·7 to 0·6)\t0·93 (0·57 to 1·53)\t0·96 (0·58 to 1·57)\t\nData are n (%, 95% CI), risk difference (95% CI), or relative risk (95% CI). Table includes singleton births only and women with missing data were excluded. All models were adjusted for maternal age, gravidity, and low educational attainment. ART=antiretroviral treatment.\n\n* Missing data for gestational age: 37 participants in the dolutegravir group and 129 participants in the efavirenz group.\n\n† Missing data for birthweight: 14 participants in the dolutegravir group and 45 participants in the efavirenz group.\n\n‡ Missing stillbirth status: 25 participants in the dolutegravir group and 102 participants in the efavirenz group.\n\n§ Missing neonatal death status: 28 participants in the dolutegravir group and 104 participants in the efavirenz group.\n\nResearch in context\nEvidence before this study\nDolutegravir-based antiretroviral treatment (ART) is a preferred first-line ART regimen for adults with HIV because of its efficacy, tolerability, high barrier to resistance, and minimal drug–drug interactions. However, outcomes of only a small number of exposures in pregnancy have been published to date, which precludes evaluation of whether the use of dolutegravir in pregnancy might lead to increases in preterm birth, small for gestational age, stillbirth, neonatal death, or congenital abnormalities. Therefore, dolutegravir is not included as a first-line recommended regimen in pregnancy by WHO or by HIV guideline committees in the USA or Europe. Unavailability of pregnancy safety data has also hampered use of dolutegravir for all adults in low-income and middle-income countries where women of reproductive age make up a large proportion of the HIV-positive population.\n\nAdded value of this study\nIn 2016, Botswana became the first country to change its national ART guidelines to recommend the start of dolutegravir-tenofovir-emtricitabine in pregnancy, rather than the current WHO-recommended regimen of efavirenz-tenofovir-emtricitabine. Our study compared adverse birth outcomes before and after this change in guidelines, among 1729 women who initiated dolutegravir-based ART and 4593 women who initiated efavirenz-based ART. We found no increased risk for adverse birth outcomes, including severe adverse birth outcomes, among women initiating dolutegravir-based ART in pregnancy. These findings support updates to current HIV treatment guidelines to allow initiation of dolutegravir-based ART as a first-line regimen in pregnancy.\n\nImplications of all the available evidence\nThe results of this study should decrease the barriers to use of dolutegravir in women of reproductive age around the world once further data are gathered regarding the safety of dolutegravir from conception. These findings are particularly important for low-income and middle-income countries where harmonisation of first-line ART for adults and pregnant women is a key factor in the success of HIV treatment strategies.\n==== Refs\n1 Günthard HF Saag MS Benson CA Antiretroviral drugs for treatment and prevention of HIV infection in adults [2016] recommendations of the International Antiviral Society—USA Panel JAMA 2016 316 191 210 27404187 \n2 Department for Health and Human Services Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents 2016 https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf accessed Nov 8, 2017 \n3 Venter F Kaiser B Pillay Y Cutting the cost of South African antiretroviral therapy using newer, safer drugs South Afr Med J 2017 107 28 30 \n4 Barnhart M Shelton J ARVs: the next generation. Going boldly together to new frontiers of HIV treatment Glob Health Sci Prac 2015 1 1 11 \n5 Vitoria M Ford N Claden P Pozniak A Hill A When could new antiretrovirals be recommended for national treatment programs in low and middle income countries: results of a WHO think tank Curr Op HIV AIDS 2017 12 414 22 \n6 Antiretroviral Pregnancy Registry Steering Committee Antiretroviral Pregnancy Registry Interim Report for 1 January 1989 through 31 July 2017 Wilmington, NC Registry Coordinating Center 2017 \n7 Zash R Souda S Chen JY Reassuring birth outcomes with tenofovir/emtricitabine/efavirenz used for prevention of mother-to-child transmission of HIV in Botswana J Acquir Immune Defic Syndr 2016 71 428 36 26379069 \n8 Zash R Jacobson DL Diseko M Comparative safety of antiretroviral treatment regimens in pregnancy JAMA Pediatr 2017 171 e172222 28783807 \n9 Botswana Ministry of Health Handbook of the Botswana 2016 Integrated HIV Clinical Care Guidelines 2016 http://apps.who.int/medicinedocs/documents/s22413en/s22413en.pdf accessed Nov 8, 2017 \n10 Statistics Botswana Health Statistics Report 2009 Gaborone Statistics Botswana 2012 \n11 Botswana Ministry of Health 2012 Botswana National HIV & AIDS Treatment Guidelines Gaborone Botswana Ministry of Health 2012 \n12 Villar J Cheikh Ismail L Victora CG International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project Lancet 2014 384 857 68 25209487 \n13 Villar J Giuliani F Fenton TR INTERGROWTH-21st very preterm size at birth reference charts Lancet 2016 387 844 45 26898853 \n14 Thorne C Favarato G Peters H Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir 9th IAS Conference on HIV Science Paris, France July 23–26, 2017 4549 \n15 Sibiude J Warszawski J Blanche S Evaluation of the risk of birth defects among children exposed to raltegravir in utero in the ANRS-French Perinatal Cohort EPF 9th IAS Conference on HIV Science Paris, France July 23–26, 2017 3037 \n16 Mulligan N Best B Capparelli E Dolutegravir pharmacokinetics in HIV-infected pregnant and postpartum women Conference on Retroviruses and Opportunistic Infections Boston, MA, USA February 22–25, 2016 438 \n17 Thorne C Favarato G Peters H Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir 9th IAS Conference on HIV Science Paris, France July 23–26, 2017 4549 \n18 Watson B Hennrikus W Postaxial type-B polydactyly. Prevalence and treatment J Bone Joint Surg Am 1997 79 65 68 9010187 \n19 Chen JY Ribaudo HJ Souda S Highly active antiretroviral therapy and adverse birth outcomes among HIV-infected women in Botswana J Infect Dis 2012 206 1695 705 23066160 \n20 Cohen MS Chen YQ McCauley M Prevention of HIV-1 infection with early antiretroviral therapy N Engl J Med 2011 365 493 505 21767103 \n21 Turner AN Tabbah S Mwapasa V Severity of maternal HIV-1 disease is associated with adverse birth outcomes in Malawian women: a cohort study J Acquir Immune Defic Syndr 2013 64 392 99 23846560\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-109X",
"issue": "6(7)",
"journal": "The Lancet. Global health",
"keywords": null,
"medline_ta": "Lancet Glob Health",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D001902:Botswana; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D010078:Oxazines; D010879:Piperazines; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D011728:Pyridones; D055815:Young Adult",
"nlm_unique_id": "101613665",
"other_id": null,
"pages": "e804-e810",
"pmc": null,
"pmid": "29880310",
"pubdate": "2018-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study; D052061:Research Support, N.I.H., Extramural",
"references": "28783807;23066160;28410249;9010187;27404187;21767103;23846560;25209487;25745115;26379069;28112085;26898853",
"title": "Comparative safety of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in Botswana: an observational study.",
"title_normalized": "comparative safety of dolutegravir based or efavirenz based antiretroviral treatment started during pregnancy in botswana an observational study"
} | [
{
"companynumb": "BW-GILEAD-2017-0289034",
"fulfillexpeditecriteria": "1",
"occurcountry": "BW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOLUTEGRAVIR"
},
"drugadditional": "3",
... |
{
"abstract": "Delayed methotrexate (MTX) elimination after treatment with high-dose (HD) MTX may result in life-threatening toxicities as well as acute kidney injury (AKI). Treatment includes administration of glucarpidase, an enzyme that rapidly inactivates MTX. Dosing of glucarpidase is based on body weight; however, recommendations for dosage adjustments in obese patients are lacking. We describe three obese adult patients (body mass index [BMI] range 31-43 kg/m2 ) who received HD-MTX following all precautions for its treatment. Although peak MTX concentrations were within the expected range (308-368 µmol/L), MTX concentrations after 24 hours or later were markedly increased (97, 52, and 19 µmol/L, respectively). Two patients experienced AKI. After a single intravenous dose of glucarpidase 4000 units (50 units/kg on the basis of ideal body weight [IBW]) was administered to each patient 38, 46, and 60 hours, respectively, after the start of MTX, MTX concentrations dropped quickly to 1.37, 0.07, and 0.03 µmol/L, respectively, and further decreased steadily. Over time, clinical status and renal function improved in all patients. Glucarpidase is a highly hydrophilic molecule with a volume of distribution of 3.6 L, representing the intravascular volume of an adult. Therefore, we used IBW for glucarpidase dose calculations, allowing us to reduce the dose that would have been determined by using total body weight. This approach resulted in a rapid decrease of MTX serum concentrations and may reduce treatment costs of this highly expensive drug.",
"affiliations": "Hospital Pharmacy, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department of Oncology and Hematology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department of Oncology and Hematology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department of Oncology and Hematology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department of Oncology and Hematology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department of Oncology and Hematology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Department of Oncology and Hematology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.;Hospital Pharmacy, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.",
"authors": "Krüger|Caroline|C|;Engel|Nils|N|;Reinert|Jochim|J|;Alsdorf|Winfried|W|;Fiedler|Walter|W|;Dierlamm|Judith|J|;Bokemeyer|Carsten|C|;Langebrake|Claudia|C|0000-0003-1249-4223",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; C000629556:glucarpidase; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.2390",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "40(5)",
"journal": "Pharmacotherapy",
"keywords": "glucarpidase; high dose; methotrexate; obesity",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D005260:Female; D006801:Humans; D056865:Ideal Body Weight; D015448:Leukemia, B-Cell; D016393:Lymphoma, B-Cell; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D009767:Obesity, Morbid; D011994:Recombinant Proteins; D011623:gamma-Glutamyl Hydrolase",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "479-483",
"pmc": null,
"pmid": "32239519",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful Treatment of Delayed Methotrexate Clearance Using Glucarpidase Dosed on Ideal Body Weight in Obese Patients.",
"title_normalized": "successful treatment of delayed methotrexate clearance using glucarpidase dosed on ideal body weight in obese patients"
} | [
{
"companynumb": "DE-MYLANLABS-2019M1041884",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPatients with advanced cancer need multiple drugs to control symptoms and to treat cancer and concomitant diseases. At the same time, the goal of treatment changes as life expectancy becomes limited. This results in a risk for polypharmacy, maintained use of unneeded drugs, and drug-drug interactions (DDIs).\n\n\nOBJECTIVE\nThe aim of the study was to analyze the use of medications and to identify unneeded drugs, and drugs and drug combinations with a risk for DDIs in a cohort of advanced cancer pain patients, defined by a need for a World Health Organization analgesic ladder Step III opioid.\n\n\nMETHODS\nAll drugs taken within a study day by cancer patients receiving opioids for moderate or severe pain (Step III opioids) were analyzed. Nonopioids and adjuvants were analyzed for their use across countries. Unneeded medications and drugs and drug combinations with a risk for pharmacodynamic and pharmacokinetic DDIs were identified on the basis of published literature and electronic resources.\n\n\nRESULTS\nIn total, 2282 patients from 17 centers in 11 European countries were included. They received a mean of 7.8 drugs (range 1-20). Over one-quarter used 10 or more medications. The drugs and drug classes most frequently coadministered with opioids were proton pump inhibitors, laxatives, corticosteroids, paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, metoclopramide, benzodiazepines, anticoagulants, antibiotics, anticonvulsants, diuretics, and antidepressants. The use of nonopioids and essential adjuvants varied across countries. Approximately 45% of patients received unnecessary or potentially unnecessary drugs, and about 7% were given duplicate or antagonizing agents. Exposures to DDIs were frequent and increased the risk of sedation, gastric ulcerations, bleedings, and neuropsychiatric and cardiac complications. Many patients were exposed to pharmacokinetic DDIs involving cytochrome P450, including about 58% who used a Step III opioid CYP3A4 (izoenzyme of cytochrome P450) substrate, and more than 10% who were given major CYP3A4 inhibitors or inducers.\n\n\nCONCLUSIONS\nPatients with cancer treated with a World Health Organization Step III opioid use a high number of drugs. Nonopioid analgesics and corticosteroids are frequently used, but different patterns of use between countries were found. Many patients receive unneeded drugs and are at risk of serious DDIs. These findings demonstrate that drug therapy in these patients needs to be evaluated continuously.",
"affiliations": "Department of Palliative Medicine Karol Marcinkowski University of Medical Sciences, Poznan, Poland; Hospice Palium, University Hospital of the Lord's Transfiguration, Poznan, Poland. Electronic address: alemieszek@ump.edu.pl.;Palliative Care Unit, Department of Medicine, Telemark Hospital Trust, Skien, Norway; European Palliative Care Research Centre, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.;European Palliative Care Research Centre, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Oncology, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.;Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Anaesthesiology and Intensive Care Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.",
"authors": "Kotlinska-Lemieszek|Aleksandra|A|;Paulsen|Ornulf|O|;Kaasa|Stein|S|;Klepstad|Pål|P|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0885-3924",
"issue": "48(6)",
"journal": "Journal of pain and symptom management",
"keywords": "Pharmacotherapy; adjuvants; cancer pain; coanalgesics; drug-drug interactions; nonopioids; opioids; palliative care; polypharmacy; unnecessary drugs; unneeded drugs",
"medline_ta": "J Pain Symptom Manage",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D017024:Chemotherapy, Adjuvant; D003430:Cross-Sectional Studies; D005060:Europe; D005260:Female; D006801:Humans; D057970:Inappropriate Prescribing; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D010146:Pain; D019338:Polypharmacy; D055815:Young Adult",
"nlm_unique_id": "8605836",
"other_id": null,
"pages": "1145-59",
"pmc": null,
"pmid": "24780183",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Polypharmacy in patients with advanced cancer and pain: a European cross-sectional study of 2282 patients.",
"title_normalized": "polypharmacy in patients with advanced cancer and pain a european cross sectional study of 2282 patients"
} | [
{
"companynumb": "PL-JNJFOC-20141213366",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Lichen planus (LP) is a mucocutaneous inflammatory disease that involves papulosquamous eruption of the skin, scalp, nails, and mucous membranes. This uncommon condition has a higher prevalence in African Americans and females. Women accounts for 50% of cutaneous LP (CLP) and 60% to 75% of oral LP (OLP) cases. Diagnosis is centered around clinical presentation. Patient evaluation requires a comprehensive physical examination to identify any potential sites of involvement. LP is usually described by the \"Six P's\": planar, purple, polygonal, pruritic, papules, and plaques. Drug-induced LP, or lichenoid drug reactions, is uncommon and usually indiscernible from other forms of LP. Lichenoid drug reactions exhibit parakeratosis, dermal infiltrates of eosinophils, or perivascular lymphocytic infiltrates affecting the reticular dermis. An extended time interval between the initiation of drug to the onset of symptoms usually does not exclude potential diagnosis of a lichenoid drug reaction. We describe a case of hydrochlorothiazide-induced LP without prolonged exposure to sunlight diagnosed in the emergency department (ED). In this case, a pharmacist-conducted medication reconciliation played an integral role in accurately recognizing this adverse drug reaction. Our case report adds to the limited available literature on the topic, most of which originated more than 30 years ago.",
"affiliations": "1 Division of Pharmacy Practice, LIU Pharmacy (Arnold and Marie Schwartz College of Pharmacy), Brooklyn, NY, USA.;2 The Brooklyn Hospital Center, Brooklyn, NY, USA.;3 Department of Emergency Medicine, The Brooklyn Hospital Center, Brooklyn, NY, USA.",
"authors": "Sin|Billy|B|;Miller|Morgan|M|;Chew|Edward|E|",
"chemical_list": "D004232:Diuretics; D006852:Hydrochlorothiazide",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190016630879",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "30(2)",
"journal": "Journal of pharmacy practice",
"keywords": "emergency department; hydrochlorothiazide; lichen planus",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000369:Aged, 80 and over; D004232:Diuretics; D004636:Emergency Service, Hospital; D006801:Humans; D006852:Hydrochlorothiazide; D008010:Lichen Planus; D008297:Male",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "266-269",
"pmc": null,
"pmid": "26864620",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydrochlorothiazide Induced Lichen Planus in the Emergency Department.",
"title_normalized": "hydrochlorothiazide induced lichen planus in the emergency department"
} | [
{
"companynumb": "US-ALLERGAN-1722590US",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LABETALOL\\LABETALOL HYDROCHLORIDE"
},
"drugaddit... |
{
"abstract": "OBJECTIVE\nThere is limited data on the treatment of coronavirus disease 2019 (COVID-19) in pregnancy. Arkansas saw an increase in COVID-19 cases in June 2020. The first critically ill pregnant patient was admitted to our institution on May 21st, 2020. The objective of this study was to evaluate outcomes in critically ill pregnant women with COVID-19 at a single tertiary care center who received remdesivir and convalescent plasma (CCP).\n\n\nMETHODS\nThis is a retrospective observational review of critically ill pregnant women with COVID-19 who received remdesivir and CCP. This study was approved by the institutional review board (#261354).\n\n\nRESULTS\nSeven pregnant patients with COVID-19 were admitted to the intensive care unit (ICU). All received remdesivir and CCP. Six received dexamethasone. The median ICU length of stay (LOS) was 8 days (range 3-17). Patient 1 had multi-organ failure requiring vasopressors, renal dialysis, and had an intrauterine fetal demise. Patients 4 and 6 required mechanical ventilation, were delivered for respiratory distress and were extubated at 2 and 1 days postpartum, respectively. The only common risk factor was obesity. There were no adverse events noted with remdesivir or CCP.\n\n\nCONCLUSIONS\nThere is little data regarding the use of remdesivir or CCP for the treatment of COVID-19 in pregnant women. In our cohort, these were well tolerated with no adverse events. Previously reported median ICU LOS in critically ill pregnant women with COVID-19 was 8 days (range 4-15).1 Our study found a similar ICU LOS (8 days; range 3-17). Patient 1 did not receive remdesivir or CCP until transport to our facility on hospital day 3. Excluding patient 1, median ICU LOS was 6.5 days (range 3-9). Our institution's treatment of pregnant women with critical illness with remdesivir, CCP and dexamethasone combined with delivery in select cases has thus far had good outcomes.\n\n\nCONCLUSIONS\n· Combined therapy: remdesivir, CCP, dexamethasone.. · Remdesivir, CCP and dexamethasone was effective in treating critically ill pregnant women with COVID-19.. · No adverse events were associated with combined therapy.. · Delivery improved respiratory status..",
"affiliations": "Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for the Medical Sciences, Little Rock, Arkansas.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for the Medical Sciences, Little Rock, Arkansas.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for the Medical Sciences, Little Rock, Arkansas.;Department of Obstetrics and Gynecology, University of Arkansas for the Medical Sciences, Little Rock, Arkansas.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for the Medical Sciences, Little Rock, Arkansas.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for the Medical Sciences, Little Rock, Arkansas.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Arkansas for the Medical Sciences, Little Rock, Arkansas.",
"authors": "Pagan|Megan E|ME|0000-0003-0598-438X;Ramseyer|Abigail M|AM|;Whitcombe|Dayna D|DD|;Doiron|Tucker E|TE|;Magann|Everett F|EF|;Sandlin|Adam T|AT|;Hughes|Dawn S|DS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0041-1739292",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1631",
"issue": null,
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": null,
"nlm_unique_id": "8405212",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34775583",
"pubdate": "2021-11-14",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of Critically Ill Pregnant Patients with COVID-19 Infection in a Rural State.",
"title_normalized": "management of critically ill pregnant patients with covid 19 infection in a rural state"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2022SP003190",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugaddition... |
{
"abstract": "OBJECTIVE\nLong-chain acylcarnitines have been postulated to be sensitive biomarkers of acetaminophen (APAP)-induced hepatotoxicity in mouse models. In the following study, the relationship of acylcarnitines with other known indicators of APAP toxicity was examined in children receiving low-dose (therapeutic) and high-dose ('overdose' or toxic ingestion) exposure to APAP.\n\n\nMETHODS\nThe study included three subject groups: group A (therapeutic dose, n = 187); group B (healthy controls, n = 23); and group C (overdose, n = 62). Demographic, clinical and laboratory data were collected for each subject. Serum samples were used for measurement of APAP protein adducts, a biomarker of the oxidative metabolism of APAP and for targeted metabolomics analysis of serum acylcarnitines using ultra performance liquid chromatography-triple-quadrupole mass spectrometry.\n\n\nRESULTS\nSignificant increases in oleoyl- and palmitoyl-carnitines were observed with APAP exposure (low dose and overdose) compared with controls. Significant increases in serum ALT, APAP protein adducts and acylcarnitines were observed in overdose children that received delayed treatment (time to treatment from overdose >24 h) with the antidote N-acetylcysteine. Time to peak APAP protein adducts in serum was shorter than that of the acylcarnitines and serum ALT.\n\n\nCONCLUSIONS\nPerturbations in long-chain acylcarnitines in children with APAP toxicity suggest that mitochrondrial injury and associated impairment in the β-oxidation of fatty acids are clinically relevant as biomarkers of APAP toxicity.",
"affiliations": "Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA and Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.",
"authors": "Bhattacharyya|Sudeepa|S|;Yan|Ke|K|;Pence|Lisa|L|;Simpson|Pippa M|PM|;Gill|Pritmohinder|P|;Letzig|Lynda G|LG|;Beger|Richard D|RD|;Sullivan|Janice E|JE|;Kearns|Gregory L|GL|;Reed|Michael D|MD|;Marshall|James D|JD|;Van Den Anker|John N|JN|;James|Laura P|LP|",
"chemical_list": "D015415:Biomarkers; C116917:acylcarnitine; D000082:Acetaminophen; D000410:Alanine Transaminase; D002331:Carnitine; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.2217/bmm.13.150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1752-0363",
"issue": "8(2)",
"journal": "Biomarkers in medicine",
"keywords": null,
"medline_ta": "Biomark Med",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000293:Adolescent; D000367:Age Factors; D000410:Alanine Transaminase; D015415:Biomarkers; D002331:Carnitine; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D016002:Discriminant Analysis; D005260:Female; D006801:Humans; D016018:Least-Squares Analysis; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D012737:Sex Factors",
"nlm_unique_id": "101312535",
"other_id": null,
"pages": "147-59",
"pmc": null,
"pmid": "24521011",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23431354;23979652;24080264;16737880;19256530;3059186;18093979;11197064;20037589;19439490;21205919;11901099;16317692;18923390;21085649;24958141;16530510;23227182;4746326;8742320;11812920;21274877;7992315;12700423;4746329;17241210;23052410;15466245",
"title": "Targeted liquid chromatography-mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children.",
"title_normalized": "targeted liquid chromatography mass spectrometry analysis of serum acylcarnitines in acetaminophen toxicity in children"
} | [
{
"companynumb": "US-JNJFOC-20140211622",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "The outcomes for patients with metastatic or recurrent esophageal cancer are dismal, with 1-year survival rates of approximately 20%. In this phase II study, we studied the combination of docetaxel (Taxotere) and irinotecan (CPT-11, Camptosar) in patients with metastatic or recurrent esophageal cancer. Eligible patients included those with histologic or cytologic diagnosis of adenocarcinoma or squamous cancer of the esophagus or gastroesophageal junction who had received no previous chemotherapy for metastatic esophageal cancer. Previous chemotherapy in the neoadjuvant or adjuvant setting was allowed. Patients received irinotecan at 160 mg/m2 over 90 minutes followed by docetaxel at 60 mg/m2 intravenously over 1 hour, with chemotherapy cycles repeated every 21 days. Patients were reevaluated every two cycles. Of a planned 40 patients, 15 were enrolled, with 14 patients evaluable for toxicity and 10 evaluable for response and survival. The combination of docetaxel and irinotecan resulted in a response rate of 30%. An additional 40% achieved stable disease. The median survival was 130 days, with three patients still alive at the time of this analysis. The toxicities included 71% incidence of grade 4 hematologic toxicities, with 43% febrile neutropenia. One patient died of cecal perforation after one cycle. There was no evidence of pharmacokinetic interaction, as systemic clearance of both drugs was similar to that seen after single-agent administration. In conclusion, the regimen of docetaxel and irinotecan is active in metastatic or recurrent esophageal cancer. However, this combination chemotherapy regimen has an unacceptable rate of febrile neutropenia. This regimen needs to be modified to reduce the incidence of febrile neutropenia.",
"affiliations": "Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. rgovinda@im.wustl.edu",
"authors": "Govindan|Ramaswamy|R|;Read|William|W|;Faust|Joan|J|;Trinkaus|Kathryn|K|;Ma|Margaret K|MK|;Baker|Sharyn D|SD|;McLeod|Howard L|HL|;Perry|Michael C|MC|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D000077146:Irinotecan; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-9091",
"issue": "17(9 Suppl 8)",
"journal": "Oncology (Williston Park, N.Y.)",
"keywords": null,
"medline_ta": "Oncology (Williston Park)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D000077143:Docetaxel; D004938:Esophageal Neoplasms; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016019:Survival Analysis; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "8712059",
"other_id": null,
"pages": "27-31",
"pmc": null,
"pmid": "14569845",
"pubdate": "2003-09",
"publication_types": "D016430:Clinical Trial; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Phase II study of docetaxel and irinotecan in metastatic or recurrent esophageal cancer: a preliminary report.",
"title_normalized": "phase ii study of docetaxel and irinotecan in metastatic or recurrent esophageal cancer a preliminary report"
} | [
{
"companynumb": "US-PFIZER INC-2019154431",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nGiven the high incidence (1.5%-10%) of invasive aspergillosis (IA) after liver transplantation and the associated mortality, prophylaxis according to the patients' circumstances is a reasonable approach. The purpose of this investigation was to determine the effect and significance of risk factors for IA in a specialized transplantation center.\n\n\nMETHODS\nWe collected data from patients who underwent liver transplantation at the Transplantation Center of the University Hospital Heidelberg (Germany) between December 2001 and December 2004 in a specifically designed database for retrospective analysis. Invasive aspergillosis was defined according to the European Organization for Research and Treatment of Cancer classifications. Univariate analysis and logistic regression were performed to assess the influence of each assumed risk factor.\n\n\nRESULTS\nA total of 195 liver transplantations were performed in 170 patients, with two patients (1.2%) developing a proven IA, seven (4.1%) developing a probable IA, and five developing a possible IA (2.9%). All patients received oral itraconazole prophylaxis. Of these 14 patients with proven, probable or possible IA, 13 died within 4 weeks after the initial diagnosis; this represents 33.3% of all patients with a fatal outcome. Univariate significant factors were retransplantation (p = 0.004), cytomegalovirus (CMV) infection (p = 0.024), dialysis (p < 0.001), renal insufficiency (p = 0.05), thrombocytopenia (p = 0.001), and leukocytopenia (p = 0.002). Multivariate analysis showed an independent influence of CMV infection (OR 6.032, 95% CI 1.446-25.163) and dialysis (OR 14.985, 95%CI 2.936-76.486).\n\n\nCONCLUSIONS\nThe rate of IA found in this investigation is within the range reported in published studies. Based on our data, extended antifungal prophylaxis should be given to liver transplant patients with specific risk factors, such as renal insufficiency, requirement for dialysis, CMV infection, or thrombocytopenia. Additional focus should be on the prevention of CMV infections.",
"affiliations": "Pharmacy Dept., University Hospital of Heidelberg, Heidelberg, Germany. maike.rosenhagen@med.uni-heidelberg.de",
"authors": "Rosenhagen|M|M|;Feldhues|R|R|;Schmidt|J|J|;Hoppe-Tichy|T|T|;Geiss|H K|HK|",
"chemical_list": "D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D017964:Itraconazole",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-008-8124-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "37(4)",
"journal": "Infection",
"keywords": null,
"medline_ta": "Infection",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001228:Aspergillosis; D018890:Chemoprevention; D005260:Female; D005858:Germany; D006785:Hospitals, University; D006801:Humans; D007166:Immunosuppressive Agents; D017964:Itraconazole; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D014180:Transplantation",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "313-9",
"pmc": null,
"pmid": "19629387",
"pubdate": "2009-08",
"publication_types": "D016428:Journal Article",
"references": "15714417;1431256;12491201;8286639;12167683;11731939;18177225;10195093;15714416;15668868;10394848;12352887;2542634;15247928;17251531;16882611;12122510;10554799;17143808;9311708;17251530;9274893;18192906;16120634;12424723;11807679;15653818;10350395;1539220;14550704;12821834;11428968;14563893;18217899;2542701;8254858;10987719",
"title": "A risk profile for invasive aspergillosis in liver transplant recipients.",
"title_normalized": "a risk profile for invasive aspergillosis in liver transplant recipients"
} | [
{
"companynumb": "DE-JNJFOC-20140118985",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Carcinoma penis is one of the common malignancies in developing world especially among rural population. Multimodality treatment with surgery, radiation and chemotherapy for advanced penile carcinoma with groin nodal metastasis is crucial to optimise the outcome. Cisplatin, fluorouracil, methotrexate, vinorelbine, bleomycin and paclitaxel are the common chemotherapeutic agents used along with local therapy. Paucity of data to show superiority of one chemotherapeutic regime over another and only modest response to any combination chemotherapy. Progression of disease after surgery, radiation and chemotherapy is associated with poor outcome and quality of life. Nimotuzumab, Anti EGFR monoclonal antibody, along with paclitaxel in our case of resistant metastatic penile carcinoma has shown good symptomatic palliation and clinical response.",
"affiliations": "Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India.",
"authors": "Pandey|Avinash|A|;Noronha|Vanita|V|;Joshi|Amit|A|;Tongaonkar|Hemant|H|;Bakshi|Ganesh|G|;Prabhash|Kumar|K|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.4103/0971-5851.113411",
"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-34-2410.4103/0971-5851.113411Case ReportResistant metastatic penile carcinoma and response to biochemotherapy with paclitaxel and epidermal growth factor receptor monoclonal antibody, nimotuzumab Pandey Avinash Noronha Vanita Joshi Amit Tongaonkar Hemant 1Bakshi Ganesh 1Prabhash Kumar Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India1 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, IndiaAddress for correspondence: Dr. Avinash Pandey, 18, Department of Medical Oncology, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra, India. E-mail: dr.avinashp9@rediffmail.comJan-Mar 2013 34 1 24 27 Copyright: © Indian Journal of Medical and Paediatric Oncology2013This 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.Carcinoma penis is one of the common malignancies in developing world especially among rural population. Multimodality treatment with surgery, radiation and chemotherapy for advanced penile carcinoma with groin nodal metastasis is crucial to optimise the outcome. Cisplatin, fluorouracil, methotrexate, vinorelbine, bleomycin and paclitaxel are the common chemotherapeutic agents used along with local therapy. Paucity of data to show superiority of one chemotherapeutic regime over another and only modest response to any combination chemotherapy. Progression of disease after surgery, radiation and chemotherapy is associated with poor outcome and quality of life. Nimotuzumab, Anti EGFR monoclonal antibody, along with paclitaxel in our case of resistant metastatic penile carcinoma has shown good symptomatic palliation and clinical response.\n\nBiochemotherapymetastatic penile carcinomanimotuzumab\n==== Body\nINTRODUCTION\nCarcinoma penis is one of the common malignancies in developing world especially among rural population.[1] Poor genital hygiene, promiscuity, phimosis, human papillomavirus (HPV), and tobacco consumption are the common risk factors.[2] The presence and extent of inguinal lymph node metastases are the most important prognostic factors in patients with penile cancer.[3] Local and regional recurrences are common during the first 2 years of follow-up. Cisplatin, fluorouracil, methotrexate, vinorelbine, bleomycin, and paclitaxel are the common chemotherapeutic agents used along with local therapy to improve the outcome in terms of disease control or symptomatic relief.\n\nCASE REPORT\nA 59-year-old male presented with penile ulcer since 1 month with reactive left inguinal lymphadenopathy. Wide excision of lesion with 1 cm margin was done after biopsy revealed squamous cell carcinoma. Subsequently on follow-up, he developed inguinal lymph nodal metastasis 3 months later for which he received bilateral groin radiation to a dose of 54.8 Gy/16 # with direct portal. Recurrence was seen in bilateral inguinal nodes within 3 months for which bilateral groin node dissection was done and adjuvant three cycles of paclitaxel and cisplatin were given in view of multiple groin node involvement and perinodal extension. After 6 months of follow-up, patient developed scrotal edema with multiple perineal nodules and inguinal lymphadenopathy confirmed as metastasis of squamous cell carcinoma on FNAC. In view of good performance status and paucity of alternative treatment option, second-line chemotherapy with two cycles of oxaliplatin and capecitabine were given on compassionate ground which produced no response. There was local progression and involvement of bilateral external iliac lymph nodes. Third-line chemotherapy was administered with four cycles of gemcitabine and vinorelbine. Patient again had no response to therapy. The patient still had an excellent performance status and was very desirous of continuing systemic therapy; hence, it was decided to administer biochemotherapy with nimotuzumab and paclitaxel at a dose of 200 mg and 80 mg/m2 weekly, respectively. After 12 weeks, clinically, there was reduction in scrotal edema and resolution in skin nodules. Response evaluation of PET-CT revealed no change in the status of left inguinal lymphadenopathy with persistent SUV max of 4.0; however, right-sided inguinal metastasis disappeared after biochemotherapy [Figures 1 and 2]. Patient developed grade 3 peripheral neuropathy after 12 weeks; hence, paclitaxel was discontinued and patient is now continuing on weekly nimotuzumab and has completed 23 weeks of nimotuzumab till date.\n\nFigure 1 (a and b) Baseline PET-CT showing bilateral groin lymphadenopathy with scrotal edema. (c and d) Post 12 weeks resolution of right groin lymphadenopathy with persistent disease on left side. (e and f) Showing resolution of lower inguinal lymphadenopathy with persistent scrotal edema-post 12 weeks of therapy\n\nFigure 2 (a and b) Clinical response post 12 weeks of bio-chemotherapy with significant resolution of cutaneous nodules and scrotal edema\n\nDISCUSSION\nCarcinoma penis comprises less than 1% of all malignancies among western population with median age at diagnosis around 60 years and 30% presenting with advanced disease.[4] The incidence is as high as 10-17% in African countries while the age standardized rate in India varies from 0.8 to 1.8 per lakh population with Chennai registry having the highest incidence.[56] Neonatal circumcision commonly practiced in Jews has a preventive role as demonstrated by decrease in incidence of penile carcinoma among men who were circumscribed in early childhood.[57] Higher incidence of penile and cervical carcinoma with concordance among married couple in Hindu population but not in Muslims reiterates the significance of circumcision, HPV infection, and poor post-coital genital hygiene as risk factors for carcinogenesis.[89]\n\nEarly localized penile carcinoma has an excellent outcome with more than 70% long-term survival with local penile conservative approach using surgery or radiotherapy. About 30-40% of patients present with lymph node metastases in which long-term survival is just 20-30%.[3] Multimodality treatments with surgery, radiation, and chemotherapy for advanced penile carcinoma with groin nodal metastasis is crucial to optimize the outcome with minimal toxicity and morbidity. Penile squamous cell carcinoma is chemosensitive. Chemotherapeutic agents including cisplatin, 5-fluorouracil, Bleomycin, methotrexate, and vincristine have been used in various combinations to downstage the tumor and improve resectability in patients with groin node metastases. Earlier, small studies using single drugs such as cisplatin, methotrexate, and bleomycin have shown only modest response rates varying from 15% to 30% with majority of partial response and durability from 1 to 3 months.[1011] Haas et al. in a prospective, multi-institutional Phase II study using cisplatin, bleomycin, and methotrexate demonstrated improvement in response rate upto 32% with 12% complete response with median duration of response upto 16 weeks. However, it came with significant toxicity with 11% treatment-related death and 17% life-threatening complications precluding the establishment of this combination as standard therapy.[12]\n\nLong-term survival post-radical groin node dissection using weekly vincristine, bleomycin, and methotrexate was demonstrated by Pizzocaro et al. They also proposed the potential of curative resection in case of inoperable inguinal nodal metastasis following neoadjuvant chemotherapy.[13] Roth et al., in a small cohort of patients, demonstrated potential benefit of intra-arterial chemotherapy using methotrexate, mitomycin, and bleomycin with 75% response rates and 37% complete responses with two out of three complete responders achieving long-term control rates. Use of bleomycin as a radiosensitizer in low-grade tumors has shown equivalent results to surgery with the potential for penile conservation.[14] Combination of cisplatin and 5-FU in neoadjuvant therapy improved the response rates upto 80% with 40% complete responses.[15] Impressive results of adding taxanes to cisplatin and 5-FU (TPF) in locally advanced head and neck carcinomas with higher complete response rates and trend toward better survival inspired investigators to attempt the same in metastatic penile carcinoma.[16] Complete pathological response was demonstrated in patients completing four cycles of TPF albeit with higher toxicity and 50% of patients had complete clinical response among patients receiving at least two cycles.[17]\n\nNo large-scale prospective trials have been designed to ascertain the optimal timing and regimens of chemotherapy in carcinoma penis partly due to the rarity of the disease. No conclusive data exists to show superiority of one chemotherapeutic regimen over any other in recurrent and metastatic carcinoma with all described combinations resulting in only modest responses. Extensive literature search did not reveal any studies on second-line or beyond chemotherapy, thus limiting options for such subgroup of patients. Increased expression of epidermal growth factor receptor (EGFR) is associated with poorer outcome in advanced head and neck cancer.[18] Overstimulation of EGFR-mediated signaling can contribute to uncontrolled cell division and thus to oncogenic signaling and tumor angiogenesis and metastasis, protecting cancer cells from undergoing apoptosis. Availability of anti-EGFR therapy has shown improvement in response rates with or without chemotherapy in head and neck squamous cell carcinoma in the recurrent or metastatic second-line setting.[19] EGFR overexpression has recently been shown in penile carcinoma with 80% being strongly positive; however, there are no published studies using monoclonal antibodies or tyrosine kinase inhibitors therapeutically in the recurrent or metastatic setting.[20] Taking analogy with head and neck cancer, anti-EGFR therapy may produce similar responses in recurrent or metastatic penile carcinoma. Nimotuzumab is a humanized therapeutic monoclonal antibody against EGFR approved for tumors of epithelial origin expressing EGFR such as head and neck squamous cell carcinoma.[21] No studies using targeted therapy in recurrent or metastatic penile carcinoma has been reported so far. Our result of clinical response to biochemotherapy after progression on multiple lines of chemotherapy possibly opens a new horizon in management of recurrent or metastatic penile carcinoma. Larger prospective studies are necessary to corroborate our experience within the metastatic setting and perhaps also in the neoadjuvant and adjuvant settings.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Misra S Chaturvedi A Misra NC Penile carcinoma: A challenge for the developing world Lancet Oncol 2004 5 240 7 15050955 \n2 Pow-Sang MR Ferreira U Pow-Sang JM Nardi AC Destefano V Epidemiology and natural history of penile cancer Urology 2010 76 S2 6 20691882 \n3 Kulkarni JN Kamat MR Prophylactic bilateral groin node dissection versus prophylactic radiotherapy and surveillance in patients with N0 and N1-2A carcinoma of the penis Eur Urol 1994 26 123 8 7957466 \n4 Greenlee RT Murray T Bolden S Wingo PA Cancer statistics, 2000 CA Cancer J Clin 2000 50 7 33 10735013 \n5 Owor R Carcinoma of the penis in Uganda IARC Sci Publ 1984 63 493 7 6536621 \n6 HPV prevalence in penile carcinomas Last accessed on 2013 Apr 08 Available from:\nhttp://www.apps.who.int/hpvcentre/statistics/dynamic/ico/country_pdf/IND.pdf \n7 Onuigbo WI Carcinoma of skin of penis Br J Urol 1985 57 465 6 4027519 \n8 Boon ME Susanti I Tasche MJ Kok LP Human papillomavirus (HPV)-associated male and female genital carcinomas in a Hindu population. The male as vector and victim Cancer 1989 64 559 65 2544257 \n9 Gajalakshmi CK Shanta V Association between cervical and penile cancers in Madras, India Acta Oncol 1993 32 617 20 8260177 \n10 Ahmed T Sklaroff R Yagoda A Sequential trials of methotrexate, cisplatin and bleomycin for penile cancer J Urol 1984 132 465 8 6206239 \n11 Sklaroff RB Yagoda A Cis-diamminedichloride platinum II (DDP) in the treatment of penile carcinoma Cancer 1979 44 1563 5 498030 \n12 Haas GP Blumenstein BA Gagliano RG Russell CA Rivkin SE Culkin DJ Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: A Southwest Oncology Group study J Urol 1999 161 1823 5 10332445 \n13 Pizzocaro G Piva L Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis Acta Oncol 1988 27 823 4 2466471 \n14 Modig H Duchek M Sjödin JG Carcinoma of the penis. Treatment by surgery or combined bleomycin and radiation therapy Acta Oncol 1993 32 653 5 7505090 \n15 Roth AD Berney CR Rohner S Allal AS Morel P Marti MC Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: An active treatment modality with curative potential Br J Cancer 2000 83 1637 42 11104558 \n16 Hitt R López-Pousa A Martínez-Trufero J Escrig V Carles J Rizo A Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer J Clin Oncol 2005 23 8636 45 16275937 \n17 Pizzocaro G Nicolai N Milani A Taxanes in combination with cisplatin and fluorouracil for advanced penile cancer: Preliminary results Eur Urol 2009 55 546 51 18649992 \n18 Rubin GJ Melhem MF Gooding WE Day R Holst VA Wagener MM Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival J Natl Cancer Inst 1998 90 824 32 9625170 \n19 Baselga J Trigo JM Bourhis J Tortochaux J Cortés-Funes H Hitt R Gascón P Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck J Clin Oncol 2005 23 5568 77 16009950 \n20 Lavens N Gupta R Wood LA EGFR overexpression in squamous cell carcinoma of the penis Curr Oncol 2010 17 4 6 20179797 \n21 Ramakrishnan MS Eswaraiah A Crombet T Piedra P Saurez G Iyer H Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin MAbs 2009 1 41 8 20046573\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-5851",
"issue": "34(1)",
"journal": "Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology",
"keywords": "Biochemotherapy; metastatic penile carcinoma; nimotuzumab",
"medline_ta": "Indian J Med Paediatr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9604571",
"other_id": null,
"pages": "24-7",
"pmc": null,
"pmid": "23878483",
"pubdate": "2013-01",
"publication_types": "D002363:Case Reports",
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"title": "Resistant metastatic penile carcinoma and response to biochemotherapy with paclitaxel and epidermal growth factor receptor monoclonal antibody, nimotuzumab.",
"title_normalized": "resistant metastatic penile carcinoma and response to biochemotherapy with paclitaxel and epidermal growth factor receptor monoclonal antibody nimotuzumab"
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"abstract": "Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that does not cross an intact blood-brain barrier. In the EMILIA trial of T-DM1 vs capecitabine/lapatinib for HER2 positive advanced breast cancer, all patients had baseline brain imaging, and 9/450 (2%) of patients with negative baseline imaging developed new brain disease during T-DM1. We assessed the frequency of brain progression in clinical practice, without routine baseline imaging. We undertook a retrospective study of all patients treated with T-DM1 at the Royal Marsden Hospital from 2011 to 2016. Data collected included baseline characteristics, previous treatment for advanced breast cancer, sites of metastatic disease, duration of T-DM1, sites of progression, and treatment of CNS progression. Fifty-five patients were identified who had received a median of two prior lines of treatment (range 0-5). All were HER2 positive; 45 patients had IHC 3+ tumors and 10 were ISH positive. Patients received a median of 12 cycles of T-DM1 (range 1-34), and six remain on treatment at the time of analysis. Before commencing T-DM1, 16/55 (29%) had known brain metastases (treated with whole brain [9] stereotactic radiotherapy [6] or both [1]). Brain was the first site of progression in 56% (9/16) patients, with a median time to brain progression of 9.9 months (95% CI 3.9-12.2). In patients without known baseline brain metastases, 17.9% (7/39) developed new symptomatic brain disease during T-DM1, after a median of 7.5 months (95%CI 3.8-9.6). Brain progression was isolated, with control of extra-cranial disease in 4/7 patients. Only one patient was suitable for stereotactic radiotherapy. Median time to extra-cranial progression in all patients was 11.5 months (95% CI 9.1-17.7), and median OS in all patients was 17.8 months (95% CI 14.2-22). In patients not screened for brain metastases at baseline, the brain was the first site of progression in a significant proportion. Baseline brain imaging may have a role in standard practice for patients commencing T-DM1 therapy.",
"affiliations": "The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.;The Royal Marsden NHS Foundation Trust, London and Surrey, UK.",
"authors": "Okines|Alicia|A|0000-0002-2068-2593;Irfan|Tazia|T|;Khabra|Komel|K|;Smith|Ian|I|;O'Brien|Mary|M|;Parton|Marina|M|;Noble|Jill|J|;Stanway|Susie|S|;Somaiah|Navita|N|;Ring|Alistair|A|;Johnston|Stephen|S|;Turner|Nicholas|N|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D008453:Maytansine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine",
"country": "United States",
"delete": false,
"doi": "10.1111/tbj.12906",
"fulltext": null,
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"issn_linking": "1075-122X",
"issue": "24(3)",
"journal": "The breast journal",
"keywords": "HER2 positive; T-DM1; brain metastases",
"medline_ta": "Breast J",
"mesh_terms": "D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D001932:Brain Neoplasms; D001943:Breast Neoplasms; D002543:Cerebral Hemorrhage; D005260:Female; D006801:Humans; D008453:Maytansine; D008875:Middle Aged; D018719:Receptor, ErbB-2; D012189:Retrospective Studies; D000068878:Trastuzumab; D016896:Treatment Outcome",
"nlm_unique_id": "9505539",
"other_id": null,
"pages": "253-259",
"pmc": null,
"pmid": "28833867",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Development and responses of brain metastases during treatment with trastuzumab emtansine (T-DM1) for HER2 positive advanced breast cancer: A single institution experience.",
"title_normalized": "development and responses of brain metastases during treatment with trastuzumab emtansine t dm1 for her2 positive advanced breast cancer a single institution experience"
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{
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"activesubstancename": "TRASTUZUMAB"
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{
"abstract": "BACKGROUND\nNevirapine has been used as antiretroviral agent since early '90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity.\n\n\nMETHODS\nWe retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from May 2011 to December 2015. All patients treated with nevirapine who underwent a genotyping for the functional variants mapping into ABCB1, CYP2B6, CYP3A4 and CYP3A5 genes were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3-4 AST/ALT increase during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods. Hardy Weinberg equilibrium was tested by χ2 test. A multivariable logistic regression model was constructed using a backward elimination method.\n\n\nRESULTS\nThree hundred and sixty-two patients were included in the analysis, of which 8 (2.2%) experienced a severe liver toxicity. We observed no differences between patients with and without liver toxicity as regards gender, ethnicity, age and immune-virological status. A higher prevalence of HCV coinfection (75.0% vs 30.2%; p = .0013) and higher baseline AST (58 IU/L vs 26 IU/L; p = 0.041) and ALT (82 IU/L vs 27 IU/L; p = 0.047) median levels were observed in patients with liver toxicity vs those without toxicity. The genotypes CT/TT at ABCB1 rs1045642 single nucleotide polymorphism (SNP), showed a protective effect for liver toxicity when compared with genotype CC (OR = 0.18, 95%CI 0.04-0.76; p = 0.020) in univariate analysis. In the multivariate model, HCV coinfection was independently associated with higher risk of developing liver toxicity (aOR = 8.00, 95%CI 1.27-50.29; p = 0.027), whereas ABCB1 rs1045642 CT/TT genotypes (aOR = 0.10, 95%CI 0.02-0.47; p = 0.004) was associated with a lower risk.\n\n\nCONCLUSIONS\nAccording to our findings HCV coinfection and ABCB1 rs1045642 SNP represent independent determinants of severe liver toxicity related to nevirapine. This genetic evaluation could be included as toxicity assessment in HIV-1-positive subjects treated with nevirapine.",
"affiliations": "Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy. andrea.giacomelli@unimi.it.;Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy.;ASST Fatebenefratelli-Sacco, Clinical Pharmacology Unit, Milan, Italy.;Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy.;ASST Fatebenefratelli-Sacco, Clinical Pharmacology Unit, Milan, Italy.;ASST Fatebenefratelli-Sacco, Clinical Pharmacology Unit, Milan, Italy.;Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy.;Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy.;Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy.;ASST Fatebenefratelli-Sacco, Clinical Pharmacology Unit, Milan, Italy.;Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy.;Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy.;Infectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157, Milan, Italy.",
"authors": "Giacomelli|Andrea|A|http://orcid.org/0000-0003-3685-4289;Riva|Agostino|A|;Falvella|Felicia Stefania|FS|;Oreni|Maria Letizia|ML|;Cattaneo|Dario|D|;Cheli|Stefania|S|;Renisi|Giulia|G|;Di Cristo|Valentina|V|;Lupo|Angelica|A|;Clementi|Emilio|E|;Rusconi|Stefano|S|;Galli|Massimo|M|;Ridolfo|Anna Lisa|AL|",
"chemical_list": "D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D019829:Nevirapine",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-018-3462-5",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 346210.1186/s12879-018-3462-5Research ArticleClinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy http://orcid.org/0000-0003-3685-4289Giacomelli Andrea +39.02.50319761andrea.giacomelli@unimi.itdott.giacomelli@gmail.com 1Riva Agostino agostino.riva@unimi.it 1Falvella Felicia Stefania stefania.falvella@asst-fbf-sacco.it 2Oreni Maria Letizia letizia.oreni@alice.it 1Cattaneo Dario dario.cattaneo@asst-fbf-sacco.it 2Cheli Stefania stefania.cheli@asst-fbf-sacco.it 2Renisi Giulia giulia.renisi@libero.it 1Di Cristo Valentina valentina.dicristo@hotmail.it 1Lupo Angelica angelica.lupo@guest.unimi.it 1Clementi Emilio emilio.clementi@unimi.it 23Rusconi Stefano stefano.rusconi@unimi.it 1Galli Massimo massimo.galli@unimi.it 1Ridolfo Anna Lisa annalisa.ridolfo@gmail.com 11 0000 0004 1757 2822grid.4708.bInfectious Diseases Unit, DIBIC Luigi Sacco - University of Milan, Via G.B. Grassi, 74, 20157 Milan, Italy 2 ASST Fatebenefratelli-Sacco, Clinical Pharmacology Unit, Milan, Italy 3 grid.420417.4E. Medea Scientific Institute, Bosisio Parini, Italy 12 11 2018 12 11 2018 2018 18 55613 12 2017 31 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\nNevirapine has been used as antiretroviral agent since early ‘90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity.\n\nMethods\nWe retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from May 2011 to December 2015. All patients treated with nevirapine who underwent a genotyping for the functional variants mapping into ABCB1, CYP2B6, CYP3A4 and CYP3A5 genes were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3–4 AST/ALT increase during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods. Hardy Weinberg equilibrium was tested by χ2 test. A multivariable logistic regression model was constructed using a backward elimination method.\n\nResults\nThree hundred and sixty-two patients were included in the analysis, of which 8 (2.2%) experienced a severe liver toxicity. We observed no differences between patients with and without liver toxicity as regards gender, ethnicity, age and immune-virological status. A higher prevalence of HCV coinfection (75.0% vs 30.2%; p = .0013) and higher baseline AST (58 IU/L vs 26 IU/L; p = 0.041) and ALT (82 IU/L vs 27 IU/L; p = 0.047) median levels were observed in patients with liver toxicity vs those without toxicity. The genotypes CT/TT at ABCB1 rs1045642 single nucleotide polymorphism (SNP), showed a protective effect for liver toxicity when compared with genotype CC (OR = 0.18, 95%CI 0.04–0.76; p = 0.020) in univariate analysis. In the multivariate model, HCV coinfection was independently associated with higher risk of developing liver toxicity (aOR = 8.00, 95%CI 1.27–50.29; p = 0.027), whereas ABCB1 rs1045642 CT/TT genotypes (aOR = 0.10, 95%CI 0.02–0.47; p = 0.004) was associated with a lower risk.\n\nConclusions\nAccording to our findings HCV coinfection and ABCB1 rs1045642 SNP represent independent determinants of severe liver toxicity related to nevirapine. This genetic evaluation could be included as toxicity assessment in HIV-1-positive subjects treated with nevirapine.\n\nKeywords\nNevirapinePharmacogeneticHepatotoxicityABCB1issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nNevirapine (NVP) is a potent non-nucleoside reverse transcriptase inhibitor widely prescribed in low-income countries for HIV treatment and prevention of mother-to-child transmission of HIV [1]. In high-resource countries, NVP is no longer included among antiretrovirals recommended for initial antiretroviral treatment (ART), although it still remains a valid component of regimens used as ART simplification strategy due to its high efficacy, good metabolic profile, convenience, and low cost [2–4].\n\nAlthough generally well tolerated and effective, some individuals exposed to NVP develop in the short-term hypersensitivity reactions which can manifest as hepatotoxicity and/or severe cutaneous adverse reactions [5]. Hepatotoxicity, in particular, has been reported more commonly with NVP than with other antiretroviral drugs [6, 7]. Higher baseline and nadir CD4 cell count have been found to independently influence the risk of NVP-related adverse reactions and the use of NVP in naive women (with CD4 > 250 cells/uL) and males (with CD4 > 400 cells/uL) is disallowed [8]. The role of the immune system, i.e. higher CD4 cells count, in the development of NVP induced skin and liver toxicity is corroborated by the higher incidence of these events in HIV negative patients receiving NVP as a component of post exposure prophylaxis [5]. Nevertheless, when NVP is used in ART-experienced patients with a controlled viremia the risk of development hepatic or cutaneous adverse events significantly decrease and there is no evident association with CD4 cell count [9–11].\n\nA series of demographic and clinical factors have been found to correlate with an increased risk of NVP-toxicity. In particular, risk factors for ALT and AST elevations during NVP therapy included alteration of liver enzymes before NVP start, co-infection with hepatitis B or hepatitis C viruses, female gender and low body weight [6, 12].\n\nA number of studies have also investigated the possible predictive role of genetic polymorphisms of CYP enzymes or drug-transporters involved in NVP metabolism in predisposing to NVP-related adverse effects. NVP is metabolized by cytochrome P450 enzymes CYP2B6 and CYP3A4 with a minor contribution from CYP3A5 [13]. Single nucleotide polymorphisms (SNPs) have been found to impact NVP pharmacokinetics in ethnic mix populations [14–16]. The genotype TT (c.516/rs3745274) in the CYP2B6 gene, in particular, has been associated with higher plasma concentrations of NVP and its possible role in increasing the risk of hepatotoxicity has been hypothesized [14]. However, there is contrasting evidence of interactions between the presence of variant alleles of CYP2B6 and the development of NVP-induced hepatotoxicity [17–19]. The role of CYP3A4 and CYP3A5 variants in determining NVP plasma concentration and the development of liver toxicity is more controversial, with only one report of association between CYP3A5 variants and transaminase values in African patients exposed to NVP [20]. Moreover, although effects of the efflux transporter P-glycoprotein encoded by the ATP Binding Cassette Subfamily B Member 1 (ABCB1) gene on NVP pharmacokinetics remains controversial, two studies have found a protective effect of ABCB1 c.3435 T allele against NVP-related hepatotoxicity [19, 20].\n\nThe majority of the studies that evaluated the correlation between pharmacogenetic profiles and NVP-related hepatotoxicity have been performed mainly on African population. However, genetic variant frequencies can differ markedly between different populations and only few data are available on the mentioned pharmacogenetic profiles in non-African populations.\n\nWith this in mind, we assessed clinical and pharmacogenetic factors associated with the risk of severe NVP induced liver toxicity in a population of HIV-positive patients attending a clinical center in Italy.\n\nMethods\nThis study was conducted on a cohort of adult HIV-positive patients attending the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan between May 1 2011 and December 31 2015. Patients who have ever received or were receiving a NVP-containing cART at our clinical center were eligible for the analysis.\n\nPatient’s demographic (age, gender, and ethnicity), epidemiological (HIV acquisition risk) and clinical (CDC stage, body mass index, coinfections, previous and current antiretroviral regimens, immune-virological and hemato-biochemical parameters) data registered during medical visits (on average every three months) are routinely collected in a structured database, allowing the use of the database for clinical, epidemiological or therapeutic studies.\n\nSevere hepatotoxicity was defined as ACTG grade 3–4 AST and/or ALT increase (AST or ALT elevation above 5 time the upper reference limit) during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods (RUCAM) [21]. According to the RUCAM, patients were firstly assessed for hepatocellular, cholestatic or mixed liver injury. Subsequently, the score was applied and single cases of NVP-induced liver injury were classified accordingly to the RUCAM total score interpretation and causality grading: ≤0, excluded; 1–2, unlikely; 3–5, possible; 6–8, probable and ≥ 9 highly probable [21].\n\nAll patients who met the inclusion criteria underwent a genotyping for the functional variants mapping in ABCB1 (c.3435/rs1045642), CYP2B6 (c.516/rs3745274), CYP3A5 (*3/rs776746) and CYP3A4 (*22/rs35599367) genes. Genomic DNA was isolated from peripheral blood cells using an automatic DNA extraction system (Maxwell® 16 System, Promega) according to the manufacturer’s instructions. All genotypes were determined by Real-Time PCR, using a panel of LightSNiP from TIB-MolBiol (assays based on SimpleProbe®). At the end of the amplification a melting curve analysis was performed (LightCycler 480, Roche).\n\nStatistical analysis\nBaseline clinical characteristics and genotypes of the two groups of interest, i.e. patients who developed severe hepatotoxicity and those who did not, were compared using the χ2 or Fisher’s exact test for categorical variables and the Mann-Whitney test for continuous variables.\n\nHardy Weinberg equilibrium was tested by χ2 test.\n\nThe association of clinical and genotypic variables with the development of sever liver toxicity was tested by means of a univariate logistic regression model, and all variables were incorporated into a multivariate logistic regression model with a backward elimination method. Statistical significance was defined at 2-sided P value < 0.05. The risks were expressed as adjusted odds ratios (aOR) with relative confidence intervals (95% CI). To perform statistical analysis we used the SAS software version 9.3.\n\nThe study was reviewed and approved by our ethics committee (Comitato Etico Interaziendale, Milano area 1); all subjects signed a dedicated informed consent.\n\nResults\nA total of 362 patients were included in the analysis. Most of them were ART-experienced at the time of initiation of NVP-containing regimen, whereas a minority (16.1%) were ART-naïve. Overall 8 (2.2%) patients experienced a severe liver toxicity during the first three months from NVP initiation. Table 1 shows the comparison of patients who experienced a severe hepatotoxicity and those who did not. There was no significant difference as regards gender, ethnicity, age and baseline immune-virological status between the two groups although females showed a trend towards a higher frequency of NVP-induced hepatotoxicity (75.0% vs 35.9%; p = 0.055). Conversely, patients who developed severe hepatotoxicity were more frequently HCV-coinfected (75.0% vs 30.2%: p = 0.013), showed higher baseline AST and ALT median levels (58 IU/L vs 26 IU/L p = 0.041, 82 IU/L vs 27 IU/L p = 0.047, respectively), and a lower median baseline body mass index value (19.9 kg/m2 vs 22.6 kg/m2; p = 0.017).Table 1 Baseline characteristics\n\n\tTotal\nn = 362\tHepatotoxicity\nn = 8\tNo hepatotoxicity\nn = 354\tp*\t\nAge, median (IQR)\t38.5 (33.7–45.8)\t39.6 (32.7–40.7)\t38.5 (33.8–45.9)\t0.479\t\nFemale, n (%)\t133 (36.7)\t6 (75.0)\t127 (35.9)\t0.055\t\nNaïve patients, n (%)\t58 (16.0)\t1 (12.5)\t57 (16.1)\t0.783\t\nRisk group, n (%)\t\n Eterosexual\t181 (50.0)\t4 (50.0)\t177 (50.0)\t0.213\t\n MSM\t83 (22.9)\t0 (0.0)\t83 (23.5)\t\n IVDUs\t84 (23.2)\t4 (50.0)\t80 (22.6)\t\n Others\t14 (3.9)\t0 (0.0)\t14 (3.9)\t\nCaucasian, n (%)\t330 (91.1)\t7 (87.5)\t323 (91.2)\t0.527\t\nBMI, median (IQR)\t22.4 (20.5–24.5)\t19.9 (18.3–22.0)\t22.6 (20.6–24.5)\t\n0.017\n\t\nAIDS, n (%)\t63 (17.4)\t1 (12.5)\t62 (17.5)\t0.999\t\nCD4+/mL, median (IQR)\t436 (306–593)\t555 (479–611)\t433 (300–592)\t0.157\t\nHIV-RNA log10 cp/mL,median (IQR)\t1.75 (0.00–4.09)\t0.00 (0.00–2.16)\t1.79 (0.00–4.10)\t0.229\t\nHCV coinfection, n (%)\t131 (31.2)\t6 (75.5)\t107 (30.2)\t\n0.013\n\t\nHBV coinfection, n (%)\t21 (5.8)\t1 (12.5)\t20 (5.65)\t0.383\t\nAST U/L, median (IQR)\t26 (20–38)\t58 (29–92)\t26 (20–37)\t\n0.041\n\t\nALT U/L, median (IQR)\t28 (18–50)\t82 (37–122)\t27 (18–49)\t\n0.047\n\t\nARV backbone, n (%)\t\n ABC\t32 (8.8)\t1 (12.5)\t31 (8.8)\t0.311\t\n AZT/DDI/D4T\t223 (61.6)\t7 (87.5)\t216 (61.0)\t\n TDF\t86 (23.7)\t0 (0.0)\t86 (24.3)\t\n Others\t21 (5.8)\t0 (0.0)\t21 (5.9)\t\nAbbreviations: n number, yrs. years, IQR Inter Quartile Range, MSM Man how have sex with man, IVDUs Intra venous drug users, BMI Body Mass Index, cps copies, ABC abacavir, TDF tenofovir diproxil fumarate. *p-values are for χ2 or Fisher’s exact test and Mann-Whitney test\n\n\n\nAccording to RUCAM, the 8 cases of NVP-induced liver toxicity were classified as hepatocellular injury and the likelihood of NVP-induced liver toxicity resulted possible for 3 patients and probable for 5 patients as shown in Table 2. A brief narration for each of the 8 cases is reported in Table 3.Table 2 Updated RUCAM for the nevirapine-induced hepatocellular injury with the total scores for each patient\n\nRUCAM items\tPt 1\tPt 2\tPt 3\tPt 4\tPt 5\tPt 6\tPt 7\tPt 8\t\n1. Time to onset from the beginning of the drug\n • 5–90 days (rechallenge: 1–15 days) (+ 2)\n • < 5 or > 90 days (rechallenge: > 15 days) (+ 1)\nAlternative: Time to onset from cessation of the drug\n • ≤15 days (except for slowly metabolized chemicals: > 15 days) (+ 1)\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t\n2. Course of ALT after cessation of the drug\n • Percentage difference between ALT peak and N\n • Decrease ≥50% within 8 days (+ 3)\n • Decrease ≥50% within 30 days (+ 2)\n • No information or continued drug use (0)\n • Decrease ≥50% after the 30th day (0)\n • Decrease < 50% after the 30th day or recurrent increase (− 2)\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t+ 3\t+ 2\t0\t\n3. Risk factors\n • Alcohol use (current drinks/d: > 2 for women, > 3 for men) (+ 1)\n • Alcohol use (current drinks/d: ≤2 for women, ≤3 for men) (0)\n • Age ≥ 55 years (+ 1)\n • Age < 55 years (0)\t0\t0\t+ 1\t0\t+ 1\t+ 0\t0\t0\t\n4. Concomitant drug(s)\n • None or no information (0)\n • Concomitant drug/herb with incompatible time to onset (0)\n • Concomitant drug/herb with compatible or suggestive time to onset (1)\n • Concomitant drug/herb known as hepatotoxin and with compatible or suggestive time to onset delete marking right side above (− 2)\n • Concomitant drug/herb with evidence for its role in this case (positive rechallenge or validated test) (− 3)\t0\t0\t− 2\t0\t0\t0\t0\t0\t\n5. Search for alternative causes Tick if negative Tick if not done\nGroup I (7 causes)\n • HAV: Anti-HAV-IgM\n • Hepatobiliary sonography / colour Doppler\n • HCV: Anti-HCV, HCV-RNA\n • HEV: Anti-HEV-IgM, anti-HEV-IgG, HEV-RNA\n • Hepatobiliary sonography/colour Doppler sonography of liver vessels/endosonography/CT/MRC\n • Alcoholism (AST/ALT ≥2)\n • Acute recent hypotension history (particularly if underlying heart disease)\nGroup II (5 causes)\n • Complications of underlying disease(s) such as sepsis, metastatic malignancy, autoimmune hepatitis, chronic hepatitis B or C, primary biliary cholangitis or sclerosing cholangitis, genetic liverdiseases\n • Infection suggested by PCR and titer change for\n - CMV (anti-CMV-IgM, anti-CMV-IgG)\n - EBV (anti-EBV-IgM, anti-EBV-IgG)\n - HSV (anti-HSV-IgM, anti-HSV-IgG)\n - VZV (anti-VZV-IgM, anti-VZV-IgG)\nEvaluation of groups I and II\n • All causes-groups I and II—reasonably ruled out (+ 2)\n • The 7 causes of group I ruled out (+ 1)\n • 6 or 5 causes of group I ruled out (0)\n • Less than 5 causes of group I ruled out (− 2)\n • Alternative cause highly probable (− 3)\t0\t0\t0\t0\t−2\t+ 1\t0\t0\t\n6. Previous hepatotoxicity of the drug\n • Reaction labelled in the product characteristics (+ 2)\n • Reaction published but unlabelled (+ 1)\n • Reaction unknown (0)\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t+ 2\t\n7. Response to unintentional reexposure\n • Doubling of ALT with the drug/herb alone, provided ALT below 5 N before reexposure (+3)\n • Doubling of ALT with the drug(s)/herb(s) already given at the time of first reaction (+ 1)\n • Increase of ALT but less than N in the same conditions as for the first administration (−2)\n • Other situations (0)\t0\t0\t0\t0\t0\t0\t0\t0\t\nTotal\t+ 6\t+ 6\t+ 5\t+ 6\t+ 5\t+ 8\t+ 6\t+ 4\t\nAbbreviations: pt. Patient, ALT Alanine aminotransferase, AST Aspartate aminotransferase, CMV Cytomegalovirus, CT Computer tomography, EBV Epstein Barr virus, HAV Hepatitis A virus, HBc Hepatitis B core, HBsAg Hepatitis B antigen, HBV Hepatitis B virus, HCV Hepatitis C virus, HEV Hepatitis E virus, HSV Herpes simplex virus, MRC Magnetic resonance cholangiography, N upper limit of the normal range, RUCAM Roussel Uclaf Causality Assessment Method, VZV Varicella zoster virus\n\nTotal score and resulting causality grading: ≤0, excluded; 1–2, unlikely; 3–5, possible; 6–8, probable; and ≥ 9, highly probable\n\nTable 3 Clinical characteristics of the 8 cases of NVP-induced liver injury. *HLAB5701 tested absent\n\n\tPt 1\tPt 2\tPt 3\tPt 4\tPt 5\tPt 6\tPt 7\tPt 8\t\nHCV coinfection\tno\tyes\tyes\tyes\tyes\tno\tyes\tyes\t\nARV status\tExperienced\tExperienced\tExperienced\tExperienced\tNaive\tExperienced\tExperienced\tExperienced\t\nConcomitant ARV\td4T + 3TC\td4T + 3TC\tABC* + 3TC\tAZT + 3TC\tAZT + 3TC\td4T + ddi\tAZT + 3TC\td4T + ddi\t\nNVP exposure before treatment interruption (days)\t28\t61\t29\t28\t58\t28\t50\t38\t\nConcomitant medication\tnone\tnone\tVitamin D and folinic acid\tnone\tPhenobarbital and alprazolam\tnone\tNone\tFolinic acid\t\nSymptoms\tNausea and severe weakness\tnone\tNausea\tnone\tWeakness\tnone\tNausea\tNone\t\nRequired hospitalization\tyes\tno\tyes\tno\tno\tno\tno\tno\t\nOutcome\tRecovered without sequelae\tRecovered without sequelae\tRecovered without sequelae\tRecovered without sequelae\tRecovered without sequelae\tRecovered without sequelae\tRecovered without sequelae\tRecovered without sequelae\t\nRUCAM\tProbable\tProbable\tPossible\tProbable\tPossible\tProbable\tProbable\tPossible\t\nAbbreviations: Pt Patient, HCV Hepatitis C virus, ARV Antiretroviral, d4T Stavudine, 3TC Lamivudine, ABC Abacavir, AZT Zidovudine, ddi Didanosine, RUCAM Roussel Uclaf Causality Assessment Method\n\n\n\nDistribution of different genotypes of ABCB1 rs1045642, CYP2B6 rs3745274 and CYP3A4/A5 combined are shown in Table 4. A statistical significant difference was observed in patient with and without NVP-induced hepatotoxicity according to ABCB1 rs1045642 genotypes (p = 0.019).Table 4 Disposition of polymorphisms involved in nevirapine metabolism\n\n\tTotal\tHepatotoxicity\tNo hepatotoxicity\t\np*\n\t\nn = 362\tn = 8\tn = 354\t\nABCB1 c.3435/rs1045642, n (%)\t\t\t\t\n0.019\n\t\n CC\t86 (23.8)\t5 (5.8)\t81 (94.2)\t\t\n CT\t178 (49.2)\t1 (0.6)\t177 (99.4)\t\t\n TT\t98 (27.0)\t2 (2.0)\t96 (98.0)\t\t\nCYP2B6 c.516/rs3745274, n (%)\t\t\t\t0.706\t\n GG\t196 (54.1)\t6 (3.1)\t190 (96.9)\t\t\n GT\t141 (39.0)\t2 (1.4)\t139 (98.6)\t\t\n TT\t25 (6.9)\t0 (0.0)\t25 (100.0)\t\t\nCYP3A4/A5 **, n (%)\t\t\t\t0.602\t\n Extensive\t58 (16.1)\t0 (0.0)\t58 (100.0)\t\t\n Intermediate\t270 (74.5)\t8 (3.0)\t262 (97.0)\t\t\n Poor\t25 (6.9)\t0 (0.0)\t25 (100.0)\t\t\n nd\t9 (2.5)\t0 (0.0)\t9 (100.0)\t\t\nAbbreviations: n number, nd not determined, ABCB ATP Binding Cassette Subfamily B, CYP Cytochrome P450 enzyme\n\n*χ2 test ** CYP3A4*22/rs35599367 and CYP3A5*3/rs776746 combined genotypes for comprehensive functional evaluation [33, 34]\n\n\n\nIn univariate analysis (Table 5), male gender (OR = 0.19 95%CI 0.04–0.94; p = 0.042), HCV coinfection (OR = 6.93 95%CI 1.38–34.87; p = 0.019), AST (OR = 1.02, 95%CI 1.01–1.03; p = 0.008) and ALT (OR = 1.01, 95%CI 1.00–1.02; p = 0.015) median level at the beginning of NVP have been associated with an increased risk of severe NVP-induced liver toxicity. On the other hand, genotypes CT/TT of ABCB1 rs1045642 (OR = 0.18, 95%CI 0.04–0.76; p = 0.020) and greater value of body mass index (OR = 0.7 95%CI 0.51–0.94, p = 0.02) showed a protective effect.Table 5 Backward logistic regression of factors involved in nevirapine induced liver toxicity\n\n\tOR (95%CI)\t\np\n\taOR (95%CI)\t\np\n\t\nMale vs Female\t0.19 (0.04–0.94)\t\n0.042\n\t0.27 (0.06–1.30)\t0.102\t\nAge (× 1 year more)\t0.96 (0.88–1.04)\t0.293\t–\t\t\nMSM vs HE\t0.24 (0.01–4.51)\t0.338\t–\t\t\nIVDUs vs HE\t2.20 (0.58–8.41)\t0.247\t–\t\t\nOther vs HE\t1.36 (0.06–29.16)\t0.844\t–\t\t\nCaucasian vs Non-Caucasian\t0.67 (0.08–5.64)\t0.714\t–\t\t\nBMI (× 1 more)\t0.70 (0.51–0.94)\t\n0.020\n\t0.72 (0.52–1.00)\t0.050\t\nPrevious AIDS\t0.67 (0.08–5.56)\t0.713\t–\t\t\nPrevious therapy duration (× 1 year more)\t1.05 (0.90–1.23)\t0.518\t–\t\t\nCD4 200–500 cell/μL vs < 200 cell/μL\t1.17 (0.05–25.7)\t0.920\t1.51 (0.07–32.23)\t0.790\t\nCD4 > 500 cell/μL vs < 200 cell/μL\t3.97 (0.21–74.51)\t0.357\t8.12 (0.42–156.90)\t0.166\t\nHIV-RNA (× 1 log10 more)\t0.80 (0.54–1.18)\t0.260\t–\t\t\nAST (× 1 more)\t1.02 (1.01–1.03)\t\n0.008\n\t1.01 (0.99–1.03)\t0.144\t\nALT (× 1 more)\t1.01 (1.00–1.02)\t\n0.015\n\t–\t\t\nHCV coinfection\t6.93 (1.38–34.87)\t\n0.019\n\t8.00 (1.27–50.29)\t\n0.027\n\t\nHBV coinfection\t2.39 (0.28–20.36)\t0.427\t–\t\t\nARV Backbone: AZT/DDI/D4T vs ABC\t0.73 (0.12–4.47)\t0.731\t–\t\t\nARV Backbone: TDF vs ABC\t0.12 (0.01–3.141)\t0.204\t–\t\t\nARV Backbone: Other vs ABC\t0.49 (0.02–13.47)\t0.672\t–\t\t\nABCB1 rs1045642 CT/TT vs CC\t0.18 (0.04–0.76)\t\n0.020\n\t0.10 (0.02–0.47)\t\n0.004\n\t\nAbbreviations: OR Odds Ratio, aOR adjusted Odds Ratio, CI confidence interval, HE Heterosexual, MSM Man how have sex with man, IVDUs Intra venous drug users, BMI Body Mass Index, cps copies, ABC abacavir, TDF tenofovir diproxil fumarate, BMI Body Mass Index, ABCB ATP Binding Cassette Subfamily B\n\n\n\nIn the multivariate logistic regression model (Table 5), HCV coinfection was confirmed to be independently associated with a higher risk of developing liver toxicity (aOR = 8.00, 95%CI 1.27–50.29; p = 0.027), whereas ABCB1 CT/TT genotypes (aOR = 0.10, 95%CI 0.02–0.47; p = 0.004) has been associated with a lower risk; a higher body mass index (aOR = 0.72, 95%CI 0.519–1.000; p = 0.050) has been barely related to a lower risk (Table 5). On the contrary, the association between gender, baseline AST levels and NVP-induced liver toxicity wasn’t confirmed in the final multivariate model.\n\nDiscussion\nIn this study conducted in a monocentric cohort of HIV-1 positive patients exposed to NVP we observed, during the first three months of treatment, an incidence of severe liver toxicity of 2.2%. This finding is similar to that reported by other cohorts when NVP was used in experienced patients [10, 22]. We did not observe a significant association between the development of hepatotoxicity and high CD4 cells count at NVP start, supporting the observation of low frequency of NVP induced liver toxicity in experienced patients [10]. The mechanisms involved in the development of severe hepatotoxicity are not well explained and it could be that in patients never exposed to antiretroviral therapy immune-mediated process leading to immune-reconstitution could elicit the development of liver toxicity [23]. On the contrary, in experienced patients with a stable immune-virological situation, hepatotoxicity could be driven by a direct effect of the drug in susceptible patients [24]. We confirm previous findings supporting the importance of HCV coinfection as independent factor associated to the development of NVP-related liver toxicity; HCV infection could play a direct role causing liver injury and also could interfere with the metabolism of the drug [8, 11, 25]. The enhanced risk of development hepatotoxicity in HCV coinfected patients treated with NVP seems to be independent from NVP plasmatic concentrations, since comparable NVP concentration are observed in patients with and without HCV coinfection [26].\n\nA significant correlation between low value of body mass index (< 18.5) such as for increased NVP plasma concentration and increased risk for hepatotoxicity has been previously reported [12, 18], in our study we observed a trend of body weight in predisposing to NVP-hepatotoxicity albeit not confirmed in the multivariate model.\n\nIn accordance with previous studies, we did not found a statistically significant association between polymorphisms in CYPs genes (CYP2B6, CYP3A4, CYP3A5) and the development of severe hepatotoxicity. Although these genes are involved in NVP metabolism [27] and their functional variants may significantly affect NVP plasma concentrations [28–30], their role in predisposing NVP induced hepatotoxicity remains unclear [19, 31].\n\nThe ABCB1 gene encodes for P-glycoprotein, one of the most important efflux pomp involved in the transport of both NVP and efavirenz and a modification of this protein could determine an alteration in the intracellular concentration of these drugs [32].\n\nInterestingly, the functional variant c.3435 C > T of ABCB1 gene was associated with an increases risk for severe liver toxicity in a previous study conducted by Hass et al. in South-Africa [19]. Moreover, the variant ABCB1 c.3435 C > T resulted protective for NVP-associated hepatic adverse events in another study conducted in Mozambique [20]. No statistically significant association between ABCB1 c.3435 C > T and NVP adverse events was found in another study conducted by Yuan J et al. in an ethnic mixed population. However, these authors found a significant association between ABCB1 c.3435 C > T variant and hepatic adverse events among Africans but not Asians or Caucasians, despite these latter groups showed increased T-allele frequencies [31].\n\nOverall our study, which was conducted on a prevalently European Caucasian population, disagrees with the study by Yan et al. On the contrary it supports the protective role of T allele of ABCB1 rs1045642 for NVP-hepatotoxicity evidenced by Hass et al. and Ciccacci et al.\n\nThe present study has some limitations. In particular, due to the retrospective design we cannot exclude the presence of possible bias related to loss of data. A sub-optimal performance of RUCAM, which is more fitted for a prospective patient evaluation, could be hypothesized because of the retrospective nature of the study. Moreover, if on one hand the limited number of NVP induced hepatic adverse events supports the good safety profile of this drug in ART-experienced patients, on the other hand our study could not exclude that the prevalence of the investigated polymorphisms could be driven by chance. Moreover, the prevalence of Caucasian ethnicity limited the comparison of our findings between different ethnic groups.\n\nConclusion\nBeyond to clinical conditions well known to drive the development of hepatotoxicity during NVP treatment, i.e. HCV coinfection and body mass index, pharmacogenomic profiles could also play a role in this phenomenon. Our results suggest the independent role of ABCB1 rs1045642 as a predictive marker of severe liver toxicity related to NVP. Further validation studies, to assess possible clinical application of this marker in countries in which NVP is still widely used and/or in patients with other risk factors for nevirapine related toxicity, are warranted.\n\nAbbreviations\nABCBATP Binding Cassette Subfamily B\n\naORAdjusted Odds Ratio\n\nARTAntiretroviral treatment\n\nCIConfidence interval\n\nCYPCytochrome P450 enzyme\n\nHIV-1Human immunodeficiency virus type 1\n\nIQRInter quartile range\n\nNVPNevirapine\n\nOROdds Ratio\n\nRUCAMRoussel Uclaf Causality Assessment Methods\n\nSNPsSingle nucleotide polymorphisms\n\nAcknowledgements\nWe thank Mrs. Tiziana Formenti for the excellent technical help.\n\nFunding\nNo financial support to this study.\n\nAvailability of data and materials\nThe data sets used and/or analyzed during the current study available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAG, ALR, AR, FSF, MLO, MG, SR designed the study. GR, VDC, AL assessed the patient’s documentation and evaluated the inclusion in the study. AG, ALR, GR, VDC, AL, were involved in data collection and interpretation. FSF, EC, DC, SC performed laboratory analyses. AG, MLO were responsible for the statistical analyses. All authors interpreted the data and drafted the manuscript. All authors have critically revised and approved the final version.\n\nEthics approval and consent to participate\nThe study was reviewed and approved by our ethics committee (Comitato Etico Interaziendale, Milano area 1); all subjects signed a dedicated informed consent.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nS.R. has received consultancy payments and speaking fee from Bristol-Myers Squibb, Gilead, ViiV Healthcare, Merck Sharp Dohme, ABBvie and Janssen. M.G. has received consultancy payments and speaking fee from Bristol-Myers Squibb, Gilead, ViiV Healthcare, Merck Sharp Dohme, ABBvie, Janssen and Roche.\n\nPreliminary data of this study were presented as poster presentation (PE10/15) at the 16th European AIDS conference, October 25–27, 2017 Milan, Italy.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Milinkovic A Martínez E Nevirapine in the treatment of HIV Expert Rev Anti-Infect Ther 2004 2 367 373 10.1586/14787210.2.3.367 15482202 \n2. De Boissieu P Dramé M Raffi F Dat’AIDS study group. Long-term efficacy and toxicity of abacavir/lamivudine/nevirapine compared to the most prescribed ARV regimens before 2013 in a French Nationwide cohort study Medicine (Baltimore) 2016 95 37 e4890 10.1097/MD.0000000000004890 27631261 \n3. 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Multiple genetic variants predict steady-state nevirapine clearance in HIV-infected Cambodians Pharmacogenet Genomics 2012 22 12 868 876 10.1097/FPC.0b013e32835a5af2 23104099 \n15. Penzak SR Kabuye G Mugyenyi P Cytochrome P450 2B6 (CYP2B6) G516T influences nevirapine plasma concentrations in HIV-infected patients in Uganda HIV Med 2007 8 2 86 91 10.1111/j.1468-1293.2007.00432.x 17352764 \n16. Wyen C Hendra H Vogel M Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients J Antimicrob Chemother 2008 61 914 918 10.1093/jac/dkn029 18281305 \n17. Rotger M Colombo S Furrer H Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients Pharmacogenet Genomics 2005 15 1 5 10.1097/01213011-200501000-00001 15864119 \n18. Gozalo C Grard L Loiseau P For the ANRS 081 study group pharmacogenetics of toxicity, plasma trough concentration and treatment outcome with Nevirapine-containing regimen in anti-retroviral-nave HIV-infected adults: an exploratory study of the TRIANON ANRS 081 trial Basic & Clinical Pharmacology & Toxicology 2011 109 513 520 10.1111/j.1742-7843.2011.00780.x 21824325 \n19. Haas DW Bartlett JA Andersen JW Pharmacogenetics of nevirapine-associated hepatotoxicity: an adult AIDS Clinical Trials Group collaboration Clin Infect Dis 2006 43 783 786 10.1086/507097 16912957 \n20. Ciccacci C Borgiani P Ceffa S Nevirapine-induced hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique Pharmacogenomics 2010 11 23 31 10.2217/pgs.09.142 20017669 \n21. Danan G Teschke R RUCAM in drug and herb induced liver injury: the update Int J Mol Sci 2016 17 1 14 10.3390/ijms17010014 \n22. Brück S Witte S Brust J Hepatotoxicity in patients prescribed efavirenz or nevirapine Eur J Med Res 2008 13 343 348 18700192 \n23. Bekker Z Walubo A du Plessis JB The role of the immune system in Nevirapine-induced subclinical liver injury of a rat model ISRN Pharmaceutics 2012 2012 932542 10.5402/2012/932542 22957276 \n24. Núñez M Hepatotoxicity of antiretrovirals: incidence, mechanisms and management J Hepatol 2006 44 1 Suppl S132 S139 10.1016/j.jhep.2005.11.027 16364487 \n25. Sulkowski MS Thomas DL Chaisson RE Moore RD Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection JAMA 2000 283 74 80 10.1001/jama.283.1.74 10632283 \n26. Vogel M Bertram N Wasmuth JC Wyen C Voigt E Schwarze-Zander C Sudhop T Fätkenheuer G Rockstroh JK Reichel C Nevirapine pharmacokinetics in HIV-infected and HIV/HCV-coinfected individuals J Antimicrob Chemother 2009 63 5 988 991 10.1093/jac/dkp044 19270314 \n27. Wen B Chen Y Fitch WL Metabolic activation of nevirapine in human liver microsomes: dehydrogenation and inactivation of cytochrome P450 3A4 Drug Metab Dispos 2009 37 7 1557 1562 10.1124/dmd.108.024851 19364830 \n28. Schipani A Wyen C Mahungu T German competence network for HIV/AIDS. Integration of population pharmacokinetics and pharmacogenetics: an aid to optimal nevirapine dose selection in HIV-infected individuals J Antimicrob Chemother 2011 66 6 1332 1339 10.1093/jac/dkr087 21441248 \n29. Mahungu T Smith C Turner F Cytochrome P450 2B6 516G-->T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population HIV Med. 2009 10 5 310 317 10.1111/j.1468-1293.2008.00689.x 19228205 \n30. Giacomelli A Rusconi S Falvella FS Clinical and genetic determinants of nevirapine plasma trough concentration SAGE Open Med 2018 6 2050312118780861 10.1177/2050312118780861 29899984 \n31. Yuan J Guo S Hall D Nevirapine Toxicogenomics study team. Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent AIDS 2011 25 10 1271 1280 10.1097/QAD.0b013e32834779df 21505298 \n32. Owen A Pirmohamed M Khoo HS Back DJ Pharmacogenetics of HIV therapy Pharmacogenet Genomics 2006 16 693 703 10.1097/01.fpc.0000236338.41799.57 17001288 \n33. Zanger UM Schwab M Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation Pharmacol Ther 2013 138 1 103 141 10.1016/j.pharmthera.2012.12.007 23333322 \n34. Kitzmiller JP Sullivan DM Phelps MA Wang D Sadee W CYP3A4/5 combined genotype analysis for predicting statin dose requirement for optimal lipid control Drug Metabol Drug Interact 2013 28 1 59 63 10.1515/dmdi-2012-0031 23314529\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2334",
"issue": "18(1)",
"journal": "BMC infectious diseases",
"keywords": "ABCB1; Hepatotoxicity; Nevirapine; Pharmacogenetic",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D056486:Chemical and Drug Induced Liver Injury; D004359:Drug Therapy, Combination; D005260:Female; D020022:Genetic Predisposition to Disease; D006678:HIV; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index",
"nlm_unique_id": "100968551",
"other_id": null,
"pages": "556",
"pmc": null,
"pmid": "30419834",
"pubdate": "2018-11-12",
"publication_types": "D016428:Journal Article",
"references": "18700192;14722442;23104099;27631261;17591022;16364487;17001288;23333322;28222098;22957276;15482202;16912957;17352764;14562855;20542847;10632283;26107265;15717255;15864119;18281305;19487907;21505298;19228205;14986279;29899984;26712744;19270314;10421616;23314529;19364830;22413955;20017669;21824325;21441248",
"title": "Clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of HIV positive patients receiving nevirapine-based antiretroviral therapy.",
"title_normalized": "clinical and genetic factors associated with increased risk of severe liver toxicity in a monocentric cohort of hiv positive patients receiving nevirapine based antiretroviral therapy"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1069785",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": "3",
... |
{
"abstract": "The number of breast cancer survivors is gradually increasing and a subset of these patients experience long-term adverse effects of adjuvant systemic therapy, including cognitive decline. Surprisingly, relatively little is known about the long-term adverse effects of endocrine treatment on cognition. As 75% of all patients with breast cancer are eligible to receive hormonal treatment, understanding the potential neurocognitive adverse effects of such therapy is of utmost importance. Concerns about adverse cognitive effects of adjuvant endocrine therapy are timely, as recently updated guidelines recommend increasing the length of such therapy from 5 years to 10 years for a subset of patients. The decline of cognitive functions can have a detrimental impact on quality of life and might interfere with independent living. This Review discusses the tissue-selective side effects of endocrine therapies and specifically their impact on cognitive function, on the basis of clinical data; the neurobiological effects of endocrine therapies as observed in preclinical models are also discussed. We highlight the critical issues that need to be addressed in future preclinical and clinical studies in order to best assess the cognitive effects of endocrine treatment in patients with breast cancer.",
"affiliations": "Department of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, Netherlands.;Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, Netherlands.;Department of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, Netherlands.;Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, Netherlands.",
"authors": "Zwart|Wilbert|W|;Terra|Huub|H|;Linn|Sabine C|SC|;Schagen|Sanne B|SB|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal",
"country": "England",
"delete": false,
"doi": "10.1038/nrclinonc.2015.124",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1759-4774",
"issue": "12(10)",
"journal": "Nature reviews. Clinical oncology",
"keywords": null,
"medline_ta": "Nat Rev Clin Oncol",
"mesh_terms": "D018931:Antineoplastic Agents, Hormonal; D001943:Breast Neoplasms; D003072:Cognition Disorders; D003657:Decision Making; D005260:Female; D006801:Humans",
"nlm_unique_id": "101500077",
"other_id": null,
"pages": "597-606",
"pmc": null,
"pmid": "26196252",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "23980635;24384646;22047059;18551510;21046229;17214869;20689282;22750586;15886402;21474379;24520097;16084253;12090977;11289127;19204204;18073378;18342840;19813133;23993385;14741674;22699893;21417532;10581405;17898668;12771112;17307102;17476147;18823033;12488359;23917950;15742545;10579320;22658913;25423896;10680789;25267747;16682732;23188540;20385495;23483375;11226319;19217534;22285935;24138841;24277439;21392408;17439378;10368776;25071135;19472057;22095746;18061360;21354373;11061547;25222701;23793983;24508665;10414967;21320576;20332105;11457488;16382061;20967847;19470131;20506473;14766964;12106699;11194452;22004260;24336141;23219286;21247627;24291380;17570500;24333009;16556737;19183965;16523200;23371464;15511601;25032035;24157828;23873768;21826442;11749982;20142601;24802975;18292188;23008308;20097718;17148777;18753366;22453825;17980408;22353807;10984637;16083887;10564741;25156329;9794460;25205317;20821047;19085975;21749911;25349302;20336566;14551341;25483452;24977455;17761551;22138012;23511253;9638261;17019432;15083379;25332252;11812532;18768369;1893376;14745746;22289042",
"title": "Cognitive effects of endocrine therapy for breast cancer: keep calm and carry on?",
"title_normalized": "cognitive effects of endocrine therapy for breast cancer keep calm and carry on"
} | [
{
"companynumb": "NL-MYLANLABS-2015M1035729",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine whether the rate of serious infection is higher in anti-tumor necrosis factor (anti-TNF)-treated rheumatoid arthritis (RA) patients compared with RA patients treated with traditional disease-modifying antirheumatic drugs (DMARDs).\n\n\nMETHODS\nThis was a national prospective observational study of 7,664 anti-TNF-treated and 1,354 DMARD-treated patients with severe RA from the British Society for Rheumatology Biologics Register. All serious infections, stratified by site and organism, were included in the analysis.\n\n\nRESULTS\nBetween December 2001 and September 2005, there were 525 serious infections in the anti-TNF-treated cohort and 56 in the comparison cohort (9,868 and 1,352 person-years of followup, respectively). The incidence rate ratio (IRR), adjusted for baseline risk, for the anti-TNF-treated cohort compared with the comparison cohort was 1.03 (95% confidence interval 0.68-1.57). However, the frequency of serious skin and soft tissue infections was increased in anti-TNF-treated patients, with an adjusted IRR of 4.28 (95% confidence interval 1.06-17.17). There was no difference in infection risk between the 3 main anti-TNF drugs. Nineteen serious bacterial intracellular infections occurred, exclusively in patients in the anti-TNF-treated cohort.\n\n\nCONCLUSIONS\nIn patients with active RA, anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment, after adjustment for baseline risk. In contrast, the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues.",
"affiliations": "British Society for Rheumatology Biologics Register Control Centre Consortium, Manchester, UK.",
"authors": "Dixon|W G|WG|;Watson|K|K|;Lunt|M|M|;Hyrich|K L|KL|;Silman|A J|AJ|;Symmons|D P M|DP|;|||",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": "10.1002/art.21978",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-3591",
"issue": "54(8)",
"journal": "Arthritis and rheumatism",
"keywords": null,
"medline_ta": "Arthritis Rheum",
"mesh_terms": "D000068879:Adalimumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001424:Bacterial Infections; D015331:Cohort Studies; D018563:Disease Notification; D000068800:Etanercept; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007074:Immunoglobulin G; D007155:Immunologic Factors; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D006113:United Kingdom",
"nlm_unique_id": "0370605",
"other_id": null,
"pages": "2368-76",
"pmc": null,
"pmid": "16868999",
"pubdate": "2006-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register.",
"title_normalized": "rates of serious infection including site specific and bacterial intracellular infection in rheumatoid arthritis patients receiving anti tumor necrosis factor therapy results from the british society for rheumatology biologics register"
} | [
{
"companynumb": "GB-PFIZER INC-2018481345",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Statins are contraindicated in patients with myopathies. Until a few years ago, in those patients with Familial Hypercholesterolemia who also presented muscular dystrophies and didńt reach adequate cholesterol plasmatic levels, the next therapeutic ladder was lipoapheresis. When iPCSK9 first appeared, lipoapheresis could be suspended in some of these patients, sustaining nevertheless proper levels of cholesterol. We present the case of a 27 year-old male, diagnosed with Congenital Muscular Dystrophy in the early childhood. He was referred to the Unit of Lipidology presenting hypercholesterolemia which, after genetic test, was assessed as Heterozygous Familial Hypercholesterolemia. Despite of treatment with diet and ezetimibe, cLDL blood levels abide high, being consequently included in lipoapheresis programme, therewith obtained levels of cLDL of 70mg/dl. In providing iPCSK9, lipoapheresis was withdrawn and treatment with alirocumab 150mg fortnightly introduced, unveiling a positive response, and sustaining cLDL levels around 75mg/dl.",
"affiliations": "Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, La Rioja, España. Electronic address: sarnedo@riojasalud.es.;Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, La Rioja, España.;Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, La Rioja, España.;Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, La Rioja, España.;Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, La Rioja, España.;Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, La Rioja, España.;Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, La Rioja, España.;Unidad de Lípidos, Servicio de Medicina Interna, Hospital San Pedro, Logroño, La Rioja, España.",
"authors": "Arnedo Hernández|Sergio|S|;Mosquera Lozano|José Daniel|JD|;Martínez de Narvajas Urra|Iratxe|I|;Menéndez Fernández|Estela|E|;Rabadán Pejenaute|Elisa|E|;Baeza Trinidad|Ramón|R|;Casañas Martínez|Marta|M|;Brea Hernando|Angel|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; C571059:alirocumab",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.arteri.2019.01.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0214-9168",
"issue": "31(6)",
"journal": "Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis",
"keywords": "Cholesterol-LDL; Colesterol-LDL; Distrofia muscular; Hipercolesterolemia; Hypercholesterolemia; Muscular dystrophy",
"medline_ta": "Clin Investig Arterioscler",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; D006801:Humans; D006937:Hypercholesterolemia; D008297:Male; D009136:Muscular Dystrophies; D000091362:PCSK9 Inhibitors",
"nlm_unique_id": "9208512",
"other_id": null,
"pages": "278-281",
"pmc": null,
"pmid": "30979437",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "iPCSK9 treatment of Familial Hypercholesterolemia in a patient diagnosed as Congenital Muscular Dystrophy with contraindication for statin use.",
"title_normalized": "ipcsk9 treatment of familial hypercholesterolemia in a patient diagnosed as congenital muscular dystrophy with contraindication for statin use"
} | [
{
"companynumb": "ES-ALKEM LABORATORIES LIMITED-ES-ALKEM-2019-03675",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EZETIMIBE"
},
"drugad... |
{
"abstract": "Electroconvulsive therapy (ECT) may be considered for treatment of severe, treatment-resistant, and emergent depression associated with MDD or bipolar disorder. Patients with epilepsy usually take medications that raise the seizure threshold, which poses challenges during ECT. We report a 66-year-old male with epilepsy taking levetiracetam extended-release (XR), lorazepam, and zonisamide requiring ECT for severe MDD. After literature review, the XR form of levetiracetam was changed to higher doses of the immediate-release (IR) formulation, and zonisamide was discontinued 2 days prior to ECT in the hospital and was resumed when the patient underwent outpatient continuation ECT. The patient was treated to remission after receiving 8 acute bilateral ECT treatments before being transitioned to continuation ECT. We provide a brief review of medication management of antiepileptic drugs and other medications that increase the seizure threshold during ECT. To our knowledge, this is the first reported case describing the management of levetiracetam, lorazepam, and zonisamide concomitantly during ECT. Our case suggests that utilizing the IR formulation of levetiracetam, administering the evening dose early the day prior to the procedure, and temporarily discontinuing zonisamide prior to bilateral ECT is effective for the treatment of severe MDD while maintaining seizure prophylaxis.",
"affiliations": "PGY-1 Pharmacy Resident, Providence St Patrick Hospital, Department of Pharmacy, Missoula, Montana.;PGY-1 Pharmacy Resident, Providence St Patrick Hospital, Department of Pharmacy, Missoula, Montana.;Student, Skaggs School of Pharmacy, College of Health, The University of Montana, Missoula, Montana.;Psychiatrist, Providence St Patrick Hospital, Department of Psychiatry, Missoula, Montana.;Psychiatrist, Providence St Patrick Hospital, Department of Psychiatry, Missoula, Montana.",
"authors": "McGrane|Ian R|IR|https://orcid.org/0000-0002-9889-7260;Tenison|Rachel E|RE|https://orcid.org/0000-0002-8144-5508;Bimler|Dana M|DM|https://orcid.org/0000-0002-2452-9780;Munjal|Robert C|RC|https://orcid.org/0000-0003-2709-6981;Molinaro|Jason R|JR|https://orcid.org/0000-0002-1410-2310",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.9740/mhc.2021.01.023",
"fulltext": "\n==== Front\nMent Health Clin\nMent Health Clin\nmhcl\nMent Health Clin\nThe Mental Health Clinician\n2168-9709 College of Psychiatric & Neurologic Pharmacists \n\n10.9740/mhc.2021.01.023\nMHC-D-20-00038\nCase Reports\nSuccessful bilateral electroconvulsive therapy in a patient with a seizure disorder taking levetiracetam, lorazepam, and zonisamide: A case report\nhttps://orcid.org/0000-0002-9889-7260McGrane Ian R. PharmD https://orcid.org/0000-0002-8144-5508Tenison Rachel E. PharmD2 https://orcid.org/0000-0002-2452-9780Bimler Dana M. PharmD candidate3 https://orcid.org/0000-0003-2709-6981Munjal Robert C. MD4 https://orcid.org/0000-0002-1410-2310Molinaro Jason R. MD5 \n2 PGY-1 Pharmacy Resident, Providence St Patrick Hospital, Department of Pharmacy, Missoula, Montana\n\n\n3 Student, Skaggs School of Pharmacy, College of Health, The University of Montana, Missoula, Montana\n\n\n4 Psychiatrist, Providence St Patrick Hospital, Department of Psychiatry, Missoula, Montana\n\n\n5 Psychiatrist, Providence St Patrick Hospital, Department of Psychiatry, Missoula, Montana\n\n1 Assistant Professor, Skaggs School of Pharmacy, College of Health, The University of Montana, Missoula, Montana, ian.mcgrane@umontana.eduDisclosures: This article was completed without any external funding. No commercial organizations had any role in the writing of this paper for publication. I.R.M. receives royalties from Hogrefe Publishing Corp. R.E.T., D.M.B., R.C.M., and J.R.M. have no conflicts of interest.\n\n\n1 2021 \n8 1 2021 \n11 1 23 26\n© 2021 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists.2021This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Electroconvulsive therapy (ECT) may be considered for treatment of severe, treatment-resistant, and emergent depression associated with MDD or bipolar disorder. Patients with epilepsy usually take medications that raise the seizure threshold, which poses challenges during ECT. We report a 66-year-old male with epilepsy taking levetiracetam extended-release (XR), lorazepam, and zonisamide requiring ECT for severe MDD. After literature review, the XR form of levetiracetam was changed to higher doses of the immediate-release (IR) formulation, and zonisamide was discontinued 2 days prior to ECT in the hospital and was resumed when the patient underwent outpatient continuation ECT. The patient was treated to remission after receiving 8 acute bilateral ECT treatments before being transitioned to continuation ECT. We provide a brief review of medication management of antiepileptic drugs and other medications that increase the seizure threshold during ECT. To our knowledge, this is the first reported case describing the management of levetiracetam, lorazepam, and zonisamide concomitantly during ECT. Our case suggests that utilizing the IR formulation of levetiracetam, administering the evening dose early the day prior to the procedure, and temporarily discontinuing zonisamide prior to bilateral ECT is effective for the treatment of severe MDD while maintaining seizure prophylaxis.\n\nseizure disorderepilepsymajor depressive disorderelectroconvulsive therapyzonisamidelevetiracetamanticonvulsantbenzodiazepine\n==== Body\nBackground\nMost treatment guidelines support the use of electroconvulsive therapy (ECT) in severe, treatment-resistant, or emergent cases of MDD.1,2 The neuronal mechanism of ECT seen in MDD is unclear with the main theory being that seizures induce changes in neurotransmitters, neuroplasticity, and brain tissue connectivity.1,3 Patients with epilepsy requiring ECT likely receive seizure threshold–raising medications, such as benzodiazepines (BZDs) or antiepileptic drugs (AEDs). The goal of medication management in such cases is to achieve adequate seizure (eg, 30 to 90 seconds) during ECT without causing spontaneous seizures.4,5 ECT is often delivered using brief pulse width and electrical intensity and titrated based on minimum intensity to exceed the seizure threshold.1 Because BZDs and AEDs may diminish ECT response, considerations can be made to alter the anesthetic regimen prior to ECT, use flumazenil prior to ECT in patients using BZDs, and decrease or withhold the evening and/or morning doses of seizure threshold–increasing medications prior to ECT.5 Contradictory to this, studies have shown unilateral, bifrontal, or bitemporal ECT to be effective in patients with primarily nonepileptic mood disorders taking AEDs,6-8 and BZDs may not negatively affect ECT outcomes in patients with depression.3 In patients with seizure disorders undergoing ECT, it has been suggested to continue AEDs with neurology consultation and, in the event of medication alterations, return AEDs to previously prescribed doses after ECT is concluded.4 To our knowledge, we report the first patient with MDD and a seizure disorder managed with bilateral ECT who was taking levetiracetam, lorazepam, and zonisamide.\n\nCase Report\nOur patient is a 66-year-old male with MDD with psychotic features, unspecified anxiety disorder, and generalized tonic-clonic seizures admitted to the psychiatric hospital with suicidal thoughts. He presented with profound psychomotor retardation, cognitive latency, thought blocking, anorexia with weight loss, and difficulty with sleep maintenance. The patient also had nihilistic-type delusions that he was already dead or imminently dying. The patient had been seizure-free with no AED changes for at least 1 year. Medications at admission included fluoxetine 20 mg daily, levetiracetam 750 mg extended-release (XR) nightly, lorazepam 1 mg every morning and 2 mg every evening, and zonisamide 300 mg nightly. He initiated fluoxetine and lorazepam within the preceding month. Previous trials of escitalopram and quetiapine were not effective; mirtazapine was briefly effective. Fluoxetine and lorazepam were discontinued on the day of admission due to ineffectiveness and the possibility of worsening cognitive dysfunction, respectively. Oral venlafaxine 75 mg daily and mirtazapine 15 mg nightly were initiated on admission with considerations to start ECT if ineffective. Two days later, he began to refuse all medications and required assistance eating. On the third evening, he had an approximate 60-second seizure, which required transfer to the emergency department and treatment with IV levetiracetam and lorazepam and oral zonisamide. Lorazepam was continued IV at 0.5 mg 4 times daily on day 4, which improved his ability to take medications and make decisions. It was determined that ECT would be appropriate, but the patient was not ready to consent. Nonetheless, pharmacotherapy was modified in order to prepare for ECT. After literature review and discussion with neurology, levetiracetam was switched to 1000 mg immediate-release (IR) twice daily with the evening dose to be given at 2 pm the night prior to ECT while holding the morning dose on the day of ECT. Lorazepam was reduced to 0.25 mg 4 times daily on the seventh day of hospitalization and discontinued on the ninth day. Zonisamide was tapered and discontinued 2 days prior to the first ECT session and withheld during the remainder of hospitalization. The patient was observed to have a limited-duration seizure 2 days prior to initial ECT that may have been related to downward taper of AEDs. After deliberation, the patient agreed to ECT, and the acute series was initiated on day 12 for a total of 8 sessions (Table). ECT was administered with the Thymatron System IV (Somatics, LLC, Venice, FL) with a pulse width of 0.5 ms, 30 Hz, 40 joules, and duration of 7.5 seconds. Methohexital was the anesthesia-inducing agent used. Adequate seizure activity was seen (Table). He restarted oral lorazepam 0.5 mg twice daily after the first ECT for continued neurovegatative symptoms while holding the nightly dose prior to ECT. After the second ECT, improvements were robust across all domains of prior dysfunction; the patient was engaging socially, smiling, eating, and sleeping; mood was much improved, and delusions resolved. Following the fourth ECT, lorazepam was no longer indicated and discontinued. The patient discharged home after the fifth ECT, completed 8 acute treatments, and received continuation ECT following this. Following the acute ECT series, the patient resumed zonisamide and levetiracetam XR at previously prescribed doses. The patient held these AEDs 4 days prior to each continuation ECT and utilized twice daily levetiracetam 1000 mg IR monotherapy with the last dose at least 24 hours before ECT. Nights following continuation ECT, zonisamide and levetiracetam XR were resumed. After the 10th treatment, the patient sustained resolution of depressive symptoms, denying insomnia, anhedonia, and suicidal thoughts.\n\nTABLE Electrode placement and seizure duration during electroconvulsive therapy (ECT) course\n\nTreatment No.\t1\t2\t3\t4\t5\t6\t7\t8\t9\t10\t11\t12\t\nDays since ECT initiation\t0\t2\t5\t7\t9\t12\t14\t16\t30\t44\t65\t100\t\nElectrode placement\tBT\tBT\tBT\tBF\tBT\tBT\tBT\tBT\tRUL\tBT\tBT\tBT\t\nSeizure duration, s\t\t\t\t\t\t\t\t\n Motor\t28\t39\t28\t32\t27\t25\t24\t24\t16\t30\t21\t38\t\n EEG\t51\t63\t51\t48\t53\t51\t42\t38\t39\t64\t48\t68\t\nBF = bifrontal; BT = bitemporal; EEG = electroencephalogram; RUL = right unilateral.\n\nDiscussion\nIt is not clearly understood how AEDs affect ECT response, and there is no consensus on AED management. Although several studies report successful ECT with AEDs,6-8 no reports are available for the management of levetiracetam combined with zonisamide during ECT. We implemented a careful administration schedule for our patient's AEDs based on their pharmacokinetic properties, balancing the goals of seizure prevention with ECT response. It was of high importance to obtain rapid depression improvement, and given our patient's seizure-free duration prior to admission, antiepileptic medications were reduced with input from neurology. Our patient had adequate seizures during ECT with no restimulations required and no breakthrough seizures once ECT was initiated.\n\nZonisamide was discontinued 2 days prior to ECT initiation and resumed after acute ECT series completion. Zonisamide achieves peak concentrations 2 to 6 hours after administration and reaches concentration steady-state in approximately 2 weeks.9 In an effort to reduce seizure occurrence when not being administered ECT and also allow for quicker AED elimination on nights prior to ECT, levetiracetam was switched from the XR formulation to a higher dose of the IR formulation. Levetiracetam XR peak plasma concentrations occurs after 4 hours with peak time being 3 hours longer than the IR formulation. The elimination half-life of levetiracetam is 9 hours in the elderly with comparable bioavailability between the XR and IR formulations.10 Given its elimination half-life, zonisamide would likely have had detectable serum concentrations during this patient's course of treatment, yet it did not prevent adequate seizure duration during ECT. Similarly, we did not see adverse impacts on treatment response or occurrence of breakthrough seizure from the increased levetiracetam IR dose prescribed.\n\nThere is debate regarding the optimal anesthetic agent to be used during ECT.11 Although etomidate monotherapy or adding ramifentanyl to lower doses of methohexital for anesthesia induction if inadequate seizures occur during ECT can be considered,5 we continued our current practice of using the barbituric acid derivative, methohexital, as an inducing agent and altered the AEDs as described previously. One randomized, double-blind, crossover trial12 compared etomidate, methohexital, and propofol as inducing agents for ECT in 10 patients with MDD; however, none of these patients had seizure disorders or took AEDs. Briefly, EEG seizures were longest after etomidate induction and shortest with propofol, and the clinical meaningfulness of this effect was not assessed.12 Etomidate had no dose-related differences in EEG seizure duration although higher weight-based doses of methohexital and propofol reduced seizure duration. Cognitive recovery was longer in patients with longer seizure duration, and discharge time from recovery room was 5 to 7 minutes longer with etomidate compared with other agents.12 A meta-analysis, including open-label trials and case series, found etomidate EEG seizure duration to be 2.23 seconds (95% CI = –3.62, 8.01; P = .456) longer than methohexital.12 Based on this data, etomidate as an inducing agent does not clearly offer an advantage in patients with epilepsy taking AEDs but could be considered.\n\nOur use of low-dose lorazepam with brief washout periods the night prior to ECT procedures also appeared to have little impact on bitemporal ECT effectiveness. Data suggest BZDs decrease the efficacy of unilateral ECT13,14 but perhaps not during bilateral ECT. Retrospective data suggest patients receiving BZDs had higher depression remission rates than those not receiving BZDs (81.8% vs 52%, P = .017) during primarily bilateral ECT.3 Another retrospective study found patients with monopolar depression who received an average of 17.95 mg (SD 20.3) diazepam equivalents had a response rate of 98.9% and a remission rate of 90% with bitemporal ECT.15\n\nOur case demonstrates that bilateral ECT effectiveness was not compromised with the use of low-dose lorazepam, levetiracetam, and lack of complete zonisamide elimination prior to the procedure. Limitations to our case include that it represents a single patient, AED and BZD serum concentrations were not monitored, and no standardized depression rating scales were utilized. Although our management of this case appears promising for successfully continuing lorazepam, levetiracetam, and zonisamide during ECT, more research and case reports are necessary to recommend safe and effective utilization of AEDs and BZDs during ECT.\n\nConclusion\nManagement of AEDs and BZDs during ECT poses challenges, especially in patients with seizure disorders. Valproate, carbamazepine, and lamotrigine have been successfully continued during ECT in patients without epilepsy,6-8 and a large case series supports AED continuation in most patients with epilepsy receiving ECT.4 BZDs do not usually impact ECT effectiveness when the dose is held the morning prior to bilateral ECT procedures.3,15 Our case suggests that utilizing the IR formulation of levetiracetam, administering the evening dose early the day prior to the procedure, and temporarily discontinuing zonisamide dosing prior to bilateral ECT is effective for the treatment of severe MDD while maintaining seizure prophylaxis.\n==== Refs\nReferences\n1 Milev RV Giacobbe P Kennedy SH Blumberger DM Daskalakis ZJ Downar J Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. Neurostimulation treatments Can J Psychiatry 2016 61 9 561 75 DOI: 10.1177/0706743716660033 PubMed PMID: 27486154 PubMed Central PMCID: PMC4994792 27486154 \n2 The Management of Major Depressive Disorder Working Group VA/DoD clinical practice guideline for the management of major depressive disorder Version 30 Washington Veterans Health Administration and Department of Defense; 2016 \n3 Delamarre L Galvao F Gohier B Poulet E Brunelin J How much do benzodiazepines matter for electroconvulsive therapy in patients with major depression? J ECT 2019 35 3 184 8 DOI: 10.1097/YCT.0000000000000574 PubMed PMID: 30720551 30720551 \n4 Lunde ME Lee EK Rasmussen KG Electroconvulsive therapy in patients with epilepsy Epilepsy Behav 2006 9 2 355 9 DOI: 10.1016/j.yebeh.2006.06.013 PubMed PMID: 16876485 16876485 \n5 Zolezzi M Medication management during electroconvulsant therapy Neuropsychiatr Dis Treat 2016 12 931 9 DOI: 10.2147/NDT.S100908 PubMed PMID: 27143894 PubMed Central PMCID: PMC4844444 27143894 \n6 Rakesh G Thirthalli J Kumar CN Muralidharan K Phutane VH Gangadhar BN Concomitant anticonvulsants with bitemporal electroconvulsive therapy J ECT 2017 33 1 16 21 DOI: 10.1097/YCT.0000000000000357 PubMed PMID: 27668943 27668943 \n7 Sienaert P Roelens Y Demunter H Vansteelandt K Peuskens J Van Heeringen C Concurrent use of lamotrigine and electroconvulsive therapy J ECT 2011 27 2 148 52 DOI: 10.1097/YCT.0b013e3181e63318 PubMed PMID: 20562637 20562637 \n8 Penland HR Ostroff RB Combined use of lamotrigine and electroconvulsive therapy in bipolar depression J ECT 2006 22 2 142 7 DOI: 10.1097/00124509-200606000-00013 PubMed PMID: 16801832 16801832 \n9 Zonegran (zonisamide) [package insert] Dublin: Concordia Pharmaceuticals; 2020 \n10 Keppra XE (levetiracetam XR) [package insert] Smyrna (GA) UCB Inc; 2019 \n11 Singh PM Arora S Borle A Varma P Trikha A Goudra BG Evaluation of etomidate for seizure duration in electroconvulsive therapy J ECT 2015 31 4 213 25 DOI: 10.1097/YCT.0000000000000212 PubMed PMID: 25634566 25634566 \n12 Avramov MN Husain MM White PF The comparative effects of methohexital, propofol, and etomidate for electroconvulsive therapy Anesth Analg 1995 81 3 596 602 DOI: 10.1097/00000539-199509000-00031 PubMed PMID: 7653829 7653829 \n13 Pettinati HM Stephens SM Willis KM Robin SE Evidence for less improvement in depression in patients taking benzodiazepines during unilateral ECT Am J Psychiatry 1990 147 8 1029 35 DOI: 10.1176/ajp.147.8.1029 PubMed PMID: 2375437 2375437 \n14 Jha A Stein G Decreased efficacy of combined benzodiazepines and unilateral ECT in treatment of depression Acta Psychiatr Scand 1996 94 2 101 4 DOI: 10.1111/j.1600-0447.1996.tb09832.x PubMed PMID: 8883570 8883570 \n15 Gálvez V Loo CK Alonzo A Cerrillo E Menchón JM Crespo JM Do benzodiazepines moderate the effectiveness of bitemporal electroconvulsive therapy in major depression? J Affect Disord 2013 150 2 686 90 DOI: 10.1016/j.jad.2013.03.028 PubMed PMID: 23668903 23668903\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2168-9709",
"issue": "11(1)",
"journal": "The mental health clinician",
"keywords": "anticonvulsant; benzodiazepine; electroconvulsive therapy; epilepsy; levetiracetam; major depressive disorder; seizure disorder; zonisamide",
"medline_ta": "Ment Health Clin",
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"nlm_unique_id": "101728585",
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"publication_types": "D002363:Case Reports",
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"title": "Successful bilateral electroconvulsive therapy in a patient with a seizure disorder taking levetiracetam, lorazepam, and zonisamide: A case report.",
"title_normalized": "successful bilateral electroconvulsive therapy in a patient with a seizure disorder taking levetiracetam lorazepam and zonisamide a case report"
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"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
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"abstract": "High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980 to 2009, 215 patients aged >1 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year event-free survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy.",
"affiliations": "Department of Pediatric Oncology, Centre Hospitalier Universitaire, Angers, France.;Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France.;Biostatistics and Epidemiology Unit, Gustave Roussy, Villejuif, France.;Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France.;Biostatistics and Epidemiology Unit, Gustave Roussy, Villejuif, France.;Biostatistics and Epidemiology Unit, Gustave Roussy, Villejuif, France.;Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France.;Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France.;Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France.;Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France.",
"authors": "Proust-Houdemont|S|S|;Pasqualini|C|C|;Blanchard|P|P|;Dufour|C|C|;Benhamou|E|E|;Goma|G|G|;Semeraro|M|M|;Raquin|M-A|MA|;Hartmann|O|O|;Valteau-Couanet|D|D|",
"chemical_list": "D002066:Busulfan; D008558:Melphalan",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2016.75",
"fulltext": null,
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"issn_linking": "0268-3369",
"issue": "51(8)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000293:Adolescent; D016026:Bone Marrow Transplantation; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008558:Melphalan; D009447:Neuroblastoma; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1076-81",
"pmc": null,
"pmid": "27042850",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article",
"references": "19171716;9701390;15546135;3048471;16427213;8336186;15659499;2400986;16129365;22364685;10231141;16116154;10800060;17393167;16007101;8420443;22742881;3180059;9396394;6355849;16116153;23341514;23970413;3152918;19047290;9103126;10519894;12603688;1855085;20567002;1403039;19361744;14595385;5120301;3049951;8712747;14635085",
"title": "Busulfan-melphalan in high-risk neuroblastoma: the 30-year experience of a single institution.",
"title_normalized": "busulfan melphalan in high risk neuroblastoma the 30 year experience of a single institution"
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"abstract": "Rheumatic diseases are not commonly associated with cytomegalovirus (CMV) retinitis. We report a case of bilateral CMV retinitis in a human immunodeficiency virus-seronegative patient with systemic lupus erythematosus (SLE) who was undergoing hemodialysis for end-stage renal disease. The CMV retinitis in this patient was associated with combined azathioprine and low-dose corticosteroid therapy for lupus flare. This association may have important clinical implications because this drug combination is used routinely to treat active SLE. Our patient responded to discontinuation of azathioprine, reduction of the corticosteroid dose, and systemic administration of ganciclovir. We recommend that clinicians maintain heightened awareness of the possibility of CMV retinitis in patients with SLE and end-stage renal disease who are receiving azathioprine and low-dose corticosteroids.",
"affiliations": "Department of Medicine, Mount Sinai Services at Queens Hospital Center, Jamaica, NY 11432, USA.",
"authors": "Shahnaz|Sabiha|S|;Choksi|Mamta T|MT|;Tan|Irene J|IJ|",
"chemical_list": "D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D006886:Hydroxychloroquine; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.4065/78.11.1412",
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"issue": "78(11)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001379:Azathioprine; D017726:Cytomegalovirus Retinitis; D005260:Female; D018023:HIV Seronegativity; D006801:Humans; D006886:Hydroxychloroquine; D007166:Immunosuppressive Agents; D007676:Kidney Failure, Chronic; D008180:Lupus Erythematosus, Systemic; D006435:Renal Dialysis",
"nlm_unique_id": "0405543",
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"references": null,
"title": "Bilateral cytomegalovirus retinitis in a patient with systemic lupus erythematosus and end-stage renal disease.",
"title_normalized": "bilateral cytomegalovirus retinitis in a patient with systemic lupus erythematosus and end stage renal disease"
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"activesubstancename": "AZATHIOPRINE"
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"abstract": "Antipsychotic medications are associated with adverse cutaneous reactions (ACRs) in approximately 2-3% of patients. We present three cases of possible risperidone induced periorbital oedema in the absence of any other systemic or local cause responsible for the oedema. The development of periorbital oedema after the initiation of risperidone therapy, and disappearance after the discontinuation of this drug, suggests a possible causal relationship between periorbital oedema and risperidone. To our knowledge, there are very few reports of risperidone therapy and development of periorbital oedema. Risperidone is a valid and effective choice amongst antipsychotic medications, but these cases call for caution regarding ACRs at the time of prescribing.",
"affiliations": "Institute of Human Behaviour & Allied Sciences (IHBAS),Dilshad Garden,Delhi,India.;Institute of Human Behaviour & Allied Sciences (IHBAS),Dilshad Garden,Delhi,India.;Institute of Human Behaviour & Allied Sciences (IHBAS),Dilshad Garden,Delhi,India.;Institute of Human Behaviour & Allied Sciences (IHBAS),Dilshad Garden,Delhi,India.;Institute of Human Behaviour & Allied Sciences (IHBAS),Dilshad Garden,Delhi,India.;Institute of Human Behaviour & Allied Sciences (IHBAS),Dilshad Garden,Delhi,India.",
"authors": "Bajaj|Vikrant|V|;Srivastava|Ankur|A|;Sengupta|Somnath|S|;Mehrotra|Saurabh|S|;Vedi|Shaveta|S|;Pathak|Prashant|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1017/S0790966700001579",
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"issue": "27(4)",
"journal": "Irish journal of psychological medicine",
"keywords": null,
"medline_ta": "Ir J Psychol Med",
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"nlm_unique_id": "8900208",
"other_id": null,
"pages": "216-217",
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"pubdate": "2010-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risperidone induced periorbital oedema.",
"title_normalized": "risperidone induced periorbital oedema"
} | [
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"activesubstancename": "RISPERIDONE"
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{
"abstract": "Tenofovir is a nucleotide analog reverse transcriptase inhibitor approved for the treatment of HIV and hepatitis B infections. It is widely prescribed and an integral part of the recommended regimens for the treatment of HIV infection in antiretroviral-naive patients. Tenofovir is implicated in renal proximal tubular dysfunction, which can be associated with Fanconi syndrome and hypokalemia. When the hypokalemia is severe, it can lead to life-threatening complications. We describe the case of a 59-year-old woman who suffered a cardiac arrest secondary to severe hypokalemia from tenofovir use.",
"affiliations": "Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL, USA.;Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL, USA.",
"authors": "Koratala|Abhilash|A|;Ruchi|Rupam|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X17741010",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1774101010.1177_2050313X17741010Case ReportHypokalemia: A potentially life-threatening complication of tenofovir therapy Koratala Abhilash Ruchi Rupam Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL, USAAbhilash Koratala, Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, P.O. Box 100224, Gainesville, FL 32610, USA. Email: akoratsla@ufl.edu14 11 2017 2017 5 2050313X1774101027 2 2017 12 10 2017 © The Author(s) 20172017SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Tenofovir is a nucleotide analog reverse transcriptase inhibitor approved for the treatment of HIV and hepatitis B infections. It is widely prescribed and an integral part of the recommended regimens for the treatment of HIV infection in antiretroviral-naive patients. Tenofovir is implicated in renal proximal tubular dysfunction, which can be associated with Fanconi syndrome and hypokalemia. When the hypokalemia is severe, it can lead to life-threatening complications. We describe the case of a 59-year-old woman who suffered a cardiac arrest secondary to severe hypokalemia from tenofovir use.\n\nHypokalemiatenofovirrenal tubular acidosiscover-dateJanuary-December 2017\n==== Body\nIntroduction\nTenofovir is a nucleotide reverse transcriptase inhibitor used for the treatment of HIV infection and is a key component of the commonly used anti-retroviral drug, Truvada®. Tenofovir-induced proximal tubulopathy and dyselectrolytemia with or without Fanconi syndrome have been documented in the literature.1,2 However, in general practice, the severity of these electrolyte disorders is often underestimated. We recently cared for a patient with HIV who developed severe hypokalemia and renal tubular acidosis (RTA) from tenofovir that lead to cardiac arrest.\n\nCase presentation\nA 59-year-old White female presented to our institution for weakness, failure to thrive, and hypokalemia. She had a history of HIV for ~8 years, well controlled on tenofovir containing anti-retroviral therapy. Before 4 months to presentation, she suffered a sudden cardiac arrest after a diarrheal episode and required intensive care unit (ICU) stay at an outside facility where she was told that her serum potassium at admission was “almost zero.” Cardiac catheterization did not reveal any ischemic etiology, and she was discharged with oral potassium supplementation 40 mEq twice a day. However, she was feeling sick with weakness, nausea, intermittent vomiting, and weight loss and thus came to us. At presentation, her serum potassium was 2.5 mmol/L (3.5–5.1), magnesium 1.9 mg/dL (1.5–2.8), phosphate 1.6 mg/dL (2.7–4.5), and bicarbonate 13 mmol/L (22–28) with an anion gap of 14. Her renal function was preserved and had a mild proteinuria of ~0.5 g/g creatinine. Initial workup was negative for malignancy. We noted that she had glycosuria with normal serum glucose and had a potassium–creatinine ratio of 250 mmol/g and fractional excretion of phosphate 65%. We diagnosed her with tenofovir-induced proximal RTA with Fanconi syndrome. Her anti-retroviral therapy was changed to non-tenofovir–based regimen. At 2-month follow-up visit, her serum potassium was stable at 4.1 mmol/L on 40 mEq/day oral potassium supplementation.\n\nDiscussion\nTenofovir is a known mitochondrial toxin and inhibits DNA polymerase gamma, the enzyme responsible for replication of mitochondrial DNA. With limited anaerobic adenosine triphosphate (ATP)-generating capacity, the proximal tubule is vulnerable to mitochondrial dysfunction and may manifest as RTA or full-blown Fanconi syndrome.3 The latter is characterized by hyperphosphaturia, renal glycosuria, aminoaciduria, and tubular proteinuria in addition to proximal (type 2) RTA. Decreased proximal tubular bicarbonate excretion is the hallmark of type 2 RTA, which leads to renal bicarbonate wasting and fall in serum bicarbonate levels. This increased delivery of bicarbonate results in increased intraluminal negativity in the distal nephron resulting in potassium secretion and wasting.4 Patients on tenofovir therapy are prone to developing severe hypokalemia, especially when combined with gastro-intestinal losses and/or poor eating. Severe hypokalemia can result in complications such as cardiac arrhythmias as in our case or spontaneous rhabdomyolysis,5 which in turn can lead to acute renal failure. These patients should be frequently monitored with urinalysis and renal function panel while on therapy. Raising the awareness among clinicians with regard to this potential side effect is vital for early intervention and prevention of life-threatening complications.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n==== Refs\nReferences\n1 \nShepp DH Curtis S Rooney JF. \nCauses and consequences of hypokalemia in patients on tenofovir disoproxil fumarate . AIDS \n2007 ; 21 (11 ): 1479 –1481 .17589195 \n2 \nGracey DM Snelling P McKenzie P et al \nTenofovir-associated Fanconi syndrome in patients with chronic hepatitis B monoinfection . Antivir Ther \n2013 ; 18 (7 ): 945 –948 .23839869 \n3 \nHall AM Hendry BM Nitsch D et al \nTenofovir-associated kidney toxicity in HIV-infected patients: a review of the evidence . Am J Kidney Dis \n2011 ; 57 : 773 –780 .21435764 \n4 \nSebastian A McSherry E Morris RC et al \nOn the mechanism of renal potassium wasting in renal tubular acidosis associated with the Fanconi syndrome (type 2 RTA) . J Clin Invest \n1971 ; 50 (1 ): 231 –243 .5101297 \n5 \nKishore B Thurlow V Kessel B. \nHypokalaemic rhabdomyolysis . Ann Clin Biochem \n2007 ; 44 (Pt 3 ): 308 –311 .17456302\n\n",
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"title": "Hypokalemia: A potentially life-threatening complication of tenofovir therapy.",
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"abstract": "A 4.5-year-old child with severe idiopathic pulmonary arterial hypertension underwent right-heart catheterisation, showing suprasystemic pulmonary pressure and a tiny patent ductus arteriosus with trivial right-to-left shunting. The ductus arteriosus was successfully stented with a bare metal stent. At 1-year follow-up, a remarkable improvement was observed in clinical status, functional capacity, and serology. Echocardiography confirmed a favourable cardiac remodelling.",
"affiliations": "1Department of Cardiology,Second University of Naples,Naples,Italy.;1Department of Cardiology,Second University of Naples,Naples,Italy.;1Department of Cardiology,Second University of Naples,Naples,Italy.;2Cardiology and Cardiac Surgery Department,Bambino Gesù Children's Hospital,IRCCS,Rome,Italy.;1Department of Cardiology,Second University of Naples,Naples,Italy.",
"authors": "D'Alto|Michele|M|;Santoro|Giuseppe|G|;Palladino|Maria T|MT|;Parisi|Francesco|F|;Russo|Maria G|MG|",
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"abstract": "Hemorrhage associated with anticoagulation therapy is a feared and relatively common complication. Few cases have been documented of spontaneous pancreatic hemorrhage related to anticoagulation, and fewer yet of ruptured pancreatic pseudocyst secondary to anticoagulation-related bleeding. We describe the case of a 74-year-old female with massive intra- and extraperitoneal hemorrhage secondary to an anticoagulation-related ruptured hemorrhagic pancreatic pseudocyst that was treated successfully with coil embolization. An inferior vena cava filter was placed at the same time as the embolization procedure, as she had a contraindication for anticoagulation in the setting of submassive pulmonary emboli and lower extremity deep venous thrombosis.",
"affiliations": "Department of Radiology, University of Missouri, One Hospital Drive, Columbia, MO 65212.;Department of Radiology, University of Missouri, One Hospital Drive, Columbia, MO 65212.;Department of Radiology, Madigan Army Medical Center, 9040 Jackson Ave, Tacoma, WA 98431.",
"authors": "Atkins|Naomi K|NK|;Kramer|Blake M|BM|;Kitley|Charles A|CA|",
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"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(19)30249-310.1016/j.radcr.2019.07.006Interventional RadiologyTranscatheter embolization of anticoagulation related pancreatic pseudocyst hemorrhage: A case report Atkins Naomi K. DOatkinsn@health.missouri.edua⁎Kramer Blake M. DOkramerB@health.missouri.eduaKitley Charles A. MDkitleyc@health.missouri.eduba Department of Radiology, University of Missouri, One Hospital Drive, Columbia, MO 65212b Department of Radiology, Madigan Army Medical Center, 9040 Jackson Ave, Tacoma, WA 98431⁎ Corresponding author. atkinsn@health.missouri.edu02 8 2019 10 2019 02 8 2019 14 10 1202 1208 9 7 2019 17 7 2019 17 7 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Hemorrhage associated with anticoagulation therapy is a feared and relatively common complication. Few cases have been documented of spontaneous pancreatic hemorrhage related to anticoagulation, and fewer yet of ruptured pancreatic pseudocyst secondary to anticoagulation-related bleeding. We describe the case of a 74-year-old female with massive intra- and extraperitoneal hemorrhage secondary to an anticoagulation-related ruptured hemorrhagic pancreatic pseudocyst that was treated successfully with coil embolization. An inferior vena cava filter was placed at the same time as the embolization procedure, as she had a contraindication for anticoagulation in the setting of submassive pulmonary emboli and lower extremity deep venous thrombosis.\n\nKeywords\nEmbolizationAnticoagulationHemorrhagePancreasPseudocyst\n==== Body\nIntroduction\nHemorrhagic complications occur in approximately 2% of patients treated with anticoagulation. The most common bleeding site is within the gastrointestinal tract, with the overall highest mortality site occurring in cases of intracranial hemorrhage [1]. Few cases have been reported of spontaneous bleeding into the pancreas or a pancreatic pseudocyst related to anticoagulation. Hemorrhage associated with pancreatic pseudocysts is a rare complication of acute and chronic pancreatitis, with high mortality rates. Pancreatic pseudocyst rupture with associated intraabdominal hemorrhage is an even rarer subset of these bleeds. Only 4 other cases of spontaneous pancreatic hemorrhage associated with anticoagulation were found in the literature [2], [3], [4]. None of these were treated with endovascular embolization.\n\nCase report\nA 74-year-old female with no history of prior thromboembolism presented to the Emergency Department with worsening shortness of breath. She was found to have acute bilateral obstructive segmental pulmonary emboli (PE) with pulmonary infarcts and extensive acute left lower extremity deep venous thrombosis (DVT). She had a simple appearing pancreatic cyst which was noted on her Computed Tomography (CT) angiogram of the chest (Fig. 1), without evidence of hemorrhage on the initial study. She was admitted to the hospital and started on heparin drip for her PEs while she underwent further evaluation of the pancreatic cyst.Fig. 1 Partially imaged cyst (white arrows) associated with the head of the pancreas as visualized on the CT angiogram of the chest done for pulmonary emboli while the patient was in the emergency room.\n\nFig 1\n\nThe pseudocyst had been previously noted on a CT angiogram of the chest almost 3 years prior to this hospital stay and was stable in appearance. CT of the abdomen was performed with a differential diagnosis to include uncomplicated pancreatic pseudocyst versus side branch intraductal papillary mucinous neoplasm (Fig. 2a) with no evidence of hemorrhage. Magnetic Resonance Cholangiopancreatography was also performed which confirmed the finding to represent an uncomplicated pancreatic pseudocyst (Fig. 2b).Fig. 2 Contrast enhanced CT of the abdomen (a) obtained during admission better visualizes the cyst (white arrows) with an adjacent vessel branching from the SMA (green arrow). MRCP (b) obtained following the CT demonstrates a simple cyst most consistent with a pancreatic pseudocyst. No hemorrhage was noted on the CT or MRCP.\n\nFig 2\n\nThe patient had no symptoms of pancreatitis upon admission for her PE, however she began having abdominal pain 5 days after admission and her pancreatic enzymes were checked on day 6 of her hospitalization and were found to be mildly elevated. The patient had previously been transitioned from a heparin drip to low-molecular weight heparin approximately 12 hours prior for treatment of her PE. Over the course of the next 6 hours she began to have hemodynamic instability, worsening pain, and acute anemia, with significant drops in her blood pressure and baseline hemoglobin levels, requiring higher level care and eventually intubation. Emergent imaging was then requested to evaluate for a source of hemorrhage causing her acute hemodynamic decline.\n\nA CT of the abdomen was completed using a GI bleed protocol including venous and delayed imaging. She was noted to have a large intraperitoneal and retroperitoneal hematoma with internal hematocrit levels measuring 12.4 × 20.1 × 21.1 cm (Fig. 3), which was new from prior imaging. Additionally, the arterial and delayed imaging demonstrated active extravasation in the area of the previously noted pancreatic pseudocyst (Fig. 4). No vascular aneurysms were identified adjacent to the pseudocyst or within the visualized vessels. Interventional radiology was consulted to determine if endovascular treatment could be utilized as the patient remained hemodynamically unstable and was a poor surgical candidate.Fig. 3 Axial (a), coronal (b), and sagittal (c) images from a contrast enhanced CT angiogram of the abdomen obtained after the patient became hemodynamically unstable demonstrates a large intraperitoneal (green arrows) and extraperitoneal hemorrhage (white arrowheads) extending outside of the previously visualized pancreatic pseudocyst (white arrows).\n\nFig 3Fig. 4 Axial arterial (a) and delayed (b) images from the contrast enhanced CT angiogram of the abdomen demonstrate an area of relative hypodensity on arterial phase images (white arrow) followed by layering of the hyperdense contrast on delayed imaging (black arrow). Sagittal arterial (c) and delayed (d) images from the contrast enhanced CT angiogram of the abdomen demonstrate a bright spot on the arterial images (black arrow) followed by layering of the hyperdense contrast on delayed imaging (black arrow). Findings are consistent with active extravasation of contrast.\n\nFig 4\n\nThe patient was brought to the angiography suite intubated and sedated. An existing right femoral arterial catheter was prepped and exchanged for a 5 French vascular access sheath over a 0.035 Bentson wire. Using a 5 French Mickelson catheter (Cook Medical, Bloomington, IN), the celiac artery was cannulated and a subselective celiac arteriogram was then performed. The celiac artery demonstrated normal branching anatomy.\n\nA 2.8F Progreat microcatheter (Terumo Medical, Somerset, NJ) and 0.016 Fathom microwire (Boston Scientific, Marlborough, MA) were then used to cannulate the gastroduodenal artery, and a superselective arteriogram of the gastroduodenal artery was performed. The gastroduodenal artery appeared spasmed with multiple irregular vessels branching distally in the area of the known pseudocyst (Fig. 5a). Given the appearance, four 4 mm Azur microcoils (Terumo Medical, Somerset, NJ) were then used to embolize the gastroduodenal artery to prevent extravasation and collateral flow into the area of hemorrhage seen on prior CT. A repeat angiogram of the gastroduodenal artery did not show any evidence of active extravasation and there was significantly decreased flow through the gastroduodenal artery (Fig. 5b). The 5 French Mickelson catheter was then used to access the superior mesenteric artery, and a subselective arteriogram of the superior mesenteric artery was performed. The SMA angiogram demonstrated a small area of blush and active extravasation from the first branch supplying the inferior pancreaticoduodenal artery (Fig. 6a). Superselective arteriography of this vessel demonstrated a large amount of rapid active extravasation (Fig. 6b, 6c). The 2.8F Progreat microcatheter and 0.016 Fathom wire were then used to cannulate the vessel adjacent to the hemorrhage and one 2 × 4 mm Cook tornado microcoil (Cook Medical, Bloomington, IN) was used to embolize this branch. Repeat arteriogram after embolization demonstrated complete cessation of flow to the area of focal hemorrhage within this vessel (Fig. 7a, 7b). No additional areas of active extravasation were identified. All wires and catheters were removed and the vascular sheath was secured in place with a Vicryl suture to be used as an arterial line upon recovery in the intensive care unit.Fig. 5 Digital subtraction arteriographic images of the gastroduodenal artery (a) which appears spasmed (black arrows) with multiple irregular appearing branches in the distribution of the pseudocyst and intra-abdominal hemorrhage (black arrowheads). Digital subtraction images following coil embolization (b) demonstrates little to no flow in the gastroduodenal artery (black arrow).\n\nFig 5Fig. 6 Digital subtraction images of selective SMA arteriogram (a) demonstrates a small area of active extravasation of contrast (black arrow). The rounded area of dense contrast more superiorly represents a tortuous area within a lumbar artery (white arrowhead). Subtracted (b) and unsubtracted (c) images of a superselective arteriogram of the pancreaticoduodenal artery demonstrates rapid extravasation of contrast (black arrows). There was mild irregularity of the vessel proximal to the area of active bleeding (arrow head).\n\nFig 6Fig. 7 Unsubtracted (a) and subtracted (b) arteriographic images following coil embolization of the pancreaticoduodenal artery (black arrows) demonstrate no flow beyond the coil mass. Residual extravasated contrast is seen within the area of hemorrhage on the unsubtracted images (a) (white arrowhead). The coil mass in the GDA (white arrow) is also visualized on subtracted images (b).\n\nFig 7\n\nAs the patient had extensive thromboembolic disease including multiple acute PEs and extensive left lower extremity DVT, the primary team had requested an inferior vena cava (IVC) filter to be placed at the time of the angiogram given her current contraindication to anticoagulation. Following the angiogram, the right neck and chest were prepped and the right internal jugular was accessed with a micropuncture system under direct ultrasound guidance. A vascular access sheath from a Gunther Tulip delivery kit (Cook Medical, Bloomington, IN) was advanced into the distal inferior vena cava, and an inferior vena cavogram was performed. The initial venogram of the iliac veins and inferior vena cava demonstrated significant compression on the proximal IVC due to the large intraabdominal hematoma. The IVC was patent, however, with multiple large collaterals visualized within the abdomen surrounding the area of hemorrhage (Fig. 8a). The IVC filter was then successfully deployed within the infrarenal IVC above the iliac vein bifurcation using direct fluoroscopic visualization, with the tip of the filter positioned at the level of L2 in the distal IVC due to compression of the more proximal IVC. Postprocedure images demonstrated successful placement of the inferior vena cava filter with all legs deployed successfully and in good position (Fig. 8b). The patient tolerated both procedures well and there were no complications.Fig. 8 Subtracted images of inferior venocavogram (a) demonstrates compression and displacement of the IVC (white arrowhead) with multiple large collateral vessels to allow for blood return (black arrows). Unsubtracted images (b) following IVC filter placement demonstrate the IVC filter (white arrowhead) and 2 coil masses, GDA (white arrow) and pancreaticoduodenal artery (black arrow).\n\nFig 8\n\nDiscussion\nHemorrhage associated with acute and chronic pancreatitis is a well-known complication with a mortality rate of up to 40% [5], [6], [7]. Rates of hemorrhage vary across multiple studies, ranging from 1%-31% [5]. The majority of hemorrhagic complications discussed in the literature are related to bleeding within the GI tract or development of pseudoaneurysms. Bleeding into a pancreatic pseudocyst is less common. Pancreatic pseudocysts complicate up to 10% of acute and chronic pancreatitis cases, and up to 5% of pancreatic pseudocysts will bleed [5]. Endovascular treatment of pancreatitis-related vascular pseudoaneurysms is well-established. Management of ruptured and hemorrhagic pancreatic pseudocysts, however, has previously been thought to be almost exclusively surgical [7]. Even when endovascular treatments are considered, they are often used as a stabilizing procedure prior to surgery [6], [8]. Postsurgical mortality rates associated with both hemorrhagic pancreatic pseudocysts and pseudoaneurysms are very high, ranging from 20% to 43% [5], [9], [10].\n\nIn the setting of anticoagulation-related hemorrhage into a pseudocyst without pancreatitis, no cases described in the literature underwent surgical intervention [2], [3], [4]. Given that there is no significant underlying pancreatic inflammation causing the hemorrhage, partial pancreatectomy or necrosectomy is not necessary. In patients who were hemodynamically stable, reversal of the anticoagulation alone was sufficient to stop the hemorrhage [2], [3]. Chiu et al discussed 2 patients who presented with the appearance of masses within the pancreas that were small, contained, and mistaken for malignancy. In their series, hemorrhage stopped upon reversal of the anticoagulation alone [2]. Rigaux et al also described a patient who was on anticoagulation who presented with severe abdominal pain and developed a large intra- and extraperitoneal hemorrhage on imaging. Once again, the hemorrhage stopped with reversal of anticoagulation, and no interventions were necessary [3]. In the case reported by Hong et al, hemorrhage was reported through the ampulla of Vater, and the patient presented with a gastrointestinal hemorrhage and hemodynamic instability [4]. Arteriography was performed, but no active extravasation was visualized, and no further therapy was performed. The patient died of cardiac arrest soon after.\n\nEndovascular therapy of hemorrhages associated with pancreatic pseudocysts have become more prevalent in the scientific literature [8], [9], [10], [11]. There are several benefits of embolization specifically in populations with anticoagulation-related bleeds, primarily due to the minimally invasive nature of embolization in this subset of patients who are deemed poor surgical candidates. Patients on anticoagulation for PE and DVT can also have IVC filters placed at the time of the embolization while in the IR suite to prevent worsening of pulmonary symptoms while recovering off of anticoagulation.\n\nEmbolization with coils, N-butyl cyanoacrylate, and microparticles have been used for endovascular treatment of pancreatitis related hemorrhages. Combinations of these therapies are also often used together. Small or tortuous vessels are often successfully treated with N-butyl cyanoacrylate when unable to be reached by coiling. Larger vessels, such as hemorrhage related to the splenic artery, have been treated successfully with covered stent placement to prevent splenic infarction. When a smaller vessel is visualized with active extravasation, aneurysm, or pseudoaneurysm, coil embolization is typically the preferred option for treatment if the vessel is easily accessed. Placement of coils distal to proximal helps to prevent bleeding from backflow or collateral vascular flow to the injured vessel. Rebleeding following embolization therapy has been widely variable in the literature, but recent studies have shown very low rates, most of which were successfully treated with repeat embolization [11].\n\nConclusion\nEmbolization of hemorrhage associated with bleeding and ruptured pancreatic pseudocyst is a reasonable option for treatment. In patients with anticoagulation-related hemorrhages, embolization has the potential to be first line therapy, as patients may be poor surgical candidates and will possibly require concomitant IVC filter placement given contraindications to use of anticoagulation in the acute clinical setting.\n\nDeclaration of Competing Interest: The authors declare that they have no conflict of interest.\n\nThe views expressed are those of the author(s) and do not reflect the official policy of the Department of the Army, the Department of Defense, or the US Government.\n==== Refs\nReferences\n1 Shoeb M. Fang M.C. Assessing bleeding risk in patients taking anticoagulants J Thromb Thrombolysis 35 3 2013 312 319 23479259 \n2 Chiu K. Razack A. Maraveyas A. Isolated pancreatic heamorrhage in association with anticoagulation Thromb J 11 1 2013 20 24228740 \n3 Rigaux J. Poreddy V. Al-Kawas F. Intraperitoneal and retroperitoneal hemorrhage associated with coumadin-induced bleeding into a pancreatic pseudocyst Clin Gastroenterol Hepatol 5 6 2007 A32 \n4 Hong D. Gately J.F. Heggtveit H.A. Pancreatic pseudocyst: Heparin-induced haemorrhage through the ampulla of Vater J R Coll Surg Edinb 44 4 1999 271 273 10453153 \n5 Balthazar E.J. Fisher L.A. Hemorrhagic complications of pancreatitis: radiologic evaluation with emphasis on CT imaging Pancreatology 1 4 2001 306 313 12120209 \n6 Okamura K. Ohara M. Kaneko T. Shirosaki T. Fujiwara A. Yamabuki T. Pancreatic pseudocyst ruptured due to acute intracystic hemorrhage Case Rep Gastroenterol 11 3 2017 755 762 29430229 \n7 Hsu J.T. Yeh C.N. Hung C.F. Chen H.M. Hwang T.L. Jan Y.Y. Management and outcome of bleeding pseudoaneurysm associated with chronic pancreatitis BMC Gastroenterol 6 2006 3 16405731 \n8 Jain S.K. Rajendran V. Jain M.K. Kori R. Hemorrhagic pseudocyst of pancreas treated with coil embolization of gastroduodenal artery: a case report and review of literature Case Rep Surg 2015 2015 480605 \n9 Phillip V. Rasch S. Gaa J. Schmid R.M. Algul H. Spontaneous bleeding in pancreatitis treated by transcatheter arterial coil embolization: a retrospective study PLoS One 8 8 2013 e72903 23977371 \n10 Novacic K. Vidjak V. Suknaic S. Skopljanac A. Embolization of a large pancreatic pseudoaneurysm converted from pseudocyst (hemorrhagic pseudocyst) JOP 9 3 2008 317 321 18469446 \n11 Kim J. Shin J.H. Yoon H.K. Ko G.Y. Gwon D.I. Kim E.Y. Endovascular intervention for management of pancreatitis-related bleeding: a retrospective analysis of thirty-seven patients at a single institution Diagn Interv Radiol 21 2 2015 140 147 25616269\n\n",
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"issue": "14(10)",
"journal": "Radiology case reports",
"keywords": "Anticoagulation; Embolization; Hemorrhage; Pancreas; Pseudocyst",
"medline_ta": "Radiol Case Rep",
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"title": "Transcatheter embolization of anticoagulation related pancreatic pseudocyst hemorrhage: A case report.",
"title_normalized": "transcatheter embolization of anticoagulation related pancreatic pseudocyst hemorrhage a case report"
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"abstract": "BACKGROUND\nAlthough the standard treatment for stromal tumours is surgery, in locally advanced forms, it is often necessary to achieve tumour downstaging to improve surgical outcomes. Neoadjuvant treatment in gastrointestinal stromal tumours (GISTs) with tyrosine kinase inhibitors, including imatinib, has been shown to be effective in several studies, but the duration of this treatment is still a subject of debate.\n\n\nMETHODS\nWe report a case of a large GIST of the stomach in a 51-year-old patient with atypical presentation that was initially unresectable. Neoadjuvant treatment with imatinib for 16 months resulted in a good response, allowing secondary surgical excision.\n\n\nCONCLUSIONS\nImatinib in neoadjuvant therapy should be continued as long as there is a good response and tolerance to the medication to obtain tumour downsizing compatible with carcinologic excision.",
"affiliations": "Department of Visceral Surgery, University Teaching Hospital of Lomé, Lomé, Togo. alassanifousseni@yahoo.fr.;Department of Visceral Surgery, University Teaching Hospital of Lomé, Lomé, Togo.;Department of Hepato-Gastro-Enterology, University Teaching Hospital of Lomé, Lomé, Togo.;Department of Medical Oncology, University Teaching Hospital of Lomé, Lomé, Togo.;Department of General Surgery, University Teaching Hospital of Lomé, Lomé, Togo.;Department of Pathology, University Teaching Hospital of Lomé, Lomé, Togo.;Department of Visceral Surgery, University Teaching Hospital of Lomé, Lomé, Togo.",
"authors": "Alassani|Fousséni|F|http://orcid.org/0000-0002-8739-0624;Tchangai|Boyodi|B|;Bagny|Aklesso|A|;Adani-Ife|Ablavi A|AA|;Amavi|Kossigan A|KA|;Darre|Tchin|T|;Attipou|Komla|K|",
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"fulltext": "\n==== Front\nOncol Ther\nOncol Ther\nOncology and Therapy\n2366-1070\n2366-1089\nSpringer Healthcare Cheshire\n\n32699986\n101\n10.1007/s40487-019-00101-4\nCase Report\nExcision of a Large Gastrointestinal Stromal Tumour Following 16 Months of Neoadjuvant Therapy with Imatinib (Case Report)\nhttp://orcid.org/0000-0002-8739-0624\nAlassani Fousséni alassanifousseni@yahoo.fr\n\n1\nTchangai Boyodi 1\nBagny Aklesso 2\nAdani-Ife Ablavi A. 3\nAmavi Kossigan A. 4\nDarre Tchin 5\nAttipou Komla 1\n1 Department of Visceral Surgery, University Teaching Hospital of Lomé, Lomé, Togo\n2 Department of Hepato-Gastro-Enterology, University Teaching Hospital of Lomé, Lomé, Togo\n3 Department of Medical Oncology, University Teaching Hospital of Lomé, Lomé, Togo\n4 Department of General Surgery, University Teaching Hospital of Lomé, Lomé, Togo\n5 Department of Pathology, University Teaching Hospital of Lomé, Lomé, Togo\n2 11 2019\n2 11 2019\n12 2019\n7 2 159164\n23 8 2019\n© The Author(s) 2019\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nIntroduction\n\nAlthough the standard treatment for stromal tumours is surgery, in locally advanced forms, it is often necessary to achieve tumour downstaging to improve surgical outcomes. Neoadjuvant treatment in gastrointestinal stromal tumours (GISTs) with tyrosine kinase inhibitors, including imatinib, has been shown to be effective in several studies, but the duration of this treatment is still a subject of debate.\n\nCase report\n\nWe report a case of a large GIST of the stomach in a 51-year-old patient with atypical presentation that was initially unresectable. Neoadjuvant treatment with imatinib for 16 months resulted in a good response, allowing secondary surgical excision.\n\nConclusion\n\nImatinib in neoadjuvant therapy should be continued as long as there is a good response and tolerance to the medication to obtain tumour downsizing compatible with carcinologic excision.\n\nElectronic supplementary material\n\nThe online version of this article (10.1007/s40487-019-00101-4) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nGIST\nImatinib\nNeoadjuvant therapy\nSurgery\nissue-copyright-statement© The Author(s) 2019\n==== Body\nKey Summary Points\n\nThe duration of neoadjuvant treatment of GISTs with imatinib remains a subject of debate\t\nSome authors recommend not to exceed 12 months. But there is no scientific basis for this delay\t\nThrough this clinical case, the authors report a good tolerance and a good tumour response after 16 months of neoadjuvant treatment with imatinib, allowing the excision of a large gastric stromal tumour, and discuss the criteria to determine the duration of the neoadjuvant treatment\t\nThe authors suggest, in the context of neoadjuvant therapy, to continue treatment as long as there is good tumour response and tolerance allowing carcinologic excision\t\n\nIntroduction\n\nGastrointestinal stromal tumours (GISTs) are tumours that are derived from Cajal cells or their precursors. These are the most frequent mesenchymal tumours of the digestive tract [1]. They represent 0.1–3% of all gastrointestinal tumours, and gastric localisation is the most frequent [2]. Although the standard of care is surgery, the prognosis of these tumours has been improved by tyrosine kinase inhibitors, which have increased overall and disease-free survival rates [3–7]. GISTs may sometimes be diagnosed at a locally advanced stage, and the use of these inhibitors may be necessary to obtain tumour downsizing before surgery [7]. Neoadjuvant treatment in GISTs has been shown to be effective in several studies, but the duration of this treatment has been the subject of debate. We report a good response after 16 months of neoadjuvant therapy with imatinib in a large atypical stomach GIST, allowing secondary surgical excision\n\nCase report\n\nA 51-year-old female patient had upper gastrointestinal bleeding with haematemesis and melena in the context of an altered general condition. The physical examination revealed weight loss (15 kg) and an abdominal mass of approximately 20 cm in size on the major axis, located in the epigastrium and left hypochondrium. The mass was not very mobile and was poorly limited. A blood test showed anaemia (8 g/dl). A computed tomography (CT) scan revealed a voluminous mass of approximately 22 cm in size from the rear cavity of the epiploon with a predominant mix of aerobic and fluid components. The mass had a thickened and irregular wall and pushed back the stomach (Fig. 1). This observation was suggestive of a gastric duplication with blocked communication. An oesophagogastroduodenoscopy did not reveal any lesion up to the 3rd duodenum apart from an aspect of extrinsic compression of the anterior side of the cardio-tuberosity junction. An exploratory laparotomy was decided upon, as the ultrasound endoscopy was not available. During this exploration, a large tumour of a suspicious nature was found at the expense of the posterior gastric wall extending from the spleen to the left hepatic lobe and left diaphragmatic cupola. There was no hepatic metastasis, suspicious adenopathy or peritoneal carcinosis. Nevertheless, the lesion seemed to be inextirpable. We therefore ended the procedure by performing, via a short gastrotomy, four biopsies of the lesion that communicated with the gastric lumen through an orifice admitting a finger. The postoperative outcomes were simple. The biopsy results were in favour of a stromal tumour, with positive CD117, CD34 and Dog1 antibodies (Figs. 2, S1, S2 and S3). The Ki-67 index was positive at 4%.Fig. 1 First CT scan showing the tumour\n\nFig. 2 CD117 positivity on immunohistochemistry\n\nA treatment with imatinib at the initial dosage of 800 mg twice daily was initiated. Poor tolerance to treatment (i.e., severe asthenia and aggravation of anaemia following repeated digestive bleeding) required a reduction in the dosage to 400 mg/day and transfusion. Under this treatment, the patient’s condition constantly improved, with a regular regression of the mass that was no longer palpable after 16 months of treatment. The total weight gain was then 8 kg. The CT scan showed a partial response with an estimated residual mass of 8 cm on its largest axis (Fig. 3). A second laparotomy was performed after 16 months of imatinib treatment. An en bloc resection made of an upper polar gastrectomy with part of hepatic segment 3 and splenectomy was performed because of residual invasion of the spleen hilum and left hepatic lobe. Immediate oeso-antral anastomosis was performed at the same time. The outcomes of this operation were simple. The resection was histologically R0. Imatinib treatment was continued at a daily dose of 400 mg. After a 12-month follow-up, no recurrence was noted.Fig. 3 Tumour aspect on CT scan after neoadjuvant therapy\n\nThe authors received consent to both publish and participate from the patient. This case also received approval from the head of the Surgery Department of the Sylvanus Olympio University Hospital (Ref. N06/2019/DCS/CHUSO) to be reported and published.\n\nDiscussion\n\nSurgery remains the curative treatment of GISTs to this day [3]. However, the surgical option may be reconsidered in the case of a large tumour, which, via its extension to neighbouring organs, may potentially impose organ sacrifice with the risk of not obtaining a negative margin [8], thus posing the problem of resectability. The case we reported fits into this situation, with an unusual predominant mix of aerobic and cystic components, creating additional diagnostic difficulties related to its confusion with gastric duplication. Indeed, the exploration tools at our disposal did not allow us to make a diagnosis, and the predominant cystic component of the tumour increased the risk of tumour rupture in the event of a percutaneous biopsy. Hence, our first laparotomy, the main goal of which was clearly surgical excision for a histological diagnosis on the surgical specimen. The limitation of our objective to perform an exclusively diagnostic procedure in view of the operative findings during this first operation supports the need for a histological diagnosis to plan the management of our patient as well as the need for neoadjuvant therapy for large tumours to obtain downstaging for a better carcinologic result.\n\nThe introduction of targeted therapy, including imatinib, whose administration is well codified in adjuvant therapy, has improved patient prognosis [3]. Targeted therapy has provided neoadjuvant perspectives for large tumours with a high risk of malignancy. The preoperative use of imatinib in locally advanced GISTs is based on the assumption that in neoadjuvant therapy, imatinib could reduce the risk of tumour rupture and incomplete resections as well as minimise the intraperitoneal dissemination of tumour cells and thus the recurrence rate [8]. In fact, the preoperative use of imatinib is becoming more common, but the duration of this neoadjuvant treatment, which varies from one study to another, remains a point of controversy. Blanke [9] proposed a duration of 3–6 months in a randomized trial. In 2009, the ESMO recommended a duration of 3–12 months until a maximum response was obtained [10]. However, for most studies, the median duration of neoadjuvant treatment is between 6 and 8 weeks and generally does not exceed 1 year [11–17]. These studies remained within these limits based on the idea that the optimal response would be achieved between 4 and 12 months, with a low risk of developing secondary resistance and a better surgical outcome [17].\n\nThe extension of this duration to 16 months in our patient was justified by the good clinical response illustrated by the progressive and regular disappearance of the mass on palpation and by an objective response to the control on the CT scan. According to a study by Chaoyong Shen [16], one patient remained sensitive to imatinib after 57 months of treatment, suggesting that the optimal duration of preoperative treatment may vary from one individual to another. Recent data on the tumour response to imatinib based on the molecular profile of GISTs seem to confirm this interindividual difference in the treatment response by showing a better response of KIT exon 11 and 13 mutations, while KIT exon 9 mutations and PDGFRA gene mutations are associated with a poor response [6]. Furthermore, by comparing the median duration of the neoadjuvant treatments of several series, it appears that a longer duration is associated with a higher resectability rate and, consequently, a better tumour response [11–15, 17].\n\nIt can be concluded from the above results that the response to treatment varies from one individual to another and that the longer the duration of neoadjuvant treatment is, the better the tumour response. Regarding the expectation of surgical excision, we believe that the duration of optimal treatment should depend on the tumour response to treatment and be the option that provides better tumour reduction for carcinologic excision.\n\nFor very large tumours, the duration of treatment must therefore be extended as long as the tumour responds to treatment, as in our patient, for whom 16 months were necessary. In our opinion, the regular monitoring and, if possible, molecular typing of GISTs are decisive criteria that should be considered in the neoadjuvant treatment of GISTs. Indeed, one of the objectives of follow-up is to identify adverse side effects that may lead to a reconsideration of imatinib dosage, as was the case in our patient. In the context of neoadjuvant therapy, the main objective of follow-up is to assess the response to imatinib therapy, which should be key in decision making to continue or not continue treatment, especially in the absence of molecular typing to predict a tumour response. This response can be evaluated with a CT or PET scan [18]. However, according to the ESMO’s recommendations in 2014 [3], PET scans show high sensitivity in the early assessment of the tumour response and could therefore be very useful in neoadjuvant treatment where response prediction is particularly important. However, for regular monitoring, CT is most commonly used because it provides more anatomical information [19]. We based our follow-up essentially on the clinic because of the difficult accessibility of the CT scan under our working conditions and performed a CT scan only when the mass disappeared after abdominal palpation.\n\nThe 16-month neoadjuvant treatment thus allowed tumour removal in two stages. Despite tumour reduction, the persistence of infiltration in the splenic hilum and inferior side of the left lobe indicated splenectomy, and a notch in the left lobe suggested a potential gain in organ preservation if treatment had continued.\n\nLimitations\n\nFor technical reasons, the molecular profile used to determine the type of mutation involved was not performed, although this had little impact on the management of our patient.\n\nConclusion\n\nNeoadjuvant treatment is necessary in patients with large GISTs to achieve tumour downsizing before surgery. The treatment should be continued as long as there is a good tumour response and tolerance to the medication to obtain tumour downsizing compatible with carcinologic excision.\n\nElectronic supplementary material\n\nBelow is the link to the electronic supplementary material. Supplementary material 1 (DOCX 1834 kb)\n\nAbbreviations\n\nGIST Gastrointestinal stromal tumour\n\nCT Computed tomography\n\nCD Cluster of differentiation\n\nKIT Tyrosine protein kinase cKIT\n\nPDGFRA Platelet-derived growth factor receptor α\n\nPET Positron emission tomography\n\nEORTC European Organisation for Research and Treatment of Cancer\n\nRTOG Radiation Therapy Oncology Group\n\nESMO European Society for Medical Oncology\n\nAcknowledgements\n\nWe thank the patient for giving us permission to report this clinical case. We would also like to thank Mr. Liloudini Arouna for the free English translation of the manuscript.\n\nFunding\n\nNo funding or sponsorship was received for this study or publication of this article.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nAuthorship Contributions\n\nFousséni Alassani was responsible for the design of the study and data collection and wrote the manuscript. Boyodi Tchangai, Aklesso Bagny, Ablavi A. Adani-Ife and Kossigan A. Amavi participated in the data collection and reading and redaction of the manuscript. Tchin Darre and Komla Attipou were responsible for overall scientific management and manuscript preparation.\n\nDisclosures\n\nFousséni Alassani, Boyodi Tchangai, Aklesso Bagny, Ablavi A Adani-Ife, Kossigan A Amavi, Tchin Darre and Komla Attipou declare that they have no competing interest.\n\nCompliance with Ethical Guidelines\n\nWe received consent to both publish and participate from the patient. This case also received approval from the head of the Surgery Department of the Sylvanus Olympio University Hospital (Ref. N°06/2019/DCS/CHUSO) to be reported and published.\n\nData Availability\n\nAll data generated or analyzed during this study are included in this published article/as supplementary information files.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced digital features\n\nTo view enhanced digital features for this article go to 10.6084/m9.figshare.10028495.\n==== Refs\nReferences\n\n1. Wang L Liu L Liu Z Tian Y Lin Z Giant gastrointestinal stromal tumor with predominantly cystic changes: a case report and literature review World J Surg Oncol. 2017 15 220 10.1186/s12957-017-1285-2 29237476\n2. Miettinen M Lasota J Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis Arch Pathol Lab Med 2006 130 1466 1478 17090188\n3. ESMO/European Sarcoma Network Working Group Gastrointestinal stromal tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol. 2014 25 Suppl Suppl 3 21 26 10.1093/annonc/mdu255\n4. Joensuu H Martin-Broto J Nishida T Reichardt P Schöffski P Maki RG Follow-up strategies for patients with gastrointestinal stromal tumour treated with or without adjuvant imatinib after surgery Eur J Cancer 2015 51 12 1611 1617 10.1016/j.ejca.2015.05.009 26022432\n5. Koo D-H Ryu M-H Kim K-M Asian consensus guidelines for the diagnosis and management of gastrointestinal stromal tumor Cancer Res Treat Off J Korean Cancer 2016 48 4 1155 1166 10.4143/crt.2016.187\n6. Nishida T Blay J-Y Hirota S Kitagawa Y Kang Y-K The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines Gastric Cancer 2016 19 1 3 14 10.1007/s10120-015-0526-8 26276366\n7. Asif S Gupta N Gupta G Mehta A Singh S Effective downsizing of a gastroesophageal GIST using neoadjuvant imatinib mesylate: aA case report J Gastrointest Cancer 2017 48 2 198 200 10.1007/s12029-016-9816-6 27006070\n8. Wang CY Ser KH Kuan WS Lee WJ Surgical intervention of a giant gastric gastrointestinal stromal tumor following neoadjuvant therapy with imatinib Formos J Surg 2018 51 162 166\n9. Blanke CD, Joensuu H, Demetri GD, Heinrich MC, Eisenberg B, Fletcher J, et al. Outcome of advanced gastrointestinal stromal tumor (GIST) patients treated with imatinib mesylate: four-year follow-up of a phase II randomized trial. AIn: SCO Gastrointestinal Cancers Symposium Proceeding 2006; p. abstr 7.\n10. Casali PG Jost L Reichardt P Schlemmer M Blay JY ESMO Guidelines Working Group Gastrointestinal stromal tumors: ESMO clinical recommendations for diagnosis treatment and follow up Ann Oncol. 2009 20 Suppl 4 64 67 19454466\n11. Andtbacka RH Ng CS Scaife CL Cormier JN Hunt KK Pisters PW Surgical resection of gastrointestinal stromal tumors after treatment with imatinib Ann Surg Oncol 2007 14 1 14 24 10.1245/s10434-006-9034-8 17072676\n12. Eisenberg BL Harris J Blanke CD Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665 J Surg Oncol 2009 99 42 47 10.1002/jso.21160 18942073\n13. Hohenberger P Langer C Wendtner CM Neoadjuvant treatment of locally advanced GIST: results of APOLLON, a prospective, open label phase II study in KIT- or PDGFRA-positive tumors J Clin Oncol 2012 30 abstr 10031\n14. Tielen R Verhoef C van Coevorden F Surgical treatment of locally advanced, non-metastatic, gastrointestinal stromal tumours after treatment with imatinib Eur J Surg Oncol 2013 39 150 155 10.1016/j.ejso.2012.09.004 23084087\n15. Rutkowski P Gronchi A Hohenberger P Bonvalot S Schöffski P Bauer S Neoadjuvant Imatinib in locally advanced gastrointestinal stromal tumors (GIST): the EORTC STBSG Experience Ann Surg Oncol. 2013 20 9 2937 2943 10.1245/s10434-013-3013-7 23760587\n16. Shen C Chen H Yin Y Chen J Zhang B Chen Z Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor Clinics. 2014 69 11 758 762 10.6061/clinics/2014(11)09 25518034\n17. Ramaswamy Anant Jain Deepak Sahu Arvind Ghosh Joydeep Prasad P Deodhar K Neoadjuvant imatinib: longer the better, need to modify risk stratification for adjuvant imatinib J Gastrointest Oncol 2016 7 4 624 631 10.21037/jgo.2016.03.13 27563454\n18. Crosby JA Catton CN Davis A Malignant gastrointestinal stromal tumors of the small intestine: a review of 50 cases from a prospective database Ann Surg Oncol 2001 8 50 59 10.1007/s10434-001-0050-4 11206225\n19. Gold Jason S De Matteo Ronald P Combined surgical and molecular therapy: the gastrointestinal stromal tumor model Ann Surg 2006 244 176 184 10.1097/01.sla.0000218080.94145.cf 16858179\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2366-1089",
"issue": "7(2)",
"journal": "Oncology and therapy",
"keywords": "GIST; Imatinib; Neoadjuvant therapy; Surgery",
"medline_ta": "Oncol Ther",
"mesh_terms": null,
"nlm_unique_id": "101677510",
"other_id": null,
"pages": "159-164",
"pmc": null,
"pmid": "32699986",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article",
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"title": "Excision of a Large Gastrointestinal Stromal Tumour Following 16 Months of Neoadjuvant Therapy with Imatinib (Case Report).",
"title_normalized": "excision of a large gastrointestinal stromal tumour following 16 months of neoadjuvant therapy with imatinib case report"
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"abstract": "BACKGROUND\nOsimertinib is a third-generation EGFR-tyrosine kinase inhibitor approved for the treatment of T790M-positive non-small-cell lung cancer. More recently, osimertinib demonstrated improved disease control compared to other EGFR-TKIs. Multiple mechanisms of resistance have been described in T790M-positive patients who experienced treatment failure with osimertinib.\n\n\nMETHODS\nWe report the case of a 78-year-old non-smoker woman with stage IV EGFR L858R-positive lung adenocarcinoma presented with T790M mutation after five years of treatment with gefitinib. The patient was started on osimertinib, but after two and a half years of treatment experienced disease progression. The analyses of circulating tumor DNA using next-generation sequencing showed, together with the pre-existing T790M and exon 21 L858R, the presence of the EGFR C797G resistance mutation.\n\n\nCONCLUSIONS\nOur case report revealed a rare EGFR-dependent acquired resistance mutation to osimertinib in circulating tumor DNA. Liquid biopsy appears to be a promising resource to understand the biology of osimertinib resistance by clonal evolution monitoring and the identification of novel resistance mechanisms.",
"affiliations": "Clinical Oncology Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy; elisa.decarlo@cro.it.;Molecular Oncology Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Oncology Department, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy.;Nuclear Medicine Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Clinical Oncology Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Clinical Oncology Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Clinical Oncology Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Molecular Oncology Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Molecular Oncology Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.;Clinical Oncology Department - Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.",
"authors": "DE Carlo|Elisa|E|;Schiappacassi|Monica|M|;Pelizzari|Giacomo|G|;Baresic|Tania|T|;Del Conte|Alessandro|A|;Stanzione|Brigida|B|;DA Ros|Valentina|V|;Doliana|Roberto|R|;Baldassarre|Gustavo|G|;Bearz|Alessandra|A|",
"chemical_list": "D000178:Acrylamides; D000814:Aniline Compounds; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Greece",
"delete": false,
"doi": "10.21873/invivo.12586",
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"issn_linking": "0258-851X",
"issue": "35(5)",
"journal": "In vivo (Athens, Greece)",
"keywords": "EGFR C797G; Non-small-cell lung cancer; liquid biopsy; osimertinib",
"medline_ta": "In Vivo",
"mesh_terms": "D000178:Acrylamides; D000368:Aged; D000814:Aniline Compounds; D002289:Carcinoma, Non-Small-Cell Lung; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D000073890:Liquid Biopsy; D008175:Lung Neoplasms; D009154:Mutation; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "8806809",
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"references": "32693293;26181354;33230339;25939061;27086175;30588029;29068003;29807405;27959700;31564718;29506987;31769875;29713646;29885479;29151359;31751012;32918064;28625641;28149764;31864549",
"title": "Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report.",
"title_normalized": "acquired egfr c797g mutation detected by liquid biopsy as resistance mechanism after treatment with osimertinib a case report"
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"abstract": "To compare efficacy and safety of tapentadol prolonged release (PR) vs oxycodone controlled release (CR) in younger patients (<65 years of age) and in elderly patients (≥65 and ≥75 years of age) in the treatment of moderate-to-severe chronic osteoarthritis (OA) knee pain.\n\n\n\nData from two double-blind, randomized, placebo-, and oxycodone CR-controlled phase 3 trials were pooled and stratified by age. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point).\n\n\n\nA total of 1357 patients <65 years, 653 patients ≥65 years, and 176 patients ≥75 years of age were assessed. The comparison between tapentadol PR and oxycodone CR showed numerically better pain relief under tapentadol PR for both primary end-points in all three age groups. More favorable improvements were also observed for patient global impression of change, the Short Form-36 physical component score, and EuroQoL-5Dimensions health status index. In the elderly, incidences of dizziness and somnolence were comparable between active treatments, but incidences of nausea, vomiting, and constipation were considerably lower under tapentadol PR. Treatment completion rates were lowest under oxycodone CR; > 50% of elderly oxycodone CR patients named side-effects as the main reason for discontinuation.\n\n\n\nTapentadol PR was effective in the treatment of moderate-to-severe chronic OA pain in elderly and younger patients. Compared to oxycodone CR, the overall and the gastrointestinal tolerability profile in particular were better in all tapentadol PR groups, regardless of age.",
"affiliations": "a Grünenthal GmbH , Aachen , Germany.;a Grünenthal GmbH , Aachen , Germany.;a Grünenthal GmbH , Aachen , Germany.;a Grünenthal GmbH , Aachen , Germany.",
"authors": "Lange|Bernd|B|;Sohns|Melanie|M|;Tempero|José|J|;Elling|Christian|C|",
"chemical_list": "D003692:Delayed-Action Preparations; D010098:Oxycodone; D000077432:Tapentadol",
"country": "England",
"delete": false,
"doi": "10.1080/03007995.2018.1520085",
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"issue": "34(12)",
"journal": "Current medical research and opinion",
"keywords": "Chronic osteoarthritis pain; Elderly patients; Oxycodone CR; Pain relief; Quality-of-life; Tapentadol PR",
"medline_ta": "Curr Med Res Opin",
"mesh_terms": "D000368:Aged; D059350:Chronic Pain; D017326:Clinical Trials, Phase III as Topic; D003248:Constipation; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005260:Female; D006305:Health Status Indicators; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea; D020370:Osteoarthritis, Knee; D010098:Oxycodone; D016032:Randomized Controlled Trials as Topic; D000077432:Tapentadol; D014717:Vertigo; D014839:Vomiting",
"nlm_unique_id": "0351014",
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"pages": "2113-2123",
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"pmid": "30200781",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy and safety of tapentadol prolonged release formulation in the treatment of elderly patients with moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind, randomized, placebo-, and active-controlled trials.",
"title_normalized": "efficacy and safety of tapentadol prolonged release formulation in the treatment of elderly patients with moderate to severe chronic osteoarthritis knee pain a pooled analysis of two double blind randomized placebo and active controlled trials"
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"abstract": "A 65-year-old man presented to our hospital with a chief complaint of abdominal pain during defecation. Abdominal contrast-enhanced CT showed circumferential wall thickening with contrast effects in the sigmoid colon, and multiple metastases in the liver. Colonoscopy revealed a type 2 colon tumor that was obstructing the passage. A diagnosis of sigmoid colon cancer and multiple liver metastases was made based on laparoscopic sigmoidectomy plus D3 dissection. Pathologically, the resected specimen was diagnosed as colorectal neuroendocrine cell carcinoma(NEC)that was positive for synaptophysin and CD56. Postoperatively, 8 courses of FOLFOX plus bevacizumab(BV)therapy were administered, but CT showed remarkable increase in liver metastasis, and he died 5 months after the operation. Colorectal NEC is a very rare disease, for which no chemotherapy has been shown to be effective. Since we encounterd a case of sigmoid colon NEC with multiple liver metastases that followed a rapid course, we have presented it along with a literature review.",
"affiliations": "Dept. of Gastrointestinal and Pediatric Surgery, Tokyo Medical University Hospital.",
"authors": "Watanabe|Mitsuru|M|;Sumi|Tetsuo|T|;Udou|Ryutaro|R|;Enomoto|Masaya|M|;Matsudo|Takaaki|T|;Tachibana|Shingo|S|;Mimuro|Akihiro|A|;Katsumata|Kenji|K|;Tsuchida|Akihiko|A|",
"chemical_list": null,
"country": "Japan",
"delete": false,
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"issn_linking": "0385-0684",
"issue": "47(4)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D018278:Carcinoma, Neuroendocrine; D012809:Colon, Sigmoid; D003672:Defecation; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D055099:Neuroendocrine Cells; D012811:Sigmoid Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "703-705",
"pmc": null,
"pmid": "32389990",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Sigmoid Colon Neuroendocrine Cell Carcinoma Discovered by Defecation Disorder.",
"title_normalized": "a case of sigmoid colon neuroendocrine cell carcinoma discovered by defecation disorder"
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"abstract": "Carboplatin administration can usually be safely continued via a so-called desensitisation protocol when hypersensitivity reactions arise. Severe break-through reactions that occur early during desensitisation are likely to be IgE-mediated; in that case, addition of omalizumab premedication should be strongly considered.",
"affiliations": "1Department of Allergology and Internal Medicine, Internal address code AA21, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.;1Department of Allergology and Internal Medicine, Internal address code AA21, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.;1Department of Allergology and Internal Medicine, Internal address code AA21, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.;1Department of Allergology and Internal Medicine, Internal address code AA21, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.",
"authors": "Oude Elberink|Hanneke N G|HNG|;Jalving|Mathilde|M|;Dijkstra|Hilda|H|;van de Ven|Annick A J M|AAJM|0000-0001-7032-9571",
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"fulltext": "\n==== Front\nClin Transl AllergyClin Transl AllergyClinical and Translational Allergy2045-7022BioMed Central London 30910.1186/s13601-020-0309-0Letter to the EditorModified protocol of omalizumab treatment to prevent carboplatin-induced drug hypersensitivity reactions: a case study Oude Elberink Hanneke N. G. 123Jalving Mathilde 123Dijkstra Hilda 123http://orcid.org/0000-0001-7032-9571van de Ven Annick A. J. M. a.a.j.m.van.de.ven@umcg.nl 1231 0000 0000 9558 4598grid.4494.dDepartment of Allergology and Internal Medicine, Internal address code AA21, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands 2 0000 0000 9558 4598grid.4494.dDepartment of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands 3 0000 0000 9558 4598grid.4494.dDepartment of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands 29 1 2020 29 1 2020 2020 10 530 9 2019 12 1 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Carboplatin administration can usually be safely continued via a so-called desensitisation protocol when hypersensitivity reactions arise. Severe break-through reactions that occur early during desensitisation are likely to be IgE-mediated; in that case, addition of omalizumab premedication should be strongly considered.\n\nKeywords\nCarboplatinDesensitisationDrug hypersensitivityOmalizumabissue-copyright-statement© The Author(s) 2020\n==== Body\nTo the editor\nPlatinum-based chemotherapy is the cornerstone in the treatment of various solid tumours, including gynaecologic malignancies. The incidence of drug hypersensitivity reactions (DHRs) is high; up to 12% for carboplatin in gynaecological tumours [1]. The pathogenesis of platin-related DHRs may vary but for carboplatin, IgE-specific basophil activation has been demonstrated [2].\n\nFortunately, patients with a DHR to carboplatin can generally still be safely treated with carboplatin using a desensitisation protocol [3]. Protocols rely on two main principles, namely gradually increasing the dose of drug and using a premedication consisting of a combination of H1-, H2-antihistamines, corticosteroids and in some cases a leukotriene antagonist [3]. This method is successful for most patients; however, some still suffer from symptoms despite intense pre-treatment and extra anti-allergy medication during the desensitisation procedure. We describe a patient who developed a systemic allergic reaction at the first step (1 mg carboplatin/hour) of the desensitisation schedule on two separate occasions. Carboplatin treatment could, however, be successfully continued after pre-treatment with omalizumab and no further adverse events occurred.\n\nThe case concerns a now 57-year-old woman diagnosed with stage III ovarian cancer of the endometrioid type in 2008 (Table 1). In 2014, she had a platinum-sensitive relapse without rational surgical options and palliative chemotherapy with carboplatin/paclitaxel was initiated. During the second cycle, she developed an allergic reaction consisting of patchy erythema, coughing, throat and chest discomfort. The chemotherapy was stopped and referral to an allergologist followed. Carboplatin hypersensitivity was diagnosed based on the clinical presentation in combination with skin tests positive for carboplatin (Table 2). Three subsequent cycles of carboplatin were given according to a 10-step desensitisation schedule and were uneventful. (Figure 1a).Table 1 Summary of clinical events and treatment over time\n\nYear\tEvent\tSurgical debulking\tAdjuvant chemotherapy\tAllergology\t\n2008\tStage III ovarian cancer of the endometrioid type\tYes\t6 Cycles of carboplatin and paclitaxel\t\t\n2009\t\n2010\tDisease relapse\tYes\tNo\t\t\n2011\t\n2012\t\n2013\tDisease relapse\tYes\tNo\t\t\n2014\tSymptomatic platinum-sensitive disease relapse\tNot possible\t2 Cycles of carboplatin/paclitaxel\n\nCycle 3 omitted\n\nCycle 4–6 according to 10-step desensitisation schedule\n\n\tCycle 2: allergic reaction\n\nSkin tests positive for carboplatin, negative for paclitaxel\n\n\t\n2015\t\n2016\t\n2017\tSymptomatic platinum-sensitive disease relapse\tNo\t6 Cycles of carboplatin/paclitaxel according to 10-step desensitisation schedule\tSkin tests positive for carboplatin\t\n2018\tSymptomatic platinum-sensitive disease relapse\tNo\t6 Cycles of carboplatin monotherapy according to 10-step desensitisation schedule with additional omalizumab for cycle 4–6\tCycle 1: flushing, pruritus and erythema of the face and chest\n\nCycle 2 + 3: Anaphylaxis\n\nSkin tests positive for carboplatin (negative for cisplatin)\n\nCycle 4–6: Uneventful\n\nSkin tests persistently positive\n\n\t\n2019\tSymptomatic platinum-sensitive disease relapse\tNo\t6 Cycles of carboplatin monotherapy according to 10-step desensitisation schedule with additional omalizumab\tNo events\t\n\nTable 2 Diagnostic testing in suspected carboplatin allergy\n\nTime after initial diagnosis (years)\t6.5\t9.5\t11\t11.2\t\nStatus\tPrior to 2nd series of carboplatin/paclitaxel\tPrior to 3rd series of carboplatin/paclitaxel\tAfter 3 cycles carboplatin monotherapy (4th series), 0x omalizumab\tAfter 6 cycles carboplatin (4th series) and 4x omalizumab*\t\nSaline, diameter (mm)\t0\t0\t0\t0\t\nHistamine, diameter (mm)\t9.5\t4\t7.5\t6\t\nDrugs tested: diameter of wheal in mm\t\n Carboplatin 0.01 mg/ml\t8.5\t0\t6\t0\t\n Carboplatin 0.1 mg/ml\tN/A\t0\t7\t6.5\t\n Carboplatin 1 mg/ml\tN/A\t4.5\t7.5\t5.5\t\n Paclitaxel 0.001 mg/ml\t0\tN/A\tN/A\tN/A\t\n Paclitaxel 0.01 mg/ml\t0\tN/A\tN/A\tN/A\t\n Paclitaxel 0.1 mg/ml\t0\tN/A\tN/A\tN/A\t\n Paclitaxel 1 mg/ml\t0\tN/A\tN/A\tN/A\t\n Cisplatin 0.01 mg/ml\tN/A\tN/A\t0\t0\t\n Cisplatin 0.1 mg/ml\tN/A\tN/A\t0\t0\t\n Cisplatin 1 mg/ml\tN/A\tN/A\t0\t0\t\nOverview of intracutaneous testing for carboplatin and other chemotherapeutics. Positive results are shown in italics. Diameter = average of the length and width of the wheal, read 15–20 min after intracutaneous injection of the drug\n\nN/A not assessed\n\n* Skin tests were performed 8 weeks after the last omalizumab injection\n\n\nFig. 1 Management of carboplatin allergy. a 10-step desensitisation schedule for carboplatin. Cumulative dose as administered in the 6th and last cycle of the course. b Overview of carboplatin and omalizumab administration in relation to the adverse allergic reactions\n\n\n\n\nThe desensitisation procedure was successfully repeated with a relapse 3 years later. In 2018, carboplatin monotherapy was initiated due to a third symptomatic platinum-sensitive relapse. During the first cycle, an allergic reaction occurred at the last desensitisation step (Fig. 1b). The reaction consisted of flushing, pruritus and erythema of the face and chest. The carboplatin infused was stopped and intravenous clemastine was administered resulting in resolution of symptoms within minutes. The desensitisation was successfully continued at the penultimate infusion rate. 3 weeks later she experienced a more severe reaction moments after commencing the first infusion step, despite pre-treatment with H1/H2-antihistamines and dexamethasone. She had symptoms of flushing, hypotension, dyspnoea with chest discomfort, throat tightness and abdominal discomfort. Additional administration of clemastine, ranitidine and dexamethasone had insufficient effect and 0.5 mg of intramuscular epinephrine was required to relieve symptoms. There was no alternative explanation for this reaction, i.e. no co-factors such as concurrent infection, recent exercise or use of novel medications. After administration of the abovementioned medication, the desensitisation could be continued according to protocol without further additional medication or adverse events. During administration of the third cycle, despite optimizing premedication (20 mg dexamethasone i.v., 50 mg ranitidine i.v., 2 mg clemastine i.v. and 10 mg montelukast orally, all ≥ 1 h prior to the first infusion), a similar anaphylactic reaction occurred at the first infusion step. Intramuscular epinephrine halted the allergic reaction and again, the desensitisation could be completed without other events.\n\nSince further dilution of the carboplatin to allow an even slower desensitisation was not possible (in accordance to the SmPC of Carboplatin), other potential solutions were explored. Ojaimi et al. [4] described a patient who failed their 2-day and subsequently 4-day desensitisation protocol for carboplatin. After 3 fortnightly doses of 300 mg of omalizumab, a monoclonal anti-IgE antibody, carboplatin was successfully administered over 4 days.\n\nWe opted to aim to reduce the burden of anti-carboplatin IgE-antibodies by administering omalizumab. Our patient received one dose of omalizumab 300 mg 2 weeks before the 4th cycle of carboplatin was administered, and continued fortnightly (Fig. 1b). The following three administrations of carboplatin occurred without any side effects and no adaptations to the desensitisation protocol were required. Omalizumab was well tolerated. She had a good clinical and partial radiological response to the chemotherapy with 73% decreased CA-125 titres and commenced maintenance treatment with niraparib 6 weeks after the last cycle of chemotherapy. Unfortunately, she relapsed within 6 months and carboplatin monotherapy was reinitiated. The anti-allergy premedication regimen included omalizumab 300 mg every 14 days (first injection was given 11 days prior to the first cycle) and the desensitisation procedure was carried out uneventfully.\n\nWe here describe the successful addition of omalizumab to the conventional anti-allergic medication in a patient with severe break-through allergic reactions to carboplatin despite an optimized desensitisation schedule. To our knowledge, this is the second time omalizumab has been used as an adjuvant during carboplatin desensitisation. Ojaimi and colleagues added omalizumab to a more conservative desensitisation protocol. Our results confirm their findings and suggest that one dose of omalizumab prior to the start of desensitisation may already be sufficient, thereby minimizing treatment delay and enabling desensitisation procedures to be kept at the regular time schedule of 3.5 h.\n\nThere is limited but growing experience using omalizumab for desensitisation of DHR; case-reports or small case series describe positive results for aspirin [5], insulin [6], Elosulfase A, [7] and recently oxaliplatin [8]. Careful selection of patients remains pivotal and sufficient knowledge regarding the underlying pathogenic mechanism of the allergic reaction is essential. Non-IgE-mediated reactions are less likely to fully respond to this therapy. Consequently, the mechanism of hypersensitivity reactions should ideally be substantiated by diagnostics in order to identify those patients that might benefit from the addition of omalizumab. Carboplatin-induced DHR are IgE-mediated, as specific anti-carboplatin IgE antibodies can be detected in patients with DHR to carboplatin [9]. Iwamoto et al. nicely demonstrated in vitro an IgE-dependent mechanism in patients with carboplatin DHR [2]. The carboplatin reactivity was transferable when plasma of these patients was added to healthy control basophils, but could be almost completely blocked when cells were pre-treated with omalizumab.\n\nFor our patient, measurement of anti-carboplatin IgE was not available and a basophil activation test was unsuccessful probably due to the presence of low levels of omalizumab in the sample. Skin tests however repeatedly showed reactivity to carboplatin, which supports the presence of an IgE-mediated DHR.\n\nTaken together, for patients with continued allergic reactions of established or strongly suspected IgE-mediated origin despite a desensitisation schedule including conventional anti-allergic medication, we recommend additional pre-treatment with one dose of omalizumab 1–3 weeks prior to each cycle of chemotherapy.\n\nIn conclusion, omalizumab can be a valuable addition to the allergologist’s repertoire for desensitisation in case of patients suffering from adverse reactions suggestive of an IgE-mediated allergy.\n\nAbbreviation\nDHRdrug hypersensitivity reaction\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors would like to thank Annechien Lambeck and Laura Bungener for fruitful discussions and excellent laboratory assistance.\n\nAuthors’ contributions\nMJ was the treating oncologist of the patient, HOE and AvdV managed and supervised the desensitisation procedure; HD was responsible for drug delivery and (co-) developed the desensitisation schedule. HOE and AvdV wrote the article, AvdV drafted the figures, MJ and HD critically revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNo funding was provided specifically for this study. H.N.G. Oude Elberink’s institution has received consultancy fees from ALK-Abelló. H.N.G. Oude Elberink has received fees for delivering lectures from Chiesi, ALK-Abelló and Meda; has received consultancy fees from ALK-Abello; has received research support from Novartis, MEDA Pharma, Mead Johnson, ALK-Abello, Shire, and Chiesi; and has received payment for developing educational presentations from ALK-Abello. M. Jalving’s institution has received consultancy fees from Merck, BMS, Novartis, PierreFabre, Tesaro, AstraZenica and fees for delivering lectures from Sanofi. The other authors declare that they have no relevant conflicts of interest.\n\nAvailability of data and materials\nThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent for publication\nInformed consent for publication was provided by the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Markman M Kennedy A Webster K Elson P Peterson G Kulp B Clinical features of hypersensitivity reactions to carboplatin J Clin Oncol. 1999 17 4 1141 10.1200/JCO.1999.17.4.1141 10561172 \n2. Iwamoto T Hirai H Yamaguchi N Kobayashi N Sugimoto H Tabata T Carboplatin-induced severe hypersensitivity reaction: role of IgE-dependent basophil activation and FcepsilonRI Cancer Sci 2014 105 11 1472 1479 10.1111/cas.12538 25230301 \n3. Castells MC Tennant NM Sloane DE Hsu FI Barrett NA Hong DI Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases J Allergy Clin Immunol 2008 122 3 574 580 10.1016/j.jaci.2008.02.044 18502492 \n4. Ojaimi S Harnett PR Fulcher DA Successful carboplatin desensitization by using omalizumab and paradoxical diminution of total IgE levels J Allergy Clin Immunol In Pract. 2014 2 1 105 106 10.1016/j.jaip.2013.08.009 24565780 \n5. Lang DM Aronica MA Maierson ES Wang XF Vasas DC Hazen SL Omalizumab can inhibit respiratory reaction during aspirin desensitization Ann Allergy Asthma Immunol. 2018 121 1 98 104 10.1016/j.anai.2018.05.007 29777744 \n6. Yong PF Malik R Arif S Peakman M Amiel S Ibrahim MA Rituximab and omalizumab in severe, refractory insulin allergy N Engl J Med. 2009 360 10 1045 1047 10.1056/NEJMc0808282 19264698 \n7. Arroabarren E Aznal E Anda M Sanchez-Valverde F Anaphylaxis after Elosulfase A infusion: omalizumab as coadyuvant for enzyme replacement therapy desensitization Pediatr Allergy Immunol. 2019 31 491 10.1111/pai.13049 \n8. Prieto-Garcia A Noguerado B Rojas P Torrado I Rodriguez-Fernandez A Tornero P Unexpected anaphylaxis after completing a desensitization protocol to oxaliplatin: successful adjuvant use of omalizumab J Investig Allergol Clin Immunol 2019 29 1 53 55 10.18176/jiaci.0326 \n9. Caiado J Venemalm L Pereira-Santos MC Costa L Barbosa MP Castells M Carboplatin-, oxaliplatin-, and cisplatin-specific IgE: cross-reactivity and value in the diagnosis of carboplatin and oxaliplatin allergy J Allergy Clin Immunol Pract. 2013 1 5 494 500 10.1016/j.jaip.2013.06.002 24565621\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7022",
"issue": "10()",
"journal": "Clinical and translational allergy",
"keywords": "Carboplatin; Desensitisation; Drug hypersensitivity; Omalizumab",
"medline_ta": "Clin Transl Allergy",
"mesh_terms": null,
"nlm_unique_id": "101576043",
"other_id": null,
"pages": "5",
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"pubdate": "2020",
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"title": "Modified protocol of omalizumab treatment to prevent carboplatin-induced drug hypersensitivity reactions: a case study.",
"title_normalized": "modified protocol of omalizumab treatment to prevent carboplatin induced drug hypersensitivity reactions a case study"
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"abstract": "To determine the incidence of common adverse events after botulinum toxin A (BoNT-A) injections in children with cerebral palsy (CP) and to identify whether the severity of CP influences the incidence of adverse events.\n\n\n\nThis was an observational study of patients attending a BoNT-A clinic at a tertiary paediatric hospital (2010-2014). Data examined included procedural adverse events at the time of injection and at follow-up. Systemic adverse events were defined as lower respiratory tract illnesses, generalized weakness, dysphagia, and death. Severity of CP was categorized by the Gross Motor Function Classification System (GMFCS). The relationships between GMFCS and adverse events were analysed using negative binomial regression models.\n\n\n\nIn total, 591 children underwent 2219 injection episodes. Adverse events were reported during the procedure (130 [6%] injection episodes) and at follow-up (492 [22%] injection episodes). There were significantly increased rates of systemic adverse events in injection episodes involving children in GMFCS level IV (incidence rate ratio [IRR] 3.92 [95% confidence interval] 1.45-10.57]) and GMFCS level V (IRR 7.37 [95% confidence interval 2.90-18.73]; p<0.001).\n\n\n\nAdverse events after BoNT-A injections are common but mostly mild and self-limiting. Children in GMFCS levels IV and V are at increased risk of systemic adverse events. The relationship between CP severity and BoNT-A adverse events is complex and further research is required to better understand this relationship.\n\n\n\nAdverse events reported at the time of botulinum toxin A injection occurred in 6% of injection episodes. Adverse events were reported at follow-up in 22% of injection episodes. Children in Gross Motor Function Classification System (GMFCS) levels IV and V have increased rates of systemic adverse events. Children in GMFCS levels IV and V report less local weakness and pain.",
"affiliations": "University of Sydney, Sydney, NSW, Australia.;The Children's Hospital at Westmead, Westmead, NSW, Australia.;The Children's Hospital at Westmead, Westmead, NSW, Australia.;Sydney Children's Hospital, Randwick, NSW, Australia.;Child and Adolescent Health Services, Perth, WA, Australia.;The Children's Hospital at Westmead, Westmead, NSW, Australia.",
"authors": "Swinney|Caitlyn M|CM|0000-0002-5285-3393;Bau|Karen|K|;Burton|Karen L Oakley|KLO|;O'Flaherty|Stephen J|SJ|;Bear|Natasha L|NL|;Paget|Simon P|SP|",
"chemical_list": "D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A",
"country": "England",
"delete": false,
"doi": "10.1111/dmcn.13686",
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"issn_linking": "0012-1622",
"issue": "60(5)",
"journal": "Developmental medicine and child neurology",
"keywords": null,
"medline_ta": "Dev Med Child Neurol",
"mesh_terms": "D019274:Botulinum Toxins, Type A; D002547:Cerebral Palsy; D002648:Child; D003680:Deglutition Disorders; D005260:Female; D006801:Humans; D008297:Male; D009465:Neuromuscular Agents; D012141:Respiratory Tract Infections; D012189:Retrospective Studies; D012720:Severity of Illness Index",
"nlm_unique_id": "0006761",
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"pmid": "29451702",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Severity of cerebral palsy and likelihood of adverse events after botulinum toxin A injections.",
"title_normalized": "severity of cerebral palsy and likelihood of adverse events after botulinum toxin a injections"
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"abstract": "We present Boston Children's Hospital's clinic model for pegvaliase therapy in adults with phenylketonuria (PKU) and clinical outcomes in 46 patients over the first 1.5 years of commercial therapy. Approximately 70% (18/26) of patients starting pegvaliase achieved blood phenylalanine (Phe) <360 μmol/L, with an average of a 68 ± 24% decrease in blood Phe from baseline. All patients experienced at least minor side effects, but in most, management of the side effects allowed for treatment to continue.",
"affiliations": "Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States of America.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States of America.;Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America.;Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America.;Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States of America.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States of America.;Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States of America.",
"authors": "Sacharow|Stephanie|S|;Papaleo|Cassandra|C|;Almeida|Kyla|K|;Goodlett|Benjamin|B|;Kritzer|Amy|A|;Levy|Harvey|H|;Martell|Leslie|L|;Wessel|Ann|A|;Viau|Krista|K|",
"chemical_list": null,
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"doi": "10.1016/j.ymgmr.2020.100603",
"fulltext": "\n==== Front\nMol Genet Metab Rep\nMol Genet Metab Rep\nMolecular Genetics and Metabolism Reports\n2214-4269 Elsevier \n\nS2214-4269(20)30049-5\n10.1016/j.ymgmr.2020.100603\n100603\nShort Communication\nFirst 1.5 years of pegvaliase clinic: Experiences and outcomes\nSacharow Stephanie stephanie.sacharow@childrens.harvard.edub⁎ Papaleo Cassandra a Almeida Kyla a Goodlett Benjamin b Kritzer Amy b Levy Harvey b Martell Leslie a Wessel Ann a Viau Krista a a Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States of America\nb Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America\n⁎ Corresponding author. stephanie.sacharow@childrens.harvard.edu\n25 5 2020 \n9 2020 \n25 5 2020 \n24 10060324 1 2020 3 5 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present Boston Children's Hospital's clinic model for pegvaliase therapy in adults with phenylketonuria (PKU) and clinical outcomes in 46 patients over the first 1.5 years of commercial therapy. Approximately 70% (18/26) of patients starting pegvaliase achieved blood phenylalanine (Phe) <360 μmol/L, with an average of a 68 ± 24% decrease in blood Phe from baseline. All patients experienced at least minor side effects, but in most, management of the side effects allowed for treatment to continue.\n==== Body\n1 Introduction\nPegvaliase, an enzyme substitution therapy, reduces blood phenylalanine (Phe) in adults with phenylketonuria (PKU) and often allows for diet normalization [1,2]. It provides an alternative therapeutic approach to PKU when standard treatments, including dietary Phe restriction, medical foods, and cofactor therapy with sapropterin, are inadequate to achieve target blood Phe concentrations (120–360 μmol/L) [3].\n\nPegvaliase is comprised of pegylated phenylalanine ammonia lyase (PAL), a non-human enzyme that converts Phe to ammonia and trans-cinnamic acid [4,5]. As such, it invariably causes an immune response in humans [6]. Due to risk for anaphylaxis and non-systemic side effects, pegvaliase is initiated and titrated slowly, and patients are advised to pre-dose with H1 and H2 blocking antihistamines and required to carry auto-injectable epinephrine [7].\n\nHere we present our clinic model and clinical outcomes in a large cohort (n = 46) of adults with PKU being treated with pegvaliase in the “PAL Clinic” at Boston Children's Hospital between August 2018 and December 2019.\n\n2 Clinic design\nThe PAL Clinic is a specialty clinic within the Dr. Harvey Levy Program for PKU and Related Conditions at Boston Children's Hospital that provides care for patients with PKU receiving pegvaliase. Our team includes biochemical geneticists, metabolic dietitians, a psychologist, a clinic nurse and a clinic coordinator. Prior to initiation, patients are required to have a baseline metabolism visit within the previous 12 months and a documented blood Phe ≥600 μmol/L. Group information sessions are offered to help manage patient expectations, including time to efficacy and potential side effects, and to provide Risk Evaluation and Mitigation Strategies (REMS) training for anaphylaxis.\n\nOur clinic provides ongoing education and training during observed injection visits of the initiation phase and with each dosage increase. Pegvaliase doses are sent directly to the hospital pharmacy and provided in clinic for self-injection. Home observer(s) are highly recommended but not mandatory, and are encouraged to attend clinic visits for training. Medical visits occur during dosage increases and approximately every two months; nutrition visits occur every 3–6 months with more frequent visits while making dietary changes; and neuropsychological assessments occur at baseline and every 12 months as needed. Patients have access to 24-hour on-call coverage in the event that a patient experiences medication side effects.\n\nOn initiation, baseline labs are obtained including amino acids, chemistry, nutritional labs (e.g., 25-OH vitamin D, vitamin B12, prealbumin, iron studies and zinc) and inflammatory markers (e.g., erythrocyte sedimentation rate and C-reactive protein). Blood Phe and tyrosine are monitored every 4 weeks throughout initiation and titration, and 1–2 weeks after each dosage increase. Weekly blood Phe monitoring is advised as blood Phe decreases in order to make timely modifications to protein intake. Intact protein is generally increased by 10–20 g/day and often accompanied by a concurrent decrease in medical food when blood Phe is <120 μmol/L [7]. While blood tyrosine concentrations are generally within the reference range, tyrosine concentrations repeatedly below 30 μmol/L are addressed on a case-by-case basis. For the purpose of our discussion, we consider responders to be those with both a Phe decrease >50% and Phe <360 μmol/L.\n\n3 Results and discussion\nOur team transitioned 20 patients to commercial therapy from the pegvaliase clinical trials [1] and started 25 new patients, two of whom had previous exposure to pegvaliase during the clinical trials. One additional patient transferred to our clinic. The mean age of patients was 35.9 ± 10.5 years (range 19.1–55.4), and 37% (n = 17) were male. Of the 46 patients on therapy, four of the post-trial patients transferred to their local clinics and three patients discontinued therapy, one due to personal choice, one due to anxiety and one due to side effects described below. One female discontinued therapy for pregnancy and resumed after breastfeeding on an accelerated titration schedule [8].\n\nPost-trial patients had been in the trial for an average of 4.8 ± 1.2 years. At the first clinical visit after the study closed, four patients had blood Phe >360 μmol/L, two had Phe of 30–360 μmol/L and 11 had low blood Phe (<30 μmol/L). Three patients had no post-study Phe reported due to discontinuation or site transfer. Medication adherence declined after study close-out in six patients, as noted by patient report and worsening metabolic control. Team members increased contact with patients to help reinforce consistent dosing. To help with injection fatigue, we offered weekly dosing reduction by giving a higher dose in a single injection fewer times per week. Phe levels generally remained consistent when maintaining the same weekly dose given in fewer injections. We advised dosing a minimum of twice weekly to avoid potential side effects from dose interruption. No side effects were observed with weekly dosing reduction. Additionally the weekly dose was reduced in patients with low blood Phe (<30 μmol/L).\n\nPatients initiating commercial therapy started pegvaliase on a rolling basis and were treated for an average of 45 ± 18 weeks (range 10–71 weeks). Mean blood Phe decreased from 1031 ± 385 μmol/L at baseline (n = 26) to 654 ± 509 μmol/L at 12 months of therapy (n = 9). Nearly all patients (24/26) had a ≥ 30% decrease in Phe from baseline with an average decrease of 56 ± 30%. Eighteen patients (69%) had a ≥ 50% decrease in Phe, corresponding to at least one blood Phe concentration < 360 μmol/L (Fig. 1A). The initial blood Phe response (<360 μmol/L) in these 18 patients occurred while on 10 mg (3/18), 20 mg (8/18), 40 mg (5/18) and 60 mg (2/18) pegvaliase/day at an average of 13 ± 10.5 weeks, 16.1 ± 7.7 weeks, 36.4 ± 2.9 weeks and 58 ± 5.7 weeks after starting pegvaliase therapy, respectively. One patient, who initially responded on 40 mg at 33 weeks, had a rebound increase in blood Phe that remained elevated on 60 mg/day at 62 weeks of therapy. Six patients had low blood Phe concentrations (<30 μmol/L) on ≥2 samples. There were subjective improvements in quality of life, verbal communication and daily functioning among responders, but objective data were unavailable for the majority of patients. Some patients reported more work-related compliments and being promoted.Fig. 1 Blood phenylalanine (Phe) concentrations (A) and side effects (B) in 26 adults with phenylketonuria on commercial pegvaliase therapy. (A) Treatment response classified as having ≥1 blood Phe concentration < 360 μmol/L. Mean ± SD blood Phe concentrations demonstrated an overall decrease of 68 ± 24% for responders (n = 18) and 24 ± 18% for non-responders (n = 8) when comparing most recent blood Phe to baseline. (B) Rate of side effects for treatment naïve patients. For most, pegvaliase was increased to 10 mg at 6 weeks, 20 mg at 10 weeks and 40 mg at 34 weeks. *ISR, injection site reactions.\n\nFig. 1\n\nAt pegvaliase initiation, the majority of patients (16/26) consumed a Phe-restricted diet with medical food (formula), 8/26 consumed a moderate protein restriction with inadequate medical food (≤50% of prescribed) and 2/26 had discontinued all dietary treatment. Most patients had minor fluctuation in BMI (0.14 ± 1.1 kg/m2) after starting pegvaliase; however, 5/26 experienced >5% weight change that corresponded to an improvement in BMI in 4/5. Of the 18 patients with a blood Phe response, 50% tolerated a normal intact protein intake (≥0.8 g/kg/day) with no medical food. Several patients experienced fluctuations in blood Phe while making diet modifications, which slowed diet liberalization. Patients on a normalized vs. liberalized diet had an earlier blood Phe response prior to data collection (22 ± 19 weeks vs. 16 ± 8 weeks, respectively). At the time of data collection, patients with ongoing diet modifications (n = 9) had a median of a 50% increase in intact protein and 25% decrease in medical food protein.\n\nAll patients experienced side effects, which included injection-site reaction (including erythema, 23/26), arthralgia (18/26), rash (18/26), fatigue (12/26), headache (9/26), gastrointestinal symptoms (7/26), chills (6/26), hair loss (5/26), inguinal or axillary lymphadenopathy (4/26), dizziness (2/26) and anaphylaxis (1/26). There were often reactions 1–2 weeks after initiation, and the frequency decreased over the course of treatment (Fig. 1B).\n\nSide effects were managed allowing continuation of therapy for most. One patient experienced gastrointestinal symptoms from the premedication, which lead us to start premedication dosing prior to initiation in subsequent patients. The titration schedule [7] was slowed due to side effects in 4/26 patients, including one patient who experienced anaphylaxis at 6 weeks of therapy and was successfully re-challenged at week 10. One patient was concurrently receiving immunotherapy for environmental allergies, and developed an injection site reaction that became cellulitic with central scabbing, and later severe joint pain, leading to discontinuation. Oral steroids were prescribed to treat joint pain, hives or marked injection site reaction in 11/26 patients. Substantial hair loss characterized by global thinning without alopecia was noted in one patient after a period of low blood Phe combined with suboptimal total protein intake. Symptoms improved after an increase in dietary protein.\n\n4 Conclusion\nWhile there are many challenges with pegvaliase therapy, including a significant side-effect profile and delay of drug efficacy, it has proven to be a powerful new treatment for adults with PKU. Given the potential for cognitive and psychiatric co-morbidities in adults with PKU, this clinic model has offered patients ongoing education, emotional support and close monitoring throughout the phases of therapy. The majority of our patients were able to achieve efficacy (Phe <360 μmol/L) with diet liberalization or normalization and continue on therapy even through side effects, including one case of anaphylaxis. A multidisciplinary clinic with excellent psychosocial support is beneficial for patient experience and adherence. As our clinic expands in the future with a broader PKU population base, we hope to continually improve clinic practices involving this new treatment modality.\n==== Refs\nReferences\n1 Thomas J. Levy H. Amato S. Vockley J. Zori R. Dimmock D. Harding C.O. Bilder D.A. Weng H.H. Olbertz J. Pegvaliase for the treatment of phenylketonuria: results of a long-term phase 3 clinical trial program (PRISM) Mol. Genet. Metab. 124 1 2018 27 38 10.1016/j.ymgme.2018.03.006 29653686 \n2 Harding C.O. Amato R.S. Stuy M. Longo N. Burton B.K. Posner J. Weng H.H. Merilainen M. Gu Z. Jiang J. Pegvaliase for the treatment of phenylketonuria: a pivotal, double-blind randomized discontinuation phase 3 clinical trial Mol. Genet. Metab. 124 1 2018 20 26 10.1016/j.ymgme.2018.03.003 29628378 \n3 Jurecki E.R. Cederbaum S. Kopesky J. Perry K. Rohr F. Sanchez-Valle A. Viau K.S. Sheinin M.Y. Cohen-Pfeffer J.L. Adherence to clinic recommendations among patients with phenylketonuria in the United States Mol. Genet. Metab. 120 3 2017 190 197 10.1016/j.ymgme.2017.01.001 28162992 \n4 Hoskins J.A. Holliday S.B. Greenway A.M. The metabolism of cinnamic acid by healthy and phenylketonuric adults: a kinetic study Biomed Mass Spectrom. 11 6 1984 296 300 10.1002/bms.1200110609 6743769 \n5 Levy H.L. Sarkissian C.N. Scriver C.R. Phenylalanine ammonia lyase (PAL): from discovery to enzyme substitution therapy for phenylketonuria Mol. Genet. Metab. 124 4 2018 223 229 10.1016/j.ymgme.2018.06.002 29941359 \n6 Gupta S. Lau K. Harding C.O. Shepherd G. Boyer R. Atkinson J.P. Knight V. Olbertz J. Larimore K. Gu Z. Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials EBioMedicine 37 2018 366 373 10.1016/j.ebiom.2018.10.038 30366815 \n7 Longo N. Dimmock D. Levy H. Viau K. Bausell H. Bilder D.A. Burton B. Gross C. Northrup H. Rohr F. Evidence- and consensus-based recommendations for the use of pegvaliase in adults with phenylketonuria Genet. Med. 21 8 2019 1851 1867 10.1038/s41436-018-0403-z 30546086 \n8 Rohr F. Kritzer A. Harding C.O. Viau K. Levy H.L. Discontinuation of Pegvaliase therapy during maternal PKU pregnancy and postnatal breastfeeding: a case report Mol. Genet. Metab. Rep. 22 2020 100555 10.1016/j.ymgmr.2019.100555 31956506\n\n",
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"affiliations": "Division of Emergency Medicine, Department of Medicine, University of Toronto, Canada.;Department of Emergency Medicine, University of Maryland School of Medicine, United States. Electronic address: amalmattu@comcast.net.;Department of Emergency Medicine, University of Virginia School of Medicine, United States.;Department of Emergency Medicine, University of Maryland School of Medicine, United States.",
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"abstract": "CSF-venous fistula is a recently reported cause of spontaneous intracranial hypotension that may occur in the absence of myelographic evidence of CSF leak. Information about this entity is currently very limited, but it is of potential importance given the large percentage of cases of spontaneous intracranial hypotension associated with negative myelography findings. We report 3 additional cases of CSF-venous fistula and describe the \"hyperdense paraspinal vein\" sign, which may aid in its detection.",
"affiliations": "From the Departments of Radiology (P.G.K., T.J.A., L.G.) peter.kranz@duke.edu.;From the Departments of Radiology (P.G.K., T.J.A., L.G.).;Department of Neurosurgery (W.I.S.), Cedars-Sinai Medical Center, Los Angeles, California.;Neurosurgery (I.O.K.), Duke University Medical Center, Durham, North Carolina.;From the Departments of Radiology (P.G.K., T.J.A., L.G.).",
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"abstract": "BACKGROUND Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing regions. In high-income countries, hepatitis E is an emergent zoonotic disease of increasing concern. Clinically, the infection is usually acute and self-limited in immunocompetent individuals, although rare chronic cases in immunocompromised patients have been reported. Both acute and chronic infections have been recently associated with several extrahepatic manifestations, including neurological and hematological disorders. CASE REPORT A case of autochthonous chronic HEV infection in a liver-transplanted man from a non-endemic country is presented. Phylogenetic analysis revealed a swine origin of the HEV human infection. Chronic hepatitis E was treated with a 9-week course of ribavirin, after which viral clearance was achieved. Subsequently, the patient developed a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoma. At the time of lymphoma diagnosis, the patient had shown a strong reactivation of Epstein-Barr virus (EBV) infection. After additional antiviral ganciclovir therapy and chemotherapy, the patient had a complete recovery with no sequelae. CONCLUSIONS The differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by appropriate nucleic acid techniques (NATs). Cases of HEV infection with an atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.",
"affiliations": "National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay.;National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay.;National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay.;National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay.;Virology Section, Science Faculty, University of the Republic, Montevideo, Uruguay.;Virology Section, Science Faculty, University of the Republic, Montevideo, Uruguay.;Virology Section, Science Faculty, University of the Republic, Montevideo, Uruguay.",
"authors": "Mainardi|Victoria|V|;Gerona|Solange|S|;Ardao|Gonzalo|G|;Ferreira|Noelia|N|;Ramírez|Gabriel|G|;Arbiza|Juan|J|;Mirazo|Santiago|S|",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3130266410.12659/AJCR.916253916253ArticlesLocally Acquired Chronic Hepatitis E Followed by Epstein-Barr Virus Reactivation and Burkitt Lymphoma as a Suspected Extrahepatic Manifestation in a Liver Transplant Recipient Mainardi Victoria BCDEF1Gerona Solange CD1Ardao Gonzalo BCD1Ferreira Noelia CD1Ramírez Gabriel CD2Arbiza Juan EF2Mirazo Santiago ADEF2\n1 National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay\n2 Virology Section, Science Faculty, University of the Republic, Montevideo, UruguayAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Santiago Mirazo, e-mail: smirazo@fcien.edu.uy2019 14 7 2019 20 1016 1021 15 3 2019 19 5 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 62\n\nFinal Diagnosis: Chronic hepatitis E • Burkitt’s limphoma\n\nSymptoms: Elevated liver enzymes\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Gastroenterology and Hepatology\n\nObjective:\nUnusual clinical course\n\nBackground:\nHepatitis E virus (HEV) is a common cause of acute hepatitis in developing regions. In high-income countries, hepatitis E is an emergent zoonotic disease of increasing concern. Clinically, the infection is usually acute and self-limited in immunocompetent individuals, although rare chronic cases in immunocompromised patients have been reported. Both acute and chronic infections have been recently associated with several extrahepatic manifestations, including neurological and hematological disorders.\n\nCase Report:\nA case of autochthonous chronic HEV infection in a liver-transplanted man from a non-endemic country is presented. Phylogenetic analysis revealed a swine origin of the HEV human infection. Chronic hepatitis E was treated with a 9-week course of ribavirin, after which viral clearance was achieved. Subsequently, the patient developed a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoma. At the time of lymphoma diagnosis, the patient had shown a strong reactivation of Epstein-Barr virus (EBV) infection. After additional antiviral ganciclovir therapy and chemotherapy, the patient had a complete recovery with no sequelae.\n\nConclusions:\nThe differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by appropriate nucleic acid techniques (NATs). Cases of HEV infection with an atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.\n\nMeSH Keywords:\nHepatitis, ChronicLiver TransplantationLymphoproliferative DisordersEpstein-Barr Virus Infection\n==== Body\nBackground\nHepatitis E virus (HEV), which belongs to the Orthohepevirus genus within the Hepeviridae family, is the etiological agent of acute hepatitis E, an emerging disease of increasing concern in public health [1]. Globally, 20 million infections with HEV occur per year, with 3.3 million symptomatic cases [1]. Four main genotypes are able to infect humans (HEV-1 to HEV-4). HEV-1 and HEV-2 (in Asia, North Africa, and a few Latin American countries) are regarded as anthroponotic with no other animal reservoir, whereas HEV-3 (in Europe, the Americas, and Asia) and HEV-4 (mainly in Asia) were found to infect several animal species [1,2]. In industrialized and non-endemic countries, HEV infection occurs as sporadic autochthonous cases and moderate to elevated rates of anti-HEV antibodies and RNA detection have been reported [3]. Commonly, the source of HEV infection in this epidemiological setting is undetermined, but increasing evidence supports the hypothesis of zoonotic transmission of infection from pigs and wild boars [4], serving as the main reservoir for human infections. In immunocompetent individuals, HEV typically causes an acute and self-limiting disease [5]. Unknown effects of HEV infection have been recently reported in non-endemic and high-income countries, such as clinical presentation with a wide range of extrahepatic manifestations, and the possibility of the disease to become chronic in immunocompromised individuals and transplanted patients [5].\n\nThe ability of HEV, mainly HEV-3, to progress to a chronic state is of major concern in solid organ transplant recipients [6]. This group is thought to be the main population at risk, which is well documented among liver and kidney transplant recipients [7,8]. Furthermore, chronic HEV-3 infection has been shown to occur in patients with other conditions associated with immunosuppression, such as lymphoma, leukemia, and HIV infection [9]. Overall, the prevalence of acquired HEV in the post-liver transplantation population is about 1% [7].\n\nHerein, we present a case of autochthonous chronic HEV infection in a liver-transplanted man who afterwards showed a reactivation of Epstein-Barr virus (EBV) infection with subsequent development of a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoblastic leukemia, 3 years after liver transplant.\n\nThe study was approved by the Ethics Committee of the Central Hospital of the Armed Forces and the patient gave written consent prior to inclusion in this study.\n\nCase Report\nIn May 2014, a 62-year-old man underwent orthotopic liver transplantation (LT) for non-alcoholic steatohepatitis and cirrhosis. He had an isolated hepatitis B virus (HBV) core antibody (anti-HBc)-positive, and received a hepatitis B surface antigen (HBs Ag) and anti-HBc-negative, hepatitis B surface antibody (anti-HBs)-positive graft. The serological status donor/receptor for EBV was +/− and for cytomegalovirus (CMV) it was +/+.\n\nAs prophylactic therapy of HBV reactivation, the patient received lamivudine. Initial immunosuppression was performed with tacrolimus (2 mg 2×/day), mycophenolate mofetil (MMF) (500 mg 2×/day), and steroids (methylprednisolone 500 mg in the induction, with subsequent tapering). In the first week after LT, he presented an acute rejection, with good immune response to steroid pulse of 3 g of methylprednisolone, with histological resolution and normalizing of liver parameters at 40 days after surgery.\n\nAt the second month after transplant, the patient presented a CMV reactivation without alteration of liver enzymes, which was successfully treated with valganciclovir. Therefore, progressive reduction of immunosuppression was performed in the follow-up, with suspension of steroid and MMF. Tacrolimus therapy was continued.\n\nIn January 2016 (1 year and 6 months after LT) the patient presented asymptomatic elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), and alkaline phosphatase (AP) (Figure 1). HBV infection and CMV reactivation, as common causes of liver disease, were ruled out by PCR. Liver biopsy evidenced dense lobular inflammatory infiltrate composed mainly of neutrophils, and mixed minimal inflammatory infiltrate portal, ruling out rejection and hepatotoxicity (Figure 2A). Liver enzymes diminished spontaneously, but did not achieve normal values. In March 2016, a recurrent elevation was observed, and steroid therapy was reinitiated (prednisone 10 mg/day) with no response (Figure 1). A new liver biopsy showed expanded portal tracts with inflammatory infiltrate composed of lymphocytes, plasma cells, and neutrophils. Minimum bile duct damage with leukocyte permeation and piecemeal necrosis was noted. At the lobule, a mixed inflammatory infiltrate and endothelialitis compatible with acute rejection of low entity was found. A pulse of steroids was performed (methylprednisolone 2 g, followed by prednisone 20 mg/day) with a subsequent reintroduction of MMF (500 mg 2×/day). During the next 3 months the patient exhibited oscillation of enzymes levels, and a new liver biopsy showed portal infiltrate composed mainly of lymphocytes with piecemeal necrosis (Figure 2B). Pursuing viral etiologies as causative of the biochemical and histological features, additional PCR tests for HBV, Hepatitis C virus (HCV), and CMV were performed, with negative results. Herpes Simplex virus was also rule out by PCR. PCR for EBV showed a weak positive result, with a viral DNA copy number of 75 copies/mL (24 UI/mL) (slightly higher than the cut-off value, according to manufacturer`s product data-sheet) (LightCycler® EBV Quantitative Kit, Roche, Switzerland). The classical form of EBV, infectious mononucleosis, is frequently associated (in almost half of the patients) with hepatitis and transient liver enzyme elevations. Serological testing for HEV showed specific IgG and IgM antibodies (recomWell HEV IgG/IgM, Mikrogen, Germany), and HEV RNA was detected by reverse transcription – nested PCR (RTnPCR) of a 287-bp region within the viral ORF2 in serum and stool samples [10]. Real-time PCR assay showed the HEV viral load in serum was 8×105 RNA copies/mL [10]. Sequencing and phylogenetic analysis clustered the isolate within HEV-3, very closely related to swine and human strains from Uruguay (Figure 3). Consequently, an attempt to reduce immunosuppressive therapy was undertaken, with diminished doses of tacrolimus (0.5 mg 2×/day) and suspension of steroids. The MMF dose was maintained. From then on, oscillation of the level of liver enzymes was observed, with a sharp peak in January 2017. A new liver biopsy ruled out acute rejection, while it maintained characteristics of hepatic lesion consistent with hepatitis E (Figure 2B). In February 2017, based on an altered liver enzymogram (Figure 1), HEV viremia, and histologic evidence of HEV infection, chronic hepatitis E was suspected as per definition [11], and treatment with ribavirin (1200 mg/day) was initiated (the patient weighed 102 pounds). After 1 week of treatment, a decrease in liver enzymes levels was detected, reaching normal levels after 3 weeks (Figure 1). Four weeks after the initiation of ribavirin treatment, HEV RNA was undetectable in serum. Unfortunately, no fecal specimen was available for testing HEV shedding in stool. Shortly thereafter, the patient presented fever and rhinorrhea, so a course of antibiotic (amoxicillin-clavulanic 500–125 mg 3×/day for 10 days) was indicated. As he remained febrile, a sinus facial, thorax, and abdominal scan was performed, which showed images compatible with microabscess in the liver (data not shown). Liver enzymes, on the other hand, were constantly normal, and as HEV remained undetectable and hemoglobin level diminished progressively, ribavirin was suspended after 9 weeks of treatment. A subsequent liver biopsy showed sinusoidal dilatation with megakaryocytes, compatible with extramedullary hematopoiesis (Figure 2C). Myelogram and cytogenetic analysis (data not shown) confirmed acute lymphoblastic leukemia L3/Burkitt. PCR for EBV was positive, with a viral load of 1×104.66 DNA copies/mL (45 800 UI/mL) and intravenous ganciclovir therapy was initiated. The patient received 8 courses of chemotherapy based on rituximab, hyper-CVAD (hyper-fractionated-cyclophosphamide, sodium mercaptoethanesulfonate, vincristine, doxorubicin, and dexamethasone), methotrexate and Ara-C for treatment of leukemia, with a complete recovery. Clearance of EBV was also found. Throughout the 24-week follow-up after ending ribavirin therapy, liver enzyme levels remained normal and the patient had a sustained virologic response (SVR) with undetectable levels of HEV RNA in serum and stool samples (Figure 1).\n\nDiscussion\nZoonotic transmission of HEV-3 and HEV-4 from swine has been proven [1,2]. Phylogenetic analyses strongly suggest that this is the most likely route of infection in humans in non-endemic areas and high-income countries [2,4].\n\nIn immunocompetent individuals, HEV infection is commonly asymptomatic, but in patients with underlying chronic liver disease, acute fulminant hepatitis can occur. Furthermore, HEV-3 infection may lead to chronic infection in immunocompromised patients, such as solid organ transplant recipients under immunosuppressive therapy. Additionally, several extrahepatic manifestations have been associated with both acute and chronic hepatitis E [8]. Clinical diagnosis of chronic hepatitis E infection is challenging. Such infections are largely asymptomatic and can be misdiagnosed as drug-induced liver injury or rejection, since histological appearance on liver biopsy may not clearly distinguish lesions associated with viral replication.\n\nChronic hepatitis E has been reported in patients with several hematological disorders, which is attributable to their diminished immune response [12,13]. Persistent infection with HEV has been also diagnosed concomitantly with the onset or even before the development of several different types of hematologic malignancies [14,15]. However, despite several published case reports, convincing data on the association between HEV and such extrahepatic manifestations of the disease is lacking [16].\n\nAt 18 and 20 months after LT, our patient showed 2 marked unexplained liver enzyme peaks. No histological evidences of acute rejection or hepatotoxicity were observed in the first biopsy, and retrospectively it showed elements compatible with acute hepatitis E. HEV infection was diagnosed by serological testing and by nucleic acid techniques (NATs), and viral RNA could be steadily detected in the patient during at least 3 months (November to February 2016). Surprisingly, HEV clearance was successfully achieved after only 9 weeks of ribavirin therapy, when severe anemia caused treatment suspension. However, previous studies suggest that complete clearance of HEV can be accomplished with at least a 3-month course of ribavirin [14]. A shorter therapy also eliminated the virus, thus reducing the risk of liver fibrosis and cirrhosis. In addition, it reduces the probability of emergence of ribavirin-resistant mutants, which might hinder the achievement of SVR in patients [17]. Viral clearance was accompanied by a sharp reduction and subsequent normalization of liver enzymes levels, which strongly suggested that HEV was playing a crucial role in the development of the liver disease. On the other hand, HEV RNA levels stayed undetectable in serum and stool during the 24-week follow-up after therapy.\n\nDuring ribavirin treatment, a liver biopsy provided evidence of a lymphoproliferative disorder. Myelogram and cytogenetic results were compatible with Burkitt’s lymphoblastic leukemia. The rapid progression of the disease observed in this case was also suggestive of this type of lymphoma, which is etiologically linked to EBV [18]. Although EBV DNA levels were almost undetectable a few months before the development of the hematologic malignancy, at the time of the diagnosis, the patient showed a strong reactivation of EBV infection, as shown by real-time PCR. EBV serological status donor/receptor +/− is a major risk factor for development of PTLD, since this virus has a primordial pathogenic role in these syndromes. Nevertheless, the risk is thought to be higher in the first year after transplant, when T cell function is most suppressed. Interestingly a link between hepatitis E and reactivation of EBV in an immunosuppressed patient with rheumatoid arthritis has been previously documented. In Schultze et al. [19], both viral infections presented together and resolved after suspension of immunosuppression therapy. Conversely, in the present case, the reactivation of Epstein-Barr (EBV) infection occurred after chronic hepatitis E, under ribavirin treatment, and, most importantly, under minimal immunosuppressive therapy. However, EBV did not reactivate when the patient was most immunosuppressed and without antiviral therapy. Alternatively, a superinfection, instead of reactivation, could explain the EBV viremia at that time, suggesting that ribavirin is probably ineffective for the treatment of EBV infection. Finally, after antiviral treatment of EBV infection and following chemotherapy, the patient had a complete recovery with no sequelae.\n\nThe detailed analysis of the case presented here demonstrates the difficulty of suspecting and diagnosing HEV infection in transplanted patients and immunocompromised individuals, and the need to include this agent in the differential diagnosis in cases of unexplained elevation of liver enzymes levels. However, the results of the biopsies clearly reinforce the importance of histological documentation of clinical conditions of uncertain significance, in this case, a PTLD.\n\nTo the best of our knowledge, this is the first published case of chronic autochthonous hepatitis E in a transplanted patient followed by a strong reactivation of EBV infection and subsequent development of a PTLD. The potential role of HEV infection in this scenario needs to be further investigated in light of the recent findings of the UK Clinical Practice Research Datalink (CPRD). In that report, extensive data analysis associated infectious hepatitis with elevated risk of Burkitt lymphoma among those 60+ years old [20]. In general, the causative relationship between HEV infection and hematological disorders is difficult to establish, and less severe cases have remained unnoticed and underreported [21]. Particularly, in this patient, whether HEV infection could have contributed to the progression of PTLD through reactivation of EBV infection remains to be elucidated, and our results should thus be cautiously interpreted. Alternatively, the effect of long-term immunosuppression is a plausible explanation for the development and progression of the malignancy.\n\nMolecular analysis showed that the HEV strain detected in our patient was closely related to previously documented human and swine isolates from Uruguay [10]. Furthermore, the patient, who had never traveled to endemic areas, and did not report travels outside of the country in the last 3 months, reported frequent consumption of undercooked pork, suggesting an autochthonous zoonotic route for HEV infection in this case.\n\nConclusions\nThe differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by use of appropriate NATs. Cases of HEV infection with atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.\n\nAuthors would like to thank Programa de Desarrollo de la Ciencias Básicas (PEDECIBA) and Agencia Nacional de Investigación e Innovación for the administrative support. We are also grateful to the patient for permission to publish this case report.\n\nConflict of interests\n\nNone.\n\nFigure 1. Paraclinical data and therapeutic interventions in the 21-month follow-up of the 62-year-old LT patient. Oscillation of liver enzymes levels are graphed. Hepatitis E Virus (HEV) and Epstein-Barr (EBV) PCR results are shown. Periods of increasing and decreasing immunosuppression (IS) are indicated. RBV – ribavirin therapy; ChT – chemotherapy; AST – aspartate aminotransferase; ALT – alanine aminotransferase; RNA – ribonucleic acid; * u/d – undetectable (DNA copies/mL slightly higher than the cut-off value). See text for detailed information.\n\nFigure 2. Histologic changes in the liver biopsies from the 62-year-old LT patient. Main histological findings observed throughout the study are shown. Hematoxylin-eosin stain. (A) Lobular inflammatory infiltrate composed mainly of neutrophils, compatible with acute hepatitis, observed at 1 year and 6 months after LT (original magnification 40×). (B) Dense portal inflammatory infiltrate composed mainly of lymphocytes with piecemeal necrosis, compatible with chronic hepatitis observed concomitantly with the detection of HEV RNA (10×). (C) Sinusoidal dilatation with megakaryocytes compatible with extramedullary hematopoiesis (20×).\n\nFigure 3. Phylogenetic tree based on the partial 287-nt region within the ORF1. The tree was generated using the neighbor-joining algorithm, using Tamura-Nei as the best substitution model as tested by ModelTest v3.7 tool. The robustness of the trees was determined by bootstrap for 1000 replicates. Only values ≥60% are shown. HEV-3 strain isolated form the patient, named HEV-BL (GenBank accession number MG182431) is shown in bold.\n==== Refs\nReferences:\n1. Doceul V Bagdassarian E Demange A Pavio N Zoonotic hepatitis E virus: Classification, animal reservoirs and transmission routes Viruses 2016 8 10 pii: 270 \n2. Pavio N Doceul V Bagdassarian E Johne R Recent knowledge on hepatitis E virus in Suidae reservoirs and transmission routes to human Vet Res 2017 48 1 78 29157309 \n3. Kumar S Subhadra S Singh B Panda BK Hepatitis E virus: The current scenario J Infect Dis 2012 17 228 33 \n4. Lewis HC Wichmann O Duizer E Transmission routes and risk factors for autochthonous hepatitis E virus infection in Europe: A systematic review Epidemiol Infect 2010 138 145 66 19804658 \n5. Kamar N Marion O Abravanel F Extrahepatic manifestations of hepatitis E virus. Liver Int 2016 36 4 467 472 27005692 \n6. Fang SY Han H Hepatitis E viral infection in solid organ transplant patients Curr Opin Organ Transplant 2017 22 4 351 55 28582320 \n7. Pischke S Suneetha PV Baechlein C Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients Liver Transpl 2010 16 74 82 19866448 \n8. Gerolami R Moal V Colson P Chronic hepatitis E with cirrhosis in a kidney-transplant recipient N Engl J Med 2008 358 859 60 18287615 \n9. le Coutre P Meisel H Hofmann J Reactivation of hepatitis E infection in a patient with acute lymphoblastic leukaemia after allogeneic stem cell transplantation Gut 2009 58 699 702 19359434 \n10. Mirazo S Ramos N Russi JC Arbiza J Genetic heterogeneity and subtyping of human Hepatitis E virus isolates from Uruguay Virus Res 2013 173 364 70 23339897 \n11. Kamar N Rostaing L Legrand-Abravanel F Izopet J How should hepatitis E virus infection be defined in organ-transplant recipients? Am J Transplant 2013 13 7 1935 36 23659713 \n12. Gauss A Wenzel JJ Flechtenmacher C Chronic hepatitis E virus infection in a patient with leukemia and elevated transaminases: A case report. J Med Case 2012 6 334 \n13. Ollier L Tieulie N Sanderson F Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab Ann Intern Med 2009 150 430 31 \n14. Tavitian S Peron JM Huguet F Ribavirin for chronic hepatitis prevention among patients with hematologic malignancies Emerg Infect Dis 2015 21 8 1466 69 26197210 \n15. Mallet V Bruneau J Zuber J Hepatitis E virus-induced primary cutaneous CD30(+) T cell lymphoproliferative disorder J Hepatol 2017 67 6 1334 39 28860025 \n16. Kamar N Pischke S Acute and persistent hepatitis E virus genotype 3 and 4 infection: Clinical features, pathogenesis, and treatment Cold Spring Harb Perspect Med 2018 [Epub ahead of print] \n17. Todt D Gisa A Radonic A In vivo evidence for ribavirin-induced mutagenesis of the hepatitis E virus genome Gut 2016 65 10 1733 43 27222534 \n18. Molyneux EM Rochford R Griffin B Burkitt’s lymphoma Lancet 2012 379 9822 1234 44 22333947 \n19. Schultze D Mani B Dollenmaier G Acute hepatitis E virus infection with coincident reactivation of Epstein-Barr virus infection in an immunosuppressed patient with rheumatoid arthritis: A case report BMC Infect Dis 2015 15 474 26511098 \n20. Karimi P Birmann BM Anderson LA Risk factors for Burkitt lymphoma: A nested case-control study in the UK Clinical Practice Research Datalink Br J Haematol 2018 181 4 505 14 29676453 \n21. Pischke S Hartl J Pas SD Hepatitis E virus: Infection beyond the liver? J Hepatol 2017 66 5 1082 95 27913223\n\n",
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"issue": "20()",
"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D002051:Burkitt Lymphoma; D020031:Epstein-Barr Virus Infections; D016751:Hepatitis E; D006521:Hepatitis, Chronic; D006801:Humans; D016867:Immunocompromised Host; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged",
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"title": "Locally Acquired Chronic Hepatitis E Followed by Epstein-Barr Virus Reactivation and Burkitt Lymphoma as a Suspected Extrahepatic Manifestation in a Liver Transplant Recipient.",
"title_normalized": "locally acquired chronic hepatitis e followed by epstein barr virus reactivation and burkitt lymphoma as a suspected extrahepatic manifestation in a liver transplant recipient"
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"abstract": "We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with KRAS wild-type (KRASWT) tumors (4 of 17). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASWT tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC.Significance: Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as NRG1 fusions as disease-driving events in KRASwt tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. Cancer Discov; 8(9); 1087-95. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.",
"affiliations": "Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.;Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany.;DKTK, Heidelberg, Germany.;German Cancer Research Center (DKFZ), Heidelberg, Germany.;German Cancer Research Center (DKFZ), Heidelberg, Germany.;DKTK, Heidelberg, Germany.;DKTK, Heidelberg, Germany.;Division of Radiology, DKFZ, Heidelberg, Germany.;Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.;Institute of Pathology, Technical University Munich, Munich, Germany.;DKTK, Heidelberg, Germany.;DKTK, Heidelberg, Germany.;Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany.;Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany.;Division of Theoretical Bioinformatics, DKFZ, Heidelberg, Germany.;Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.;Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany.;Division of Applied Functional Genomics, DKFZ, Heidelberg, Germany.;Department of Oncology, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany.;Department of Oncology, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany.;Department of Oncology, Sana Kliniken Lübeck, Lübeck, Germany.;Department of Gastroenterology, Hepatology and Infectious Diseases, Tübingen University Hospital, Tübingen, Germany.;Department of Gastroenterology, Hepatology and Infectious Diseases, Tübingen University Hospital, Tübingen, Germany.;DKTK, Tübingen, Germany.;Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.;Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.;Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.;Department of Medical Oncology, NCT, Heidelberg, Germany.;DKTK, Heidelberg, Germany.;Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.;German Cancer Research Center (DKFZ), Heidelberg, Germany.;Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany.;Institute of Pathology, Technical University Munich, Munich, Germany.;DKTK, Heidelberg, Germany.;Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.;DKTK, Heidelberg, Germany.;DKTK, Heidelberg, Germany.;Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and DKFZ, Heidelberg, Germany. hanno.glimm@nct-dresden.de stefan.froehling@nct-heidelberg.de.;Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany. hanno.glimm@nct-dresden.de stefan.froehling@nct-heidelberg.de.",
"authors": "Heining|Christoph|C|;Horak|Peter|P|0000-0003-4536-9306;Uhrig|Sebastian|S|0000-0002-0068-5957;Codo|Paula L|PL|;Klink|Barbara|B|;Hutter|Barbara|B|;Fröhlich|Martina|M|;Bonekamp|David|D|;Richter|Daniela|D|;Steiger|Katja|K|;Penzel|Roland|R|;Endris|Volker|V|;Ehrenberg|Karl Roland|KR|;Frank|Stephanie|S|;Kleinheinz|Kortine|K|;Toprak|Umut H|UH|;Schlesner|Matthias|M|;Mandal|Ranadip|R|;Schulz|Lothar|L|;Lambertz|Helmut|H|;Fetscher|Sebastian|S|;Bitzer|Michael|M|;Malek|Nisar P|NP|;Horger|Marius|M|;Giese|Nathalia A|NA|;Strobel|Oliver|O|;Hackert|Thilo|T|;Springfeld|Christoph|C|;Feuerbach|Lars|L|;Bergmann|Frank|F|;Schröck|Evelin|E|;von Kalle|Christof|C|;Weichert|Wilko|W|;Scholl|Claudia|C|;Ball|Claudia R|CR|;Stenzinger|Albrecht|A|;Brors|Benedikt|B|;Fröhling|Stefan|S|;Glimm|Hanno|H|",
"chemical_list": "C117307:KRAS protein, human; C094131:NRG1 protein, human; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)",
"country": "United States",
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"doi": "10.1158/2159-8290.CD-18-0036",
"fulltext": null,
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"issn_linking": "2159-8274",
"issue": "8(9)",
"journal": "Cancer discovery",
"keywords": null,
"medline_ta": "Cancer Discov",
"mesh_terms": "D000328:Adult; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D051379:Mice; D008875:Middle Aged; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; D010190:Pancreatic Neoplasms; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D054852:Small Molecule Libraries; D014178:Translocation, Genetic; D016896:Treatment Outcome; D000073336:Whole Genome Sequencing; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult",
"nlm_unique_id": "101561693",
"other_id": null,
"pages": "1087-1095",
"pmc": null,
"pmid": "29802158",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer.",
"title_normalized": "nrg1 fusions in kras wild type pancreatic cancer"
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"abstract": "Evidence suggests that combined gemcitabine-cisplatin chemotherapy extends survival in patients with advanced biliary tract cancer (BTC). We conducted a systematic review in order to collate this evidence and assess whether gemcitabine-cisplatin efficacy is influenced by primary tumor site, disease stage, or geographic region, and whether associated toxicities are related to regimen. MEDLINE (1946-search date), EMBASE (1966-search date), ClinicalTrials. gov (2008-search date), and abstracts from major oncology conferences (2009- search date) were searched (5 Dec 2013) using terms for BTC, gemcitabine, and cisplatin. All study types reporting efficacy (survival, response rates) or safety (toxicities) outcomes of gemcitabine-cisplatin in BTC were eligible for inclusion; efficacy data were extracted from prospective studies only. Evidence retrieved from one meta-analysis (abstract), four randomized controlled trials, 12 nonrandomized prospective studies, and three retrospective studies supported the efficacy and safety of gemcitabine-cisplatin for BTC. Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable. Heterogeneity in study designs and data collected prevented formal meta-analysis, however exploratory assessments suggested that efficacy did not vary with primary tumor site (gallbladder vs. others), disease stage (metastatic vs. locally advanced), or geographic origin (Asia vs. other). Incidence of grade 3/4 toxicities was not related to gemcitabine dose or cisplatin frequency. Despite individual variation in study designs, the evidence presented suggests that gemcitabine-cisplatin is effective in patients from a diverse range of countries and with heterogeneous disease characteristics. No substantial differences in toxicity were observed among the different dosing schedules of gemcitabine and cisplatin.",
"affiliations": "Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.;Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.;Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.;National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.;Eli Lilly Interamerica Inc., Buenos Aires, Argentina.;Eli Lilly Korea Ltd., Seoul, Korea.;Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Park|Joon Oh|JO|;Oh|Do-Youn|DY|;Hsu|Chiun|C|;Chen|Jen-Shi|JS|;Chen|Li-Tzong|LT|;Orlando|Mauro|M|;Kim|Jong Seok|JS|;Lim|Ho Yeong|HY|",
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"doi": "10.4143/crt.2014.308",
"fulltext": "\n==== Front\nCancer Res TreatCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 2598980110.4143/crt.2014.308crt-2014-308Review ArticleGemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer: A Systematic Review Park Joon Oh MDPhD1Oh Do-Youn MDPhD2Hsu Chiun MDPhD3Chen Jen-Shi MD4Chen Li-Tzong MDPhD5Orlando Mauro MD6Kim Jong Seok MD7Lim Ho Yeong MDPhD11 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea2 Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea3 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan4 Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan5 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan6 Eli Lilly Interamerica Inc., Buenos Aires, Argentina7 Eli Lilly Korea Ltd., Seoul, KoreaCorrespondence: Ho Yeong Lim, MD, PhD Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea Tel: 82-2-3410-0914 Fax: 82-2-3410-1754 E-mail: hoylim@skku.edu7 2015 18 5 2015 47 3 343 361 27 10 2014 4 3 2015 Copyright © 2015 by the Korean Cancer Association2015This 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 noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Evidence suggests that combined gemcitabine-cisplatin chemotherapy extends survival in patients with advanced biliary tract cancer (BTC). We conducted a systematic review in order to collate this evidence and assess whether gemcitabine-cisplatin efficacy is influenced by primary tumor site, disease stage, or geographic region, and whether associated toxicities are related to regimen. MEDLINE (1946-search date), EMBASE (1966-search date), ClinicalTrials. gov (2008-search date), and abstracts from major oncology conferences (2009- search date) were searched (5 Dec 2013) using terms for BTC, gemcitabine, and cisplatin. All study types reporting efficacy (survival, response rates) or safety (toxicities) outcomes of gemcitabine-cisplatin in BTC were eligible for inclusion; efficacy data were extracted from prospective studies only. Evidence retrieved from one meta-analysis (abstract), four randomized controlled trials, 12 nonrandomized prospective studies, and three retrospective studies supported the efficacy and safety of gemcitabine-cisplatin for BTC. Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable. Heterogeneity in study designs and data collected prevented formal meta-analysis, however exploratory assessments suggested that efficacy did not vary with primary tumor site (gallbladder vs. others), disease stage (metastatic vs. locally advanced), or geographic origin (Asia vs. other). Incidence of grade 3/4 toxicities was not related to gemcitabine dose or cisplatin frequency. Despite individual variation in study designs, the evidence presented suggests that gemcitabine-cisplatin is effective in patients from a diverse range of countries and with heterogeneous disease characteristics. No substantial differences in toxicity were observed among the different dosing schedules of gemcitabine and cisplatin.\n\nBiliary tract neoplasmsCholangiocarcinomaCisplatinGallbladder neoplasmsGemcitabine\n==== Body\nIntroduction\nBiliary tract cancer (BTC) refers to a group of cancers of the biliary tract, including gallbladder cancer, cholangiocarcinoma of intrahepatic and extrahepatic bile ducts, and cancers of the ampulla and papilla of Vater [1,2]. Despite its relatively rarity, the incidence of BTC varies widely in different geographic regions, with the lowest incidence rates in Western countries, including the United States and western Europe, and the highest rates in Asia and Latin America [3]. Gallbladder cancer is the most common type of BTC; however, the proportion of BTC tumors that originate in the gallbladder varies geographically [3,4]. Most patients with BTC are diagnosed at a late stage, in part because there are few, if any, specific symptoms [5]. Surgery is the only curative treatment; however, most patients are ineligible for surgery, either because their tumors are unresectable or because they have other comorbidities that preclude surgical intervention [2,5]. The prognosis for patients with advanced (unresectable and/or metastatic) BTC is very poor, and most survive for less than a year after diagnosis [5,6].\n\nAlthough surgery remains the only curative treatment, chemotherapy can extend survival of patients with BTC [2]. For example, in an early randomized controlled trial (RCT) of chemotherapy in BTC and pancreatic cancer, treatment with 5-fluorouracil and leucovorin, with or without etoposide, increased median survival of patients with BTC to 6.5 months, compared with 2.5 months achieved with best supportive care [7]. Historically, due to the relative rarity of BTC, conduct of clinical studies of potential therapies has been difficult, and physicians have often used chemotherapy regimens that benefit patients with other gastrointestinal cancers, particularly pancreatic cancer. One such chemotherapeutic agent is gemcitabine, which is a standard of care for patients with advanced, unresectable pancreatic cancer [8], and has been approved by the Food and Drug Administration (FDA) as monotherapy for these patients [9]. In pancreatic cancer, additional survival benefit can be achieved by combining gemcitabine and a platinum agent, such as cisplatin; however, combination therapy may be associated with greater toxicity than gemcitabine monotherapy [10].\n\nEvidence of the efficacy of several gemcitabine-based combination therapies, such as gemcitabine-oxaliplatin and combinations involving targeted therapies, in patients with BTC has been reported [2,11-14], with the most substantial evidence reported for gemcitabine combined with cisplatin.\n\nEvidence of the efficacy of gemcitabine-cisplatin combination therapy was initially provided by small observational and retrospective studies [15]. The first major RCT to assess the efficacy and safety of gemcitabine-cisplatin in BTC was the phase 2 ABC-01 trial [16], which was extended into the phase 3 ABC-02 trial, the largest (n=410) RCT in patients with BTC [17]. In the ABC-02 trial, gemcitabine-cisplatin significantly improved overall survival (OS), progression-free survival (PFS), and tumor control rates compared with gemcitabine monotherapy [17]. Based on the ABC-02 trial, gemcitabine-cisplatin combination therapy has rapidly been accepted as the standard first-line treatment for advanced BTC. Currently, gemcitabine-cisplatin is approved as a firstline treatment for BTC in Korea and Chile, and gemcitabine monotherapy is approved in Thailand, Mexico, Ukraine, and Japan.\n\nThe ABC-02 trial is the largest RCT conducted to date, although many smaller clinical studies have been conducted in patients with BTC. However, due to the relative rarity of BTC, enrolling an adequate sample size has often limited these prospective studies. In addition, patients with biliary tract obstruction or infection, which are common concurrent conditions, are excluded from most clinical studies. To maximize enrollment, many studies have used broad inclusion criteria, resulting in heterogeneity of patient characteristics, including primary tumor site and cancer stage (i.e., locally advanced vs. metastatic). However, some evidence suggests that the efficacy of chemotherapy may differ for different tumor types and cancer stages. For example, higher response rate has been reported for patients with gallbladder cancer, but OS was lower after chemotherapy compared to patients with other forms of BTC [18]. Similarly, both intrahepatic cholangiocarcinoma (compared with gallbladder and other BTC sites) and metastatic disease (compared with locally advanced disease) have been identified as independent predictors of poor prognosis in patients receiving chemotherapy [19]. However, the possible effect of primary tumor site on prognosis and response to chemotherapy has yet to be confirmed. Another complicating factor in the assessment of gemcitabine-cisplatin efficacy is the range of regimens used. Most recent studies have followed the ABC-02 trial regimen (1,000 mg/m2 gemcitabine and 25 mg/m2 cisplatin administered on days 1 and 8 of a 21-day cycle [17]); however, other regimens have also been used. Thus, questions remain regarding the optimal regimen for maximizing efficacy while minimizing toxicity. Finally, given the higher incidence of BTC in Asia compared with most Western countries, it is important to assess whether the efficacy and safety of gemcitabine-cisplatin in Asian patients is similar to that in patients from other countries.\n\nThe primary objective of this systematic review is to present collated evidence from randomized and nonrandomized prospective studies for the efficacy of gemcitabine-cisplatin in patients with advanced or metastatic BTC. We chose to focus on the gemcitabine-cisplatin combination, rather than other chemotherapeutic regimens, because of its current status as the treatment of choice for BTC and because the relatively large number of studies provide an opportunity to explore potential subgroup differences in efficacy and safety. As such, the secondary objectives of the review are to assess whether the efficacy of gemcitabine-cisplatin is influenced by primary tumor site, disease stage, or geographic region, and to present collated evidence from prospective and retrospective studies of toxicities, including whether these toxicities are influenced by the dose or regimen used.\n\nMaterials and Methods\n1. Literature search strategy\nThe following databases were searched on 5 December 2013: MEDLINE via PubMed (1946-search date); EMBASE (1966-search date); ClinicalTrials.gov results database (2008-search date); and abstracts from American Society of Clinical Oncology, European Society for Medical Oncology (ESMO), ESMO Gastrointestinal Cancer, and European CanCer Organisation conferences (2009-2013). Free-text terms and medical subject heading (MeSH) or EMTREE terms were used where possible to search for gemcitabine (‘gemcitabine’ and ‘Gemzar’), cisplatin (‘cisplatin’), and BTC (‘biliary tract cancer’ and ‘biliary tract neoplasms’), including specific BTC types and tumor sites (‘gallbladder’, ‘bile duct’, ‘papilla of Vater’, ‘ampulla of Vater’, ‘Klatskin’, and ‘cholangiocarcinoma’). Searches were conducted using truncation symbols and Boolean operators (AND, OR) as needed. There were no restrictions on publication type or language, although the search output was restricted to human studies where possible.\n\n2. Eligibility criteria\nIncluded publications/studies evaluated patients who received gemcitabine-cisplatin combination therapy, at any dose or regimen, as first-line treatment for advanced and/or metastatic BTC. Study types considered included metaanalyses, systematic reviews, randomized and nonrandomized clinical trials, and both prospective and retrospective observational studies. Full-text publications, abstracts, and ClinicalTrial.gov trials with posted results were eligible for inclusion. Excluded publications included studies not conducted in humans; studies of patients with cancers other than BTC; studies of therapies other than gemcitabinecisplatin (including gemcitabine alone or combined with other agents); studies of gemcitabine-cisplatin used as second-line therapy, as part of chemoradiotherapy, or administered intra-arterially; studies in which data for gemcitabinecisplatin therapy were pooled with data for other therapies; studies that did not report relevant outcomes (e.g., retrospective studies that did not report safety outcomes); and conference abstracts of retrospective studies. Narrative reviews, systematic reviews that did not report original data, case reports, case series, nonclinical letters, editorials, and commentaries were also excluded.\n\n3. Study selection and data extraction\nThe literature search and screening of titles, abstracts, and, where necessary, full text of all publications retrieved were performed by one person (not an author) using the predefined eligibility criteria. Reference lists of systematic reviews and other relevant publications were hand screened for identification of additional publications. The publications identified for inclusion were reviewed and approved by all authors.\n\nData collected from the included publications included publication type and year, country of origin, study design, patient characteristics, treatment regimen, and efficacy and safety outcomes. Aspects relating to study quality (e.g., presence/absence and method of randomization, presence/absence of blinding, study population used for analysis) were also assessed.\n\nEfficacy outcome data were extracted from prospective studies only and included OS, PFS, overall response rate (complete response [CR]+partial response [PR]), CR rate, PR rate, stable disease (SD) rate, progressive disease rate, disease control rate (CR+PR+SD), and any other reported efficacy outcomes. Safety outcome data were extracted from all prospective and retrospective studies and included the type, frequency, and severity of toxicities, deaths and discontinuations related to toxicity, and any other reported safety outcomes.\n\nResults\n1. Literature search results\nA total of 782 potentially relevant publications retrieved from MEDLINE via PubMed and EMBASE were screened for inclusion (Fig. 1). No relevant unpublished trials were identified on ClinicalTrials.gov. Manual screening identified two additional conference abstracts [20,21]. Overall, 16 fulltext publications [16,17,22-35] and 4 abstracts [20,21,36,37] met the eligibility criteria for inclusion (Table 1).\n\n2. Overview of study characteristics\nThe included studies were conducted in a broad range of countries from North America, Europe, Australia, Asia, and Africa (Table 1). Most studies included participants with Eastern Cooperative Oncology Group performance status of 0 or 1, and with primary tumors from various sites. Sample sizes ranged from 10 [21] to 410 [17] participants; 912 participants received gemcitabine-cisplatin. In almost all studies, gemcitabine was administered intravenously at a dose of 1,000 to 1,250 mg/m2 on day 1 and day 8 of a 21-day cycle. The dose of cisplatin was more variable, ranging from 20 to 80 mg/m2, and was usually administered either once (day 1) or twice (days 1 and 8) per cycle.\n\nOf the 17 publications of prospective studies (Table 1), four described open-label RCTs [16,17,27,32]. The ABC-01 [16], ABC-02 [17], and BT-22 [32] trials compared gemcitabinecisplatin with gemcitabine monotherapy, whereas the fourth RCT compared gemcitabine-cisplatin with S-1 plus cisplatin [27]. All RCTs used the intention-to-treat population for efficacy analyses; however, only the ABC-02 trial publication specified the allocation method used for randomization (centralized telephone system). One abstract which described a meta-analysis of the ABC-02 and BT-22 trials [37] was published in full after conduct of our literature search [38]. The 12 remaining publications described nonrandomized, prospective studies [20,21,23,25,26,28-31,33,34,36], of which none were comparative and most included fewer than 50 participants. Of the three retrospective studies that reported safety outcomes, one compared gemcitabine-cisplatin with all other treatments [24], whereas two studies were not comparative [22,35].\n\n3. Efficacy outcomes\n1) Overall\nThe most common efficacy outcomes reported in publications of prospective studies were OS and response rates (Table 2, Fig. 2). One abstract [21] which reported conflicting response rates is not included in Table 2 or Fig. 2. Median OS ranged from 4.6 months (reported as 20 weeks) [23] to 11.7 months [17] and overall response rates ranged from 17.1% [30] to 36.6% [23] (Fig. 2). Interestingly, the study reporting both the lowest median OS and the highest response rate consisted exclusively of participants with gallbladder cancer [23]. Disease control rates ranged from 45.7% [30] to 81.4% [17] (Table 2). In the ABC-02 trial, significantly greater OS, PFS, and disease control rate were observed (p < 0.001 for OS and PFS; p=0.049 for disease control rate) in the gemcitabinecisplatin group compared with the gemcitabine only group [17]. In the BT-22 trial, despite numerically better OS, PFS, response rate, and disease control rate in the gemcitabinecisplatin group compared with the gemcitabine group, the differences were not statistically significant [32]. This finding may simply reflect the smaller sample size of the BT-22 trial (n=83) compared with the ABC-02 trial (n=410). However, in a meta-analysis of these two RCTs, significantly greater OS and PFS were observed (p < 0.001) in the gemcitabinecisplatin group than in the gemcitabine only group [37]. In the RCT by Kang et al. [27], no significant differences in OS or PFS were observed between gemcitabine-cisplatin and S-1 plus cisplatin groups.\n\n2) Exploratory subgroup analyses\nThe percentage of participants with gallbladder cancer varied from 0% [29] to 100% [23], although in most studies, the percentage was between 30% and 50% (Table 1, Fig. 3A). Subgroup analyses of efficacy based on primary tumor site were performed in three studies; however, no statistical comparison between tumor site groups was performed. In the ABC-02 trial [17], there was no difference in treatment effect relative to gemcitabine monotherapy on OS between participants with gallbladder, intrahepatic, extrahepatic, hilar, or ampulla tumors. However, the response rate of participants with gallbladder cancer (37.7%; 23 of 61) was numerically higher than for those with other primary tumor sites (19.0%; 19 of 100). In the BT-22 trial [32], the median OS was numerically lower (9.1 months) in participants with gallbladder cancer compared to those with other primary tumor sites (13.0 months). In a non-randomized trial [30], participants with gallbladder cancer showed a numerically higher response rate (28.6%; 4 of 14) than those with other primary tumor sites (9.5%; 2 of 21). Among all of the studies, there was no apparent relationship between the percentage of participants with gallbladder cancer and OS (Fig. 3A), response rate (Fig. 3A), or disease control rate.\n\nWhere reported, the percentage of participants with metastatic disease ranged from 53% [25] to 91% [30] (Table 1, Fig. 3B). The ABC-02 trial found no difference in the treatment effect relative to gemcitabine monotherapy on OS between participants with locally advanced disease and those with metastatic disease [17]. However, a lower hazard ratio was observed in participants with locally advanced disease (0.47; 95% confidence interval [CI], 0.29 to 0.74) compared to those with metastatic disease (0.74; 95% CI, 0.57 to 0.95). Among all of the studies, there was no apparent relationship between the percentage of participants with metastatic disease and OS (Fig. 3B), response rate (Fig. 3B), or disease control rate.\n\nThe diversity of countries in which the included studies were conducted enabled comparison of the efficacy of gemcitabine-cisplatin in participants from Asian countries [23,27-30,32-34,36] with that in participants from Western or other non-Asian countries [17,20,25,26,31]. However, no apparent relationship was found between the study region and OS or response rate (Fig. 4).\n\n4. Safety outcomes\n1) Overall\nAll included publications reported safety outcomes, except for an abstract that reported a meta-analysis of efficacy results [37]. Most publications reported grade 3/4 hematologic and nonhematologic toxicities (Table 3), and many also reported lower grade toxicities and/or treatment-related deaths and discontinuations. The incidence of the most commonly reported grade 3/4 hematologic toxicities varied widely (anemia, 2.4%-36%; neutropenia, 1.73%-56.1%; thrombocytopenia, 0%-39.0%). The most commonly reported grade 3/4 nonhematologic toxicities were nausea and vomiting, with incidence ranging from 0% to approximately 30%. Few treatment-related deaths (n=5 of 526 participants in studies reporting deaths; 1.0%) or discontinuations due to toxicities (n=55 of 427 participants in studies reporting treatment-related discontinuations; 12.9%) were reported. However, not all studies explicitly reported deaths or discontinuations.\n\nDespite the limitations associated with retrospective studies, safety data from these studies were included in order to maximize retrieval of toxicity-related information. As indicated, only three retrospective study publications met our inclusion criteria [22,24,35]; the incidence of treatmentrelated toxicities in these studies varied widely, as did those in the prospective studies (Table 3).\n\n2) Exploratory subgroup analyses\nGemcitabine at a dose of 1,000 to 1,250 mg/m2 (Table 1) was used in most included studies, although one abstract reported the use of 300 mg/m2 gemcitabine [21]. There was no apparent relationship between gemcitabine dose (1,000 mg/m2 vs. 1,200-1,250 mg/m2) and the incidence of grade 3/4 anemia, neutropenia, and thrombocytopenia (Fig. 5A), or between gemcitabine dose and the incidence of nausea, vomiting, or other nonhematologic toxicities.\n\nWhere reported, cisplatin was administered once (usually on day 1) or twice (usually on days 1 and 8) per cycle (Table 1). In most studies in which cisplatin was administered twice per cycle, lower doses (20-30 mg/m2) were used, compared with studies in which cisplatin was administered once per cycle (60-75 mg/m2). There was no apparent relationship between the frequency of cisplatin administration and the incidence of grade 3/4 anemia, neutropenia, and thrombocytopenia (Fig. 5B), or between cisplatin frequency and the incidence of nausea, vomiting, or other nonhematologic toxicities.\n\nOnly five studies reported dose intensities of gemcitabine and cisplatin, most commonly as relative dose intensities (RDIs) [23,28-30,33]. The RDI for gemcitabine ranged from 77.8% to 95%, and the RDI for cisplatin ranged from 78.6% to 99% (Table 1). Given the small number of studies that reported dose intensity, its relationship with either efficacy or safety outcomes remains to be determined.\n\nDiscussion\nThis systematic review presents collated evidence for the efficacy and acceptable safety profile of gemcitabine-cisplatin combination therapy for treatment of advanced BTC. Seventeen publications of prospective studies and three publications of retrospective studies, involving a total of almost 1,000 participants, were summarized. Despite heterogeneity in study design, disease characteristics, and treatment regimen, the results from these studies provide a large evidence base supporting the efficacy and safety profile of gemcitabine-cisplatin in patients with advanced BTC. Although the ABC-02 trial was pivotal in establishing the efficacy of gemcitabine-cisplatin [17], the collective results of the observational studies included in this review confirm that gemcitabine-cisplatin is effective in patients from diverse countries and with heterogeneous disease characteristics.\n\nOur review provides collective evidence for the beneficial effects of gemcitabine-cisplatin on survival and tumor response in patients with BTC. Although not directly compared in a RCT, the results from prospective studies suggest that gemcitabine-cisplatin extends OS (approximately 5 to 12 months) compared with best supportive care (historically 2.5 to 4.5 months [7,13,18]). In addition, a sizeable proportion of participants in these studies responded to treatment, with tumor response rates ranging from 17.1% to 36.6% and disease control rates ranging from 45.7% to 81.4%. However, because only the four RCTs prospectively compared gemcitabine-cisplatin with other treatments [16,17,27,32], direct comparison with other chemotherapy options is limited. Compared with gemcitabine monotherapy, gemcitabine-cisplatin was associated with longer survival (OS and/or PFS) and greater response and disease control rates [16,17,32,37,38]. One retrospective study (n=85) reported no significant difference in OS or disease control rate between gemcitabine-cisplatin and all other chemotherapy regimens (gemcitabine- or capecitabine-based) [24]. However, this finding should be interpreted with caution, given the retrospective nature of the study and the inclusion of triple therapies involving gemcitabine-cisplatin within the other chemotherapy group. As the range of potential combination therapies expands, including gemcitabine paired with other platinum agents such as oxaliplatin [12,39] and carboplatin [40,41] or with targeted agents such as erlotinib [12], high-quality, prospective, comparative trials similar to the ABC-02 trial are needed for assessment of the relative efficacy of different treatments.\n\nThe prognosis for patients with advanced gallbladder cancer is worse than for patients with BTC originating at other sites, with a median survival of 2.8 months if untreated, compared with 5.5 to 10.1 months for untreated cholangiocarcinoma [42]. A pooled analysis of 104 trials (3 of which were included in this review), published in 2007, suggested that patients with gallbladder cancer respond differently to chemotherapy than those with cholangiocarcinoma [15]. Patients with gallbladder cancer (n=500) showed a higher response rate to any chemotherapy (median, 35.5% vs. 17.7%; p=0.008), but a shorter OS (median, 7.2 months vs. 9.3 months; p=0.048), than patients with cholangiocarcinoma (n=471); disease control rate did not differ between the tumor site groups. In contrast, an analysis of participants enrolled in two phase 2 studies or a retrospective cohort study conducted in South Korea identified intrahepatic cholangiocarcinoma as an independent negative prognostic factor for survival [19]. Based on these observations, we explored whether the efficacy of gemcitabine-cisplatin differed depending on the primary tumor site. In the three included studies in which subgroup analyses were performed, response rates tended to be higher [17,30], and OS shorter [32], in participants with gallbladder cancer than in those with other primary tumor sites, which is in agreement with the 2007 pooled analysis for all chemotherapies [15]. However, statistical analysis of the differences between tumor site groups was not performed (presumably because studies were underpowered for subgroup analysis). Consistent with these findings, of all the studies included in this review, the only study that exclusively enrolled participants with gallbladder cancer reported the lowest median OS (20 weeks; 4.6 months) and the highest response rate (36.6%) [23]. A formal, pooled analysis of the relationship between tumor site and efficacy from the studies included in this review was not possible because of study heterogeneity and lack of subgroup data. Based on informal assessment, there was no apparent relationship between the percentage of participants with gallbladder cancer and survival, response rate, or disease control rate. Elucidation of any dependence of efficacy on primary tumor site would require either a prespecified analysis of a large prospective study or a pooled analysis of subgroup-level data from completed studies. Such an analysis, however, would be complicated by the histological heterogeneity even within anatomical tumor sites, as described in recent guidelines on intrahepatic cholangiocarcinoma [43].\n\nWe also explored whether the presence or absence of metastatic disease was related to the efficacy of gemcitabinecisplatin. In a phase 3 trial comparing gemcitabine-cisplatin with gemcitabine monotherapy in patients with advanced pancreatic cancer, metastatic disease was identified as a predictor of poor survival [44]. Metastatic disease has also been identified as a predictor of poor outcomes in patients with BTC [19]. Among the studies included in this review, only the ABC-02 trial analyzed the efficacy of gemcitabinecisplatin in participants with or without metastatic disease. Although the advantageous response to gemcitabinecisplatin compared with gemcitabine monotherapy did not differ between groups, a lower hazard ratio was observed in participants with locally advanced disease, suggesting a greater benefit of combination therapy in these participants than in those with metastatic disease [17]. The proportion of participants with metastatic or locally advanced disease was reported in approximately two-thirds of the prospective studies included in this review. However, the available data were insufficient for performance of any formal analysis of the relationship between metastatic disease and efficacy. Once again, we did not identify any clear relationship between the percentage of participants with metastatic disease and survival or response outcomes.\n\nGiven the geographic variations in the incidence and type of BTC, it is important to examine any differences in the efficacy of gemcitabine-cisplatin among patients from different geographic regions. We were particularly interested in whether the response of patients from Asia, where both the overall incidence of BTC and the proportion of extrahepatic cholangiocarcinoma are high compared with most Western countries [3], to gemcitabine-cisplatin was similar to that of other patients. In general, similar OS and response rate were reported in studies conducted in Asia [23,27-30,32-34,36] and in Western and other non-Asian countries [17,20,25,26,31]. This observation is supported by comparison of the British ABC-02 [17] and Japanese BT 22 [25] RCTs, which reported similar median OS (11.7 and 11.2 months) and treatment effects of gemcitabine-cisplatin compared with gemcitabine monotherapy (OS hazard ratios of 0.64 [95% CI, 0.52 to 0.80] and 0.69 [0.42 to 1.13]). Collectively, this evidence suggests that gemcitabine-cisplatin is equally effective in both Asian and non-Asian patients with BTC.\n\nIn general, the reported toxicities associated with gemcitabine-cisplatin therapy were acceptable and manageable, although the incidence rates varied widely. Of particular importance, few deaths related to treatment were reported, and the overall rate of discontinuation due to toxicity was low (12.9%). In addition, no relationship was found between gemcitabine dose or cisplatin frequency and the incidence of the most common hematologic (anemia, neutropenia, thrombocytopenia) and nonhematologic (nausea, vomiting) toxicities. Although cisplatin administered at lower doses twice per cycle is intended to reduce potential toxicity, use of this approach did not result in any apparent decrease in the incidence rates of toxicities, at least among the studies examined. However, the relatively low number of studies and the differences in study design, participant characteristics, and other aspects of treatment restricts our ability to draw any conclusions. Given the lack of any clear relationship between treatment regimen and toxicity, clinicians may choose to simplify dosing by administering cisplatin at a higher dose once per cycle or to follow the ABC-02 regimen and adjust dosing as needed if high-grade toxicities occur.\n\nAs with all systematic reviews, our review is limited by the quality of the studies available for inclusion. Only four RCTs on the use of gemcitabine-cisplatin in advanced BTC have been published, and only one of these was a large, phase 3 trial. All RCTs were open-label by necessity, given the different treatment regimens involved. Most of the other included studies were nonrandomized and uncontrolled, with small sample sizes, reflecting the relative rarity of BTC. To increase recruitment, most studies included participants with different tumor origins and disease stages, resulting in heterogeneous study populations. Unfortunately, the data as presented did not allow performance of any pooled subgroup analyses of the effects of primary tumor site or disease stage. Separate analysis of specific subgroups would require larger sample sizes (e.g., through multinational, collaborative trials) or pooled subgroup-level data, but may reveal differences in the efficacy of gemcitabine-cisplatin in patients with specific disease characteristics. In addition, some studies excluded from this review reported combined data for different chemotherapeutic treatments (e.g., gemcitabine in combination with any platinum agent) or disease (e.g., pancreatic cancer), which, if reported separately, might have been useful in the assessment of gemcitabine-cisplatin in BTC. Reporting of outcomes also varied; for example, not all studies reported deaths or discontinuations. A wide range of treatment regimens were used in the included studies and none of the studies specifically examined the effect of treatment regimen on efficacy or safety/tolerability. Ideally, chemotherapy regimens should be tailored for optimal efficacy balanced with manageable levels of toxicity, and a more systematic assessment of different treatment regimens may indicate which factors (e.g., dose, frequency, cycle length) are most critical to efficacy or tolerability. Finally, there are many other clinically important issues requiring further exploration, but were not the focus of the current review. These issues include optimizing gemcitabine-cisplatin therapy in individual patients (such as those with inadequate biliary drainage), the role of new, targeted agents as adjuncts to standard chemotherapy, and strategies to facilitate conduct of future clinical trials of this rare, but aggressive, family of cancers.\n\nConclusion\nIn conclusion, this systematic review presents collective evidence from a range of study designs that supports the use of gemcitabine-cisplatin combination therapy as standard treatment for advanced or metastatic BTC. However, detailed information regarding the effectiveness of gemcitabine-cisplatin in different types of BTC, or toxicities associated with different regimens, is lacking, in part because of the difficulty of conducting studies of sufficient sample size. Of particular importance, despite heterogeneity in the study designs, no substantial difference in toxicity was observed among the different dosing schedules of gemcitabine and cisplatin. In lieu of a large, multinational, collaborative RCT powered to enable subgroup analyses, a meta-analysis of patient-level data could help to address these questions. Alternatively, individual research teams conducting smaller studies should report subgroup-level data, which could facilitate future pooled analyses.\n\nEli Lilly and Company, manufacturer/licensee of gemicitabine (Gemzar), was involved in the study design, data collection, data analysis, and preparation of the manuscript. Do-Youn Oh has received research funding from Eli Lilly. Jen-Shi Chen has received consultancy fees and honoraria from Eli Lilly, Roche, and Novartis. Li-Tzong Chen has received honoraria from Eli Lilly, Novartis, TTY Biopharm, and PharmaEngine, and support for investigator-initiated trials from Merck Serono, Novartis, Sanofi-Aventis, and TTY. Jong Seok Kim is an employee of and owns stock in Eli Lilly Korea Ltd., Republic of Korea. Mauro Orlando is an employee of and owns stock in Eli Lilly Interamerica, Argentina. Joon Oh Park, Chiun Hsu, and Ho Yeong Lim have no conflicts of interest to declare.\n\nThe authors thank Chao Zhu, PhD, of Lilly Suzhou Pharmaceutical Co. Ltd., Shanghai, China, and Helen Barraclough, MSc, of Eli Lilly Australia, Ltd., for advice and helpful discussions regarding the scope of this review. Medical writing assistance was provided by Rebecca Lew, PhD CMPP, and Mark Snape, MB BS, of ProScribe – part of the Envision Pharma Group, and was funded by Eli Lilly. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP2).\n\nFig. 1. Publication flow diagram. ASCO, American Society of Clinical Oncology; BTC, biliary tract cancer; ECCO, European CanCer Organisation; ESMO, European Society for Medical Oncology; gem/cis, gemcitabine-cisplatin therapy; GI, gastrointestinal.\n\nFig. 2. Forest plots of median overall survival (A) and overall response rate (B) reported in individual publications of prospective studies. Error bars represent 95% confidence intervals (CI; where reported). The number of participants treated with gemcitabine-cisplatin in each study is shown in parentheses.\n\nFig. 3. Forest plots of median overall survival and response rate plotted against the percentage of participants with gallbladder cancer (A) and metastatic disease (B) reported in individual publications of prospective studies. Error bars represent 95% confidence intervals (CI; where reported).\n\nFig. 4. Forest plots of median overall survival and response rate in individual publications of prospective studies, grouped by geographic region (Western countries vs. Asian countries). Error bars represent 95% confidence intervals (CI; where reported).\n\nFig. 5. Incidence of hematologic toxicities in individual publications according to gemcitabine dose (A) and frequency of cisplatin (B).\n\nTable 1. Characteristics of included publications on the use of gemcitabine-cisplatin in patients with advanced biliary tract cancer\n\nPublication\tParticipants\tMain efficacy outcomes\t\nNo.\tMedian age (rangea), yr)\tMale (%)\tPrimary tumor site (%)\tMetastatic disease (%)\tpsb) (%)\tTreatment regimen\t\nMeta-analysis\t\t\t\t\t\t\t\t\t\nMizuno et al. (2013) [37] (abstract), meta-analysis of ABC-02 (UK) and BT-22 (Japan) trials\t493\t64\t~50\tNR\tNR\tNR\tNR; as per ABC-02 and BT22\tHazard ratios for OS, PFS\t\n\t- GC: 245\t(23-84)\t\t\t\t\t\t\t\n\t- Gem: 248\t\t\t\t\t\t\t\t\nRandomized controlled trials \t\t\t\t\t\t\t\t\t\nKanget al. (2012) [27], South Korea\t96\tGC: 59\tGC: 63\tGC\t71\tGC\tGem: 1,000 mg/m2\n\tOS, PFS, RR\t\n\t- GC: 49\t(32-77)\t\t- GB: 27\t\t- PS0-1: 86\t(fixed 10 mg/m2/min)\t\t\n\t- S-l+Cis 47\t\t\t- Intrahepatic CAC: 41\t\t- PS2:14\tD1+D8\t\t\n\t\t\t\t- Extrahepatic bile duct: 27\t\t\tCis: 60 mg/m2Dl\t\t\n\t\t\t\t- Ampulla: 6\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 6 (1-14)\t\t\nOkusaka et al. (2010) [32], Japan, BT-22 trial\t83c)\tGC: 65.0\tGC: 43.9\tGC\tNR\tGC\tGem: 1,000 mg/m2 D1+D8\tOS, PFS, RR\t\n\t- GC: 41\t(43-80)\t\t- GB: 36.6\t\t- PS0: 82.9\tCis: 25 mg/m2D1+D8\t\t\n\t- Gem: 42\t\t\t- Extrahepatic bile duct: 19\t\t- PS1:17.1\tCycle: 21 days\t\t\n\t\t\t\t- Intrahepatic bile duct: 34\t\t\tMedian number of cycles (range): 6 (NR)\t\t\n\t\t\t\t- Ampulla: 9.8\t\t\t\t\t\nValle et al. (2009) [16], UK, ABC-01 trial\t86\tGC: 63\tGC: 40.5\tGC\t61.9\tKamofsky\tGem: 1,000 mg/m2 D1+D8\tPFS, RR, TTP\t\n\t- GC: 42\t(38-76)\t\t- Intrahepatic CAC: 28.6\t\t- PS100: 11.9\tCis: 25 mg/m2D1+D8\t\t\n\t- Gem: 44\t\t\t- Extrahepatic CAC: 21.4\t\t- PS90: 42.9\tCycle: 21 days\t\t\n\t- GB: 23.8\t\t\t- CAC not otherwise specified: 23.8\t\t- PS80: 28.6\tMedian number of cycles (range): 7.5 (1-8)\t\t\n\t\t\t\t- Ampulla: 2.4\t\t- PS70: 14.3\t\t\t\n\t\t\t\t\t\t- PS60: 2.4\t\t\t\nValle et al. (2010) [17], UK, ABC-02 trial (includes patients from ABC-01)\t410\tGC: 63.9\tGC: 47.1\tGC\t73\tGC\tGem: 1,000 mg/m2 D1+D8\tOS, PFS, RR\t\n\t- GC: 204\t(32.8-81.9)\t\t- GB: 35.8\t\t- PS0: 32.4\tCis: 25 mg/m2D1+D8\t\t\n\t- Gem: 206\t\t\t- Bile duct: 59.8\t\t- PS1: 54.4\tCycle: 21 days\t\t\n\t\t\t\t- Ampulla: 4.4\t\t- PS2: 13.2\tMedian number of cycles: NR\t\t\n\t\t\t\t\t\t\tMedian duration of treatment (GC): 21 weeks\t\t\nProspective, nonrandomized studies\t\t\t\t\t\t\t\t\t\nCharoentum et al. (2013) [36] (abstract), Thailand\t34c)\t56\t54\tNR\tNR\tPS0-1: 97\tGem: 1,000 mg/m2 D1+D8\tPFS, RR\t\n\t\t(34-66)\t\t\t\t\tCis: 75 mg/m2Dl\t\t\n\t\t\t\t\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 4 (3-6)\t\t\nDoval et al. (2004) [23], India\t30\t53.5\t27\tGB: 100\t66\tZubrod\tGem: 1,000 mg/m2 D1+D8 (RDI 95%)\tOS, RR, TTP, response duration\t\n\t\t\t\t\t\t- PS1: 73\tCis: 70 mg/m2 D1 (RDI 99%)\t\t\n\t\t\t\t\t\t- PS2: 27\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 4.5 (1-6)\t\t\nGiuliani et al. (2006) [25], Italy\t38\t61\t16\tGB: 26\t53\tPS0-1: 92\tGem: 1,000 mg/m2Dl+D8\tOS, RR, TTP; response duration\t\n\t\t(40-75)\t\tBile duct: 74\t\tPS2: 8\tCis: 75-80 mg/m2 (day NR)\t\t\n\t\t\t\t\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tNumber of cycles: ≥ 3\t\t\nGoldstein et al. (2011) [26], Australia / New Zealand\t50\t58.7\t46\tGB: 44\t64\tPS0: 42\tGem: 1,000 mg/m2 (fixed 10 mg/m2/ min)\tOS, PFS, RR, response duration\t\n\t\t\t\tIntra- or extrahepatic bile duct: 50\t\tPS1: 46\tD1+D8\t\t\n\t\t\t\tPapilla of Vater: 4\t\tPS2: 12\tCis: 20 mg/m2 D1+D8\t\t\n\t\t\t\tUnknown: 2\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 5 (1-21)\t\t\nKim et al. (2006) [28], South Korea\t29\t52\t76\tGB: 34\t59\tPS0: 7\tGem: 1,250 mg/m2\tOS, RR, TTP, response duration\t\n\t\t(37-69)\t\tIntrahepatic CAC: 31\t\tPS1: 76\tD1+D8 (RDI 88%)\t\t\n\t\t\t\tExtrahepatic CAC: 31\t\tPS2: 17\tCis: 60 mg/m2 D1 (RDI 91%)\t\t\n\t\t\t\tAmpulla: 3\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 4 (1-9)\t\t\nLee et al. (2006) [29], South Korea\t24\t59\t75\tGB: 0\t71\tPS0-1: 79\tGem: 1,000 mg/m2\tOS, RR, TTP\t\n\t\t(45-71)\t\tCAC: 100\t\tPS2: 21\tD1+D8 (RDI 77.8%)\t\t\n\t\t\t\t\t\t\tCis: 70 mg/m2 D1 (RDI 78.6%)\t\t\n\t\t\t\t\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 3 (2-6)\t\t\nLee et al. (2008) [30], South Korea\t35c)\t60\t66\tGB: 40.0\t91\tPS0: 20.0\tGem: 1,250 mg/m2 Dl+D8\tOS, RR, TTP, response duration, TTF\t\n\t\t(36-68)\t\tIntrahepatic bile duct: 51.4\t\tPS1: 71.4\t(RDI 84.5%)\t\t\n\t\t\t\tExtrahepatic bile duct: 5.7\t\tPS2: 8.6\tCis: 70 mg/m2 D1+D8\t\t\n\t\t\t\tPapilla of Vater: 2.9\t\t\t(RDI 94.2%)\t\t\n\t\t\t\t\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 4 (1-8)\t\t\nMahfouf et al. (2010) [20]\t143\t57.1\t37\tGB: 89.6d)\tNR\tPS0-1:100\tGem: 1,250 mg/m2 Dl+D8\tOS, PFS, RR, disease-free survival\t\n(abstract), Algeria\t\t(32-75)\t\tBTC: 10.4d)\t\t\tCis: 70 mg/m2 Dl\t\t\n\t\t\t\t\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 4 (NR)\t\t\nMeyerhardt et al. (2008) [31], USA\t33\t57\t61\tGB: 15\tNR\tPS0: 27\tGem: 1,000 mg/m2 Dl+D8\tOS, PFS, RR, response duration\t\n\t\t(42-73)\t\tIntrahepatic CAC: 76\t\tPS1: 64\tCis: 30 mg/m2 D1+D8\t\t\n\t\t\t\tExtrahepatic CAC: 9\t\tPS2: 9\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 4 (1-21+)\t\t\nPark et al. (2006) [33], South Korea\t27\tMean+SD:\t59\tGB: 48.1\t81.5\tPS1: 81.5\tGem: 1,000 mg/m2 Dl, D8, +D15 (RDI 86.7%)\tOS, RR, response duration\t\n\t\t58.9±10.6 (28-77)\t\tIntrahepatic bile duct: 33.3\t\tPS2: 18.5\tCis: 75 mg/m2 Dl (RDI 95.5%)\t\t\n\t\t\t\tExtrahepatic bile duct: 18.6\t\t\tCycle: 28 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 5 (1-9)\t\t\nSingh et al. (2011) [21]\t10\t55\t40\tGB: 100\tNR\tNR\tGem: 300 mg/m2 (for 6 hr) Dl +D8\tRR\t\n(abstract), India\t\t(33-67)\t\t\t\t\tCis: 70 mg/m2 D2\t\t\n\t\t\t\t\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 3 (1-4)\t\t\nThongprasert et al. (2005) [34], Thailand\t40c)\t50\t58\tGB: 2.5\tNR\tMedian\tGem: 1,250 mg/m2 Dl + D8\tOS, RR, TTP, response duration\t\n\t\t(31-69)\t\tIntrahepatic CAC: 87.5\t\tKamofsky\tCis: 75 mg/m2Dl\t\t\n\t\t\t\tPortahepatic CAC: 7.5\t\tPS: 80 (range, 60-90)\tCycle: 21 days\t\t\n\t\t\t\tAmpulla: 2.5\t\t\tMedian number of cycles: NR\t\t\nRetrospective studiese)\t\t\t\t\t\t\t\t\t\nCharoentum et al. (2007) [22], Thailand\t42\t51\t67\tGB: 0\t72 \tPS0-1:83\tGem: 1,250 mg/m2 Dl+D8\tOS, RR, TTP\t\n\t\t\t\tCAC: 100\t\tPS2:17\tCis: 75 mg/m2 Dl\t\t\n\t\t\t\t\t\t\tCycle: 21 days\t\t\n\t\t\t\t\t\t\tMedian number of cycles (range): 4 (1-6)\t\t\nEckmann et al. (2011) [24], USA\t85\tMean±SD:\t57.6\tGB: 0\tDisseminated: NR\t\tNR\tOS, RR, response duration\t\n\t- GC: 53\t61.0 ±11.5\t\tIntrahepatic CAC: 78.8\t51.8\t\t\t\t\n\t- Other: 32\t\t\tHilar CAC: 21.2\tMultifocal: 27.0\t\t\t\t\nWu et al. (2012) [35], Taiwan\t30\t61.5\t43%\tGB: 13.3\t70.0 \tPS0-1: 86.7\tGem: 1,000 mg/m2 Dl+D8\tOS, RR, TTP\t\n\t\t(38-85)\t\tIntrahepatic: 50.0\t\tPS2: 13.3\tCis: 30 mg/m2 D1+D8\t\t\n\t\t\t\tExtrahepatic: 10.0\t\t\tCycle: 21 days\t\t\n\t\t\t\tAmpulla: 20.0\t\t\tMedian number of cycles (range): 3 (0.5-12)\t\t\n\t\t\t\tPerihilar: 6.7\t\t\t\t\t\nGC, gemcitabine-cisplatin group; Gem, gemcitabine; NR, not reported; OS, overall survival; PFS, progression-free survival; Cis, cisplatin; GB, gallbladder; CAC, cholangiocarcinoma; PS, performance status; D, day; RR, response rates; TTP, time to progression; RDI, relative dose intensity; TTF, time to treatment failure; SD, standard deviation; BTC, biliary tract cancer.\n\na) Except where otherwise noted,\n\nb) Eastern Cooperative Oncology Group (ECOG) scale, unless otherwise noted,\n\nc) Number analyzed,\n\nd) Reported in abstract as 138 patients with GB cancer and 16 patients with BTC; calculated as percentage of 154 patients,\n\ne) Efficacy outcomes from retrospective studies were not included in overall evaluation.\n\nTable 2. Efficacy outcomes of prospective studies of gemcitabine-cisplatin in patients with advanced biliary tract cancer\n\nPublication\tMedian OS (95% CIa), mo)\tMedian PFS (95% CIa), mo)\tResponse ratesb) (95% CIa),%)\t\nOverall (CR+PR)\tDCR (CR+PR+SD)\tCR\tPR\tSD\tPD\tNE\t\nRandomized controlled trials\t\t\t\t\t\t\t\t\t\t\n Kang et al. (2012) [27]\t10.1 (7.1-13.1)\t5.7 (3.6-7.7)\t19.6 (8.1-31.1)\t71.7 (58.7-84.7)\t4.3\t15.2\t52.2\t28.3\tNA\t\n Okusaka et al. (2010) [32], BT-22 trial\t11.2 (9.1-12.5)\t5.8 (4.1-8.2)\t19.5 (8.8-34.9)\t68.3 (51.9-81.9)\t0\t19.5\t48.8\t22.0\t9.8\t\n Valle et al. (2009) [16], ABC-01 trial\tNR\t6-month PFS: 57.1% (41.0-70.3)\t27.8\t75.0\t0\t27.8\t47.2\t25.0\tNA\t\n Valle et al. (2010) [17], ABC-02 trial (includes patients from ABC-01)\t11.7 (9.5-14.3)\t8.0 (6.6-8.6)\t26.1\t81.4\t0.6\t25.5\t55.3\t18.6\tNA\t\nProspective, nonrandomized studies\t\t\t\t\t\t\t\t\t\t\n Charoentum et al. (2013) [36] (abstract)\tNR\t6 (range, 3-13)\t32.4c)\t76.5c)\t0\t32.4c)\t44.1c)\t23.5c)\tNA\t\n Doval et al. (2004) [23]\t4.6d) (3.2-7.1)\tNR\t36.6c)\t60.0c)\t13.3\t23.3\t23.3\t13.2\t27\t\n Giuliani et al. (2006) [25]\t8+ (range, 2-15)\tNR\t32\t53\t3\t29\t21\t47\tNA\t\n Goldstein et al. (2011) [26]\t6.8 (5.0-8.7)\t4 (2.5-6.8)\t26 (14.6-40.4)\t50\t0\t26\t24\t44\t6\t\n Kim et al. (2006) [28]\t11.0 (5.49-16.5)\tNR\t34.5\t48.3c)\t0\t34.5 (17.9-54.3)\t13.8\t44.8\t6.9\t\n Lee et al. (2006) [29]\t9.30 (6.43-12.17)\tNR\t20.8\t70.8c)\t0\t20.8 (4.5-37.0)\t50.0 (29.9-70.0)\t29.2 (11.0-47.3)\tNA\t\n Lee et al. (2008) [30]\t8.6 (6.1-10.4)\tNR\t17.14 (4.7-29.6)\t45.7c)\t0\t17.1\t28.6\t45.7\t8.6\t\n Mahfouf (2010) [20] (abstract)\t9.3\t4.7\t30\t52.4c)\t6.3c)\t23.8c)\t22.4c)\t47.6c)\tNA\t\n Meyerhardt et al. (2008) [31]\t9.7 (6.4-13.8)\t6.3 (4.8-14.9)\t21c)\t57.6c)\t0\t21 (7-35)\t36 (20-52)\tNR\tNA\t\n Park et al. (2006) [33]\t10.0 (8.4-11.6)\tNR\t33.3\t59.3c)\t0\t33.3\t25.9\t40.7\tNA\t\n Thongprasert et al. (2005) [34]\t8.3 (range, 0.8-21.9)d)\tNR\t27.5\t60c)\t0\t27.5\t32.5\t40\tNA\t\nFor comparative studies, data shown are for the gemcitabine-cisplatin group only. OS, overall survival; CI, confidence interval; PFS, progression-free survival; CR, complete response; PR, partial response; DCR, disease control rate; SD, stable disease; PD, progressive disease; NE, not evaluable; NA, not applicable; NR, not reported.\n\na) Where reported and except where otherwise noted,\n\nb) Reported percentages based on evaluable patients, unless otherwise noted,\n\nc) Calculated from reported data,\n\nd) Reported as weeks and converted to months.\n\nTable 3. Safety outcomes of studies of gemcitabine-cisplatin in patients with advanced biliary tract cancer\n\nPublication\tIncidence of grade 3/4 toxicities (%)\tTreatment-related deaths/discontinuations\t\nAnemia\tNeutropenia\tThrombocytopenia\tVomiting\tNausea\tFatigue\tOther (≥ 5% of participants)\t\nRandomized controlled trials\t\t\t\t\t\t\t\t\t\nKang et al. (2012) [27]\t22.4\t49.0\t22.4\t4.1\t4.1\t4.1\tLeukopenia: 24.4\tNo treatment-related deaths or discontinuations\t\n\t\t\t\t\t\t(asthenia)\tNeuropathy: 6.8\t\t\nOkusaka et al. (2010) [32], BT-22 trial\t34.1a)\t56.1\t39.0\t0\t0\tNR\tLeukopeniab): 29.3\tNo treatment-related deaths\t\n\t\t\t\t\t\t\tHemoglobin decreased: 36.6\t\t\n\t\t\t\t\t\t\tAST increased: 17.1\t\t\n\t\t\t\t\t\t\tALT increased: 24.4\t\t\n\t\t\t\t\t\t\tGGT increased: 29.3\t\t\n\t\t\t\t\t\t\tALP increased: 7.3\t\t\n\t\t\t\t\t\t\tBlood sodium decreased: 17.1\t\t\nValle et al. (2009) [16], ABC-01 trial\t2.4\t14.3\t11.9\t7.1\t0\t28.6\tInfection (non-neutropenic): 19.0\t3 Treatment-related discontinuations\t\n\t\t\t\t\t\t\tBilirubin: 11.9\t\t\n\t\t\t\t\t\t\tTransaminases: 11.9\t\t\nValle et al. (2010) [17], ABC-02 trial (includes patients from ABC-01)\tNR\t25.3\t8.6\t5.1\t4.0\t18.7\tLeukopeniab):15.7\t1 Death possibly treatment-related\t\n\t\t\t\t\t\t\tHemoglobin decreased: 7.6\t\t\n\t\t\t\t\t\t\tALT increased: 9.6\t17 Treatment-related discontinuations (of 162 ABC-02 patients only)\t\n\t\t\t\t\t\t\tOther abnormal liver function: 13.1\t\t\n\t\t\t\t\t\t\tAny abnormal liver function: 16.7\t\t\n\t\t\t\t\t\t\tInfection without neutropenia: 6.1\t\t\n\t\t\t\t\t\t\tInfection with neutropenia: 10.1\t\t\n\t\t\t\t\t\t\tAny infection: 18.2\t\t\nProspective, nonrandomized studies\t\t\t\t\t\t\t\t\t\nCharoentum et al. (2013) [36] (abstract)\t11 (Gr 3)\t6 (Gr 4)\tNR\tNR\tNR\tNR\tNone\tNo treatment-related deaths\t\n\t\t\t\t\t\t\t\t\t\nDoval et al. (2004) [23]\t36\t34c)\t17\t30\t\tNR\tLeukopenia: 17\t2 Treatment-related deaths\t\n\t\t\t\t(combined)\t\t\tHepatic: 10\t\t\n\t\t\t\t\t\t\tRenal: 6\t\t\nGiuliani et al. (2006) [25]\t11\t34\t14\t0\tNR\tNR\tNone\tNo treatment-related deaths or discontinuations\t\nGoldstein et al. (2011) [26]\t20\t40\t24\t8\t6\t16\tNeutropenic fever: 8\t1 Treatment-related death\t\n\t\t\t\t\t\t\tInfection with normal\t16% Treatment-related discontinuation\t\n\t\t\t\t\t\t\tneutrophils: 18\t\t\nKim et al. (2006) [28]\t3.4\t13.8\tNR\t3.4\t3.4\tNR\tNeutropenic fever: 7.0\tNo treatment-related deaths\t\nLee et al. (2006) [29]\t8.5\t12.5\t12.5\t0\t0\tNR\tLeukopenia: 12.5\t1 Treatment-related death\t\n\t\t\t\t\t\t\tDiarrhea: 5\t\t\nLee et al. (2008) [30]\t6.8d)\t35.8d)\t17.6d)\t2.7d)\t3.4d)\tNR\tNone\tNR\t\nMahfouf 2010 [20] (abstract) \t5\t2\t1\t20\tNR\t2\tNR\tNR\t\nMeyerhardt et al. (2008) [31]\t20\t33\t23\t13\t20\t10\tAny toxicity: 70\t33% Treatment-related discontinuation\t\n\t\t\t\t\t\t\t\t19% Withdrew consent due to toxicity\t\nPark et al. (2006) [33]\t29.6\tNR\t22.2\t18.5 (combined)\t\tNR\tLeukopenia: 25.9\tNo treatment-related deaths\t\nSingh et al. (2011) [21] (abstract)\t20 (combined)e)\t\t\t100 (combined)f)\t\tNR\tAlopecia: 40f)\tNR\t\nThongprasert et al. (2005) [34]\t4.33\t1.73\t2.97\t0\t0\tNR\tNo other Gr3/4\tNR\t\nRetrospective studies\t\t\t\t\t\t\t\t\t\nCharoentum et al. (2007) [22]\t33\t21\t5\t0\t0\tNR\tNone\tNR\t\nEckmann et al. (2011) [24]\t1.9g)\t1.9g)\t5.7g)\tNR\tNR\t3.8g)\tIncreased creatinine: 11.3g)\t30% Treatment-related discontinuations\t\nWu et al. (2012) [35]\t16.7\t13.3\t0\t0\t0\tNR\tInfection: 26.7\t\t\n\t\t\t\t\t\t\tALT increased: 6.7\tNR\t\nFor comparative studies, data shown are for the gemcitabine-cisplatin group only. Where reported separately, grade 3 and 4 toxicities were added for inclusion in this table. NR, not reported; AST, aspartate transaminase; ALT, alanine transaminase; GGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; Gr, grade.\n\na) Reported as red blood cells decreased,\n\nb) Reported as white blood cells decreased,\n\nc) Reported as granulocytopenia,\n\nd) Reported as average % per cycle,\n\ne) Described as “significant” (not graded),\n\nf) Overall (not graded),\n\ng) Discontinued due to toxicity (not graded).\n==== Refs\nReferences\n1 Noel MS Hezel AF New and emerging treatment options for biliary tract cancer Onco Targets Ther 2013 6 1545 52 24204165 \n2 Sasaki T Isayama H Nakai Y Koike K Current status of chemotherapy for the treatment of advanced biliary tract cancer Korean J Intern Med 2013 28 515 24 24009445 \n3 Randi G Malvezzi M Levi F Ferlay J Negri E Franceschi S Epidemiology of biliary tract cancers: an update Ann Oncol 2009 20 146 59 18667395 \n4 Hundal R Shaffer EA Gallbladder cancer: epidemiology and outcome Clin Epidemiol 2014 6 99 109 24634588 \n5 Leonard GD O'Reilly EM Biliary tract cancers: current concepts and controversies Expert Opin Pharmacother 2005 6 211 23 15757418 \n6 Hezel AF Zhu AX Systemic therapy for biliary tract cancers Oncologist 2008 13 415 23 18448556 \n7 Glimelius B Hoffman K Sjoden PO Jacobsson G Sellstrom H Enander LK Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer Ann Oncol 1996 7 593 600 8879373 \n8 Seufferlein T Bachet JB Van Cutsem E Rougier P ESMO Guidelines Working Group Pancreatic adenocarcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2012 23 Suppl 7 vii33 40 22997452 \n9 Gemzar (gemcitabine for injection) [prescribing information] Indianapolis Eli Lilly and Company 2013 \n10 Sun C Ansari D Andersson R Wu DQ Does gemcitabinebased combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol 2012 18 4944 58 23002368 \n11 Gruenberger B Schueller J Heubrandtner U Wrba F Tamandl D Kaczirek K Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study Lancet Oncol 2010 11 1142 8 21071270 \n12 Lee J Park SH Chang HM Kim JS Choi HJ Lee MA Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study Lancet Oncol 2012 13 181 8 22192731 \n13 Sharma A Dwary AD Mohanti BK Deo SV Pal S Sreenivas V Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study J Clin Oncol 2010 28 4581 6 20855823 \n14 Zhu AX Meyerhardt JA Blaszkowsky LS Kambadakone AR Muzikansky A Zheng H Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study Lancet Oncol 2010 11 48 54 19932054 \n15 Eckel F Schmid RM Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials Br J Cancer 2007 96 896 902 17325704 \n16 Valle JW Wasan H Johnson P Jones E Dixon L Swindell R Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study. The UK ABC-01 Study Br J Cancer 2009 101 621 7 19672264 \n17 Valle J Wasan H Palmer DH Cunningham D Anthoney A Maraveyas A Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer N Engl J Med 2010 362 1273 20375404 \n18 Yonemoto N Furuse J Okusaka T Yamao K Funakoshi A Ohkawa S A multi-center retrospective analysis of survival benefits of chemotherapy for unresectable biliary tract cancer Jpn J Clin Oncol 2007 37 843 51 17942578 \n19 Park I Lee JL Ryu MH Kim TW Lee SS Park DH Prognostic factors and predictive model in patients with advanced biliary tract adenocarcinoma receiving first-line palliative chemotherapy Cancer 2009 115 4148 55 19536892 \n20 Mahfouf H Chemotherapy using gemcitabine (G) plus cisplatin (C) in locally in stage III and IV gallbladder and biliary tract J Clin Oncol 2010 28 Suppl \n21 Singh D Kumar S Sonkar AA Jaiswal S Mishra A Role of low dose prolonged infusion of gemcitabine and cisplatin in inoperable carcinoma gallbladder: a prospective pilot study Ann Oncol 2011 22 v83 \n22 Charoentum C Thongprasert S Chewaskulyong B Munprakan S Experience with gemcitabine and cisplatin in the therapy of inoperable and metastatic cholangiocarcinoma World J Gastroenterol 2007 13 2852 4 17569122 \n23 Doval DC Sekhon JS Gupta SK Fuloria J Shukla VK Gupta S A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer Br J Cancer 2004 90 1516 20 15083178 \n24 Eckmann KR Patel DK Landgraf A Slade JH Lin E Kaur H Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: a retrospective analysis Gastrointest Cancer Res 2011 4 155 60 22295126 \n25 Giuliani F Gebbia V Maiello E Borsellino N Bajardi E Colucci G Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM) Ann Oncol 2006 17 Suppl 7 vii73 7 16760299 \n26 Goldstein D Gainford MC Brown C Tebbutt N Ackland SP van Hazel G Fixed-dose-rate gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas Cancer Chemother Pharmacol 2011 67 519 25 20461378 \n27 Kang MJ Lee JL Kim TW Lee SS Ahn S Park DH Randomized phase II trial of S-1 and cisplatin versus gemcitabine and cisplatin in patients with advanced biliary tract adenocarcinoma Acta Oncol 2012 51 860 6 22559158 \n28 Kim ST Park JO Lee J Lee KT Lee JK Choi SH A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer Cancer 2006 106 1339 46 16475213 \n29 Lee GW Kang JH Kim HG Lee JS Lee JS Jang JS Combination chemotherapy with gemcitabine and cisplatin as first-line treatment for immunohistochemically proven cholangiocarcinoma Am J Clin Oncol 2006 29 127 31 16601429 \n30 Lee J Kim TY Lee MA Ahn MJ Kim HK Lim HY Phase II trial of gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas Cancer Chemother Pharmacol 2008 61 47 52 17364190 \n31 Meyerhardt JA Zhu AX Stuart K Ryan DP Blaszkowsky L Lehman N Phase-II study of gemcitabine and cisplatin in patients with metastatic biliary and gallbladder cancer Dig Dis Sci 2008 53 564 70 17597402 \n32 Okusaka T Nakachi K Fukutomi A Mizuno N Ohkawa S Funakoshi A Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan Br J Cancer 2010 103 469 74 20628385 \n33 Park BK Kim YJ Park JY Bang S Park SW Chung JB Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer J Gastroenterol Hepatol 2006 21 999 1003 16724985 \n34 Thongprasert S Napapan S Charoentum C Moonprakan S Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma Ann Oncol 2005 16 279 81 15668284 \n35 Wu CE Hsu HC Shen WC Lin YC Wang HM Chang JW Chemotherapy with gemcitabine plus cisplatin in patients with advanced biliary tract carcinoma at Chang Gung Memorial Hospital: a retrospective analysis Chang Gung Med J 2012 35 420 7 23127347 \n36 Charoentum C Chotirosniramit A Chitapanarux T Sirivanichai C Lertprasertsuke N Chewaskulyong B Attenuated dose of gemcitabine with cisplatin in patients (pts) with unresectable or metastatic biliary tract cancer (ABC): results of single Thai institution J Clin Oncol 2013 31 Suppl 4 265 \n37 Mizuno N Valle JW Furuse J Jitlal M Beare S Wasan H Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomized trials J Clin Oncol 2013 31 Suppl 4120 \n38 Valle JW Furuse J Jitlal M Beare S Mizuno N Wasan H Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials Ann Oncol 2014 25 391 8 24351397 \n39 Thatikonda C Miller A Iyer R Meta analysis of oxaliplatinbased combination chemotherapy for advanced gallbladder and bile duct cancers (AGBC) Am J Gastroenterol 2010 105 S72 \n40 Julka PK Puri T Rath GK A phase II study of gemcitabine and carboplatin combination chemotherapy in gallbladder carcinoma Hepatobiliary Pancreat Dis Int 2006 5 110 4 16481295 \n41 Williams KJ Picus J Trinkhaus K Fournier CC Suresh R James JS Gemcitabine with carboplatin for advanced biliary tract cancers: a phase II single institution study HPB (Oxford) 2010 12 418 26 20662793 \n42 Gallardo J Rubio B Villanueva L Barajas O Gallbladder cancer, a different disease that needs individual trials J Clin Oncol 2005 23 7753 4 16234545 \n43 Bridgewater J Galle PR Khan SA Llovet JM Park JW Patel T Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma J Hepatol 2014 60 1268 89 24681130 \n44 Heinemann V Quietzsch D Gieseler F Gonnermann M Schonekas H Rost A Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer J Clin Oncol 2006 24 3946 52 16921047\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-2998",
"issue": "47(3)",
"journal": "Cancer research and treatment",
"keywords": "Biliary tract neoplasms; Cholangiocarcinoma; Cisplatin; Gallbladder neoplasms; Gemcitabine",
"medline_ta": "Cancer Res Treat",
"mesh_terms": null,
"nlm_unique_id": "101155137",
"other_id": null,
"pages": "343-61",
"pmc": null,
"pmid": "25989801",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "17597402;24204165;20375404;24009445;15668284;20662793;19672264;16234545;16724985;23002368;24351397;20855823;20628385;21071270;19932054;16921047;22997452;22295126;20461378;22559158;16601429;15083178;24634588;17325704;22192731;16475213;17569122;17364190;16760299;23127347;8879373;18448556;19536892;17942578;16481295;15757418;24681130;18667395",
"title": "Gemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer: A Systematic Review.",
"title_normalized": "gemcitabine plus cisplatin for advanced biliary tract cancer a systematic review"
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"abstract": "Angiogenesis plays an essential role in the growth and progression of breast cancer. This observational single center study evaluated the efficacy and safety of a new weekly schedule of bevacizumab/paclitaxel combination in the first-line treatment of unselected, HER2-negative, metastatic breast cancer (MBC) patients, in a real-life setting. Thirty-five patients (median age 56 years, range 40-81) with HER2-negative MBC were treated with paclitaxel (70 mg/m(2) ) dd 1,8,15 q21 (60 mg/m(2) if ≥65 years or secondary Cumulative Illness Rating Scale) plus bevacizumab (10 mg/kg) every 2 weeks. Twenty-two patients (63%) had ≥2 metastatic sites and 15 (43%) visceral disease. Eleven patients (31%) had a triple-negative breast cancer (TNBC). A clinical complete response (cCR) was observed in 6 (17%) cases after a median of seven cycles, a partial response (PR) in 22 (63%), and a stable disease (SD) in 6 (17%) cases; the overall clinical benefit rate was 97%. In TNBC subgroup, cCR occurred in 1 (9%) case, PR in 8 (73%), and SD in 2 (18%). At a median follow-up of 13 months (range 1-79 months), the median progression-free survival was 11 months and the median overall survival was 36 months. No grade 4 adverse events occurred. The main grade 3 toxicities observed were neutropenia (11.4%), hypertension (5.7%), stomatitis (2.8%), diarrhea (2.8%), and vomiting (2.8%). The administration of weekly paclitaxel plus bevacizumab in this real-life experience shows similar efficacy than previously reported schedules, with a comparable dose intensity and a good toxicity profile.",
"affiliations": "Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy. kcannita@gmail.com.;Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.;Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.;Breast Unit, S. Salvatore Hospital, L'Aquila, Italy.;Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.;Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.;Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.;Division of Radiology, S. Salvatore Hospital, L'Aquila, Italy.;Division of Radiology, S. Salvatore Hospital, L'Aquila, Italy.;Departement of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.;Departement of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.;Medical Oncology, S. Salvatore Hospital, University of L'Aquila, L'Aquila, Italy.",
"authors": "Cannita|Katia|K|;Paradisi|Stefania|S|;Cocciolone|Valentina|V|;Bafile|Alberto|A|;Rinaldi|Lucia|L|;Irelli|Azzurra|A|;Lanfiuti Baldi|Paola|P|;Zugaro|Luigi|L|;Manetta|Rosa|R|;Alesse|Edoardo|E|;Ricevuto|Enrico|E|;Ficorella|Corrado|C|",
"chemical_list": "D000068258:Bevacizumab; D018719:Receptor, ErbB-2; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.803",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 2741688210.1002/cam4.803CAM4803Original ResearchClinical Cancer ResearchOriginal ResearchNew schedule of bevacizumab/paclitaxel as first‐line therapy for metastatic HER2‐negative breast cancer in a real‐life setting Cannita Katia kcannita@gmail.com \n1\nParadisi Stefania \n1\nCocciolone Valentina \n1\n\n2\nBafile Alberto \n3\nRinaldi Lucia \n1\nIrelli Azzurra \n1\nLanfiuti Baldi Paola \n1\nZugaro Luigi \n4\nManetta Rosa \n4\nAlesse Edoardo \n2\nRicevuto Enrico \n2\n\n5\nFicorella Corrado \n1\n\n2\n1 Medical OncologyS. Salvatore Hospital, University of L'AquilaL'AquilaItaly2 Departement of Biotechnological and Applied Clinical SciencesUniversity of L'AquilaL'AquilaItaly3 Breast UnitS. Salvatore HospitalL'AquilaItaly4 Division of RadiologyS. Salvatore HospitalL'AquilaItaly5 Oncology Network ASL1 AbruzzoUOSD Oncology Territorial CareS. Salvatore Hospital, University of L'AquilaL'AquilaItaly* Correspondence\n\nKatia Cannita, Medical Oncology, S. Salvatore Hospital, University of L'Aquila, Via Vetoio, Coppito (L'Aquila) 67100, Italy. Tel: +390862368709; Fax: +390862368682; E‐mail: kcannita@gmail.com\n15 7 2016 9 2016 5 9 10.1002/cam4.2016.5.issue-92232 2239 27 1 2016 16 5 2016 20 5 2016 © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nAngiogenesis plays an essential role in the growth and progression of breast cancer. This observational single center study evaluated the efficacy and safety of a new weekly schedule of bevacizumab/paclitaxel combination in the first‐line treatment of unselected, HER2‐negative, metastatic breast cancer (MBC) patients, in a real‐life setting. Thirty‐five patients (median age 56 years, range 40–81) with HER2‐negative MBC were treated with paclitaxel (70 mg/m2) dd 1,8,15 q21 (60 mg/m2 if ≥65 years or secondary Cumulative Illness Rating Scale) plus bevacizumab (10 mg/kg) every 2 weeks. Twenty‐two patients (63%) had ≥2 metastatic sites and 15 (43%) visceral disease. Eleven patients (31%) had a triple‐negative breast cancer (TNBC). A clinical complete response (cCR) was observed in 6 (17%) cases after a median of seven cycles, a partial response (PR) in 22 (63%), and a stable disease (SD) in 6 (17%) cases; the overall clinical benefit rate was 97%. In TNBC subgroup, cCR occurred in 1 (9%) case, PR in 8 (73%), and SD in 2 (18%). At a median follow‐up of 13 months (range 1–79 months), the median progression‐free survival was 11 months and the median overall survival was 36 months. No grade 4 adverse events occurred. The main grade 3 toxicities observed were neutropenia (11.4%), hypertension (5.7%), stomatitis (2.8%), diarrhea (2.8%), and vomiting (2.8%). The administration of weekly paclitaxel plus bevacizumab in this real‐life experience shows similar efficacy than previously reported schedules, with a comparable dose intensity and a good toxicity profile.\n\nBevacizumabmetastatic breast cancernew schedulepaclitaxelreal life source-schema-version-number2.0component-idcam4803cover-dateSeptember 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:29.09.2016\n\nCancer Medicine \n2016 ; 5 (9 ):2232 –2239 \n27416882 \n\n\nS. Paradisi and V. Cocciolone equally contributed to this work.\n==== Body\nIntroduction\nAngiogenesis is essential for the development of malignancies and plays a central role in the early stages of growth, invasion, and metastatic spread of breast cancer (BC), thus representing a reasonable therapeutic target. In vivo studies showed that the acquisition of a proangiogenic phenotype represents an early event in the development of BC 1. During mammary carcinogenesis, the expression of HIF‐1, a regulatory subunit of the hypoxia‐induced factor (HIF), increases proportionally to the progression from ductal hyperplastic lesion to ductal in situ carcinoma and invasive carcinoma 2, contextually to a growing expression of proangiogenic factors, including family members of vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGF), transforming growth factor (TGF)‐B1, and thymidine phosphorylase (TP) 3. Unlike the other factors, VEGF is continuously expressed in all stages of carcinogenesis and it is the only angiogenic factor present throughout the entire tumor life cycle 4. This evidence is a solid biological rationale for the use of therapeutic agents able to interfere with the VEGF function. The recombinant monoclonal antibody bevacizumab is currently the most widely used and developed antiangiogenic drug in the treatment of BC, able to recognize all the isoforms of VEGF‐A, preventing its binding to the cellular receptor, and inhibiting the angiogenic and proliferative signal. In vivo studies showed that bevacizumab inhibits both proliferation and migration of endothelial cells induced by VEGF‐A; besides in some models of human BC, the treatment with bevacizumab was associated to a reduction in microvascular density 5. According to the Folkman model, bevacizumab would lead to the normalization of the tumor vasculature, resulting in a restoration of cancer cells susceptibility to chemotherapy. This theory is currently accompanied by the newer “action and reaction” model 6: bevacizumab enhances the antiangiogenic effect of chemotherapy, thus providing a rationale for the use of combination therapies. In particular, taxanes have an inhibitory action on the proliferation of endothelial progenitor cells, with an antiangiogenic effect at lower doses than those needed to inhibit the proliferation of cancer cells. The resulting hypoxia induces cancer cells to a kind of “reaction” through the autocrine production of proangiogenic agents, mainly belonging to the HIF‐1/VEGF pathway 7. Bevacizumab is able to inhibit this “reaction,” potentiating the antiangiogenic action of chemotherapy. This represents the biological assumption for the combination of paclitaxel with bevacizumab. Based on the preclinical evidence on the angiogenic activity of paclitaxel at lower doses, the E2100 study evaluated paclitaxel (90 mg/mq) on days 1, 8, 15 every 28 days in combination with bevacizumab (10 mg/kg) every 14 days as first‐line treatment for metastatic breast cancer (MBC) 8. Both E2100 and other two randomized phase III studies (AVADO and RIBBON‐1, which analyzed the impact of adding bevacizumab to chemotherapy in the first‐line treatment of HER2‐negative MBC), reported positive results in terms of overall response rate (ORR) and progression‐free survival (PFS). In the E2100 study, the addition of bevacizumab to paclitaxel doubled the PFS when compared with paclitaxel alone, without an overall survival (OS) gain 9, but a significant increase in grades 3–4 toxicities such as hypertension or proteinuria. The CALGB 9840 trial showed that weekly paclitaxel is superior to every‐3‐weeks paclitaxel in MBC, with a significant improvement in ORR and an important benefit in terms of PFS 10.\n\nWe report our real‐life experience with a new weekly schedule of paclitaxel in combination with bevacizumab (10 mg/kg every 14 days), which evaluated efficacy and safety of this first‐line regimen in unselected, HER2‐negative MBC patients.\n\nPatients and Methods\nPatients\nFrom February 2009 to October 2014, 35 consecutive, unselected HER2‐negative MBC patients were treated with a modified schedule of bevacizumab plus paclitaxel at the Medical Oncology Department San Salvatore Hospital, University of L'Aquila. The study was performed according to the ethical rules for medical research involving human subjects, as stipulated by the WMA Declaration of Helsinki, and all patients gave their written informed consent.\n\nPatients were treated in clinical practice, according to the indications of paclitaxel and bevacizumab approved by Agenzia Italiana del Farmaco (AIFA) for administration in label in Italian public hospitals, and published in the Gazzetta Ufficiale Repubblica Italiana (“Elenco dei Medicinali erogabili a totale carico del Servizio sanitario nazionale,” Gazzetta Ufficiale n. 146 del 24.06.08).\n\nWomen with MBC previously untreated with cytotoxic therapy were eligible for this study if they had histologically confirmed diagnosis of BC with HER2‐negative status, evaluated by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) (HER2/neu oncoprotein expression negativity was assessed using the HerceptTest, scored 0 [absent] or 1+ [weak]; the negativity of the HER2/neu gene amplification was confirmed by FISH in case of HercepTest score 2+); World Health Organization (WHO) performance status ≤2; adequate hematological, renal, and hepatic function; life expectancy more than 3 months. Previous hormonal therapy for MBC or cytotoxic adjuvant chemotherapy was allowed. Exclusion criteria were pregnancy and breast feeding, uncontrolled severe diseases, cardiovascular diseases (uncontrolled hypertension, uncontrolled arrhythmia, ischemic cardiac disease in the last year), thromboembolic disease, coagulopathy, preexisting bleeding diatheses, proteinuria >1 g/24 h urine.\n\nMethods\nThe endpoints of the study were safety, ORR and clinical benefit rate (CBR, including responses and stability of disease for at least 6 months), PFS, and OS.\n\nThe clinical evaluation of safety, the clinical status, as well as liver and renal functions was assessed before each cycle; a complete blood count was obtained before each paclitaxel infusion. Urinalysis was performed before each bevacizumab infusion. Toxicity was registered weekly according to National Cancer Institute Common Toxicity Criteria (NCI‐CTC, version 3.0). Dose‐limiting toxicities (DLTs) requiring dose reduction or treatment delay/interruption were defined as grades 3–4 nonhematological toxicity (mainly represented by hypertension, neurotoxicity, hand–foot syndrome, diarrhea, proteinuria, mucositis, asthenia, epistaxis), grade 4 hematologic toxicity, febrile neutropenia, or any toxicity determining a >2 weeks treatment delay.\n\nTo better assess toxicity in the individual patient, we evaluated limiting TS (LTS) recently reported by our group 11, consisting of at least a DLT associated or not to other limiting or grade 2 toxicities. They were classified as LTS single site (LTS‐ss) if characterized only by a DLT; LTS multiple sites (LTS‐ms), if characterized by ≥2 DLTs or DLT associated to other, at least grade 2, nonlimiting toxicities.\n\nClinical evaluation of response was performed by CT scan every three cycles; PET or bone scan were added based on investigators’ discretion, according to the standard criteria of good clinical practice. The evaluation of response was performed according to the RECIST criteria 12.\n\nPFS and OS were evaluated by Kaplan–Meier method 13. PFS was the time from the start of the treatment to disease progression or last visit; OS was the time from the start of the treatment to death or last visit.\n\nTreatment plan\nAll patients received paclitaxel 70 mg/m2 on days 1, 8, and 15 of a 21‐day cycle (weekly) and bevacizumab 10 mg/kg intravenously (i.v.) every 2 weeks (Fig. 1); the paclitaxel dose for patients ≥65 years or with secondary Cumulative Illness Rating Scale (CIRS) was 60 mg/m2. The first bevacizumab dose was infused over 90 min; the subsequent infusions were reduced to 60 min for the second dose and to 30 min thereafter. Premedication was performed with i.v. dexametasone and chlorpheniramine maleate. Dose reduction of paclitaxel to 60 mg/m2 was planned in case of grade 3 or prolonged (>2 weeks treatment delay) grade 2 nonhematological toxicity or grade 4 hematological toxicity. Paclitaxel was permanently discontinued for severe hypersensitivity reactions or grade 4 nonhematological toxicity. Treatment was interrupted for proteinuria ≥2000 mg/24 h. Antihypertensive therapy was administered at the discretion of the investigator. Patients continued combined therapy until disease progression, unacceptable toxicity, or up to a maximum of 12 cycles.\n\nFigure 1 Treatment plan: paclitaxel 70 mg/m2 on days 1, 8, and 15 of a 21‐day cycle (weekly) and bevacizumab 10 mg/kg intravenously (i.v.) every 2 weeks; the paclitaxel dose for patients ≥65 years or with secondary Cumulative Illness Rating Scale (CIRS) was 60 mg/m2.\n\nPatients who discontinued paclitaxel without disease progression could continue bevacizumab monotherapy until disease progression or unacceptable toxicity with or without endocrine therapy.\n\nStatistical analysis\nSurvival curves were calculated by Kaplan–Meier method. PFS was calculated from starting of chemotherapy to disease progression or last visit. OS was the time from starting of chemotherapy to death or last visit 13.\n\nResults\nThirty‐five consecutive patients were enrolled. The median age was 56 years (range 40–81); 7 of the 35 (20%) aged ≥65 years. Infiltrating ductal carcinoma was the predominant histological subtype (80%), followed by the lobular subtype (14%). Hormonal receptors status was positive (ER positive and/or PgR positive) in 69% of cases, classified as Luminal A subtype in 17% (6 tumors) and Luminal B subtype in 52% (18 tumors), while triple‐negative tumors (TNBC) were 31%. Among all 35 treated patients, 6 (17%) had metastatic disease at diagnosis and 29 (83%) received first‐line treatment after tumor relapse, with a disease‐free interval >24 months in 12 of the 35 (34%) and ≤24 months in 17 of the 35 (49%) patients. Twenty‐seven patients (77%) had received adjuvant chemotherapy (anthracycline‐based, 30%; taxane‐based, 7%; anthracycline and taxane‐based, 44%; and other regimens, 19%), two patients (6%) had received neoadjuvant anthracycline and taxane‐based chemotherapy, 22 patients (63%) had received adjuvant endocrine therapy (tamoxifen, 41%; aromatase inhibitor, 41%; and tamoxifen and aromatase inhibitor, 18%). Median time from the end of adjuvant treatment to disease progression was 6 months (range 3–130 months). One patient had previously received endocrine therapy for MBC (fulvestrant). Sixty‐three percent of patients had two or more sites of metastasis and 43% of patients had visceral disease. WHO Performance Status was 0 in 29/35 patients (83%) and 1 in 6/35 patients (17%). Nine patients (26%) had a controlled hypertension just before starting chemotherapy (Table 1).\n\nTable 1 Demographic characteristics of patients at baseline\n\n\t\nN. (%)\t\nMedian age (years)\t56\t\nRange\t40–81\t\n≥65 years\t7 (20)\t\nWHO performance status\t\n0\t29 (83)\t\n1\t6 (17)\t\nMedical history at study entry\t\nHypertension\t9 (26)\t\nTachycardia\t–\t\nDiabetes\t1 (3)\t\nHistological type\t\nDuctal\t28 (80)\t\nLobular\t5 (14)\t\nOther\t2 (6)\t\nHormonal receptor status\t\nER‐positive and/or PgR‐positive\t24 (69)\t\nER‐negative and PgR‐negative\t11 (31)\t\nUnknown\t–\t\nHER2 status\t\nPositive\t–\t\nNegative\t35 (100)\t\nUnknown\t–\t\nPrior treatment for primary BC\t\nHormonal therapy\t2 (6)\t\nChemotherapy (CT)\t27 (77)\t\nCT taxane\t14 (40)\t\nDisease‐free interval\t\n≤24 months\t12 (34)\t\n>24 months\t17 (49)\t\nMetastatic disease at diagnosis\t6 (17)\t\nN.MBC sites\t\n1\t13 (37)\t\n≥2\t22 (63)\t\nLocation of disease\t\nVisceral\t15 (43)\t\nNonvisceral\t20 (57)\t\nBone only\t8/20 (40)\t\nMetastatic sites\t\nBone\t23 (66)\t\nLiver\t7 (20)\t\nLung\t9 (26)\t\nOther\t20 (57)\t\nBC, breast cancer; WHO, World Health Organization.\n\nJohn Wiley & Sons, LtdOverall, 247 treatment cycles were administered; the median number of cycles was 6 (range 3–12).\n\nSafety\nAs far as safety is concerned, in our study no grade 4 toxicities were observed, with the exception of alopecia. The grade 3 toxic effects were nonfebrile neutropenia (4/35, 11.4%), hypertension (2/35, 5.7%), oral mucositis (1/35, 2.8%), fatigue (1/35, 2.8%), diarrhea (1/35, 2.8%), and vomiting (1/35; 2.8%). Among the most significant grade 2 side effects, hypertension was observed in 40% (14/35) of patients, well managed by medical treatment; neuropathy in 11.4% (4/35), ≥2 weeks in just one patient; diarrhea in 8.5% (3/35) patients; proteinuria ≥2 weeks in 2.8% (1/35) and onychodystrophy in 2.8% (1/35) patients (Table 2). The most relevant toxicity in the subgroup of elderly patients (n = 7, ≥65 years) was grade 2 hypertension (6/7, 85.7%; in three cases a controlled hypertension was already presents at baseline); the seventh patient experienced grade 1 hypertension. In this subgroup of patients, grade 3 adverse events (AEs) were represented by diarrhea (1/7, 14%) and vomiting (1/7, 14%). Grade 2 AEs were fatigue (1/7, 14%), diarrhea (1/7, 14%), rhinitis (1/7, 14%), neuropathy (1/7, 14%), and onychodystrophy (1/7, 14%). Grade 1 AEs were nausea (2/7, 28%), epistaxis (1/7, 14%), fatigue (1/7, 14%), diarrhea (1/7, 14%), rhinitis (1/7, 14%), myalgia (1/7, 14%), neuropathy (1/7, 14%), stomatitis (1/7, 14%), and constipation (1/7, 14%).\n\nTable 2 Toxicity (all grades)\n\n\nGrade\n\tPatients\t\n35\t\n1\t2\t3\t4\t\nNeutropenia (n, %)\t8 (22.8)\t5 (14.2)\t4 (11.4)\t–\t\nAnemia (n, %)\t3 (8.5)\t–\t–\t–\t\nHypertension (n. %)\t–\t14 (40)\t2 (5.7)\t–\t\nEpistaxis (n, %)\t27 (77.1)\t2 (5.7)\t–\t–\t\nProteinuria (n, %)\t–\t1 (2.8)\t–\t–\t\nStomatitis (n, %)\t15 (42.8)\t2 (5.7)\t1 (2.8)\t–\t\nGingivitis (n, %)\t1 (2.8)\t1 (2.8)\t–\t–\t\nRhinitis (n, %)\t3 (8.5)\t1 (2.8)\t–\t–\t\nConjunctivitis (n, %)\t3 (8.5)\t–\t–\t–\t\nFatigue (n, %)\t26 (74.2)\t2 (5.7)\t1 (2.8)\t–\t\nConstipation (n, %)\t6 (17)\t–\t–\t–\t\nDiarrhea (n, %)\t8 (22.8)\t3 (8.5)\t1 (2.8)\t–\t\nNausea (n, %)\t4 (11.4)\t–\t–\t–\t\nVomiting (n, %)\t–\t–\t1 (2.8)\t–\t\nNeuropathy (n, %)\t14 (40)\t4 (11.4)\t–\t–\t\nHeadache (n, %)\t5 (14.2)\t–\t–\t–\t\nMyalgia (n, %)\t18 (51.4)\t1 (2.8)\t–\t–\t\nAllergic reactions (n, %)\t1 (2.8)\t–\t–\t–\t\nOnychodystrophy (n, %)\t3 (8.5)\t1 (2.8)\t–\t–\t\n↑ Transaminase (n, %)\t5 (14.2)\t1 (2.8)\t–\t\t\nAlopecia (n, %)\t–\t–\t–\t35 (100)\t\nJohn Wiley & Sons, LtdFive patients reported LTS, all represented by LTS‐ms, characterized by G3 hypertension plus G2 proteinuria lasting ≥2 weeks plus G3 neutropenia in one patient; G3 hypertension plus G3 fatigue plus G2 neuropathy in one patient; G3 mucositis plus G2 hypertension in one patient; G3 diarrhea plus G3 vomiting plus G2 neuropathy plus G2 hypertension in one patient; and G2 neuropathy lasting ≥2 weeks plus G2 hypertension plus G2 myalgia plus G2 diarrhea in one patient.\n\nResponse and survival analysis\nAt the time of data collection, five patients were still on treatment.\n\nA clinical complete response (cCR) was achieved in 17% (6/35) of patients, a partial response (PR) in 63% (22/35) and stable disease (SD) in 17% (6/35) of patients. The ORR (cCR + PR) was 80% and the CBR (cCR + PR + SD) was 97%. Most patients (66% [23/35] of all patients; 82% [23/28] of patients achieving objective response) had an objective response after a median of three cycles of chemotherapy.\n\nIn the subgroup of TNBC, one patient (9%) achieved a cCR, eight patients (73%) had a PR, and two patients (18%) a SD, for an ORR of 82% and a CBR of 100%.\n\nIn the subgroup of elderly patients, treated with a paclitaxel dose of 60 mg/m2, six of the seven patients (86%) reported a PR and one patient (14%) had a SD.\n\nAfter a median follow‐up of 13 months (range 1–79 months), the median PFS was 11 months and the median OS 36 months (Table 3). Figure 2 shows Kaplan–Meier curves related to PFS and OS.\n\nTable 3 Activity and efficacy\n\n \tClinical response(35 patients)\t\n \t\nn.\t%\t\nComplete response (CR)\t6\t17\t\nPartial response (PR)\t22\t63\t\nStable disease (SD)\t6\t17\t\nProgression disease\t1\t3\t\nClinical benefit rate (CR + PR + SD)\t31\t97\t\nMedian duration of follow‐up\t13 months\t\nProgression‐free survival\t11 months\t\nOverall survival\t36 months\t\nJohn Wiley & Sons, LtdFigure 2 Kaplan–Meier curves of disease‐free survival (DFS) (A) and overall survival (OS) (B). After a median follow‐up of 13 months (range 1–79 months), the median PFS was 11 months and the median OS 36 months. PFS, progression‐free survival.\n\nDiscussion\nThis is a small real‐life observational study evaluating a modified schedule of paclitaxel and bevacizumab combination regimen as first‐line treatment of HER2‐negative MBC patients.\n\nThe choice of adopting the weekly schedule without the “intermittent week” stems from the following considerations. In BC chemotherapy, the weekly administration of paclitaxel, as demonstrated by several studies, is more effective than the thrice weekly schedule 10. The activity of paclitaxel is directly related to the cell cycle and a more frequent administration enhances its proapoptotic and antiangiogenetic properties, thus increasing the antineoplastic effect 14, 15, 16.\n\nOn the other hand, from a tolerability point of view, the weekly schedule of paclitaxel (80 mg/m2) significantly increases neurotoxicity compared to the thrice weekly schedule, as shown by the phase III CALGB 9840 trial 10, a consideration leading to the choice of an “intermittent weekly” schedule in the E2100 study 9. Miller et al. reported limiting grades 3–4 toxicity represented by sensory neuropathy in 23.6% of patients, hypertension in 14.5%, infection in 9.3%, and fatigue in 8.5%. In clinical practice, these well‐known side effects, even if low grade, can lead to a reduced compliance to treatment and often affect quality of life.\n\nThus, considering that traditional chemotherapy and anti‐VEGF agents are synergistic in their action, as angiogenesis inhibitors sensitize to chemotherapy, it is rational to hypothesize that the combination requires lower doses of chemotherapy 17.\n\nIn this regard, in E2100 reductions of paclitaxel due to paclitaxel‐related toxicities occurred more frequently in patients in the bevacizumab/paclitaxel group, thus preserving paclitaxel effect with bevacizumab sensitization. As previously mentioned, on the one hand taxanes affect vascular endothelium and synergize with bevacizumab at picomolar doses to prevent vascular sprouting 18 and, on the other hand, bevacizumab can modify the delivery of chemotherapeutic agents to tumors by modifying tumor vascularity 19, this synergism could have decreased the toxicities while maintaining antitumor efficacy with reduced doses of chemotherapy 17.\n\nIn order to improve the tolerability of bevacizumab and paclitaxel combination, in our real‐life experience we used a weekly paclitaxel dosage of 70 mg/m2. Even if lower than 90 mg/m2 used in the pivotal E2100 trial, this dose determines a highest weekly dose intensity (DI) (70 vs. 67.5 mg/m2), due to the absence of the “intermittent week.” In our study, the dose of paclitaxel, but not of bevacizumab, was reduced by 10% also in patients with secondary CIRS. With such dose and schedule modulation of paclitaxel, associated with biweekly bevacizumab 10 mg/kg, no grade 3 neuropathy events were observed and grade 2 neurotoxicity occurred only in 11.4% of patients, with one case of limiting (lasting more than 2 weeks) sensory neuropathy. Even if this analysis has been performed in a limited population, the incidence of limiting neuropathy was significantly lower than that reported in the E2100 trial, where grades 3–4 neuropathy occurred in 23.6% of patients in the bevacizumab/paclitaxel arm versus 17.6% in the paclitaxel‐alone arm. It was suggested that this difference could be related to a prolonged paclitaxel exposure rather than to bevacizumab exposure, because in the AVADO trial grade ≥3 neuropathy occurred in 3–4% of patients receiving bevacizumab versus 2% with placebo 20. Moreover, no grade 4 toxicities were observed, with the exception of alopecia. In our real‐life experience, the rate of grade 3 hypertension was considerably lower than that observed in E2100 study (5.7% vs. 14.5%) 9 and comparable to that of ATHENA study (4.4%), which evaluated bevacizumab 10 mg/kg every 2 weeks in combination with a taxane‐based chemotherapy in the routine oncology practice 21. In elderly population (≥ 65 years), no grade 3, but only grade 2 hypertension events were observed, with a very high incidence (85.7%). The higher incidence of hypertension in older patients confirmed the results of the subanalysis of the ATHENA trial on patients ≥70 years. In this report, only hypertension and proteinuria were more common in older than in younger patients (grade ≥3 hypertension: 6.9% vs. 4.2%, respectively; grade ≥3 proteinuria: 4.0% vs. 1.5%, respectively). Moreover, hypertension was more common in patients with active hypertension at baseline than in those with normal blood pressure (48% vs. 37%, respectively, in patients ≥70 years; 38% vs. 26%, respectively, in patients <70 years) 21.\n\nIn our study, two patients (5.7%) required bevacizumab withdrawal and four patients (11.4%) a paclitaxel dose reduction. Overall, five patients (14.2%) required an adjustment/interruption of treatment, as one patient both discontinued bevacizumab and reduced paclitaxel. These results show that this regimen is well tolerated with a low incidence of grades 3–4 side effects. We observed a very high adherence to treatment, with 247 administered cycles and a median of six cycles (range 3–12) delivered per patient.\n\nThe efficacy of bevacizumab plus paclitaxel treatment observed in our real‐life study was very encouraging: the ORR was 80% (cCR 17%; PR 63%), higher than data reported in the phase III trials evaluating the approved bevacizumab dose combined with a taxane (50% in E2100 study, 64% in AVADO study, 51% in the taxane/anthracycline cohort of RIBBON‐1 study) and 52% obtained in the ATHENA trial 9, 20, 22, 23. Moreover, the CBR was 97% and 66% of all patients obtaining a PR after a median of three cycles of chemotherapy. Probably, the high compliance to chemotherapy, together with the good safety profile and the maintenance of an adequate quality of life, allowed us to obtain very encouraging results also in a “frail” population, like patients with secondary CIRS.\n\nThe ORR and CBR achieved in the subgroup of TNBC patients, 82% and 100%, respectively, confirms conclusions of subgroups analyses of the ATHENA and E2100, AVADO, and RIBBON trials, showing that first‐line chemotherapy in combination with bevacizumab is an active regimen in poor‐prognosis patients with limited treatment options, like patients with metastatic TNBC 24, 25. In this regard, the GeparQuinto trial has suggested that, also in the neoadjuvant setting, patients with TNBC benefit more from adding bevacizumab to anthracycline/taxane‐based chemotherapy than non‐TNBC patients, being the pathological complete response rate 39.3% and 27.9% (P = 0.003) with and without bevacizumab, respectively, for TNBC patients and 7.7% and 7.8%, respectively, for patients with hormone receptor‐positive tumors (P = 1.00) 26.\n\nAfter a median follow‐up of 13 months (range 1–79 months), the median PFS was 11 months and the median OS 36 months. The median PFS is similar to that of the previously mentioned pivotal studies (11.3, 10, 9.2, and 9.5 months in E2100, AVADO, taxane/anthracycline cohort of RIBBON‐1, and ATHENA study, respectively) 9, 20, 22, 23, while the median OS is slightly higher (26.7, 30.2, 27.5, and 25.2 months in E2100, AVADO, taxane/anthracycline cohort of RIBBON‐1, and ATHENA study, respectively) 9, 20, 22, 23, probably due to the additional lines of systemic treatment that patients received after first‐line chemotherapy.\n\nConclusions\nThis modified schedule of bevacizumab and paclitaxel combination regimen used in a real‐life clinical setting results in a very high tolerability, with efficacy results consistent with those reported in other clinical trials on the first‐line treatment of HER2‐negative MBC patients.\n\nBiomarkers able to predict the response to antiangiogenic therapies are urgently needed, as they could improve patient selection and drive clinicians’ choices. 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"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "5(9)",
"journal": "Cancer medicine",
"keywords": "Bevacizumab; metastatic breast cancer; new schedule; paclitaxel; real life",
"medline_ta": "Cancer Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001943:Breast Neoplasms; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D017239:Paclitaxel; D018719:Receptor, ErbB-2; D016896:Treatment Outcome",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "2232-9",
"pmc": null,
"pmid": "27416882",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": "8988045;22508241;20498403;15637262;18160686;11917134;16322683;22276820;20958992;20819780;8797771;18375893;9041202;21383283;2469964;12544254;9816139;11181778;12549858;27416882;10655437;25449430;10850285;23894038;21444356",
"title": "New schedule of bevacizumab/paclitaxel as first-line therapy for metastatic HER2-negative breast cancer in a real-life setting.",
"title_normalized": "new schedule of bevacizumab paclitaxel as first line therapy for metastatic her2 negative breast cancer in a real life setting"
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"abstract": "BACKGROUND\nSelective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology.\n\n\nMETHODS\nHere, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans.\n\n\nRESULTS\nIn rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10mg).\n\n\nCONCLUSIONS\nWe demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.",
"affiliations": "Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz). rorickkehnlm@lilly.com.;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).;Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).",
"authors": "Rorick-Kehn|Linda M|LM|;Witcher|Jennifer W|JW|;Lowe|Stephen L|SL|;Gonzales|Celedon R|CR|;Weller|Mary Ann|MA|;Bell|Robert L|RL|;Hart|John C|JC|;Need|Anne B|AB|;McKinzie|Jamie H|JH|;Statnick|Michael A|MA|;Suico|Jeffrey G|JG|;McKinzie|David L|DL|;Tauscher-Wisniewski|Sitra|S|;Mitch|Charles H|CH|;Stoltz|Randall R|RR|;Wong|Conrad J|CJ|",
"chemical_list": "D001549:Benzamides; D009292:Narcotic Antagonists; D009294:Narcotics; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; D009020:Morphine; C000590915:Aticaprant; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nInt J NeuropsychopharmacolInt. J. NeuropsychopharmacolijnpijnpInternational Journal of Neuropsychopharmacology1461-14571469-5111Oxford University Press US 2563737610.1093/ijnp/pyu036Research ArticleDetermining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human Rorick-Kehn Linda M. PhDWitcher Jennifer W. PhDLowe Stephen L. PhDGonzales Celedon R. MSWeller Mary Ann PhDBell Robert L. MSHart John C. HSDNeed Anne B. PhDMcKinzie Jamie H. MSStatnick Michael A. PhDSuico Jeffrey G. MDMcKinzie David L. PhDTauscher-Wisniewski Sitra MDMitch Charles H. PhDStoltz Randall R. MDWong Conrad J. PhDEli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (Drs Rorick-Kehn, Witcher, Lowe, Gonzales, Bell, Hard, Need, J. McKinzie, Statnick, Suico, D. McKinzie, Tauscher-Wisniewski, Mitch, and Wong); inVentiv Health Clinical, Ann Arbor, Michigan (Dr Weller); Covance Clinical Research Unit, Inc., Evansville, Indiana (Dr Stoltz).Correspondence: Linda Rorick-Kehn, PhD, Lilly Research Laboratories; Lilly Corporate Center, DC0510; Indianapolis, IN 46285 (rorickkehnlm@lilly.com).1 2015 29 1 2015 18 2 pyu0368 2 2014 29 7 2014 © The Author 2015. Published by Oxford University Press on behalf of CINP.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nSelective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology.\n\nMethods:\nHere, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans.\n\nResults:\nIn rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60mg (minimal-to-no blockade at 4–10mg).\n\nConclusions:\nWe demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.\n\nKeywords:\ntranslational biomarkerpupillometrykappa opioid receptordynorphinLY2456302\n==== Body\nIntroduction\nAlthough antidepressants are among the most widely prescribed medications, little progress has been made in improving clinical outcomes since the introduction of selective serotonin reuptake inhibitors almost 3 decades ago. Despite being effective therapies for some patients, monoamine-based medications (including selective serotonin reuptake inhibitors, older tricyclic antidepressants, and monoamine-oxidase inhibitors) suffer from delayed onset of antidepressant response and low remission rates (Berton and Nestler, 2006). Because of recent advances in molecular, behavioral, and genetic techniques, efforts are under way to develop novel nonmonoamine-based antidepressants that have the potential to dramatically improve antidepressant treatment response (Berton and Nestler, 2006; Insel, 2012).\n\nAccumulating evidence suggests that selective kappa opioid receptor (KOR) antagonists may be beneficial in the treatment of mood and addictive disorders (Carr et al., 2010; Knoll and Carlezon, 2010; Harrison, 2013; Rorick-Kehn et al., 2014). A recent Phase 2 study demonstrated that ALKS-5461 (buprenorphine + ALKS-33), a formulation resulting in putative kappa antagonism, produced efficacy in treatment-resistant depressed patients with rapid onset of action (Harrison, 2013). In contrast, nonselective opioid antagonists, such as naltrexone, have shown no benefit on mood; rather, they produce dysphoria in certain preclinical models and patient populations (Mendelson et al., 1978; West and Wise, 1988). Preclinical data suggest that potential antidepressant-like effects of opioid antagonists are critically dependent upon KOR selectivity based on neurochemical and electrophysiological evidence that mu- and kappa-opioid systems oppose each other in the brain (Pfeiffer et al., 1986; Spanagel et al., 1992; Margolis et al., 2003). Therefore, it is hypothesized that the predominantly mu antagonist component of nonselective opioid antagonists may block the antidepressant effects of KOR antagonism. To test the hypothesis that kappa-selective opioid antagonists may have antidepressant effects, it is essential to identify in human subjects clinical exposures that selectively block KORs without evidence of mu opioid receptor (MOR) antagonism.\n\nPupillometry is a noninvasive research technique useful for studying the centrally mediated effects of opioids and other drugs in preclinical and clinical paradigms. As a translational biomarker, it is particularly useful for evaluating the potency, efficacy, and duration of action of opioid receptor agonists and antagonists (Knaggs et al., 2004; Lotsch, 2005; Matsoukova et al., 2011). Although MOR agonists produce miosis in humans, rabbits, and dogs, they produce mydriasis in other species, including rodents and cats (Klemfuss et al., 1979). Regardless of whether agonists produce pupillary constriction or dilation in the target species, it is well established that mu-preferring opioid antagonists such as naltrexone and naloxone reliably block the MOR agonist-induced effects in both animals and humans (Klemfuss et al., 1979; Greenwald et al., 1996; Jones et al., 2000).\n\nLY2456302 ((S)-3-fluoro-4-(4-((2-(3,5-dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; chemical structure shown in Figure 1b inset) is a structurally novel, selective KOR antagonist with good central penetration and in vivo receptor occupancy that demonstrates efficacy in a number of preclinical models (Rorick-Kehn et al., 2014). In single- and multiple-dose clinical studies, LY2456302 was well tolerated up to doses of 35mg (Lowe et al., 2014). In a single-dose positron emission tomography study, LY2456302 demonstrated excellent central penetration and potent receptor occupancy in healthy human subjects, with full KOR occupancy at the 10-mg dose (Tauscher et al., 2012). Because MOR antagonist activity may be observed at higher doses of LY2456302, the current study was designed to identify the dose at which LY2456302 produces MOR antagonism in healthy subjects, thus confirming that lower doses remain selective for KORs.\n\nFigure 1. Dose-dependent in vivo receptor occupancy at putative mu, kappa, and delta opioid receptors (MOR, KOR, and DOR, respectively) by naloxone and LY2456302 60 minutes after administration. a, Naloxone showed dose- and concentration-dependent occupancy of putative opioid receptors in a manner consistent with its in vitro binding affinity, with MOR and KOR fully saturated at higher doses (3–10mg/kg). The doses at which 50% of receptors were occupied (ED50) at MOR, KOR, and DOR were 0.49, 0.75, and 3.45mg/kg, respectively. b, LY2456302 saturated putative KOR at all doses tested (3–300mg/kg). At higher doses, putative MOR and DOR occupancies were observed (ED50 values = 84.4 and 214.6mg/kg, respectively). LY2456302 selectively occupies KOR in the rat at doses <100mg/kg PO. Some engagement of MOR and DOR is evident at 100 and 300mg/kg (corresponding to brain exposures >473ng/g; see supplemental Table S1). Chemical structures of naloxone and LY2456302 are shown in insets.\n\nChanges in pupil diameter in response to a mu-agonist challenge were measured as a pharmacodynamic (PD) biomarker in both rats and humans. Morphine-induced mydriasis was used in rats and fentanyl-induced miosis was used in humans to assess mu activity. Two fentanyl pupillometry studies were conducted in healthy volunteers, using a low dose of fentanyl (2 μg/kg, intravenously [IV]) that was previously well tolerated and produced robust miosis (Greenwald et al., 1996). In Study A, naltrexone was used to establish the mu-associated effects on miosis. In Study B, LY2456302 was administered to determine its effects on fentanyl-induced miosis.\n\nPreclinical Methods\nAnimals\nMale Sprague-Dawley rats (225–300g; Harlan, Indianapolis, IN) were pair-housed with ad libitum food/water and maintained on a 12-hour–light/–dark cycle. Experiments were conducted in accordance with Guidelines for Care and Use of Laboratory Animals under protocols approved by local Institutional Animal Care and Use Committee.\n\nStudy Drugs\nLY2456302 (Diaz-Buezo et al., 2009; Mitch et al., 2011) and GR103545 were synthesized at Lilly Research Laboratories (Indianapolis, IN). Naloxone HCl, naltrexone HCl, naltriben methanesulfonate hydrate (naltriben), and morphine sulphate (morphine) were purchased from Sigma Aldrich (St. Louis, MO). LY2456302 was dissolved in sterile water with the drop-wise addition of lactic acid and was orally dosed (3mL/kg). Naloxone and morphine were dissolved in 0.9% saline and dosed subcutaneously or intraperitoneally, respectively (1mL/kg). For in vivo receptor occupancy studies, nonlabeled naltrexone (10 µg/kg), naltriben (10 µg/kg), and GR103545 (1.5 µg/kg) were dissolved in saline and dosed IV, as tracers for mu, delta, and kappa receptors, respectively, in a single solution (0.5mL/kg).\n\nReceptor Occupancy\nOccupancy of LY2456302 at opioid receptors was evaluated utilizing an in vivo rat model of central receptor occupancy. Microdoses of nonlabeled naltrexone (10 μg/kg), naltriben (10 µg/kg), and GR103545 (1.5 µg/kg) were used as tracers for MOR (Divin et al., 2009), delta opioid receptors (DORs) (Szekeres and Traynor, 1997), and KOR (Tomasi et al., 2013), respectively. Receptor occupancy was determined 60 minutes after an oral dose of LY2456302 (0, 3, 10, 30, 100, or 300mg/kg, n = 4/dose) or subcutaneous dose of naloxone (0, 0.1, 0.3, 1, 3, or 10mg/kg, n = 4/dose) by measuring striatal, thalamic, and cerebellar levels of each tracer by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS; Need et al., 2007). Total binding was represented by tracer levels in striatum (for DOR and KOR) and thalamus (for MOR). The cerebellum, which contains significantly lower densities of MOR, KOR, and DOR, was used for measuring nonspecific binding (Mansour et al., 1994).\n\nReceptor occupancies were calculated using the ratio method described by Wadenberg and colleagues (2000) but substituting the tracer concentrations determined by LC-MS/MS for the radiolabeled tracer levels determined with scintillation spectrometry. The following equation was used:\n\n 100*{1 − [((ratiot − 1)⁄(ratioc − 1))]} = % occupancy Each “ratio” refers to the ratio of tracer in a target-rich brain area to the tracer level detected in the cerebellum. Ratiot refers to animals treated with test drug and ratioc refers to the average ratio in vehicle-treated animals.\n\nTissue Preparation/Analysis for In Vivo Receptor Occupancy\nRat brain tissue samples were weighed and placed in conical centrifuge tubes on ice. Four volumes (wt/vol) of acetonitrile containing 0.1% formic acid was added to each tube. The samples were centrifuged after homogenization with an ultrasonic probe. Supernatant was diluted with sterile water in high pressure liquid chromatography (HPLC) injection vials for LC-MS/MS analysis. Tracer analysis was carried out using an Agilent 1200 HPLC (Agilent Technologies, Palo Alto, CA) and an API 3000 mass spectrometer (Applied Biosystems, Foster City, CA). The chromatographic separation employed Zorbax C18 column (Agilent Technologies, Wilmington, DE) gradient from 20% to 90% acetonitrile/water, each with 0.1% formic acid. The total HPLC run time was 3.5 minutes with an additional 2.0 minutes reequilibration time. Detection of small molecule tracers was accomplished by monitoring ion transitions 342.0:324.1, 416.0:398.2, and 414.0:343.0 mass:charge ratio for naltrexone, naltriben, and GR103545, respectively. Standards were prepared by adding known quantities of analyte to brain tissue samples from nontreated rats and processed as described above.\n\nRat Pupillometry\nRats (n = 10/dose) were acclimated to the test room (30 lux, ambient lighting conditions) for 15 to 30 minutes. Pupil diameter was measured with a Nikon D80 digital camera affixed to a custom-built apparatus with a small vertical partition at a fixed distance (50cm) from the camera lens. The partition contained a circular opening (1cm) directly above a metal metric ruler also affixed to the partition. Pupil measurements were determined by briefly holding each rat (1–2 seconds) behind the partition so that the right eye was in the middle of the opening, during which time a digital photo was taken.\n\nAfter a baseline pupil measurement, rats received 0, 3, 10, 30, 100, or 300mg/kg LY2456302. A postdose baseline pupil measurement was taken 60 minutes later, after which rats were immediately intraperitoneally dosed with 10mg/kg morphine. In a separate experiment, rats received 3mg/kg naloxone or vehicle 60 minutes before morphine administration. In each experiment, pupil measurements were taken at 10, 20, 30, 50, 70, and 90 minutes after morphine administration. A single measurement of pupil diameter (in millimeters) was taken at each time point and calculated as percent of baseline by dividing each measurement by the pretreatment baseline measurement (in millimeters). Pupil diameter was measured offline in a blinded manner.\n\nStatistics\nReceptor occupancy data were calculated by Prism4 (GraphPad, San Diego, CA) and expressed as mean+standard error of the mean (SEM). Half maximal effective dose (ED50) values were calculated by fitting data to sigmoidal curves using nonlinear regression.\n\nMaximum change in pupil diameter (MaxCPD) was calculated as the ratio of peak pupil diameter for each rat minus pretreatment pupil diameter over mean maximum change of the vehicle group and correlated with rat brain exposure from the receptor occupancy study (GraphPad; San Diego, CA).\n\nFor pupillometry, pupil diameter percent of baseline AUEC (area-under-the-effect-curve for pupil diameter in rats, and area-above-the-effect-curve for pupil diameter in humans; refers to the total calculated area of dilation in rats or constriction in humans) was computed for the 90-minute period using the trapezoidal rule. The AUEC values were log-transformed and analyzed using a 1-way analysis of variance model for bioequivalence with treatment of vehicle, LY2456302, and naloxone doses defined as a fixed-effect measure. Primary results were the least-squared mean contrasts (t test) for each LY2456302 dose and naloxone from vehicle. The least-squared mean difference and 90% confidence interval (CI) were back-transformed to obtain the mean ratio and corresponding 90% CI.\n\nClinical Methods\nProtocols and informed consent documents for Studies A and B were approved by the local Ethics Review Board. The studies were conducted in accordance with applicable laws and regulations of good clinical practice and ethical principles originating in the Declaration of Helsinki. Adverse events, clinical laboratory values, vital signs (blood pressure, pulse rate), and electrocardiogram results were monitored in both studies.\n\nStudy Drugs\nNaltrexone 50mg and placebo, supplied from Amide (a division of Mallinckrodt), were each given as 1 tablet in Study A. Fentanyl for Studies A and B was provided in vials as a citrate in water-soluble white crystalline powder from commercial drug product. When diluted, each milliliter of sterile aqueous solution contained a base of 50 μg fentanyl for IV use.\n\nFor Study B, LY2456302, provided by Eli Lilly and Company, was supplied as capsules containing 2 or 25mg LY2456302, with matching placebo capsules. After an overnight fast of ≥8 hours, LY2456302 or placebo capsules were given orally, with water, in the morning. Subjects fasted for at least 4 hours after receiving LY2456302 or placebo.\n\nStudy Design\nStudy A was a randomized, subject- and investigator-blind, 3-period crossover study in healthy male subjects, ages 18 to 50 years, with a body mass index (BMI) ≥25 and ≤35kg/m2. Each period consisted of 3 days with ≥7 days washout between periods. An oral dose of naltrexone or placebo was administered on days 1 to 3. On day 3 (third period), approximately 1 hour after naltrexone or placebo administration, subjects were given an IV bolus of fentanyl 2.0 μg/kg or a total dose of 200 μg for subjects weighing ≥100kg.\n\nStudy B was a placebo-controlled, subject-blind, fixed-sequence, adaptive, crossover study with 5 treatment periods that included healthy males and females aged 18 to 65 years, with a BMI ≥18 and ≤32kg/m2. In Period 1, all subjects received a single dose of fentanyl and placebo; in Periods 2 through 5, subjects received a single dose of fentanyl and a single dose of LY2456302 at 4, 10, 25, or 60mg. Doses of LY2456302 were selected based on the safety and pharmacokinetic (PK) profile from a single ascending dose study in which doses from 2 to 60mg LY2456302 were administered to healthy volunteers (Lowe et al., 2014). Fentanyl (2.0 μg/kg or maximum total dose of 200 μg) was administered as a bolus IV injection approximately 2 hours after placebo or LY2456302, at the approximate maximal concentration of drug exposure (Cmax) of LY2456302, as previously determined (Lowe et al., 2014).\n\nBlood sampling for determination of plasma concentrations of LY2456302 occurred at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 96 hours postdose.\n\nBioanalytical Methods\nStudy B human plasma samples were analyzed at Advinus Therapeutics (Bangalore, India). Samples were analyzed for LY2456302 using LC-MS/MS. The lower limit of quantification was 0.20ng/mL and the upper limit of quantification was 202.70ng/mL. Interassay accuracy (percent relative error) ranged from −4.55% to 3.19%. Interassay precision (percent relative standard deviation) ranged from 2.10% to 4.76%.\n\nPharmacokinetic Analyses\nStudy B plasma concentration-time data for LY2456302 were analyzed by noncompartmental methods using WinNonlin Enterprise 5.3. Actual sampling times were used in the estimation of LY2456302 PK parameters with predose times set to zero.\n\nLog-linear trapezoidal rule method was used to estimate area under the plasma concentration vs time curve (AUC). Individual PK parameters estimated were Cmax, time of observed Cmax, AUC from time zero to last quantifiable time point (AUC[0-tlast]), AUC from time zero to infinity (AUC[0-∞]), half-life (t1/2), apparent clearance (CL/F), apparent volume of distribution at steady-state (Vss/F), and apparent volume of distribution (Vz/F). Mean concentration values were calculated for graphical presentation.\n\nPupillometry\nPupil diameter measurements were made with a validated infrared pupillograph (P2000SA Pupillometer, Procyon, Broomall, PA) using PupilFit software. Under scotopic light conditions (low luminosity – 0.04 lux), 3 to 5 pupil diameter measurements of each subject’s left and right eye were recorded and multiple scans (up to 5) were obtained at every 20-minute nominal time interval. Multiple measurements were aggregated to obtain a single value per nominal time point for each subject. Final mean pupil diameter and median acquisition time values were used in calculations.\n\nFor Study A, pupil diameter (millimeters) was measured on day 1 pre-naltrexone or -placebo, on day 3 pre-fentanyl, and then at 20-minute intervals for 120 minutes post-fentanyl administration. For Study B, pupil diameter (millimeters) was measured during each study period (for placebo and each dose of LY2456302) at pre-fentanyl administration and at 20-minute intervals for 180 minutes post-fentanyl administration.\n\nChange in pupil diameter (CPD) from baseline over time was calculated to graphically display the time-course of pupil diameter. The apparent nadir of the pupil diameter time-course was observed and termed MaxCPD for each subject/treatment combination. The MaxCPD ratio was calculated as the ratio of treatment to placebo for the MaxCPD endpoint. The pupil diameter AUEC was computed using the trapezoidal rule for the pupil diameter (change from baseline) values.\n\nPharmacokinetic/PD Relationship\nThe relationship between LY2456302 exposure (AUC[0-∞]) and effects on pupil diameter (MaxCPD and AUEC) was explored to characterize the exposure-response relationship. Modeling of the PK/PD relationships utilized maximum effect (Emax) models in Nonmem (Version 7) and simple linear regression (rat data).\n\nThe Emax model utilized for the MaxCPD ratio analyses is shown in Equation 1. The E0 is the baseline ratio and is fixed to a value of 1, and Emax is the estimated maximal effect on MaxCPD ratio. The EC50 is the LY2456302 AUC that produces 50% of the Emax.\n\n Equation 1:MaxCPD Ratio=E0+ Emax×AUC EC50+AUC The Emax model utilized for the AUEC analyses is shown in Equation 2. The E0 is the AUEC following fentanyl with a placebo dose for LY2456302, and the Emax is the estimated maximal effect on AUEC. The EC50 is the LY2456302 AUC that produces 50% of the Emax. Intersubject variability was utilized for the E0 parameter. \n\n Equation 2: AUEC=E0+ Emax×AUC EC50+AUC Statistics\nStudy B data were independently analyzed. Pupil diameter AUEC values were log-transformed and analyzed using a repeated-measures mixed model with treatment of placebo and LY2456302 doses defined as a fixed effect and study period within each subject as a repeated measure. The primary contrast was each LY2456302 dose compared with placebo. The mean difference and CI were back-transformed to obtain the mean ratio and corresponding CI.\n\nA meta-analysis was conducted on the log-transformed AUEC combining data from Study A and Study B. A linear mixed-effects model analyzed the natural log (AUEC) with the random effect of subject and fixed effects of clinical trial (study A and study B) and the treatment effects (placebo-Study A, placebo-Study B, LY2456302 doses and naltrexone 50-mg dose). The primary results were back-transformed to least-squares means with the corresponding 95% mean CI. Pair-wise mean contrasts and corresponding P-values were computed between all LY2456302 doses, naltrexone, and placebo-Study A compared with placebo-Study B.\n\nSample Size Statistics\nAssuming an equivalence range of +20%, a sample size of 10 subjects provided 80% probability that the 90% CI of the overall change in pupil diameter by LY2456302 dose vs placebo would not include 1 (ie, would detect reversal of mu-agonist–induced effects). Exploratory analysis of Study A revealed that the mean ratio of pupil diameter of naltrexone:placebo under scotopic light conditions during a 3-hour post-fentanyl dose was 1.38, with a within-subject coefficient of variation of 11%. Based on these findings, the sample size of 10 subjects was sufficient for detecting reversal of mu-agonist–induced effects by LY2456302, as identified when the 90% CI of the mean ratio does not include the value of 1.\n\nResults\nRat In Vivo Receptor Occupancy\nNaloxone showed a dose- and concentration-dependent increase in opioid receptor occupancy consistent with its in vitro binding affinity, with MOR and KOR fully saturated at higher doses (3–10mg/kg; Figure 1; supplementary Table S1). The doses at which 50% of MOR, KOR, and DOR were occupied (ED50) were 0.49, 0.75, and 3.45mg/kg, respectively (Figure 1a).\n\nIn rats, LY2456302 saturated KOR at all doses tested (3–300mg/kg) and demonstrated dose- and concentration-dependent increases in occupancy of MOR and DOR receptors (Figure 1b), consistent with its in vitro binding affinity (Ki at recombinant human receptors = 0.81, 24.0, and 155nM for KOR, MOR, and DOR, respectively; Rorick-Kehn et al., 2014). The increasing levels of MOR and DOR occupancy at higher doses (ED50 = 84.4 and 214.6mg/kg, respectively) were driven by proportional increases in plasma and brain exposure of LY2456302 (supplementary Table S1). Results demonstrate that LY2456302 selectively occupies KORs in rat brain with high potency and selectivity in the pharmacological dose range (1–10mg/kg; Rorick-Kehn et al., 2014), whereas MOR occupancy was observed at LY2456302 doses and exposures ≥10-fold higher than required for preclinical efficacy.\n\nClinical Demographics\nSubject demographics are presented in supplementary Table S2. Study A enrolled 15 male subjects (13 completed), and 14 received at least 1 dose of naltrexone; 1 subject received only placebo. Both noncompleters cited personal reasons for early discontinuation. Subjects had a mean age of 32.6 years (range 20–44 years) and mean BMI of 30.20kg/m2 (range 25.95–34.84kg/m2). Study B enrolled 11 (6 males) subjects with a mean age of 39.8 years (range 21–52 years), mean weight of 72.3kg (range 49.8–95.7), and mean BMI of 24.6 (range 19.9–27.3). Ten subjects received at least 1 dose of LY2456302; 1 subject received only placebo plus fentanyl. Seven subjects completed Study B; of the 4 subjects who did not, reasons for early discontinuation included subject decision (2), protocol violation (1), and lost to follow-up (1).\n\nPharmacokinetics\nIn Study B, after single-dose administration, LY2456302 was rapidly absorbed with peak plasma concentrations occurring at 1.5 to 4 hours postdose (Table 1). Pharmacokinetic results were compared with data from a previous single-ascending dose study (Table 1). Following coadministration with fentanyl, there was higher apparent clearance (CL/F) and shorter half-life (t1/2) for the 4-, 10-, and 25-mg doses compared with LY2456302 alone. In contrast, at the 60-mg dose, CL/F was comparable between LY2456302 alone and with fentanyl. Overall, the PK of LY2456302 was comparable when administered alone or with fentanyl. Exposure estimates for each subject were used in the exposure/response pupillometry analyses for pupillometry.\n\nTable 1. Noncompartmental Pharmacokinetic Parameters Following a Single Oral Dose of LY2456302 Alone and After Administration of Fentanyl in Healthy Subjects\n\n\n\tLY2456302a Geometric Mean (CV%)\tLY2456302 plus Fentanyl Geometric Mean (CV%)\t\nLY2456302 dose, mg\t2\t4\t10\t25\t60\t4\t10\t25\t60\t\nn\t6\t8\t7\t7\t7\t7\t10\t10\t10\t\nCmax, ng/mL\t4.20 (25)\t11.6 (26)\t27.6 (26)\t72.2 (33)\t129 (28)\t6.71 (94)\t23.4 (27)\t46.3 (49)\t137 (49)\t\ntmax\nc, h\t1.50 (1.50–4.00)\t2.01 (1.50–3.00)\t1.50 (1.50–3.00)\t2.00 (1.33–3.00)\t2.42 (1.50–3.08)\t3.00 (2.00–4.00)\t2.02 (1.50–3.00)\t2.57 (1.50–4.00)\t3.00 (1.50–4.00)\t\nt1/2, h\t21.3 (62)\t32.3 (42)\t38.5 (22)\t34.1 (32)\t35.1 (27)\t21.4 (55)\t22.5 (39)\t25.1 (30)\t25.1 (36)\t\nAUC(0-∞), ng⋅h/mL\t45.6 (46)\t139 (37)\t348 (36)\t924 (36)\t1730 (48)\t91.4 (43)\t268 (31)\t561 (31)\t1700 (30)\t\nCL/F, L/h\t43.9 (46)\t28.7 (37)\t28.7 (36)\t27.1 (36)\t34.8 (48)\t43.8 (43)\t37.4 (31)\t44.6 (31)\t35.2 (30)\t\nVz/F, L\t1350 (16)\t1340 (32)\t1590 (34)\t1330 (42)\t1760 (35)\t1350 (49)\t1210 (30)\t1610 (34)\t1270 (27)\t\nVss/F, L\t1070 (22)\t1020 (27)\t1160 (25)\t977 (34)\t1320 (33)\t1130 (44)\t904 (26)\t1160 (39)\t973 (27)\t\nAbbreviations: AUC(0-∞), area under concentration vs time from zero to infinity; Cmax, maximum observed drug concentration; CV, coefficient of variation; tmax, time to maximum observed drug concentration; t1/2, half-life associated with the terminal rate constant (λz) in noncompartmental analysis; CL/F, apparent total body clearance of drug calculated after extra-vascular administration; Vz/F, apparent volume of distribution during the terminal phase after extra-vascular administration; Vss/F, apparent volume of distribution at steady state after extra-vascular administration.\n\n\na Data for LY2456302 alone is included from Lowe, Wong, Witcher, Gonzales, Dickinson, Bell, et al. (unpublished data) for comparison.\n\n\nb LY2456302 plus fentanyl data obtained in Study B. Fentanyl administered 2h after LY2456302.\n\n\nc Median (range).\n\nSafety\nNo serious adverse events were reported in Studies A or B. In Study A, the most frequent adverse event (AE) reported during and after fentanyl administration was itching (n=8). In 3 subjects, nausea led to emesis at approximately 200 μg of fentanyl.\n\nIn Study B, a total of 75 AEs were reported by 11 subjects who received ≥1 dose of LY2456302 and/or placebo (supplementary Table S3). The most common AEs considered related to LY2456302 (occurring >1 incidence) were headache (4 events) and nausea (2 events), all mild in severity. After the 25-mg LY2456302 dose, 1 subject experienced severe vomiting and flushing, both short-lived and likely related to fentanyl treatment. Most AEs deemed not related to study drug were consistent with known fentanyl effects. There were no clinically significant values, changes, or trends observed in clinical laboratory data, including neurohormones (cortisol, prolactin, and luteinizing hormone), vital sign values, or electrocardiogram parameters.\n\nPupillometry\nPupil diameter was used as a PD measure to assess the ability of LY2456302 to block morphine-induced mydriasis in rats and fentanyl-induced miosis in humans. As illustrated in Figure 2a, morphine-induced mydriasis in rats was completely blocked by 3mg/kg naloxone, a dose that fully occupied MOR (CI of mean difference relative to vehicle: 0.057, 0.256), P<.001; also confirmed by AUEC analysis) (Figure 3a). At doses ≤30mg/kg, LY2456302 did not block morphine-induced mydriasis (Figure 2b; all P>.05); however, at higher doses (100 and 300mg/kg), LY2456302 partially, but significantly, blocked morphine-induced mydriasis (Figure 2b with bio-equivalence to vehicle and confirmed by AUEC analysis; see Figure 3a of 90% mean difference CI relative to vehicle; 100mg/kg: [CI: 0.156, 0.703), P=.017; 300mg/kg: [CI: 0.168, 0.753], P=.025). Hence, MOR occupancy in the range of 60% to 85% produced partial PD effects, whereas >90% MOR occupancy was required to fully block morphine-induced mydriasis in rats under the present conditions. Raw pupil diameter means (±SEM) are reported in supplementary Table S4.\n\nFigure 2. Effect of naloxone (NLX) and LY2456302 (LY) on morphine-induced mydriasis in the rat and naltrexone (NTX) and LY2456302 on fentanyl-induced miosis in healthy human subjects. a, Naloxone (3mg/kg subcutaneously) completely blocked morphine-induced mydriasis in the rat, indicating full blockade of mu opioid receptor (MOR). b, LY2456302 produced modest, but significant, blockade of morphine-induced mydriasis in the rat at the highest doses tested (100 and 300mg/kg orally), consistent with 56% and 87% MOR occupancy, respectively. At lower doses, LY2456302 showed no evidence of MOR blockade. c, Naltrexone (50mg) completely blocked fentanyl-induced miosis in healthy human subjects. d, LY2456302 produced dose- and concentration-dependent blockade of fentanyl-induced miosis in healthy subjects, with statistically significant effects at 25 and 60mg. Doses of 4 and 10mg LY2456302 did not significantly affect fentanyl-induced miosis. Data in each panel represent the mean (±SEM) pupil diameter, expressed as a percent of baseline pupil diameter. See supplementary Table S4 for raw pupil diameter values (in millimeters).\n\nFigure 3. Statistical analysis of the least squares geometric means of the area under (or above) the effect curve (AUEC) of pupil diameter in rats and healthy subjects. Mean estimates of AUEC ratio of drug: placebo across dose levels showed a dose-response relationship in rats (a) and healthy subjects (b). Dotted line indicates a ratio of 1, or no effect on fentanyl-induced mydriasis or miosis, respectively.\n\nIn Study A, naltrexone administration on day 1 (without fentanyl) did not influence pupil diameter under scotopic lighting conditions (overall treatment effect, P=.373; data not shown). Fentanyl administration on day 3 produced significant miosis in healthy subjects (after preadministration of placebo) with a maximum effect observed at 20 minutes post-fentanyl administration (the first measurement post-fentanyl; overall bioequivalence test: P<.001). Preadministration of naltrexone fully blocked the fentanyl-induced miosis (bioequivalence test: P<.001; Figure 2c, see also LS Mean Ratio AUEC analysis below and in Figure 3b). Raw pupil diameter means (±SEM) are reported in supplementary Table S4.\n\nIn Study B, fentanyl produced a rapid onset of miosis with an apparent nadir observed at 20 minutes for all groups, consistent with Study A (Figure 2d; raw pupil diameter means (±SEM) are reported in supplementary Table S4). The placebo group (fentanyl alone) had an approximately 3-mm decrease in pupil diameter at the nadir or an approximately 50% decrease from baseline. Miosis gradually dissipated during the 180-minute post-fentanyl dosing. LY2456302 produced dose- and concentration-dependent blockade of fentanyl-induced miosis in healthy subjects (bioequivalence test: P=.01; see also LS Mean Ratio AUEC analysis below and in Figure 3b). Doses of 4 and 10mg LY2456302 did not affect fentanyl-induced miosis, whereas a moderate degree of blockade was observed at the 25- and 60-mg doses (Figure 2d).\n\nThe area-under-the-pupil-diameter vs time curve, termed AUEC, was also used to evaluate the exposure- and dose-response relationships. Analysis of AUEC across dose levels and comparison with placebo showed a dose-response relationship. In Figure 3, a ratio of 1 indicates no effect on fentanyl-induced miosis (or mydriasis), and decreasing ratios indicate more blockade of mu-agonist–induced miosis (or mydriasis). A similar relationship was observed for LY2456302 in rat and human. Naloxone (rat study) and naltrexone (human Study A) produced similar results, with both having very low ratios or nearly complete blockade of mu-agonist–induced effects. In rats and humans, the naloxone and naltrexone ratios were generally lower than ratios for all LY2456302 doses. Meta-analysis showed that all LY2456302 doses were significantly different from naltrexone (data not shown).\n\nThe nadir of the pupil diameter curve, termed the maximum change in pupil diameter from baseline (MaxCPD), was used as a pupillometry endpoint to further evaluate the PK/PD relationship. In rats, the MaxCPD was the peak of the pupil diameter curve due to the observed mydriasis in rats, whereas in humans it was the nadir due to observed miosis. The MaxCPD ratio was calculated using the nadir (or peak) change from baseline for each treatment compared with placebo. A ratio of 1 indicates no blockade of fentanyl-induced miosis/mydriasis, whereas a ratio approaching zero indicates complete blockade of miosis/mydriasis. An exposure-response relationship for MaxCPD was observed in both rats and humans (Figure 4). The exposure endpoint was brain concentration in rats and plasma AUC in humans. As predicted, the MaxCPD in rats was inversely correlated with LY2456302 brain concentrations (Figure 4a). The exposure-response relationship in healthy humans (Figure 4b) was best described using a Emax (the estimated maximal effect on MaxCPD ratio) model (E0 [the baseline ratio]=1.00 [fixed]; Emax=–0.918 [36.1%]; EC50 [the AUC that produces 50% of the Emax]=1270 ng*h/mL [72.8%]). The MaxCPD ratio would approach zero at the maximum effect, based on the model parameters. Based on the model fit, the mean AUC for the 60-mg dose (1700 ng*h/mL) corresponded to a MaxCPD ratio estimate of 0.47, indicating that approximately one-half of the fentanyl-induced miosis was blocked at this dose. The EC50 estimate was 1270 ng*h/mL, suggesting the 60-mg dose produced some moderate blockade of fentanyl-induced miosis, as measured by MaxCPD ratio. Therefore, the maximum effect for the MaxCPD ratio is expected to be achieved at an LY2456302 dose outside the dose range evaluated.\n\nFigure 4. Maximum change in pupil diameter ratio. a, Maximum change in pupil diameter (MaxCPD) ratio in rats (drug:vehicle) is inversely correlated with LY2456302 brain exposure, indicating that, at higher exposures, LY2456302 reduces the magnitude of morphine-induced mydriasis observed. b, MaxCPD ratio in humans (treatment:placebo) is inversely related to LY2456302 exposure and described by the Emax (the estimated maximal effect on MaxCPD ratio) model (E0 [the baseline ratio]=1.00 [fixed]; Emax=−0.918 [36.1%]; EC50 [the AUC that produces 50% of the Emax]=1270 [72.8%]).\n\nThe AUEC exposure-response relationship was evaluated using an Emax model (supplementary Figure S1). This relationship was similar to the dose-response relationship described above for MaxCPD. Similar to MaxCPD (Figure 4), the Emax model parameters suggested that doses of 25 and 60mg produced some moderate effect, as measured by AUEC, and the maximum effect would be expected at an LY2456302 dose outside the dose range evaluated.\n\nDiscussion\nWe demonstrate here for the first time that the KOR antagonist, LY2456302, produced dose- and concentration-dependent occupancy of MOR in rats at doses and concentrations ≥10-fold higher than those producing efficacy in preclinical models (Rorick-Kehn et al., 2014). Moreover, we used pupillometry as a translational biomarker in rats and humans to determine doses of LY2456302 necessary to reverse MOR agonist-induced effects, thereby confirming that lower doses remain KOR selective. The higher exposures of LY2456302 required to block MOR-agonist–induced effects on pupil diameter were consistent with its in vitro binding affinity and preclinical in vivo pharmacology (Rorick-Kehn et al., 2014). This finding is noteworthy, because there are currently no KOR-selective antagonists available for clinical evaluation, although the mixed opioid compound buprenorphine, in combination with a mu-preferring antagonist to block its mu partial agonist properties (ALKS-5461), produced significant improvement in depressed patients after 1 week of dosing (Harrison, 2013). Importantly, our findings demonstrate that LY2456302 selectively blocks KOR without evidence of significant MOR antagonism within the dose range of 4 to 10mg in humans (1–30mg/kg in rats).\n\nIn the rat receptor occupancy study, naloxone produced dose- and concentration-dependent MOR occupancy, with an ED50 of 0.49mg/kg, consistent with reported ED50 values for blockade of morphine-induced analgesia in rodents (Vaccarino et al., 1988) as well as efficacy in treating opioid overdose and displacement of 11C-diprenorphine binding in humans (Melichar et al., 2003). In the rat pupillometry study, a 3-mg/kg dose of naloxone that produced 90% MOR occupancy completely blocked morphine-induced mydriasis. The highest doses of LY2456302 tested (100 and 300mg/kg) produced 56% and 87% MOR occupancy, respectively, and partially blocked morphine-induced mydriasis. The reason for the less robust blockade of morphine-induced mydriasis by LY2456302 is unknown but may be related to the greater overall variability observed in that study.\n\nOur data are consistent with a parametric pupillometry study demonstrating that while morphine dose-dependently increased mydriasis in rats, fluctuations in pupil diameter also dramatically increased in a dose-related manner (Klemfuss et al., 1979). The apparent incomplete blockade may also be related to the relative contributions of MOR and KOR in modulating pupil dynamics. Whereas MOR agonists are well known to regulate pupil diameter, KORs are known to modulate intraocular pressure (Russell and Potter, 2002; Rasmussen et al., 2007). Specifically, KOR agonists reduce intraocular pressure, an effect that is blocked by KOR antagonists (Russell et al., 2000; Russell and Potter, 2002; Rasmussen et al., 2007). Therefore, it is conceivable that LY2456302 effects on intraocular pressure may alter the ability of morphine to produce pupillary changes, such that greater occupancy at MOR is required to overcome alterations in pupil dynamics produced by changes in intraocular pressure. Further studies will be required to determine whether super-saturation of KOR significantly alters mu-agonist–mediated regulation of pupil dynamics.\n\nConsistent with preclinical studies, single oral doses of LY2456302 demonstrated rapid central penetration and potent receptor occupancy in healthy human subjects, with 75% to 100% KOR occupancy at doses of 2 to 25mg, as measured by displacement of the KOR-selective antagonist positron emission tomography tracer, 11C-LY2795050 (Tauscher et al., 2012). Demonstration of potent KOR occupancy after oral dosing in human subjects provides greater confidence that the clinical hypothesis that KOR-selective antagonists have antidepressant effects will ultimately be tested in Phase 2 studies. It is believed that antidepressant effects of opioid antagonists are critically dependent upon KOR selectivity over other opioid receptor subtypes due to the dysphoria produced by nonselective opioid antagonists, which may attenuate the antidepressant effects of KOR antagonism (Mendelson et al., 1978; West and Wise, 1988). Therefore, we used translational pupillometry techniques to identify clinical doses of LY2456302 that do not exhibit significant antagonism at MOR, which will be used in future efficacy studies.\n\nIn our studies in healthy subjects, fentanyl produced robust miosis under scotopic lighting conditions, consistent with previous reports that dim lighting facilitated optimal detection of pupillary changes by opiates (Weinhold and Bigelow, 1993). The fentanyl-induced miosis was completely blocked by 50mg naltrexone. LY2456302 doses of 25 and 60mg produced minimal to moderate, but statistically significant, blockade of fentanyl-induced miosis, indicating MOR antagonism. Based on observed MOR activity at 25- to 60-mg doses, a clinical dose of 4 to 10mg LY2456302 would provide robust and selective KOR occupancy. Importantly, this dose range was well tolerated in healthy subjects (Lowe et al., 2014). Therefore, the dose- and exposure-response relationships measured here can inform Phase 2 dose selection to avoid doses with notable MOR blockade.\n\nThe PK profile of LY2456302 was well characterized after single doses and compared with similar data from another study (Lowe et al., 2014). Some minor differences in mean PK profiles were noted between LY2456302 alone and when co-administered with fentanyl, most likely because of variability between subjects and periods and not related to drug-drug interactions. Overall, LY2456302 was well tolerated in healthy subjects.\n\nIn conclusion, LY2456302 maintains selectivity for KOR within the 4- to 10-mg dose range in healthy volunteers. In conjunction with receptor occupancy, pupillometry represents an excellent translational tool to determine the pharmacological selectivity of novel KOR antagonists, which can be used to test the clinical hypothesis that KOR-selective antagonists may produce antidepressant effects. Here, we provide a model for using a hypothesis-driven approach in developing translational biomarkers that have great impact on guiding dose selection in early clinical trials, based on a clear understanding of target engagement and pharmacological selectivity.\n\nSupplementary Material\nFor supplementary material accompanying this paper, visit http://www.ijnp.oxfordjournals.org/\n\n\nStatement of Interest/Disclosure\nL.M.R.-K., J.W.W., S.L.L., C.R.G., R.L.B., J.C.H., A.B.N., J.H.M., M.A.S., J.G.S., D.L.M., S.T.-W., C.H.M., and C.J.W. are employees of, and stockholders in, Eli Lilly and Company at the time the experiments were conducted. M.A.W. is an employee of inVentiv Health Clinical. R.R.S. is an employee of Covance.\n\nSupplementary Material\nhttp://www.ijnp.oxfordjournals.org/\n Acknowledgments\nStudies were sponsored and funded by Eli Lilly and Company, Indianapolis, IN. Portions of this manuscript were written by MaryAnn Weller, a technical writer employed by inVentiv Health Clinical and co-author of the paper. All other authors declare responsibility for the scientific content of the manuscript.\n==== Refs\nReferences\n\nBerton O Nestler EJ \n(2006) \nNew approaches to antidepressant drug discovery: beyond monoamines .\nNat Rev Neurosci \n7 :137 –151 .16429123 \n\nCarr GV Lucki I \n(2010) \nComparison of the kappa-opioid receptor antagonist DIPPA in tests of anxiety-like behavior between Wistar Kyoto and Sprague Dawley rats .\nPsychopharmacology (Berl) \n210 :295 –302 .20369354 \n\nDiaz-Buezo N Pedregal-Tercero C McKinzie D Mitch C \n(2009) \nKappa selective opioid receptor antagonist . 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Poster presented 4-Dec-2012 at: Annual Meeting of the American College of Neuropsychopharmacology. http://www.acnp.org/annualmeeting/programbooks.aspx, page 253, #92.\n\nTomasi G Nabulsi N Zheng MQ Weinzimmer D Ropchan J Blumberg L Brown-Proctor C Ding YS Carson RE Huang Y \n(2013) \nDetermination of in vivo Bmax and Kd for 11C-GR103545, an agonist PET tracer for kappa-opioid receptors: a study in nonhuman primates .\nJ Nucl Med \n54 :600 –608 .23424192 \n\nVaccarino AL Tasker RA Melzack R \n(1988) \nSystemic administration of naloxone produces analgesia in BALB/c mice in the formalin pain test .\nNeurosci Lett \n84 :103 –107 .3347367 \n\nWadenberg ML Kapur S Soliman A Jones C Vaccarino F \n(2000) \nDopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats .\nPsychopharmacology (Berl) \n150 :422 –429 .10958084 \n\nWeinhold LL Bigelow GE \n(1993) \nOpioid miosis: effects of lighting intensity and monocular and binocular exposure .\nDrug Alcohol Depend \n31 :177 –181 .8436062 \n\nWest TE Wise RA \n(1988) \nEffects of naltrexone on nucleus accumbens, lateral hypothalamic and ventral tegmental self-stimulation rate-frequency functions .\nBrain Res \n462 :126 –133 .3179728\n\n",
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"title": "Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.",
"title_normalized": "determining pharmacological selectivity of the kappa opioid receptor antagonist ly2456302 using pupillometry as a translational biomarker in rat and human"
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"abstract": "A 73-year-old woman presenting with weight loss was diagnosed as having ascending colon cancer with synchronous liver metastasis. The liver metastasis was solitary but it occupied the medial and anterior segments. The size was over 9 cm in diameter and was located adjacent to the left, middle, and right hepatic veins, making it initially unresectable. Following surgical resection of the primary tumor, she received mFOLFOX6 plus bevacizumab chemotherapy, resulting in a decrease in size of the liver metastasis. During the 15 courses of chemotherapy, an allergic reaction to oxaliplatin occurred and oxaliplatin administration was stopped. Although the liver metastasis was considered to be in a stable disease state according to the RECIST criteria at the time following 32 courses of chemotherapy, we discontinued chemotherapy due to various reasons of the patient. However, the liver metastasis continues to be in the stable disease state, and has not grown for over 5 years since initiating mFOLFOX6 plus bevacizumab chemotherapy and for over 3 years since discontinuing the chemotherapy.",
"affiliations": "Dept. of Surgery, Kiryu Kosei General Hospital.",
"authors": "Shibata|Koji|K|;Machiki|Yuichi|Y|;Hiromatsu|Takashi|T|;Takara|Daisuke|D|;Idetsu|Akihito|A|;Ohara|Noriaki|N|",
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"title": "A Case of Ascending Colon Cancer with Synchronous Unresectable Liver Metastasis Maintaining a Long-Term Stable Disease State after Discontinuing Chemotherapy.",
"title_normalized": "a case of ascending colon cancer with synchronous unresectable liver metastasis maintaining a long term stable disease state after discontinuing chemotherapy"
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"abstract": "Canal anal cancer is a rare tumor that accounts for 2% of all colorectal neoplasms, with a low propensity for metastasis. The spread of anal squamous cell carcinoma to the brain is exceedingly rare and has been previously reported only 5 times in the medical literature. However, the first and only case of cranial bone metastasis from anal canal carcinoma was described in 2019. The purpose of this article is to add our cases to the limited literature for the management of metastatic anal cancer. The current study presents 2 cases of patients diagnosed with squamous cell carcinoma of the anal canal how underwent chemo and radiotherapy. Despite the treatment our patients developed neurological symptoms, cerebral magnetic resonance imaging showed brain lesions for the first case, and cranial bones metastasis for the second one, histopathology confirmed these lesions to be a poorly differentiated squamous cell carcinoma, consistent with the known primary tumor of the anal canal. Unfortunately, both patients succumbed quickly to systemic complications of the disease during these treatments. Despite its rarity, brain metastasis should be considered in any patient with a history of anal cancer presented neurological symptoms.",
"affiliations": "Department of Radiotherapy, Cheikh Khalifa International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco.;Department of Radiotherapy, Cheikh Khalifa International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco.;Department of Radiology, Cheikh Khalifa International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco.;Department of Radiology, Cheikh Khalifa International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco.;Department of Radiology, Cheikh Khalifa International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco.;Department of Radiotherapy, Cheikh Khalifa International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco.",
"authors": "Chihabeddine|Meryeme|M|;Naim|Asmaa|A|;Habi|Jihane|J|;Kassimi|Mariam|M|;Mahi|Mohamed|M|;Kouhen|Fadila|F|",
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"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575\nS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com\n\n10.1159/000516037\ncro-0014-0778\nCase Report\nAnal Cancer with Atypical Brain and Cranial Bones Metastasis: About 2 Cases and Literature Review\nChihabeddine Meryeme a*\nNaim Asmaa a\nHabi Jihane b\nKassimi Mariam b\nMahi Mohamed b\nKouhen Fadila a\naDepartment of Radiotherapy, Cheikh Khalifa International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco\nbDepartment of Radiology, Cheikh Khalifa International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences, Casablanca, Morocco\n*Meryeme Chihabeddine, meriem.chihabeddine@gmail.com\nMay-Aug 2021\n8 6 2021\n8 6 2021\n14 2 778783\n13 3 2021\n16 3 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nCanal anal cancer is a rare tumor that accounts for 2% of all colorectal neoplasms, with a low propensity for metastasis. The spread of anal squamous cell carcinoma to the brain is exceedingly rare and has been previously reported only 5 times in the medical literature. However, the first and only case of cranial bone metastasis from anal canal carcinoma was described in 2019. The purpose of this article is to add our cases to the limited literature for the management of metastatic anal cancer. The current study presents 2 cases of patients diagnosed with squamous cell carcinoma of the anal canal how underwent chemo and radiotherapy. Despite the treatment our patients developed neurological symptoms, cerebral magnetic resonance imaging showed brain lesions for the first case, and cranial bones metastasis for the second one, histopathology confirmed these lesions to be a poorly differentiated squamous cell carcinoma, consistent with the known primary tumor of the anal canal. Unfortunately, both patients succumbed quickly to systemic complications of the disease during these treatments. Despite its rarity, brain metastasis should be considered in any patient with a history of anal cancer presented neurological symptoms.\n\nKeywords\n\nCanal anal tumor\nCranial metastasis\nBrain metastasis\n==== Body\nIntroduction\n\nAnal cancer is a rare tumor among gastrointestinal tract neoplasms, distinct from cancers of the colon and rectum. The most common subtype is squamous cell carcinoma. It is also notable for a relatively low incidence of metastasis [1]. When metastases are identified, the liver is the most likely location. Brain metastasis is a rare entity, with only 5 cases that have been described in the literature. For cranial bone metastasis, it is a very uncommon location accounting for <5% of all secondary bone locations [2].\n\nTo the best of our knowledge, we report 2 cases of metastatic anal carcinoma. The first one, it is a female patient, 44 years old, with a cranial bone lesion. The second one, it is a male patient with intracranial lesions above and below the tentorium.\n\nCases Presentation\n\nCase 1\n\nA 44-year-old female patient, whose medical history included Crohn's disease since 2003, was admitted to our hospital for squamous cell carcinoma of the anal canal which was accidentally discovered during a consultation to control her Crohn's disease. The patient's management was delayed due to the confinement of the COVID-19 pandemic. A physical examination showed a painful mass in the external anal sphincter and extended to the gluteal muscle. The performance status was at 2–3.\n\nPelvic magnetic resonance imaging (MRI) showed an ulcerated anoperineal tumor process in hypo signal on T1-weighted sequences, a hyper signal on T2-weighted sequences, and intensely enhanced after injection of gadolinium. This process is locally extended in gluteal soft tissue with mesorectal nodules, cutaneous nodules of the sacral region, and bone lesions of the left greater trochanter. Total body computerized tomography was performed and no systemic involvement was noted. Colonoscopy revealed no synchronous tumor.\n\nThe case was discussed in a multidisciplinary consultation meeting. A concomitant radiochemotherapy treatment has been retained. Treatment was then initiated with combined chemoradiation therapy with Capecitabine 825 mg/m2 twice daily, 5 days per week, 2 piles of 500 mg in the morning and 2 piles in the evening for a body surface of 1.28, cisplatin 80 mg/m2 with a dose reduction of 20% given the performance status at 2, and a total dose of 80 mg every 28 days. And external radiotherapy total dose of 60 Gy, 2 Gy/fraction, and 5 fractions/week.\n\nDuring the treatment, the patient presented with a 3 days history of headaches. Cerebral MRI was performed and revealed an important heterogeneous metastatic lesion in the left parietal and frontal bone extended to the adjacent soft tissue of the scalp (shown in Fig. 1). Histopathology confirmed the cerebral lesion to be a poorly differentiated squamous cell carcinoma, consistent with the known primary tumor of the anal canal. The patient underwent total brain external radiotherapy, a total dose of 20 Gy, 4 Gy per fraction, and 5 fractions per week. The patient succumbed to systemic complications of the disease during her treatment.\n\nCase 2\n\nA 60-year-old male presented to our hospital with a 12-month history of anal abscess that has been complicated by fistula. Performance status was at 1–2.\n\nColonoscopy found a mass within 3 cm of the anal margin; the patient underwent a dissected biopsy, a histological report identifying basaloid-type squamous cell carcinoma. Staging computed tomography scans of the chest, and abdomen showed secondary lung localization, external iliac, and left inguinal adenopathy.\n\nPelvic MRI showed left pelvic and inguinal metastatic lymphadenopathy without tumor wall thickening of the anal canal or mass syndrome (shown in Fig. 2). Skeletal scintigraphy was also performed, and lesions were revealed in the right sacrum, pubis, and coccyx. Biopsy of lung lesion was carried out; the anatomopathological results and immunohistochemistry profile suggesting moderately differentiated squamous cell carcinoma with positive Anti P40.\n\nPatients receive the first cure of palliative chemotherapy docetaxel, cisplatin, 5 − fluorouracil with granulocyte colony-stimulating factor, docetaxel 40 mg/m2 and, 5 fluorouracil 2,400 mg/m2 in 48 h every 2 weeks for 6 cures then evaluation. Treatment was complicated by persistent neutropenia which forced to stop the chemotherapy.\n\nA follow-up positron emission tomography scan showed moderate anal hypermetabolism, metabolically active external iliac and left inguinal adenopathies, and nonhypermetabolic bilateral pulmonary micronodules, without other hypermetabolic lesions. Programmed death-ligand 1 (PD-L1) and microsatellite instability status studies were negative.\n\nThe case was discussed in a multidisciplinary consultation meeting. The patient was treated with concomitant radiochemotherapy including external radiotherapy a total dose of 60 Gy, 2 Gy/fraction, 5 fraction per week, capecitabine 825 mg/m2 twice daily, 5 days per week, 3 piles of 500 mg in the morning and 3 piles in the evening, and cisplatin with a total dose of 100 mg every 28 days. The patient presented a good clinical evolution with subsequent disappearance of the anal margin tumor and a 50% reduction of the left inguinal ADP. A few months after, he presented to the emergency with an epileptic seizure, confusion, and memory disorders with a 15-day history of decreased tactile sensation and motor control.\n\nMRI was performed and showed multiple metastatic intracranial lesions above and below the tentorium. These lesions were rounded, well limited, with annular enhancement, and surrounded by edema (shown in Fig. 3). At this point, total brain radiotherapy was planned however the patient succumbed to his disease before starting this therapy.\n\nDiscussion\n\nCarcinomas of the anal canal are rarely observed in practice, accounting for <2% of all gastrointestinal malignancies. The disease usually occurs in the sixth decade of life. The pathogenesis of this malignancy is not entirely clear. Some risk factors such as Crohn's disease, chronic inflammation, and preexisting fistula have been hypothesized and studied [3, 4, 5]. Immunosuppression associated with human immunodeficiency virus or transplantation and smoking is also incriminated [6, 7]. Human papillomavirus infection, especially type 16, has been highly associated with the development of anal cancer, and human papillomavirus DNA has been found in up to 88% of tumors. Besides, recent work with vaccines targeting these viral serotypes has shown some reduction in the risk of developing previous lesions [8].\n\nAnal tumors can be divided into 2 categories depending on their anatomical location, anal canal, and anal margin. Anal canal tumors are predominantly squamous cell carcinomas [9]. Although tumors have traditionally been divided into well-differentiated keratinizing and nonkeratinizing types (cloacogenic/basaloid and transitional), both types share a similar natural history. Therefore, no distinction was made in their management [10]. Other less common types are adenocarcinoma, anaplastic carcinoma, undifferentiated tumors, and melanomas. Squamous cell carcinoma also predominates in the anal margin subtype, which is usually well-differentiated and keratinizing. Overall, squamous carcinomas account for 75% of anal cancers [10].\n\nBenign anal disease is very common and can be the first sign of anal cancer [11]. In one of our cases, a persistent perianal abscess was the first manifestation of the disease. Such a situation should always raise the possibility of malignancy. Patients with recurrent or unhealed perianal abscesses and fistulas should be sampled for anal cancer and be closely monitored.\n\nThe most important clinical sign is rectal bleeding (45%) and anorectal pain, 10–20% of patients' exhibit extrapelvic disseminated disease at the time of diagnosis. The most frequently observed metastatic site is the liver [9]. The 5-year stage IV survival rate is greater in epidermoid than nonepidermoid carcinoma and represents 20.9 versus 7.4%, respectively [10].\n\nExceptionally rare incidence of brain metastases from primary anal cancer can be explained by the low incidence of the disease, and the low propensity toward distant metastasis. Only a few cases of anal cancer with brain metastasis have been previously reported in the literature. The first was identified in a review of 373 cases of anorectal “transitional cloacogenic carcinomas” (now considered squamous cell carcinomas) by Klotz et al. [12], they report that 19% of patients in their series had metastatic disease, with 1 patient reported having a brain metastasis, without further detail given.\n\nIn 1991, Davidson and Yong [13] reported the case of a 61-year-old female how had initially nonmetastatic anal carcinoma treated by abdominoperineal amputation, and 8 years later, the patient develops a single brain lesion at the cerebellopontine angle. She was treated with surgery and adjuvant fractionated radiotherapy with posterior recurrence of the primary tumor [13]. Squamous cell carcinoma of the anus is also of interest because, in recent decades, the therapeutic management has changed, as it has become a nonsurgical disease, and the main treatment now consists of combined chemotherapy and radiotherapy [14].\n\nCisplatin-based chemotherapy in combination with 5FU and paclitaxel is the standard treatment for metastatic anal carcinoma, with radiotherapy being planned for local treatment. Cetuximab as anti-epidermal growth factor receptor therapy in anal carcinoma can be proposed in case of overexpression of the epidermal growth factor receptor [15].\n\nOne of our cases had the peculiarity of being a basaloid undifferentiated carcinoma, unlike the previous cases which were the squamous type (although poorly differentiated). But unfortunately, regardless of the histological type, the rare cases described in the literature have shown that canal anal cancer with cerebral metastasis has a very poor prognosis and patients succumb shortly to the disease.\n\nConclusion\n\nCerebral metastasis from anal SCC is extremely rare, and these cases are now present to enrich the literature. Based on all reported cases, it is clear that brain metastases are associated with poor prognosis, even aggressive medical, and surgical treatment. In these cases, palliative care alone may be the most justified. Also, brain metastases can occur late, even years after successful primary treatment. Therefore, the diagnosis should be considered when patients with a history of this malignancy present new neurological symptoms.\n\nStatement of Ethics\n\nWritten informed consent was obtained from the families of both patients 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\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nThe authors did not receive any funding.\n\nAuthor Contributions\n\nAll the authors participated in the writing of the article and the bibliographical research concerning the case described. They also declare having read and approved the final version of the manuscript.\n\nFig. 1 White arrow: Cerebral MRI in the axial section after injection of Gadolinium: Left frontoparietal lesion, heterogeneous, invading the soft parts of the scalp. MRI, magnetic resonance imaging.\n\nFig. 2 Pelvic MRI showed a left metastatic inguinal lymphadenopathy (white arrow) in heterogeneous signal in T2. MRI, magnetic resonance imaging.\n\nFig. 3 Brain MRI of a 60-year-old patient with brain metastases from an anal canal tumor: The sagittal section after injection of gadolinium: annular enhancement of over and under tentorial lesions (arrow). MRI, magnetic resonance imaging.\n==== Refs\nReferences\n\n1 Vasudev P Boutross-Tadross O Radhi J Basaloid squamous cell carcinoma: two case reports Cases J. 2009 2 9351 20062602\n2 Kakhki VR Anvari K Sadeghi R Mahmoudian AS Torabian-Kakhki M Pattern and distribution of bone metastases in common malignant tumors Nucl Med Rev Cent East Eur. 2013 16 (2) 66 9 24068635\n3 Johnson LG Madeleine MM Newcomer LM Schwartz SM Daling JR Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000 Cancer. 2004 101 281 8 15241824\n4 Belkacémi Y Berger C Poortmans P Piel G Zouhair A Meric JB Management of primary anal canal adenocarcinoma: a large retrospective study from the rare cancer network Int J Radiat Oncol Biol Phys. 2003 56 1274 83 12873671\n5 Tarazi R Nelson RL Anal adenocarcinoma: a comprehensive review Semin Surg Oncol. 1994 10 235 40 8085101\n6 Gervaz P Calmy A Durmishi Y Allal AS Morel P Squamous cell carcinoma of the anus: an opportunistic cancer in HIV-positive male homosexuals World J Gastroenterol. 2011 17 2987 91 21799644\n7 Shia J An update on tumors of the anal canal Arch Pathol Lab Med. 2010 134 1601 11 21043813\n8 Scholefield JH Castle MT Watson NF Malignant transformation of high-grade anal intraepithelial neoplasia Br J Surg. 2005 92 1133 6 16044425\n9 Cummings BJ Ajani JA Swallow CJ DeVita VT Jr Lawrence TS Rosenberg SA Cancer of the anal region Cancer: principles & practice of oncology 2008 8th ed Philadelphia, PA Lippincott Williams &Wilkins p. 1301 14\n10 Benson AB Bekaii-Saab T Chan E Chen YJ Choti MA Cooper HS National comprehensive cancer network. Anal carcinoma version 2013 Accessed 2013 May 3 Available from http://www.nccn.org/professionals/physician_gls/pdf/anal.pdf\n11 Abel ME Chiu YS Russell TR Volpe PA Adenocarcinoma of the anal glands. Results of a survey Dis Colon Rectum. 1993 36 383 7 8458266\n12 Klotz RG Jr Pamukcoglu T Souilliard DH Transitional cloacogenic carcinoma of the anal canal. Clinicopathologic study of three hundred seventy-three cases Cancer. 1967 20 1727 45 6058180\n13 Davidson NG Yong PP Brain metastasis from basaloid carcinoma of the anal canal 8 years after abdominoperineal resection Eur J Surg Oncol. 1991 17 227 30 2015927\n14 Klas JV Rothenberger DA Wong WD Madoff RD Malignant tumors of the anal canal: the spectrum of disease, treatment, and outcomes Cancer. 1999 85 1686 93 10223561\n15 Garg M Lee JY Kachnic LA Catalano PJ Henry DH Cooley TP Eastern cooperative oncology group (ECOG); AIDS malignancy consortium (AMC): Phase II trials of cetuximab (CX) plus cisplatin (CDDP), 5-fluorouracil (5-FU) and radiation (RT) in immunocompetent (ECOG 3205) and HIV-positive (AMC045) patients with squamous cell carcinoma (SCAC) of the anal canal: safety and preliminary efficacy results (updated after absract submission) JAMA. 2008 299 1914 21 18430910\n\n",
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"keywords": "Brain metastasis; Canal anal tumor; Cranial metastasis",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "778-783",
"pmc": null,
"pmid": "34177530",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "2015927;15241824;8458266;21043813;12873671;8085101;20062602;16044425;10223561;24068635;6058180;21799644",
"title": "Anal Cancer with Atypical Brain and Cranial Bones Metastasis: About 2 Cases and Literature Review.",
"title_normalized": "anal cancer with atypical brain and cranial bones metastasis about 2 cases and literature review"
} | [
{
"companynumb": "MA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-315996",
"fulfillexpeditecriteria": "1",
"occurcountry": "MA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"dr... |
{
"abstract": "OBJECTIVE\nTo report a case of serology-negative severe disseminated Bartonella neuroretinitis in an immunocompromised patient in which diagnosis was made by detection of B. henselae DNA by universal polymerase chain reaction of brain tissue.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nA 57-year-old man with immunoglobulin A vasculitis on immunosuppressive therapy presented with lethargy, weight loss, and bilateral decreased vision. Fundus examination revealed bilateral mild vitritis, marked optic disc edema, vascular sheathing, and numerous white inner retinal and preretinal lesions. Brain magnetic resonance imaging revealed multiple foci of restricted diffusion and a ring-enhancing focus in the left parietal lobe. Serologies, cerebrospinal fluid, and vitreous biopsies were all negative for Bartonella. A brain biopsy was performed and B. henselae DNA was detected by universal polymerase chain reaction of the specimen. The patient demonstrated resolution of fundus findings with antibiotic treatment. Repeat serological testing demonstrated seroconversion.\n\n\nCONCLUSIONS\nIn immunocompromised patients, infection by Bartonella henselae can present as severe disseminated disease. Establishing the diagnosis can be challenging as serologic testing is often unrevealing in the setting of a blunted immune response. Polymerase chain reaction has been used in select cases to establish the diagnosis.",
"affiliations": "Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan.",
"authors": "Wu|Annie M|AM|;Zhao|Peter Y|PY|;Wubben|Thomas J|TJ|;Hyde|Robert A|RA|;Paulus|Yannis M|YM|;Johnson|Mark W|MW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000995",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": null,
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32150117",
"pubdate": "2020-03-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "SEROLOGY NEGATIVE BARTONELLA NEURORETINITIS IN AN IMMUNOCOMPROMISED PATIENT.",
"title_normalized": "serology negative bartonella neuroretinitis in an immunocompromised patient"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2022SP005557",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nRecurrent hepatitis C is universal after liver transplant when viremia is present at the time of transplant, and this affects survival. Previous treatments with pegylated interferon and ribavirin with or without boceprevir or telaprevir have yielded modest sustained virologic response rates and frequent adverse effects. A combination of new antiviral agents has been used for recurrent hepatitis C. We aim to describe the outcomes of recurrent hepatitis C in liver transplant patients treated with simeprevir, sofosbuvir, and ribavirin.\n\n\nMETHODS\nFifty-three consecutive patients with recurrent hepatitis C genotype 1 were included. All patients had liver biopsy before enrollment if cirrhosis was not evident. Standard doses of simeprevir and sofosbuvir were used for 12 weeks. Ribavirin was adjusted based on hemoglobin levels. In 53 patients, 50 completed 12 weeks of treatment.\n\n\nRESULTS\nAll 50 patients who completed 12 weeks of treatment achieved sustained virologic response. One patient who completed only 6 weeks also achieved sustained virologic response. Overall, the antiviral treatment was well tolerated, with no interactions with immunosuppressive drugs.\n\n\nCONCLUSIONS\nThe combination of simeprevir and sofosbuvir with or without ribavirin yields a high sustained virologic response rate of 96% in a historically difficult to treat patient population (recurrent hepatitis C genotype 1).",
"affiliations": "From the Department of Transplant Surgery/Center of Advanced Liver Disease, Methodist University Hospital, University of Tennessee Health Science Center, Memphis, TN 38104, USA.",
"authors": "Nair|Satheesh|S|;Satapathy|Sanjaya K|SK|;Gonzalez|Humberto C|HC|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2015.0289",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "15(3)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D006801:Humans; D007166:Immunosuppressive Agents; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012189:Retrospective Studies; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "314-319",
"pmc": null,
"pmid": "26926117",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sofosbuvir and Simeprevir for Treatment of Recurrent Hepatitis C Infection After Liver Transplant.",
"title_normalized": "sofosbuvir and simeprevir for treatment of recurrent hepatitis c infection after liver transplant"
} | [
{
"companynumb": "US-009507513-1706USA011184",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "Intracranial invasion by Mucormycosis carries high mortality mostly related to arterial occlusion and ischemic necrosis. We report clinical, imaging and autopsy findings in an adult immunodeficiency syndrome (AIDS) patient with fungal infection extending from a tooth. We report a striking discordance between a restriction of fungal growth to the initial branches of the circle of Willis and extensive ischemic infarcts of deep brain structures. This lends to a suggestion of apparently lost opportunities for brain salvage and prompts a re-assessment of clinical approaches to treat mucormycosis.",
"affiliations": "Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.;Department of Imaging/Neuroradiology, Cedars-Sinai Medical Center, Los Angeles, California, USA.",
"authors": "Bannykh|Sergei I|SI|http://orcid.org/0000-0002-1542-8224;Hunt|Brice|B|;Moser|Franklin|F|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/neup.12501",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-6544",
"issue": "38(5)",
"journal": "Neuropathology : official journal of the Japanese Society of Neuropathology",
"keywords": "fungus; ischemia; mucormycosis; occlusion; treatment",
"medline_ta": "Neuropathology",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D001344:Autopsy; D002545:Brain Ischemia; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009091:Mucormycosis; D009336:Necrosis",
"nlm_unique_id": "9606526",
"other_id": null,
"pages": "539-541",
"pmc": null,
"pmid": "29974522",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Intra-arterial spread of Mucormycetes mediates early ischemic necrosis of brain and suggests new venues for prophylactic therapy.",
"title_normalized": "intra arterial spread of mucormycetes mediates early ischemic necrosis of brain and suggests new venues for prophylactic therapy"
} | [
{
"companynumb": "US-ASTELLAS-2018US046025",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": null,
... |
{
"abstract": "The combination of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin with rituximab (DA-EPOCH-R) is used for non-Hodgkin lymphoma patients. Febrile neutropenia (FN) is a common complication of treatment with myelo-suppressive chemotherapy, so preventing FN is important for maintaining chemotherapy dosage. Recently, pegfilgrastim has been used as the primary prophylaxis of FN in Japan, but there have been few cases reported using pegfilgrastim for the primary prophylaxis in DA-EPOCH-R. In this study, we retrospectively compared the efficacy of pegfilgrastim with that of filgrastim in patients receiving DA-EPOCH-R in Hiroshima University Hospital. Efficacy assessment was based on incidence of FN and serious neutropenia (neutrophil count <500/μL), hospitalization days and chemotherapy dosage level. Ten patients met the inclusion criteria: pegfilgrastim (n=5, 30 cycles) or filgrastim (n=5, 16 cycles). No difference in efficacy existed between pegfilgrastim and filgrastim in the first cycle; however, 2 of 5 patients in filgrastim group reduced dose level in the total cycles of chemotherapy, no patients in pegfilgrastim group reduced. In conclusion, pegfilgrastim seemed better than filgrastim for the primary prophylaxis in DA-EPOCH-R.",
"affiliations": "Department of Pharmacy, Hiroshima University Hospital.;Department of Pharmacy, Hiroshima University Hospital.;Department of Pharmacy, Hiroshima University Hospital.;Department of Pharmacy, Hiroshima University Hospital.;Department of Pharmacy, Hiroshima University Hospital.;Department of Pharmacy, Hiroshima University Hospital.;Department of Pharmacy, Hiroshima University Hospital.;Department of Pharmacy, Hiroshima University Hospital.",
"authors": "Kataoka|Tatsuo|T|;Sakurashita|Hiroshi|H|;Taogoshi|Takanori|T|;Nishigakiuchi|Ryo|R|;Murase|Tetsuya|T|;Izumitani|Satoru|S|;Saeki|Yasuyuki|Y|;Matsuo|Hiroaki|H|",
"chemical_list": "C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D000069585:Filgrastim; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.1248/yakushi.18-00101",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6903",
"issue": "139(4)",
"journal": "Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan",
"keywords": "dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin with rituximab chemotherapy; filgrastim; pegfilgrastim; primary prophylaxis",
"medline_ta": "Yakugaku Zasshi",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D064147:Febrile Neutropenia; D005260:Female; D000069585:Filgrastim; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011241:Prednisone; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0413613",
"other_id": null,
"pages": "629-633",
"pmc": null,
"pmid": "30930398",
"pubdate": "2019",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Comparison of Pegfilgrastim and Filgrastim for the Primary Prophylactic Effect for Preventing Febrile Neutropenia in Patients Undergoing Rituximab with Dose-adjusted EPOCH Chemotherapy.",
"title_normalized": "comparison of pegfilgrastim and filgrastim for the primary prophylactic effect for preventing febrile neutropenia in patients undergoing rituximab with dose adjusted epoch chemotherapy"
} | [
{
"companynumb": "JP-JNJFOC-20190500484",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
"... |
{
"abstract": "An adverse event is described which appeared when the macrolide antibiotic erythromycin was added to a regimen of risperidone 0.5 mg bid and clomipramine 50 mg tid in a 15-year-old male being treated for Tourette's, obsessive-compulsive, and attention-deficit hyperactivity disorders. An acute onset of behavioral symptoms, including agitation, labile mood, incessant talking, and argumentativeness, began within 24 h of starting the erythromycin and persisted for 9 days after its discontinuation. It was followed by a return to stable functioning on the prior risperidone-clomipramine regimen. Erythromycin, risperidone, and clomipramine are all metabolized by the hepatic cytochrome P450 system. It is postulated that the addition of erythromycin, a known inhibitor of CYP3A and CYP1A2, resulted in alterations in the metabolism of clomipramine and risperidone. Clomipramine metabolism is dependent upon the isoenzymes CYP2D6 and CYP1A2, and risperidone is a substrate for CYP2D6. Erythromycin would inhibit demethylation of clomipramine at the 1A2 isoenzyme and lead to a dual interaction between risperidone and clomipramine at the CYP2D6 isoenzyme. The subsequent increases in plasma levels of clomipramine, risperidone, their metabolites, or a combination of these agents could explain the adverse effects noted in this patient. In the absence of risperidone, clomipramine could have been metabolically cleared by CYP2D6. In the absence of clomipramine, risperidone clearance would not be affected by erythromycin. So the proposed mechanism requires an interaction involving all three agents: erythromycin, clomipramine, and risperidone. Alterations in plasma protein binding may also have played a role, because all three agents are extensively protein bound. Caution is urged when prescribing erythromycin with psychotropic drugs that are highly protein bound and/or are metabolized by the same P450 isoenzymes.",
"affiliations": "Division of Child and Adolescent Psychiatry, Ontario, Canada.",
"authors": "Fisman|S|S|;Reniers|D|D|;Diaz|P|P|",
"chemical_list": "D004917:Erythromycin; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D002997:Clomipramine",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.1996.6.133",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "6(2)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": null,
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000152:Acne Vulgaris; D000293:Adolescent; D002997:Clomipramine; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D004917:Erythromycin; D006801:Humans; D008297:Male; D018967:Risperidone; D005879:Tourette Syndrome",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "133-8",
"pmc": null,
"pmid": "9231305",
"pubdate": "1996",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Erythromycin interaction with risperidone or clomipramine in an adolescent.",
"title_normalized": "erythromycin interaction with risperidone or clomipramine in an adolescent"
} | [
{
"companynumb": "CA-PFIZER INC-2021374711",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CLOMIPRAMINE"
},
"drugadditional": null,
... |
{
"abstract": "Anabolic-androgenic steroids (AAS) are increasingly being used by athletes and youngsters to become masculine and to loose body fat. Long-term consumption of AAS causes multiple physical and psychological morbidities. Research has also concluded that AAS have addictive potential and AAS abuse is commonly found with other substance abuse. Abuse of AAS is rare in eastern countries. Abuse among women is even rarer. Here is a case report of an Indian woman, who was prescribed nandrolone decanoate injections by an unqualified medical practitioner to treat multiple non-specific somatic pains and reported weakness, leading to dependence for nandrolonedecanoate. This case report supports the research finding of abuse potential of AAS, raises concern about the need for spreading the awareness about AAS abuse among medical professionals, regulating medical practice by unqualified practitioners, and strict legal check against AAS availability in developing countries.",
"affiliations": "Department of Psychiatry, King Georges Medical University, Lucknow, Uttar Pradesh, India.",
"authors": "Tripathi|Adarsh|A|;Tekkalaki|Bheemsain|B|;Saxena|Shashwat|S|;Dandu|Himanshu|H|",
"chemical_list": "D045930:Anabolic Agents; D009277:Nandrolone; D000077603:Nandrolone Decanoate",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D045930:Anabolic Agents; D005260:Female; D006628:Hirsutism; D006801:Humans; D007194:India; D008875:Middle Aged; D009277:Nandrolone; D000077603:Nandrolone Decanoate; D010554:Personality Disorders; D019966:Substance-Related Disorders; D013997:Time Factors",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24503662",
"pubdate": "2014-02-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21379414;19922565;18923108;18275992;19487399;20188494;19769977;17506239",
"title": "Iatrogenic dependence of anabolic-androgenic steroid in an Indian non-athletic woman.",
"title_normalized": "iatrogenic dependence of anabolic androgenic steroid in an indian non athletic woman"
} | [
{
"companynumb": "IN-ACTAVIS-2015-07287",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate our institutional experience combining carboplatin-paclitaxel (C/T) chemotherapy with high-dose-rate (HDR) intra-vaginal brachytherapy (IVB) following comprehensive surgical staging in localized uterine serous carcinoma (USC).\n\n\nMETHODS\nInstitutional chart review identified 56 patients with FIGO 2009 stage I-II USC treated between 2000-2010. Patients underwent total hysterectomy, bilateral salpingo-oopherectomy, and comprehensive surgical staging including pelvic and para-aortic lymph node dissection, omentectomy, and peritoneal cytology. Chemotherapy was 6 cycles of C/T, and the IVB dose was 14 Gy in 2 fractions, prescribed to 0.5 cm from the cylinder surface. Kaplan-Meier methods were used to estimate recurrence-free survival (RFS) and overall survival (OS).\n\n\nRESULTS\nThe median follow-up time was 49 months (range: 9-145). The 5-yr RFS and OS were 85% and 93%, respectively. In all cases of recurrence (n = 8), the first site of failure was extra-pelvic. There were no isolated vaginal recurrences, however, there was one vaginal apex recurrence recorded at 19 months in a patient with simultaneous lung metastases. Thus, the 2-year vaginal RFS was 98%.\n\n\nCONCLUSIONS\nExcellent vaginal/pelvic control rates were observed. Further study of HDR brachytherapy dose and fractionation in combination with chemotherapy is worthwhile.",
"affiliations": "Department of Therapeutic Radiology.;Department of Therapeutic Radiology.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USA.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USA.;Department of Therapeutic Radiology.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USA.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USA.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USA.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USA.;Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USA.",
"authors": "Damast|Shari|S|;Higgins|Susan A|SA|;Ratner|Elena|E|;De Leon|Maria C|MC|;Mani|Sheida|S|;Silasi|Dan-Arin|DA|;Azodi|Masoud|M|;Santin|Alessandro|A|;Rutherford|Thomas|T|;Schwartz|Peter E|PE|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/jcb.2015.48539",
"fulltext": "\n==== Front\nJ Contemp BrachytherapyJ Contemp BrachytherapyJCBJournal of Contemporary Brachytherapy1689-832X2081-2841Termedia Publishing House 2439910.5114/jcb.2015.48539Original PaperHigh-dose-rate vaginal brachytherapy with chemotherapy for surgically staged localized uterine serous carcinoma Damast Shari MD1Higgins Susan A. MD1Ratner Elena MD2De Leon Maria C. MD2Mani Sheida MD1Silasi Dan-Arin MD2Azodi Masoud MD2Santin Alessandro MD2Rutherford Thomas MD, PhD2Schwartz Peter E. MD21 Department of Therapeutic Radiology2 Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Gynecologic Oncology, Yale University School of Medicine, New Haven, CT, USAAddress for correspondence: Shari Damast, MD, Department of Therapeutic Radiology, Yale University School of Medicine, 15 York St New Haven, CT 06510, USA. phone: +1 203-200-2635, fax: +1 203-785-4622. e-mail: shari.damast@yale.edu26 1 2015 2 2015 7 1 35 40 10 9 2014 11 10 2014 21 11 2014 Copyright © 2015 Termedia2015This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nTo evaluate our institutional experience combining carboplatin-paclitaxel (C/T) chemotherapy with high-dose-rate (HDR) intra-vaginal brachytherapy (IVB) following comprehensive surgical staging in localized uterine serous carcinoma (USC).\n\nMaterial and methods\nInstitutional chart review identified 56 patients with FIGO 2009 stage I-II USC treated between 2000-2010. Patients underwent total hysterectomy, bilateral salpingo-oopherectomy, and comprehensive surgical staging including pelvic and para-aortic lymph node dissection, omentectomy, and peritoneal cytology. Chemotherapy was 6 cycles of C/T, and the IVB dose was 14 Gy in 2 fractions, prescribed to 0.5 cm from the cylinder surface. Kaplan-Meier methods were used to estimate recurrence-free survival (RFS) and overall survival (OS).\n\nResults\nThe median follow-up time was 49 months (range: 9-145). The 5-yr RFS and OS were 85% and 93%, respectively. In all cases of recurrence (n = 8), the first site of failure was extra-pelvic. There were no isolated vaginal recurrences, however, there was one vaginal apex recurrence recorded at 19 months in a patient with simultaneous lung metastases. Thus, the 2-year vaginal RFS was 98%.\n\nConclusions\nExcellent vaginal/pelvic control rates were observed. Further study of HDR brachytherapy dose and fractionation in combination with chemotherapy is worthwhile.\n\nbrachytherapychemotherapyendometrial cancerpapillary serous\n==== Body\nPurpose\nUterine serous carcinoma (USC) is an uncommon but aggressive form of endometrial adenocarcinoma [1]. Its pattern of spread favors the peritoneum and upper abdomen, and thus adjuvant management is typically more aggressive than for the endometrioid subtypes, even when it presents in early stages [2]. In the United States, surgical staging of USC includes total hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, omentectomy, and pelvic and para-aortic lymph node dissections [2]. Historically, whole abdominal radiotherapy was the mainstay of adjuvant therapy, even in optimally resected stage I disease [3, 4]. Recently, studies have demonstrated a benefit with the use of adjuvant chemotherapy [5–7]. Contemporary adjuvant treatment of early stage (stage I-II) disease following comprehensive staging involves a combination of chemotherapy and smaller-field radiation therapy (RT) [5, 6], and an increasingly popular adjuvant treatment paradigm combines chemotherapy with intra-vaginal brachytherapy (IVB) [5, 8–13].\n\nThere have been few studies to date, which have addressed adjuvant IVB technique in early stage USC, and thus questions concerning IVB dose and sequencing with chemotherapy persist. This topic was not covered in the guidelines for adjuvant vaginal cuff brachytherapy released by the American Brachytherapy Society in 2012 [14]. Several recent institutional reports describe excellent 5-year vaginal recurrence rates of 0-3% using chemotherapy in combination with a common high-dose-rate (HDR) IVB regimen, 7 Gy x 3 fractions prescribed to a depth of 5 mm from applicator surface [9–12]. A recent phase II evaluation of endometrial patients with high-intermediate risk factors, of which 35% of the population was USC, employed this same HDR regimen followed by three cycles of adjuvant chemotherapy [15]. There is modest support for an alternate IVB dose schedule for USC patients receiving chemotherapy based on a single retrospective report, in which HDR IVB was delivered twice per week in 6 fractions of 4 Gy prescribed to the mucosal surface [13]. This fractionation schedule delivered an equivalent dose in 2 Gy/fraction (EQD2) [16] of approximately 28 Gy to the vaginal surface, which is approximately half of the mucosal dose used in the other series.\n\nAt our institution, USC patients with localized disease who have undergone comprehensive surgical staging are recommended chemotherapy with IVB. When our HDR program was first introduced in the 1990s, in the era of adriamycin-based chemotherapy, several cases of vaginal mucositis were noted by the treating physicians, and thus the HDR prescription for all USC patients receiving chemotherapy was modified from 7 Gy x 3 to 7 Gy x 2 prescribed to 0.5 cm from the cylinder surface. This lower dose prescription translates into a total equivalent dose (EQD2) of approximately 36 Gy to the vaginal mucosal surface. Previously published results from our institution have demonstrated that this regimen appeared safe and effective [8], and resulted in significantly improved vaginal control when compared to outcomes of patients with localized USC who received chemotherapy alone [5].\n\nChemotherapy for USC has since evolved, and for the past 15 years, six cycles of adjuvant carboplatin-paclitaxel (C/T) chemotherapy has become standard. The IVB prescription dose at our institution for patients treated with this chemotherapy regimen has remained 2 fractions of 7 Gy prescribed at 0.5 cm depth. In this report, we present the 5-year clinical outcomes of patients with early stage (FIGO 2009 Stage I-II) USC treated at our institution from 2000-2010 with contemporary C/T chemotherapy and this unique brachytherapy regimen.\n\nMaterial and methods\nInstitutional Review Board approval was granted to perform a retrospective chart review of all patients with stage I-II USC treated at our institution in the years 2000-2010. Patients with advanced-stage disease, or those with early stage disease who had received single modality therapy, external beam RT, other brachytherapy fractionation, or chemotherapy regimen other than C/T were excluded. Additionally, patients with biopsy-proven cancer but without residual cancer in their hysterectomy specimens were excluded. Analysis was limited to patients who received all aspects of their multi-modal treatment at our academic medical center.\n\nAll patients had biopsy-proven endometrial cancer and underwent total hysterectomy with surgical staging. Pathology was reviewed by the institution's gynecologic pathologists prior to surgery. Chemotherapy consisted of carboplatin (AUC = 5-6) and paclitaxel (175 mg/m2) in all patients, given every 3 weeks for 6 cycles. Chemotherapy was typically initiated within 4-6 weeks from the time of surgery.\n\nIntra-vaginal brachytherapy was delivered via a high-dose-rate Ir-192 source. Patients were fit with a vaginal cylinder (size ranging from 2.6-3.0 cm) at the time of radiation consultation. A dose of 14 Gy in 2 fractions (7 Gy each) was prescribed to a depth of 0.5 cm from the vaginal cylinder surface. Active source length was standardized for all patients to six dwell positions, separated by 1 cm spacing, for an active length of 5 cm. All plans were created on a phantom with a 10 Ci nominal source, and dwell times were optimized to ensure a dose of roughly 10.5-11 Gy at the cylinder surface. CT-simulation was not performed, and normal tissue point doses were not recorded.\n\nIntra-vaginal brachytherapy was started early in the course of adjuvant treatment, typically with the first fraction delivered one week prior to and the second fraction one week following the second cycle of chemotherapy. Administering chemotherapy the same week as brachytherapy was avoided to decrease likelihood of overlapping toxicities. Patients were followed by routine clinical examination, Pap smears, and tumor markers every three months. Recurrences were identified radiographically or confirmed by biopsy. Based on review of physician-recorded toxicities listed in routine follow-up documentation, toxicity scores were assigned retrospectively with the Common Terminology Criteria for Adverse Events (CTCAE) v4.0.\n\nKaplan-Meier methods were used to estimate 5-year recurrence-free survival (RFS) and overall survival (OS). Time to recurrence, last follow-up, and/or death was calculated from the date of hysterectomy. Log-rank test was employed to identify patient, tumor, and treatment characteristics associated with RFS and OS. Given the small sample size and paucity of events, a multivariate analysis was not performed. IBM SPSS Statistics v19.0 was used for all statistical analyses.\n\nResults\nFifty-six patients were identified with FIGO 2009 stage I-II USC treated from 2000-2010 with adjuvant C/T chemotherapy along with 2 fractions of IVB (7 Gy each). The majority had undergone comprehensive surgical staging including pelvic dissection (96%, median nodes removed = 18, range: 6-47), para-aortic dissection (80%, median nodes removed = 3, range: 1-37), omentectomy, and peritoneal cytology (93%). The median age was 66 (range: 47-81). According to FIGO 2009 staging, 42 patients (73%) were stage IA, 18% were stage IB, and 9% were stage II. Of the IA patients, 14 (33%) had disease confined to the endometrium, and 28 (67%) had IA invasive disease. Among the entire cohort, 21% had myometrial invasion ≥ 50%, and 29% had lymph-vascular space involvement. Forty percent of tumors consisted of USC mixed (more than 10% USC) with other endometrioid or high grade histologies. Cytology was positive in 2 patients (4%). Patient and tumor characteristics are detailed in Table 1.\n\n\nTable 1 Patient and tumor characteristics (n = 56)\n\nCharacteristic\tLevel\t% (n)\t\nAge\tMedian (range)\t66 (47-81)\t\nAge ≥ 70\tYes\t32 (18)\t\nRace\tCaucasian\nAfrican American\nUnknown/Other\t70 (39)\n20 (11)\n10 (6)\t\nObese (BMI ≥ 30)\tYes\t53 (29)\t\nSmoking history\tYes\t22 (12)\t\nOral contraceptive history\tYes\t36 (19)\t\nHistory of hormone replacement therapy\tYes\t6 (3)\t\nFamily history of cancer\tYes\t40 (22)\t\nHistology\tMixed USC/Other\nPure uterine\nserous carcinoma\t40 (22)\n60 (34)\t\nEndocervical glandular involvement\tYes\t16 (9)\t\nEndocervical stromal involvement\tYes\t9 (5)\t\nMyometrial invasion ≥ 50%\tYes\t21 (12)\t\nStage – FIGO 2009\tIA\nIB\nII\t73 (41)\n18 (10)\n9 (5)\t\nStage – FIGO 1988\tIA\nIB\nIC\nIIA\nIIB\nIIIA\t25 (13)\n41 (22)\n18 (10)\n7 (4)\n9 (5)\n4 (2)\t\nLymph-vascular space invasion\tYes\t29 (16)\t\nLower uterine segment involvement\tYes\t38 (20)\t\nCytology positive\tYes\t4 (2)\t\nAll 56 patients completed 2 IVB fractions, and 53 patients (95%) completed all 6 cycles of chemotherapy. The median time from surgery to first IVB fraction was 49 days (range: 30-113). The median follow-up time, calculated from the date of hysterectomy, was 49 months (range: 9-145). Acute toxicities were mild. Late toxicities (recorded > 90 days post-treatment) were as follows: forty-seven patients (84%) had no toxicities recorded. Three patients with disease recurrence had grade 2-3 gastrointestinal toxicities. One patient who was disease-free with a history of ulcerative colitis had grade 2 diarrhea and tenesmus. Two patients had grade 2 neuropathy, one patient had grade 2 phlebitis. One patient had grade 2 urinary incontinence. Two patients (3.6%) had grade 2 vaginal toxicities; one developed grade 2 vaginal stricture with banding, one was noted to have grade 2 vaginal atrophy.\n\nMedian survival time was not reached. The 5-year RFS and OS were 85% and 93%, respectively. Kaplan-Meier curves are shown in Figure 1 and Figure 2. Univariate results are shown in Table 2. Smoking history was associated with poorer OS (p = 0.008) and LVI (Lymph-vascular space invasion) was associated with poorer RFS (p = 0.003). Age > 70 had a borderline significant effect on OS (p = 0.062) and smoking had a borderline effect on RFS (p = 0.076). Depth of myometrial invasion ≥ 50% was significantly associated with both poorer RFS (p < 0.0001) and OS (p = 0.001). Among patients with ≥ 50% myometrial invasion, the 5-year RFS and OS was 47% and 72%, versus 94% and 97% for those with < 50% myometrial invasion.\n\n\nFig. 1 Overall survival – stage I-II uterine serous carcinoma (n = 56)\n\nFig. 2 Recurrence-free survival – stage I-II uterine serous carcinoma (n = 56)\n\nTable 2 Patient/tumor characteristics and univariate log-rank results for overall (OS) and relapse-free survival (RFS)\n\nCharacteristic\tOS, p-value\tRFS, p-value\t\nAge (≥ 70 vs. < 70)\t0.062\t0.132\t\nRace (Caucasian vs. other)\t0.716\t0.388\t\nObese (BMI ≥ 30 vs. < 30)\t0.249\t0.281\t\nSmoking history\t0.008\t0.076\t\nOral contraceptive history\t0.634\t0.182\t\nHistory of hormone replacement therapy\t0.575\t0.226\t\nFamily history of cancer\t0.502\t0.579\t\nHistology (pure USC vs. mixed)\t0.168\t0.551\t\nEndocervical glandular involvement\t0.530\t0.278\t\nEndocervical stromal involvement\t0.450\t0.768\t\nMyometrial invasion (≥ 50% vs. < 50%)\t0.001\t< 0.0001\t\nLymph-vascular space invasion\t0.971\t0.003\t\nLower uterine segment involvement\t0.388\t0.551\t\nCytology positive\t0.716\t0.587\t\nThe percentage of patients with recurrence was 14.3% (n = 8 patients). In all cases, the first site of failure was extra-pelvic. The median time to recurrence was 28.5 months (range: 16-69). Neither of the two patients with positive peritoneal cytology at diagnosis (old FIGO 1988 stage IIIA) developed recurrence. One patient with no myometrial invasion (old FIGO 1988 stage IA) developed recurrence. Sites of recurrence are shown in Table 3. The most common failure site was lung. The para-aortic region was involved in 2 patients and was an isolated failure site in 1 patient. There were no pelvic recurrences. There were no isolated vaginal recurrences, however, there was one vaginal apex recurrence at 19 months in a patient with simultaneous lung metastases. Thus, the 2-year vaginal RFS was 98%.\n\n\nTable 3 Stage I-II uterine serous carcinoma pattern of recurrence\n\nPatient number\tAge at diagnosis\tStage – FIGO 2009\tStage – FIGO 1988\tMyometrial invasion (≥ 50%)\tLVI\tSite of first recurrence\tTime from surgery to recurrence (months)\t\n1\t72\tIA\tIIA\t–\t+\tPericardium, cervical and supraclavicular nodes\t27\t\n2\t74\tIA\tIA\t–\tN/A\tLung, colon, and abdominal wall\t40\t\n3\t63\tIB\tIC\t+\t+\tLung\t16\t\n4\t81\tIB\tIC\t+\t+\tLung and vagina\t19\t\n5\t80\tIB\tIC\t+\t–\tLiver and lung\t24\t\n6\t67\tIB\tIC\t+\t+\tPeri-aortic nodes\t30\t\n7\t51\tIB\tIC\t+\t+\tPeri-aortic nodes and lung\t69\t\n8\t64\tII\tIIB\t+\t–\tLung, liver, carcinomatosis\t37\t\nDiscussion\nData concerning optimal IVB dose-fractionation in combination with chemotherapy for USC are lacking. The present report of 56 patients with surgically staged localized USC found that following aggressive surgery, an IVB dose of 14 Gy in two fractions prescribed to 5 mm depth (surface EQD2 ∼36 Gy) in combination with 6 cycles of C/T chemotherapy resulted in excellent disease control, acceptable toxicity, and very low rates of vaginal/pelvic failure. The 5-year RFS and OS were 85% and 93%, respectively. The 2-year vaginal RFS was 98%. These results do not appear inferior to those of standard-dose brachytherapy (18-21 Gy in 3 fractions prescribed at 0.5 cm, surface EQD2 ∼54 Gy) [9–12, 15, 17], and appear comparable to that achieved with other low-dose schema (24 Gy in 6 fractions, prescribed to vaginal surface, surface EQD2 ∼28 Gy) [13].\n\nFor endometrial cancer patients with endometrioid histology, there is evidence and growing interest in the concept that a lower vaginal surface dose may be as effective as the higher “classic” brachytherapy prescription dose. For example, one randomized trial from Sweden of 290 low-risk endometrial patients showed that excellent rates of vaginal control were achievable with six fractions of 2.5 Gy prescribed to 5 mm from the applicator surface (surface EQD2 ∼30 Gy) [18]. A randomized study sponsored by the PORTEC group (PORTEC-4) is investigating whether three fractions of 5 Gy prescribed at 5 mm (surface EQD2 ∼33 Gy) is non-inferior to three fractions of 7 Gy (surface EQD2 ∼54 Gy) [19]. However, patients with USC are specifically excluded from this protocol. We believe that further study of alternate dose schema in USC patients receiving chemotherapy is worthwhile. The incidence of grade 1-2 vaginal toxicity, including atrophy, shortening, and stenosis is approximately 35% when prescribing standard dose brachytherapy [19]. Concomitant chemotherapy may increase the incidence of vaginal dryness and discomfort in patients undergoing IVB [20], and furthermore, sexual dysfunction can be related to changes in body image associated with chemotherapy-induced menopause and hair loss. Therefore, lowering the dose to the vaginal mucosa in patients receiving chemotherapy may improve toxicity, however, to our knowledge, this concept has not yet been studied.\n\nIn the present series, there were no grade 3-4 vaginal toxicities, and grade 2 vaginal toxicities among the 56 patients were recorded in only two patients (3.6%), which is remarkably low, and compares favorably to the literature. However, it must be noted that due to the retrospective nature of this report, toxicity recording was not standardized, and thus grade 1-2 toxicities were likely under-reported. To truly assess a benefit of this lower dose regimen compared to standard-dose brachytherapy, particularly concerning vaginal toxicities, prospective, standardized recording of toxicities is required. This is a topic being investigated prospectively at our institution [21].\n\nThe pattern of recurrence of USC differs from that of its endometrioid counterpart, and abdominal/peritoneal recurrence is described in even clinical stage I disease [1, 2]. Support for platinum/taxane chemotherapy regimens with or without RT is mounting [5–7]. Critics of the use of RT in early stage USC might wonder, if two IVB fractions are as good as three, why not abandon RT completely. However, eliminating RT in early stage USC appears to result in very high rates of vaginal recurrence [5, 22, 23]. In one study of 74 stage I USC patients who were surgically staged, none of 43 patients who received radiation to the vaginal cuff recurred locally, however, six of the 31 (19%) patients who were not treated with vaginal radiation recurred at the vaginal cuff [5]. In another report of 60 USC (and other unfavorable histology) patients who had adjuvant radiation therapy, one had a recurrence at the vaginal apex, whereas of the 65 patients who did not have adjuvant radiation, 8 had a local-regional recurrence, which included 3 with a vaginal only recurrence, 1 vaginal, and pelvic recurrence and 4 had pelvic recurrence [22]. Further, in an investigation of the pattern of failure among 23 early stage USC patients, of those treated without RT, five of nine failures were within the pelvis, of which 4 relapsed in the vagina; however, there were no pelvic failures in women treated with adjuvant RT [23]. Thus, although the optimal IVB dose fractionation scheme for treatment of patients with early stage USC is not known, the current available data do support the importance of multi-modality therapy including comprehensive surgery [24], chemotherapy [6, 7], and RT [5, 22, 23].\n\nThere is a lack of clear evidence concerning the preferred radiotherapy approach for USC; thus adjuvant radiotherapy practices for early stage USC continue to vary by country and by institution. Some believe that IVB alone may be inadequate due to risk of non-vaginal pelvic recurrences, and therefore tumor-directed pelvic RT in combination with chemotherapy is practiced by many. For example, at MD Andersen Cancer Center, pelvic radiotherapy in combination with paclitaxel resulted in 5-year PFS of 83% among stage I-IIIA USC patients [25]. Yet other institutions have supported IVB in favor of pelvic RT due to its favorable side effect profile and the predilection of USC for distant relapse. For example, at Memorial Sloan-Kettering Cancer Center, a retrospective analysis of 77 early stage USC patients treated with IVB without pelvic RT (majority also receiving chemotherapy) found 5-year pelvic recurrence of 6%. These authors concluded that this rate was not high enough to justify routine use of pelvic RT in this population [26]. More insight into optimal radiotherapy and chemotherapy combinations for this rare disease, both with respect to disease control as well as toxicity, will likely emerge once data mature from the recently accrued GOG 249 (pelvic RT versus IVB + chemo) and ongoing PORTEC-3 (pelvic RT versus pelvic RT + chemo) trials, both of which include USC patients within the study populations.\n\nWhile the results of our early stage USC cohort were excellent overall, the majority of patients (73%) had stage IA disease. On closer analysis, stage IB patients appear to fare less well, with a 5-year RFS of 47% for those with deep myometrial invasion. The association of stage IB with relatively high risk of extra-pelvic failures is in agreement with multiple other studies [8, 24, 26, 27]. A recent population-based study from British Columbia, which studied pelvic RT in combination with 3 cycles of C/T chemotherapy [27] found a 5-year disease-free survival of 48.5% for patients with stage IB disease, and a majority of the recurrences were extra-pelvic. The application of more targeted therapies to treat USC, even in uterine-confined disease with deep myometrial invasion, may be needed.\n\nIn our series, there was a single patient who had experienced a vaginal failure. This patient had numerous risk factors for recurrence including > 50% depth myometrial invasion and lymph-vascular space involvement, as well as simultaneous lung metastases, as shown in Table 3. Whether the vaginal relapse may have been prevented had a higher dose of brachytherapy and/or pelvic radiotherapy been utilized is not known. Overall, the 2-year vaginal failure rate of 2% in this series appears comparable to that of similar cohorts of early stage USC and/or high-risk endometrial patients, which have used a median dose of 21-Gy in 3 fractions, and reported 2-5 year vaginal failure rates of 2-4% [10–12, 15, 26]. Direct comparison, however, is not possible given the heterogeneity of stages (percentage stage IA versus IB) and histologies (pure USC versus mixed).\n\nOur study has several important limitations. It is not randomized, and there is no comparison group. In addition, the cohort of patients studied is small, although comparable to other publications reporting on this rare disease. It is important to note that all patients in this series were treated with comprehensive aggressive staging by experienced gynecologic oncologists, and therefore this regimen may not be satisfactory for women who have had less aggressive surgery. Furthermore, the population described had all received C/T chemotherapy, and hence the use of 2 fractions of 7 Gy as described in this report may not be appropriate for women with other chemotherapy regimens, fewer than 6 cycles of chemotherapy, or non-serous histology. Moreover, given that, a majority of patients in this series (79%) had < 50% myometrial invasion, our findings may not be generalizable to patients with stage IB or higher disease. Also, caution should be used in applying this regimen when using cylinder sizes smaller than 2.6 cm, due to the relatively high fractional surface dose to the mucosa with this regimen. Lastly, given the retrospective nature of the study, information on vaginal toxicity was not recorded consistently. An ongoing prospective investigation at our institution examines whether this reduced-dose IVB regimen is associated with improved toxicity compared to more standard IVB schema.\n\nConclusions\nDebate continues concerning the preferred radiotherapy approach for early stage USC. In our series, when combined with contemporary chemotherapy, adjuvant HDR IVB delivered as 2 fractions of 7 Gy prescribed at a depth of 0.5 cm resulted in excellent vaginal/pelvic control rates for localized USC. Further study of brachytherapy technique in USC investigating the optimal dose, number of fractions, time interval between fractions, and when to schedule with chemotherapy is warranted.\n\nDisclosure\nAuthors report no conflict of interest.\n==== Refs\nReferences\n1 Hendrickson M Ross J Eifel P Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma The Am J Surg Pathol 1982 6 93 108 \n2 Boruta DM Gehrig PA Fader AN Management of women with uterine papillary serous cancer: a Society of Gynecologic Oncology (SGO) review Gynecol Oncol 2009 115 142 153 19592079 \n3 Sutton G Axelrod JH Bundy BN Adjuvant whole abdominal irradiation in clinical stages I and II papillary serous or clear cell carcinoma of the endometrium: a phase II study of the Gynecologic Oncology Group Gynecol Oncol 2006 100 349 354 16213007 \n4 Martinez AA Weiner S Podratz K Improved outcome at 10 years for serous-papillary/clear cell or high-risk endometrial cancer patients treated by adjuvant high-dose whole abdomino-pelvic irradiation Gynecol Oncol 2003 90 537 546 13678721 \n5 Kelly MG O'Malley DM Hui P Improved survival in surgical stage I patients with uterine papillary serous carcinoma (UPSC) treated with adjuvant platinum-based chemotherapy Gynecol Oncol 2005 98 353 359 16005947 \n6 Goldberg H Miller RC Abdah-Bortnyak R Outcome after combined modality treatment for uterine papillary serous carcinoma: a study by the Rare Cancer Network (RCN) Gynecol Oncol 2008 108 298 305 18096209 \n7 Fader AN Drake RD O'Malley DM Platinum/taxane- based chemotherapy with or without radiation therapy favorably impacts survival outcomes in stage I uterine papillary serous carcinoma Cancer 2009 115 2119 2127 19306417 \n8 Turner BC Knisely JP Kacinski BM Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy Int J Rad Oncol Biol Phys 1998 40 77 84 \n9 Alektiar KM Makker V Abu-Rustum NR Concurrent carboplatin/paclitaxel and intravaginal radiation in surgical stage I-II serous endometrial cancer Gynecol Oncol 2009 112 142 145 19019418 \n10 Kiess AP Damast S Makker V Five-year outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I-II papillary serous endometrial cancer Gynecol Oncol 2012 127 321 325 22850412 \n11 Barney BM Petersen IA Mariani A The role of vaginal brachytherapy in the treatment of surgical stage I papillary serous or clear cell endometrial cancer Int J Rad Oncol Biol Phys 2013 85 109 115 \n12 Eldredge-Hindy HB Eastwick G Anne PR Adjuvant vaginal cuff brachytherapy for high-risk, early stage endometrial cancer J Contemp Brachytherapy 2014 6 262 270 25337127 \n13 Townamchai K Berkowitz R Bhagwat M Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer Gynecol Oncol 2013 129 18 21 23262378 \n14 Small W Jr Beriwal S Demanes DJ American Brachy-therapy Society consensus guidelines for adjuvant vaginal cuff brachytherapy after hysterectomy Brachytherapy 2012 11 58 67 22265439 \n15 Landrum LM Nugent EK Zuna RE Phase II trial of vaginal cuff brachytherapy followed by chemotherapy in early stage endometrial cancer patients with high-intermediate risk factors Gynecol Oncol 2014 132 50 54 24219982 \n16 Nag S Gupta N A simple method of obtaining equivalent doses for use in HDR brachytherapy Int J Rad Oncol Biol Phys 2000 46 507 513 \n17 DuBeshter B Estler K Altobelli K High-dose rate bra-chytherapy for Stage I/II papillary serous or clear cell endometrial cancer Gynecol Oncol 2004 94 383 386 15297176 \n18 Sorbe B Straumits A Karlsson L Intravaginal high-dose-rate brachytherapy for stage I endometrial cancer: a randomized study of two dose-per-fraction levels Int J Rad Oncol Biol Phys 2005 62 1385 1389 \n19 http://www.msbi.nl/promise/Projects/PORTEC4.aspx , last accessed 03/02/2014. \n20 Vakilian S Al-Suhaibani A Bahoric B What causes vaginal stenosis in patients undergoing adjuvant intracavitary brachytherapy for endometrial cancer? Proceedings of the 53rd Annual ASTRO Meeting. Abstract 2553 Int J Rad Oncol Biol Phys 2011 81 S475 \n21 Park HS Ratner E Lucarelli L Predictors of vaginal stenosis following intra-vaginal high-dose-rate brachytherapy for endometrial carcinoma. Proceedings of the 55th Annual ASTRO Meeting. Abstract 240 Int J Rad Oncol Biol Phys 2014 90 S111 \n22 Ly D Rowley BD Dodson MK Adjuvant radiation in early stage, unfavorable histology endometrial carcinoma is associated with improved local control and survival Gynecol Oncol 2014 133 250 255 24589416 \n23 Mehta N Yamada SD Rotmensch J Outcome and pattern of failure in pathologic stage I-II papillary serous carcinoma of the endometrium: implications for adjuvant radiation therapy Int J Rad Oncol Biol Phys 2003 57 1004 1009 \n24 Slomovitz BM Burke TW Eifel PJ Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases Gynecol Oncol 2003 91 463 469 14675663 \n25 Jhingran A Ramondetta LM Bodurka DC A prospective phase II study of chemoradiation followed by adjuvant chemotherapy for FIGO stage I-IIIA (1988) uterine papillary serous carcinoma of the endometrium Gynecol Oncol 2013 129 304 309 23385150 \n26 Desai NB Kiess AP Kollmeier MA Patterns of relapse in stage I-II uterine papillary serous carcinoma treated with adjuvant intravaginal radiation (IVRT) with or without chemotherapy Gynecol Oncol 2013 131 604 608 24055615 \n27 van der Putten LJ Hoskins P Tinker A Population- based treatment and outcomes of Stage I uterine serous carcinoma Gynecol Oncol 2014 132 61 64 24219983\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2081-2841",
"issue": "7(1)",
"journal": "Journal of contemporary brachytherapy",
"keywords": "brachytherapy; chemotherapy; endometrial cancer; papillary serous",
"medline_ta": "J Contemp Brachytherapy",
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"nlm_unique_id": "101506276",
"other_id": null,
"pages": "35-40",
"pmc": null,
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"pubdate": "2015-02",
"publication_types": "D016428:Journal Article",
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"title": "High-dose-rate vaginal brachytherapy with chemotherapy for surgically staged localized uterine serous carcinoma.",
"title_normalized": "high dose rate vaginal brachytherapy with chemotherapy for surgically staged localized uterine serous carcinoma"
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"abstract": "OBJECTIVE\nThe case of a patient whose International Normalized Ratio (INR) became elevated due to a probable interaction between ceftaroline and warfarin is reported.\n\n\nCONCLUSIONS\nA 65-year-old African-American man developed an INR of >18.0 after completing 12 days of ceftaroline therapy for the treatment of cellulitis while taking warfarin therapy. The patient was on warfarin due to his history of deep vein thrombosis of a lower extremity and pulmonary embolism, and his INR was consistently therapeutic for approximately 2 years before ceftaroline therapy. The patient reported no known drug allergies, had no history of adverse drug reactions, and had no recent changes in medications or diet. Phytonadione was administered, and the patient's INR began to decrease, returning to a therapeutic range of 2.30 after approximately 48 hours, at which time warfarin was restarted. After six days of hospitalization, the patient was discharged on his previous regimen of warfarin 7.5 mg orally once daily, with a therapeutic INR of 2.11. His cellulitis had resolved, so no further antibiotic therapy was warranted. To determine the likelihood of the drug interaction between warfarin and ceftaroline in this patient, the Drug Interaction Probability Scale of Horn and colleagues was applied and yielded a score of 6, indicating a probable likelihood of an interaction. Rechallenge was not attempted, as the patient's cellulitis had resolved and there were no evident signs or symptoms of infection.\n\n\nCONCLUSIONS\nA 65-year-old man experienced an increase in INR values after the addition of ceftaroline to his medication regimen.",
"affiliations": "Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, and Department of Pharmacy, Henry Ford Hospital, Detroit, MI (nadamfarhat@gmail.com).;Department of Pharmacy, Henry Ford Hospital, Detroit, MI.;Department of Pharmacy, Henry Ford Hospital, Detroit, MI.",
"authors": "Farhat|Nada M|NM|;Hutchinson|Lisa S|LS|;Peters|Michael|M|",
"chemical_list": "D000925:Anticoagulants; D002511:Cephalosporins; C490727:T 91825; D014859:Warfarin",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp140897",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "73(2)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D002511:Cephalosporins; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004417:Dyspnea; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D014859:Warfarin",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "56-9",
"pmc": null,
"pmid": "26721534",
"pubdate": "2016-01-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Elevated International Normalized Ratio values in a patient receiving warfarin and ceftaroline.",
"title_normalized": "elevated international normalized ratio values in a patient receiving warfarin and ceftaroline"
} | [
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"companynumb": "US-ZYDUS-010023",
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"activesubstancename": "VANCOMYCIN"
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{
"abstract": "A 35-year-old woman with severe cystic fibrosis was admitted for sudden loss of strength in both legs, revealing a myelitis. The medullary lesion biopsy revealed phaeohyphomycosis caused by Cladophialophora species. Myelitis caused by Cladophialophora bantiana is a rare disease associated with high mortality.",
"affiliations": "Cystic Fibrosis Adult Referral Care Center, Department of Internal Medicine, Hospices Civils de Lyon, Université de Lyon, Lyon, France.;Institut de Parasitologie et de Mycologie médicale, Hospices Civils de Lyon, Lyon, France.;Cystic Fibrosis Adult Referral Care Center, Department of Internal Medicine, Hospices Civils de Lyon, Université de Lyon, Lyon, France.;Cystic Fibrosis Adult Referral Care Center, Department of Internal Medicine, Hospices Civils de Lyon, Université de Lyon, Lyon, France.;Institut de Parasitologie et de Mycologie médicale, Hospices Civils de Lyon, Lyon, France.;Service de Maladie Infectieuses et Tropicales, Hospices Civils de Lyon, Lyon, France.;Service de Pneumologie, Hopital Foch, Paris, France.;Cystic Fibrosis Adult Referral Care Center, Department of Internal Medicine, Hospices Civils de Lyon, Université de Lyon, Lyon, France.",
"authors": "Reynaud|Quitterie|Q|http://orcid.org/0000-0002-7055-053X;Dupont|Damien|D|http://orcid.org/0000-0002-6992-1073;Nove-Josserand|Raphaële|R|;Durupt|Stephane|S|;Persat|Florence|F|;Ader|Florence|F|;Grenet|Dominique|D|;Durieu|Isabelle|I|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12789",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "19(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "\nCladophialophora bantiana\n; cystic fibrosis; fungal myelitis; immunosuppression; pulmonary transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001203:Ascomycota; D001706:Biopsy; D002555:Cerebrospinal Fluid; D003550:Cystic Fibrosis; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016040:Lung Transplantation; D008279:Magnetic Resonance Imaging; D009187:Myelitis; D060446:Phaeohyphomycosis; D035583:Rare Diseases; D013116:Spinal Cord",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28994224",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rare and unusual presentation of Cladophialophora infection in a pulmonary transplant cystic fibrosis patient.",
"title_normalized": "rare and unusual presentation of cladophialophora infection in a pulmonary transplant cystic fibrosis patient"
} | [
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"companynumb": "FR-MYLANLABS-2017M1082144",
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"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
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"abstract": "Granulocyte colony-stimulating factor (GCSF) is currently the most widely used cytokine for stem cell mobilization. There are few studies suggesting GCSF administration may induce activation of both coagulation and endothelial cells that could favor the developing of thrombotic events. We report a 58-year-old female with vasculitis and renal impairment. She was found to have an underlying monoclonal gammopathy of unknown significance (MGUS). The monoclonal protein was felt to play a role in her underlying renal disease and peripheral neuropathy. She was considered a candidate for peripheral blood stem cell transplantation to manage the monoclonal protein. During stem cell mobilization with GCSF, she developed worsening of anemia; thrombocytopenia and worsening of renal function. She was diagnosed with thrombotic microangiopathy (TMA) which was successfully treated with therapeutic plasma exchange and rituximab. It is possible that GCSF may have directly (activating endothelial cells) or indirectly (activation of underlying autoimmune disorder) contributed to TMA in this patient.",
"affiliations": "Division of Hematology, Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, Minnesota, USA. naina.harris@mayo.edu",
"authors": "Naina|Harris V K|HV|;Gertz|Morie A|MA|;Elliott|Michelle A|MA|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1002/jca.20216",
"fulltext": null,
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"issn_linking": "0733-2459",
"issue": "24(6)",
"journal": "Journal of clinical apheresis",
"keywords": null,
"medline_ta": "J Clin Apher",
"mesh_terms": "D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance; D036102:Peripheral Blood Stem Cell Transplantation; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "8216305",
"other_id": null,
"pages": "259-61",
"pmc": null,
"pmid": "19877288",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Thrombotic microangiopathy during peripheral blood stem cell mobilization.",
"title_normalized": "thrombotic microangiopathy during peripheral blood stem cell mobilization"
} | [
{
"companynumb": "US-AMGEN-USASP2020179343",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"activesubstancename": "FILGRASTIM"
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... |
{
"abstract": "A 42-year-old woman with mixed connective tissue disease-associated interstitial lung disease underwent bilateral lung transplantation. She had an uneventful surgery and was extubated 3 h later. Induction immunosuppression therapy included methylprednisolone 500 mg intraoperatively, basiliximab (anti-IL-2 monoclonal antibody) on days 0 and 4 after transplantation, and methylprednisolone 125 mg intravenously bid for 2 days following surgery. Maintenance immunosuppression therapy consisted of prednisone 20 mg daily, mycophenolate mofetil 750 mg bid, and enteral tacrolimus 0.5 mg bid. Both the donor and the recipient were seropositive for cytomegalovirus. Infectious disease prophylaxis consisted of valganciclovir, trimethoprim-sulfamethoxazole, and voriconazole.",
"affiliations": "Division of Pulmonary Critical Care and Sleep Medicine, University of Florida, Gainesville, FL.;Division of Pulmonary Critical Care and Sleep Medicine, University of Florida, Gainesville, FL.;Division of Pulmonary Critical Care and Sleep Medicine, University of Florida, Gainesville, FL.;Division of Pulmonary Critical Care and Sleep Medicine, University of Florida, Gainesville, FL.;Division of Thoracic and Cardiovascular Surgery, University of Florida, Gainesville, FL.;Division of Pulmonary Critical Care and Sleep Medicine, University of Florida, Gainesville, FL. Electronic address: amir.emtiazjoo@medicine.ufl.edu.",
"authors": "Biswas|Abhishek|A|;Ataya|Ali|A|;Salgado|Juan C|JC|;Chandrasekharan|Satish|S|;Machuca|Tiago N|TN|;Emtiazjoo|Amir M|AM|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.chest.2016.09.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3692",
"issue": "151(3)",
"journal": "Chest",
"keywords": null,
"medline_ta": "Chest",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000740:Anemia; D065766:Atypical Hemolytic Uremic Syndrome; D001803:Blood Transfusion; D004452:Echocardiography; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D020244:Infarction, Middle Cerebral Artery; D017563:Lung Diseases, Interstitial; D016040:Lung Transplantation; D008279:Magnetic Resonance Imaging; D008947:Mixed Connective Tissue Disease; D011183:Postoperative Complications; D012769:Shock; D020521:Stroke; D013921:Thrombocytopenia",
"nlm_unique_id": "0231335",
"other_id": null,
"pages": "e63-e68",
"pmc": null,
"pmid": "28279287",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A 42-Year-Old Woman With Anemia, Shock, and Ischemic Stroke After Lung Transplantation.",
"title_normalized": "a 42 year old woman with anemia shock and ischemic stroke after lung transplantation"
} | [
{
"companynumb": "US-ACCORD-052481",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"drugauthorization... |
{
"abstract": "Longitudinal whole-body PET-CT scans with F-18-fluorodeoxyglucose (18F-FDG) in patients suffering from metastatic melanoma were analyzed and the tracer distribution in patients was compared with that of healthy controls. Nineteen patients with metastatic melanoma were scanned before, after two and after four cycles of treatment with PD-1 inhibitors (pembrolizumab, nivolumab) applied as monotherapy or as combination treatment with ipilimumab. For comparison eight healthy controls were analyzed. As quantitative measures for the comparison between controls and patients, the nonlinear fractal dimension (FD) and multifractal spectrum (MFS) were calculated from the digitized PET-CT scans. The FD and MFS measures, which capture the dispersion of the tracer in the body, decreased with disease progression, since the tracer particles tended to accumulate around metastatic sites in patients, while the measures increased when the patients' clinical condition ameliorate. The MFS measure gave better predictions and were consistent with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while FD agreed in 77% of all cases. These results agree, qualitatively, with a previous study of our group when treatment with ipilimumab monotherapy was considered.",
"affiliations": "Institute of Nanoscience and Nanotechnology, National Center for Scientific Research \"Demokritos\", 15341 Athens, Greece.;Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, 69120 Heidelberg, Germany.;Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, 69120 Heidelberg, Germany.;School of Electrical and Computer Engineering, National Technical University of Athens, 15780 Athens, Greece.;Department of Dermatology and National Center for Tumor Disease, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, 69120 Heidelberg, Germany.;Institute of Nanoscience and Nanotechnology, National Center for Scientific Research \"Demokritos\", 15341 Athens, Greece.",
"authors": "Kosmou|Anastasia|A|;Sachpekidis|Christos|C|;Pan|Leyun|L|;Matsopoulos|George K|GK|;Hassel|Jessica C|JC|0000-0001-7575-6230;Dimitrakopoulou-Strauss|Antonia|A|0000-0003-0338-9472;Provata|Astero|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13205170",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13205170\ncancers-13-05170\nArticle\nFractal and Multifractal Analysis of PET-CT Images for Therapy Assessment of Metastatic Melanoma Patients under PD-1 Inhibitors: A Feasibility Study\nKosmou Anastasia 12\nSachpekidis Christos 3\nPan Leyun 3\nMatsopoulos George K. 2\nhttps://orcid.org/0000-0001-7575-6230\nHassel Jessica C. 4\nhttps://orcid.org/0000-0003-0338-9472\nDimitrakopoulou-Strauss Antonia 3\nProvata Astero 1*\nEzziddin Samer Academic Editor\nGrisanti Salvatore Academic Editor\nKast W. Martin Academic Editor\n1 Institute of Nanoscience and Nanotechnology, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece; anast.kosmou@gmail.com\n2 School of Electrical and Computer Engineering, National Technical University of Athens, 15780 Athens, Greece; gmatso@esd.ece.ntua.gr\n3 Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, 69120 Heidelberg, Germany; c.sachpekidis@dkfz-heidelberg.de (C.S.); l.pan@dkfz-heidelberg.de (L.P.); ads@ads-lgs.de (A.D.-S.)\n4 Department of Dermatology and National Center for Tumor Disease, University Hospital Heidelberg, 69120 Heidelberg, Germany; Jessica.Hassel@med.uni-heidelberg.de\n* Correspondence: a.provata@inn.demokritos.gr; Tel.: +30-21065-03964\n15 10 2021\n10 2021\n13 20 517021 7 2021\n08 10 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nThe fractal dimension (FD) and the multifractal spectrum (MFS) are nonlinear quantitative measures which express the heterogeneity in the distribution of the tracer, F-18-fluorodeoxyglucose, (18F-FDG), in the body of patients suffering from metastatic melanoma. Given the well-documented, high accumulation of the tracer in tumor/metastatic sites, the measures expressing the tracer distribution also express the extent of metastases in the body. As such, FD and MFS can be employed to detect the presence of melanoma and to monitor the therapeutic outcome using the PET-CT follow-up digitized scans of the patients. In the present study, the FD and MFS measures of patients are evaluated before and during treatment with PD-1 inhibitors and are compared with the corresponding values of healthy controls. The MFS predictions agree with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while the FD agrees in 77% of all cases. Therefore, the quantitative MFS is proposed as an additional, alternative biomarker for monitoring the immunotherapy outcome in melanoma patients, after treatment with PD-1 inhibitors.\n\nAbstract\n\nLongitudinal whole-body PET-CT scans with F-18-fluorodeoxyglucose (18F-FDG) in patients suffering from metastatic melanoma were analyzed and the tracer distribution in patients was compared with that of healthy controls. Nineteen patients with metastatic melanoma were scanned before, after two and after four cycles of treatment with PD-1 inhibitors (pembrolizumab, nivolumab) applied as monotherapy or as combination treatment with ipilimumab. For comparison eight healthy controls were analyzed. As quantitative measures for the comparison between controls and patients, the nonlinear fractal dimension (FD) and multifractal spectrum (MFS) were calculated from the digitized PET-CT scans. The FD and MFS measures, which capture the dispersion of the tracer in the body, decreased with disease progression, since the tracer particles tended to accumulate around metastatic sites in patients, while the measures increased when the patients’ clinical condition ameliorate. The MFS measure gave better predictions and were consistent with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while FD agreed in 77% of all cases. These results agree, qualitatively, with a previous study of our group when treatment with ipilimumab monotherapy was considered.\n\nmetastatic melanoma\nPET-CT imaging\nnivolumab\npembrolizumab\nipilimumab\nfractal dimensions\nmultifractal spectrum\n==== Body\npmc1. Introduction\n\nRecent advances in immunotherapy have revolutionized cancer therapy and offer the possibility to activate the immune system against cancer cells. In particular, the use of immune checkpoint inhibitors (ICI) showed a dramatic improvement in the management of patients with metastatic melanoma leading in higher response rates and a prolongation of patient survival [1,2]. ICI treatment started with the use of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor ipilimumab, an antibody with response rates between 10% and 15% and long-term survival of approximately 20% [3,4]. In 2014, two programmed cell death protein (PD-1) inhibitors, pembrolizumab and nivolumab, were approved by the Food and Drug Administration and were then used as a monotherapy or in combination with ipilimumab. Larkin et al. reported on a median overall survival of more than 60.0 months for the combined use of nivolumab plus ipilimumab as compared with 36.9 months for nivolumab monotherapy and 19.9 months for ipilimumab monotherapy. Overall, survival at 5 years was 52% for the combination of nivolumab and ipilimumab, 44% for nivolumab and 26% for ipilimumab [5].\n\nDespite these advances in melanoma treatment, a significant percentage of patients—approximately 40–60%—do not respond to ICI [2]. Furthermore, ICI treatment demonstrates different response patterns than conventional chemotherapy due to the fact that inflammation is generated through the T-cell activation rather than tumor lysis. In particular, ICI treatment can lead to atypical response patterns, like pseudoprogression (initial increase in tumor burden followed by a decrease), hyperprogression (rapid disease progression with very poor survival), dissociated response (regression of some lesions and appearance of new lesions) and late response after therapy discontinuation. All these challenges underline the need for dedicated biomarkers that can reliably and early serve ICI treatment monitoring on a personalized basis. Imaging, in particular with hybrid techniques, like PET-CT plays an important role for immunotherapy monitoring [6].\n\nFor the assessment of the therapeutic outcome of ICI therapy 18F-FDG PET-CT can be used with good results [7,8,9,10,11,12,13]. For that purpose, a baseline PET-CT study as well as follow-up studies during treatment need to be obtained. The traditional evaluation of the PET images is based on standard Volume of Interest (VOI) based techniques and on the calculation of standardized uptake values (SUV) in the tumors and reference areas [14]. New approaches include not only linear measures of tracer uptake, like SUV calculations, but also nonlinear ones, like fractal dimensions-FD, correlation dimensions -CD, and multifractal spectrum—MFS or combinations of them [15,16,17].\n\nIn a previous analysis of our group, we studied a cohort of 31 patients suffering from metastatic melanoma under treatment with ipilimumab monotherapy [17]. The main outcome of that study was that the fractal dimension and the multifractal moments decrease as the metastases progress in the body of the patient in terms of nonresponse. The explanation of this effect is the following: In absence of metastases the tracer particles spread homogeneously in the body and thus the tracer covers uniformly the 3D space of the body (with few exceptions related to regular uptake from organs). When tumorous lesions are present, the tracer concentrates in a subspace of the 3D space, and the fractal and multifractal measures capture exactly the dimensionality of the subspace where the tracer is dispersed. Because the cancerous cells, as well as the tracer particles, travel through the body via the circulatory or the lymphatic system, it is expected that the fractal dimension Df of the metastatic melanoma, in its most extensive form, could reach values close to Df = 2.7, which are the fractal dimensions of the circulatory system as already reported in 1977 by Mandelbrot [15] and others [18,19,20,21,22].\n\nIn the present study the above ideas are further evaluated using a new cohort of patients under ICI treatment with different monoclonal antibodies, namely the PD-1 inhibitors nivolumab and pembrolizumab as well as the combination of nivolumab and ipilimumab. We use the FD and MFS nonlinear measures to record the extent of metastatic activity and evolution in melanoma patients during the stages of treatment with the different monoclonal antibodies. The current results agree qualitatively and qualitatively with the previous study where only ipilimumab monotherapy was employed. Namely, an increase of the FD and MFS measures indicates clinical amelioration of the patient while a decrease of the measures indicates clinical deterioration. The FD and MFS measures can then be used as additional biomarkers for monitoring the evolution of metastatic melanoma, independently of the medical treatment with the different monoclonal antibodies. Because of their high degree of correct evaluation of the melanoma evolution, it is proposed that the nonlinear measures can be used, on the one hand by the clinicians for taking into account in their assessments and, on the other hand, they can be added in the list of implemented biomarkers to increase of prediction ability of artificial intelligence (AI) medical evaluation algorithms.\n\nThe presentation of the work is organized as follows. In Section 2.1, the PET-CT data of all patients are presented, before and during treatment, together with their outcome according to the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) [8]. In the same section, the PET-CT data of the healthy controls are presented for comparative purposes. In Section 2.2, the definition of the FD and MFS measures as applied to the digitized PET-CT images are presented. Specific details on the FD and MFS measures and their calculations are provided in Appendix A, while particular examples are discussed in Appendix B and Appendix C. In Section 3, the results are presented. In particular, the FD and MFS measures of all controls and all patients at the different follow-up scans are reported. Moreover, the FD and MFS predictions are evaluated in comparison with both the patient outcome according to PERCIMT and the respective results derived from the controls. In Section 4, the impact of immune-related adverse events (irAEs) in PET-CT is discussed. Particular attention was paid to ICI-related colitis, since it may often cause diffuse 18F-FDG accumulation in the colon leading to false positive results in FD and MFS measures [17]. In the Discussion section, a previous study of metastatic melanoma and other related works are compared with the present approach and open problem are presented. Finally, in the Conclusions, the main results of this study are recapitulated.\n\n2. Materials and Methods\n\nIn the next Section 2.1, the PET-CT scans of patients and controls are presented, while in Section 2.2, the clinical evaluation of the patients is assessed in baseline and two follow-up PET-CT examinations. PET signs suggestive of irAEs as well as causes of non-specific tracer uptake are also discussed. In Section 2.3, the nonlinear FD and MFS measures are briefly presented and their implementation regarding the quantitative description of the extent of metastases is described.\n\n2.1. The PET-CT Data\n\nNineteen patients, indexed as P1, P2, P19, suffering from metastatic melanoma participated in this study. The age and sex of each patient are listed in Table 1, column 2. Each patient was scanned before treatment (baseline study), after two cycles of treatment with anti PD-1 antibodies (interim study) and once after four cycles of treatment (final study), see Table 1, column 3. Pembrolizumab was administered intravenously at a dose of 2 mg/kg every 3 weeks, and nivolumab was administered intravenously at a dose of 3 mg/kg every 2 weeks. The combination ICI therapy was administered as an induction of 4 cycles of nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) every 3 weeks, followed by single agent nivolumab administration (3 mg/kg) every 2 weeks. The included patients had not received chemotherapy for at least 1 month prior to the initial PET-CT studies. None of the patients had a history of diabetes. Patients gave written informed consent to participate in the study and to have their medical records released. The study was approved by the Ethical Committee of the University of Heidelberg and the Federal Agency for Radiation Protection (Bundesamt für Strahlenschutz). Part of these patients have been published elsewhere under different aspects [9,10].\n\nPatients underwent a whole-body PET-CT after intravenous administration of maximum 250 MBq 18F-FDG 60 min post-injection (p.i.). Imaging was performed from the head to the feet with an image duration of 2 min per bed position. A dedicated PET-CT system (Biograph mCT, S128, Siemens Co., Erlangen, Germany) with an axial field of view of 21.6 cm with TruePoint and TrueV, operated in a three-dimensional mode was used. A low-dose attenuation CT (120 kV, 30 mA) was used for attenuation correction of the PET data and for image fusion. All PET images were attenuation-corrected and an image matrix of (400 × 400) pixels was used for iterative image reconstruction. Iterative image reconstruction was based on the ordered subset expectation maximization (OSEM) algorithm with two iterations and 21 subsets as well as time of flight (TOF).\n\nThe patient outcome according to PERCIMT at the follow-up examinations is reported in the last column of Table 1. In particular, patient responses to ICI were classified as following: CMR: Complete Metabolic Response; PMR: Partial Metabolic Response; SMD: Stable Metabolic Disease; PMD: Progressive Metabolic Disease. The treatment is indicated for each patient in column 4 of the same Table. PET signs suggestive of irAEs as well as causes of non-specific tracer uptake are reported in column 5. Particular attention will be devoted in Section 4 in the case of colitis since it leads to false positive results in blind calculation of the fractal and multifractal measures, as will be explained in Section 4.\n\nFor comparative reasons the PET-CT scans of 8 healthy controls are also presented at the end of the same table. The controls are indexed H1, H2, H8. Only a single PET-CT study of the controls is available.\n\n2.2. Clinical Evaluation and Radiological irAEs\n\nThe PET-CT evaluation of the patients was based on the visual and quantitative evaluation of the images by two experienced nuclear medicine physicians (CS, ADS). The clinical outcome data regarding response to therapy were based on the PERCIMT criteria [8].\n\nOn the 5th column of Table 1, PET signs of irAEs as well as causes of non-specific tracer accumulation are presented, separately, for each patient. With regard to irAEs, these included radiologic signs of thyroiditis, colitis, bone marrow activation, arthritis, duodenitis, to list the most frequent ones. Among them, colitis is known to heavily affect the diagnostic ability of the FD and MFS measures. In the presence of radiologic colitis, the tracer demonstrates a diffuse accumulation in the colon, comparable to the accumulation in the metastases. For this reason, in the 2nd part of the study, Section 4, the cases of colitis are excluded from the statistics, since they always lead to false positive results due to immune related adverse effects.\n\nHigh tracer uptake, irrespective to the presence of tumorous lesions, is also recorded in the brain. To avoid this effect the brain regions are excluded from the calculations in all subjects and studies and only the areas from nose to toes are considered.\n\n2.3. The Fractal Dimension and the Multifractal Spectrum\n\nThe PET-CT images of the patients demonstrate the dispersion of the tracer 18F-FDG in the body and are valuable for tumor detection and staging since 18F-FDG has the tendency to concentrate in tumor lesions. In clinical practice, 18F-FDG images are evaluated visually and quantitatively using mostly the calculation of SUVs. The FD and MFS give additional quantitative measures of the tracer extension in the body, which also mirrors the lesion extension. Based on this alternative approach, one may evaluate the clinical deterioration or amelioration of the patient’s response to treatment, depending on the change of the FD and MFS measures of the patient.\n\nTo calculate the FD and the MFS we first digitize the PET-CT images extracting a 3D matrix which accounts for the local concentration of the tracer in the body. To this end, the Insight Segmentation and Registration Toolkit (ΙΤΚ) was used to transform the DICOM images extracted from the PET-CT scans into a 3D tracer concentration array C. The C-array comprises of 400 × 400 pixels for each planar scan and between 370–430 (without the brain) scans along the axial direction, depending on the patient. Approximately, each C-matrix comprises of 400 × 400 × 400 voxels. The voxel size then is 2 mm × 2 mm × 4 mm and this is the minimum elemental size used in the fractal and multifractal analyses. Besides the digitization with the ITK toolkit, we also used the package ImageJ to reduce the DICOM images to the ASCII form needed for the C-arrays (results not shown).\n\nThe 18F-FDG concentration C(i,j,k) in box at position (i,j,k) takes values 0 ≤ C(i,j,k) ≤ 255. In some cases, a threshold w is set on the concentration, which accounts for meaningful recording of 18F-FDG above the threshold and negligible concentration below it. In the present study, the threshold w = 1 was used, in order to take into account even the smallest 18F-FDG concentrations which could account for very small metastatic lesions. This threshold gave the best results and was the most consistent with the medical records.\n\nBased on the C(i,j,k) matrix which is directly extracted from the PET-CT data of the patients and controls, we apply the box-counting method to calculate the FD and MFS measures. The box counting technique consists in segmenting the 3D space of the body in boxes of different sizes s, and to calculate the number of boxes which contain 18F-FDG, as a function of s. A power law fitting to this data allows to directly extract the fractal dimension FD, as the exponent Df of the fit. The value of Df accounts for the fraction of the body which is covered by the 18F-FDG. For healthy controls Df takes high values <3. When Df increases between treatments then an improvement of the patient’s condition takes place (e.g., number and/or extension of metastatic sites decrease), whereas if Df decreases then the patient’s condition deteriorates (increased metastatic activity). The precise definition and calculation of the FD measure and details on the computation of Df are provided in Appendix A.\n\nTypical examples of FD calculations are shown in Figure 1. In this figure N(s) accounts for the number of 3D boxes of size s which contain the tracer, while N is the total number of boxes used in the calculations.\n\nFigure 1 depicts the normalized number of boxes N(s)/N as a function of the box size s, in a double logarithmic scale. The results concern Patient P9 at the three studies. The reference control H3 is also added, for comparison. The Df values of patient and control are reported on the figure. Note that the Df of the control is higher than the Df of the patient. This is consistent with the fact that the tracer splits more homogeneously in the 3D space of the control’s body, since there are no lesions which cause local concentrations of the tracer. Only specific organs are accumulating some amount of the tracer and that is why the calculated Df drops below 3 (takes value Df = 2.6225) even for the reference subjects. We note that the Df value for the patient, whose state is characterized as stable SMD, is consistently lower than the reference in all studies, and stays close to Df = 2.5. This means that the tracer is attracted and concentrates in the lesions, which cover a subspace lower than fractal dimensions in the case of the healthy control. Similar typical images for the cases of PMR and PMD are shown in Appendix B.\n\nTo present quantitative results on the clinical amelioration or deterioration of the patients’ conditions after treatment, we compare the FD values at the interim (j = 2) and final (j = 3) stages with the baseline stage (j = 1). Namely, if the fractal dimensions of the interim study Df(j = 2) or late study Df(j = 3) after ICI treatments are greater than the baseline study Df(j = 1), the patient’s improvement is recorded. In the opposite case, Df(j = 1) is greater than Df(j = 2) or Df(j = 3), patient’s deterioration is recorded. Finally, if |Df(j = 2) − Df(j = 1)| < 0.02 or |Df(j = 3) − Df(j = 1)| < 0.02, patient’s condition can be considered as stable between stages. The FD results on the patients and controls are presented in Section 3 and Table 2.\n\nFollowing the calculation of the FD measure, for the MFS measure the box-counting technique is also employed. After the segmentation of the body in boxes of size s, the moments Dq of integer order q, of the tracer distribution are calculated (q can take positive and negative values). The different q-moments provide details of the tracer dispersion in the body. Namely, the negative q-values represent the extent of small tracer concentrations, while the positive q-values correspond to high tracer concentrations. The precise definition of the moments and their calculation is provided in Appendix A.\n\nA typical MFS spectrum is provided in Figure 2, for −20 ≤ q ≤ +20. Here, the MFS spectrum of the reference control lies above those of the patient, similarly to FD behavior. The spectra of the patient are placed on top of one another, indicating a stable disease, without major influence by the treatment for the case of patient P12. Other typical MFS spectra of patients with PMR and PMD are presented in Appendix C.\n\nIt is worth noting here that the negative q-orders are enhanced by the very small (infinitesimal) local concentrations, which are accentuated when exponentiated on a negative power (see Appendix A). Therefore, negative q-exponents are important for detecting small tracer concentrations, which usually indicate the presence of small-size metastases, possibly non-visible by eye. On the other hand, large tracer concentrations are accentuated by positive q-orders, indicating either concentrations around tumors of large sizes, or concentrations around organs which accumulate 18F-FDG.\n\nRegarding the presence of 18F-FDG in specific organs, the tracer also accumulates in certain healthy tissues, which consume glucose, like the brain or the liver, and this should be considered in the evaluation. Note that the brain is already excluded, as discussed at the end of Section 2.2. Moreover, 18F-FDG is normally excreted by the urinary tract, leading to depiction of the kidneys, ureters and the urinary bladder. That is why it is useful to study the 18F-FDG dispersion comparatively, between patients and controls, since they all involve consumption of 18F-FDG in the healthy organs, but in additions the patients present further concentration in the metastatic lesions.\n\nWhile it is instructive to show the difference between healthy controls and patients at the different q-moments, as in Figure 2, it is also useful to define a unique, cumulative multifractal measure of clinical improvement/deterioration based on all moments. This cumulative measure ΔD(j) takes into account the difference of the moments Dq of the patient at stage j, from the baseline j = 1, [Dqj−Dq1]. These differences are averaged over many values of q, and the measure ΔD(j) is normalized. In the present study we average over 21 moments, −10 ≤ q ≤ 10, and we normalize accordingly as: ΔD(j)=∑q=−1010[Dqj−Dq1]/21. Further details on this cumulative measure are also provided in the Appendix A.\n\n3. Results\n\nIn this section, first the calculations of the FD are presented in subSection 3.1, followed by the calculations of the MFS in subSection 3.2. The results are briefly discussed at the end of each subsection, while a more extensive discussion follows in Section 5.\n\n3.1. Fractal Dimensions\n\nThe results on the FD for patients and controls are recapitulated in Table 2. In the 1st column the order number of the patients is shown in order to match with the data on Table 1. On the second column the study stage is indicated for each patient. On column 3, the FD of each patient calculated from the PET-CT data with w = 1, is recorded. The PET-irAEs and causes of non-specific tracer uptake, which may account for false positive/negative results, are provided in column 4, while the clinical evaluation of each patient follow-up PET-CT scans as a response to ICI is reported in column 5. The matching between clinical evaluation and FD results is indicated in the last column (YES = matching, NO = not matching).\n\nFor the controls, which are listed at the end of Table 2, only the fractal dimensions at the baseline (unique) study are recorded, together with their side effects.\n\nFrom the above results, the FD method matches the clinical results in 71.05% of the cases if the side-effects are not taken into account. Among the side-effects, the one which predominantly affects the tracer dispersion is colitis (see Table 1). If the cases where colitis is present are excluded, then the matching increases to 77.42%.\n\nApart from the fractal dimensions based on the box-counting method, the correlation dimensions were also estimated, and the results (not shown) were in agreement with the FD conclusions in Table 2.\n\n3.2. Multifractal Spectrum\n\nSimilar to the results on the FD presented in Section 3.1, here, the results on the MFS are recapitulated in Table 3. On the 3rd column of this table, the average multifractal index, <MFS>j, and the cumulative multifractal measure ΔD(j) are recorded of each patient and stage. For the calculations of these quantities see Section 2.3 and Appendix A. The PET-irAEs and causes of non-specific tracer uptake, as well as the patient’s clinical outcome are provided in columns 4 and 5, respectively. The matching between clinical evaluation and MFS results is indicated in the last column. For the controls listed at the end of Table 3, only the <MFS>1 is calculated.\n\nFrom the calculations of the MFS, the results match the clinical evaluation in 76.32% of the cases if the side-effects are not taken into account. If the cases of colitis (see Table 1) are excluded, then the matching increases to 80.65%. In both cases, with or without excluding colitis, the MFS confirms better the clinical evaluation than the FD measure.\n\n4. Side-Effects and the Case of Colitis\n\nAs discussed in the previous section, the presence of colitis perturbs the outcome of the FD and MFS measures because the tracer concentrates in the colon in addition to the accumulations on the metastases. In Figure 3a the PET-CT image of a metastatic melanoma patient with abnormal tracer uptake in the colon (P16) is depicted. For comparison, in Figure 3b the case of a patient (P14) with metastatic melanoma without radiological signs of side-effects as a response to the treatment is shown.\n\nVisual inspection of Figure 3a, (Patient P16) reveals increased uptake of the tracer in the colon area to a large extent, as compared to the Patient P14, in Figure 3b, where the 18F-FDG concentrates only in organs and metastatic lesions. When the FD and MFS measures are blindly applied, the uptake colon areas in Patient P16 are mistakenly considered as metastatic tissue, giving rise to false positive results. In this patient in the interim and final studies, the tracer spreads thoroughly in the body because of the colitis and as a result the FD and MFS measures increase, falsely indicating that the patients’ condition clinically ameliorates.\n\nThis is the reason why the results in Section 3 considerably improved when the cases of patients/stages with colitis were excluded from the statistics. As seen from Table 1 and Table 2, colitis was a side effect in 8/66 studies in all patients and controls.\n\nOther side-effects, such as thyroiditis, arthritis, muscular uptake and others (see Table 1), do not substantially contribute to the dispersion of the tracer and, to a good approximation, can be ignored.\n\n5. Discussion\n\nIn a previous study of our group [17], a different cohort of patients suffering from metastatic melanoma and controls were investigated. The cohort consisted of 2 healthy controls and 31 patients. The patients received four cycles of treatment with the monoclonal antibody ipilimumab as monotherapy and they were scanned at baseline, after two and after four treatment cycles. A similar fractal and multifractal analysis of the patients produced results comparable to the ones presented here. Namely, in 83% of the cases the nonlinear analysis results matched with the clinical outcome. Note that in [17] a different notation related to the outcome of the PET-CT visual interpretation was used: PR for partial remission, SD for stable disease, PD for progressive disease and MR for mixed response.\n\nThe outcome of the present study together with the previous results by Breki et al. [17], indicate that the nonlinear measures can be useful as biomarkers for metastatic cancers because they accentuate even the smallest local uptakes of the tracer (18F-FDG) on metastases of tiny sizes, not visible with the naked eye.\n\nFurther improvements of this method include:The computational exemption of organs, which accumulate or excrete the tracer. This is a major weakness of the present methods, and if solved, we could expect matching evaluations in over 95% of the cases. Possible methods from the domain of artificial intelligence may soon offer a solution to this problem.\n\nThe development of novel, more specific radiotracers which only accumulate to a markedly higher extent in the tumorous lesions rather than in the physiological tissues. Similarly to the previous case, we expect an important improvement of the matching between clinical evaluation and fractal/multifractal analysis if the non-pathological accumulation of the tracer can be excluded in one or the other way.\n\nThe use of PET-CT images of higher resolution. Such images could offer the possibility to extract more accurate FD and MFS measures. These measures in combination with conventional measures such as SUV, metabolic tumor volume (MTV), total lesion glycolysis (TLG) as well as the use of artificial intelligence (AI) algorithms for image segmentation may help to achieve a more precise evaluation of immunotherapy treatment response in the future.\n\n6. Conclusions\n\nThe fractal dimensions and the multifractal spectrum of the 18F-FDG tracer dispersion were studied in patients with metastatic melanoma before and after treatment with PD-1 inhibitors as monotherapy or in combination with the CTLA-4 inhibitor ipilimumab. The tracer distribution was extracted from the PET-CT scans of the patients after two and four cycles of treatment with nivolumab or pembrolizumab monotherapy or a combination of nivolumab and ipilimumab. It was shown that, if the fractal dimension and the average multifractal index are employed as biomarkers to assess the patient condition and the evolution of the disease, the matching with the clinical outcome is 77% when the FD measure is used and increases to 81% when the MFS measure is considered. The diagnostic ability of these nonlinear measures can further increase if the physiological uptake of 18F-FDG by the organs as well as unspecific 18F-FDG uptake due to immune related effects, like colitis, are excluded.\n\nThe present results agree with previous studies in patients treated solely with ipilimumab [17]. Namely, the fractal dimensions and the average multifractal index decrease as the disease progresses and the number of metastases increases. Based on these findings the FD and MFS measures can be used as promising computational biomarkers for diagnosis of metastatic cancers and for monitoring the therapeutic result of ICI treatment. These preliminary results should be evaluated in larger patient cohorts prospectively.\n\nAuthor Contributions\n\nConceptualization, A.D.-S. and A.P.; methodology, A.K. and A.P.; software, A.K., G.K.M. and A.P.; validation, C.S., L.P., J.C.H. and A.D.-S.; formal analysis, A.K.; investigation, C.S., A.D.-S. and L.P.; resources, A.D.-S., and J.C.H.; writing—original draft preparation, A.K., A.P. and A.D.-S.; writing—review and editing, A.K. and C.S.; visualization, A.K. and G.K.M.; supervision, G.K.M., A.P. and A.D.-S.; project administration, J.C.H. and A.D.-S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the University of Heidelberg and the Federal Agency for Radiation Protection.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nThe authors confirm that the data supporting findings of this study are available within the article and upon request to the authors.\n\nConflicts of Interest\n\nJ.C.H. declares research support from BMS; advisory board honoraria from Pierre Fabre, Sanofi, Sunpharma and MSD; speakers honoraria from BMS, MSD, Novartis, Roche, Sanofi, GSK, Amgen and Almirall and travel support from Pierre Fabre and 4SC, all outside the submitted work.\n\nAppendix A\n\nDetails on the calculations of the nonlinear measures FD, MFS and the cumulative multifractal measure are provided in the next three subsections.\n\nAppendix A1. Calculation of FD\n\nAfter extracting the local 18F-FDG concentration C(i,j,k) for each patient at the three studies (Baseline, Interim, Final), we use the box-counting method as a measure of the FD on the C-matrices, which correspond to the PET-CTs images of the patients. Namely, we cover the image with 3D boxes of linear size s and calculate the number of boxes, N(s), which contain any non-zero concentration of 18F-FDG. Note, that the actual amount of 18F-FDG is not important for the computation of FD and the calculation of the number of boxes N(s) is based on a binary (1 or 0) formula. Namely, a box of size s at position (i,j,k) is regarded as “containing 18F-FDG” in all cases where the concentration C(i,j,k) of 18F-FDG in this box takes any value greater than zero, C(i,j,k) ≥ 1. Otherwise it is considered as “empty”, C(i,j,k) = 0. The tracer distribution in the patient body is governed by the following law [15,16]:(A1) N(s)=Ms−Df \n\nIn Equation (A1), M is a constant related to the total concentration of the tracer in the body and Df is the value of the fractal dimension (FD). FD represents the dimensionality of the space covered by the tracer and if Df = 3, then the tracer is homogeneously distributed in the 3D space. If Df < 3, then the tracer covers a subspace with dimensionality smaller than the embedding dimensions. For the computation of Df the images (C-arrays) were divided in 3D boxes of linear sizes, in the range s = 1 mm, 2 mm, 49 mm. Larger boxes were not considered to avoid finite size effects (false effects or indications caused by limited statistics). When calculating the number of boxes with C(i,j,k) ≥ 1, in some cases the body cannot be covered by an integral number of boxes. To take into account this mismatching, the number of boxes N(s) was normalized by the total number N of empty and non-empty boxes covering the structure. This normalization changes quantitatively the results, but does not cause any qualitative discrepancies.\n\nTo calculate the value of Df it suffices to plot N(s)/N versus s and to fit with a power law. The absolute value of the fitted exponent corresponds to Df. Alternatively, one may plot N(s)/N versus s in a double logarithmic scale. In such a plot, the power law appears as a straight line whose tangent corresponds to Df.\n\nAppendix A2. Calculation of MFS\n\nThe MFS offers a more detailed description of the tracer dispersion because it takes into account not only the presence of the tracer in a binary form but also all the local concentrations as well as their moments. Call p(i,j,k) the normalized local concentration at position (i,j,k), defined as:(A2) p(i,j,k)=C(i,j,k)∑i,j,kC(i,j,k) \n\nIn Equation (A2), p(i,j,k) can be regarded as the probability to find tracer at position (i,j,k). In terms of probabilities, the generalized dimensions or moments, also known as MFS, are defined as follows:(A3) Dq=1q−1ln[∑i,j,kpq(i,j,k)]ln(s) for q≠1D1=∑i,j,kp(i,j,k) lnp(i,j,k)ln(s) for q=1 \n\nIn Equations (A3), the index q takes all integer values (–∞ ≤ q ≤ +∞) and denotes the order of the generalized dimension, while the ensemble of all orders composes the MFS spectrum. While FD measures the presence of 18F-FDG locally on the images, without paying attention to the amount of 18F-FDG in each box, the MFS accounts exactly for all local concentrations of the tracer and thus gives more accurate account of the diagnosis and of the evolution of the disease.\n\nFor the calculation of MFS in Equation (A3), the limit of box sizes, s → 0, is needed. For this reason, the smallest value, s = 1 mm, is used in the calculations.\n\nAppendix A3. Calculation of the Cumulative Measure ΔD(j)\n\nIt is worth noticing that the interpretation of the multifractal spectrum is more straight forward because the clinical picture (improvement or deterioration) of the patient between studies is mirrored on the relative position of the curves (and not on their slopes, as in the case of FD). To define a cumulative quantitative measure of clinical improvement or deterioration of the disease based on the MFS results, the average difference, ΔD(j), between Dq at the different stages j, for −10 ≤ q ≤ +10, is used. This is defined as:\n\n(A4) ΔD(j)=∑q=−1010[Dqj−Dq1]21 \n\nIn Equation (A4) the index j takes the values j = 2 or 3. The quantity ΔD(j) defines the average difference of the twenty-one moments, −10 ≤ q ≤ +10, between the baseline study j = 1 and the studies for j = 2 or j = 3, after ICI treatment. If ΔD(j) > 0 improvement of the patient outcome is recorded, while if ΔD(j) < 0 deterioration is recorded. To allow for potential fluctuations around the Dq values, we use a threshold u = 0.1 in this study, which defines the stable condition of the patient. Namely, if |ΔD(j)| < u the patient’s condition can be considered stable through treatments. Overall, the outcome for each patient after treatment, as presented in Section 3 and Table 3, is based on the above assumptions.\n\nEquation (A4) can also be written as the difference between the mean spectra <MFS>j:\n\n(A5) ΔD(j)=121∑q=−1010Dqj−121∑q=−1010Dq1=⟨MFSj−MFS1⟩ \n\nAs an additional approximation, in the present study the average MFS is taken over twenty-one moments, from –10 ≤ q ≤ +10.\n\nAppendix B\n\nTypical calculations of FD for patients with PMR and PMD are presented below.\n\nIn Figure A1, it is noticeable that the slope (Df) of the baseline study is smaller than the one of the reference control. And, even after two (interim study) or four (final study) cycles of therapy the patient’s slopes remain below the reference’s slope (Df = 2.6225). Because there is an improvement of the interim and final study with regards to the baseline, this case is termed PMR.\n\nFigure A1 The normalized number of boxes N(s)/N which contain the tracer as a function of the box size s in a double logarithmic scale for patient P10, whose clinical diagnosis was PMR. The blue line corresponds to the baseline study of patient P10, the orange line to the interim study and the gray line to the final study of the same patient. For comparison, the purple line representing healthy control H3, is also depicted.\n\nIn Figure A2, the slopes (Df) at the interim and final study stay smaller than the one of the first study, even after two or four cycles of therapy. Because there is no improvement and no stability of the patient’s condition, this case is termed PMD.\n\nFigure A2 The normalized number of boxes N(s)/N which contain the tracer as a function of the box size s in a double logarithmic scale for patient P11, whose clinical diagnosis was PMD. The blue line corresponds to the baseline study of patient P11, the orange line to the interim study and the gray line to the final study of the same patient. For comparison, the purple line representing healthy control H3, is also depicted.\n\nAppendix C\n\nTypical calculations of the MFS for patients with PMR and PMD are presented below. In the MFS it is easier to understand the evolution of the disease because the clinical improvement or deterioration of their disease is mirrored by the relative position of the curves (and not by their slopes, as in the case of FD).\n\nIn Figure A3, the MFS of patient P10 is presented at the three stages of PET-CT recordings. The MFS of the baseline study is considerably lower when compared to the reference control. After the first two cycles of medication the patients’ condition improves. This is mirrored in the MFS of the interim study (orange line) which levels closer to the reference. In the final study, after four cycles of medication, the patient’s condition slightly deteriorates but stays above the original baseline study. This patient is considered as PMR.\n\nFigure A3 Typical MFS spectrum of patient with PMR. The blue line corresponds to the baseline study of patient P10, the orange line corresponds to the interim study and the gray line to the final study of the same patient. For comparison, the purple line representing healthy control H5 is also depicted.\n\nIn Figure A4, we first note that the MFS spectrum of the patient P11 is considerably lower than the reference MFS, which is indicative of the diagnosed disease. After two cycles of treatment with monoclonal antibodies, at the interim study, the MFS (orange line) decreases, which points to clinical deterioration. After four cycles of treatment, at the 3rd study, the MFS improves slightly, but stays lower than the baseline study. This condition is consistent with PMD, because the patient’s condition does not improve with respect to the initial baseline diagnosis, neither in the interim study nor at the final one.\n\nFigure A4 Typical MFS spectrum of patient with PMD. The blue line corresponds to the baseline study of patient P11, the orange line corresponds to the interim study and the gray line to the final study of the same patient. For comparison, the purple line representing healthy control H5 is also depicted.\n\nFigure 1 The normalized number of boxes N(s)/N which contain the tracer as a function of the box size s in a double logarithmic scale. The blue line corresponds to the baseline study of patient P9, the orange line to the interim study and the gray line to the final study of the same patient. For comparison the purple line representing healthy control H3 is also depicted.\n\nFigure 2 Typical MFS spectrum of patient with SMD. The blue line corresponds to the baseline study of patient P12, the orange line corresponds to the interim study and the gray line to the final study of the same patient. For comparison, the purple line representing healthy control H5 is also depicted.\n\nFigure 3 MIP PET-CT images for patients with metastatic melanoma: (a) Patient P16 at final stage with signs of colitis; (b) Patient P14 at interim stage without irAEs effects.\n\ncancers-13-05170-t001_Table 1 Table 1 Presentation of patient and control data and clinical evaluation.\n\nPatients\tAge/Sex\tStudy\tMedication\tPET-irAEs and Causes of Non-Specific Tracer Uptake\tPET-CT Evaluation (PERCIMT)\t\nP1\t56/F\tBaseline\tIpilimumab/Nivolumab\t\t\t\nInterim\tthyroiditis\tPMD\t\nFinal\tcolitis\tPMD\t\nP2\t48/F\tBaseline\tIpilimumab/Nivolumab\t\t\t\nInterim\tradiopharmaceutical uptake in the injection site\tSMD\t\nFinal\tradiopharmaceutical uptake in the injection site\tCMR\t\nP3\t60/F\tBaseline\tIpilimumab/Nivolumab\t\t\t\nInterim\tradiopharmaceutical uptake in the injection site\tPMR\t\nFinal\tthyroiditis, colitis, bone marrow activation\tPMR\t\nP4\t52/M\tBaseline\tPembrolizumab\tmuscle uptake\t\t\nInterim\tarthritis, muscle uptake\tSMD\t\nFinal\tarthritis\tSMD\t\nP5\t46/F\tBaseline\tIpilimumab/Nivolumab\tradiopharmaceutical uptake in the injection site\t\t\nInterim\tduodenitis, muscle uptake\tSMD\t\nFinal\tduodenitis, colitis\tPMD\t\nP6\t68/M\tBaseline\tPembrolizumab\t\t\t\nInterim\t\tSMD\t\nFinal\t\tPMR\t\nP7\t44/F\tBaseline\tIpilimumab/Nivolumab\t\t\t\nInterim\tcolitis, bone marrow activation\tPMR\t\nFinal\tbone marrow activation\tPMR\t\nP8\t50/F\tBaseline\tIpilimumab/Nivolumab\tlaryngeal uptake\t\t\nInterim\tbone marrow activation\tSMD\t\nFinal\tarthritis, bone marrow activation, radiopharmaceutical uptake in the injection site, muscle uptake\tCMR\t\nP9\t55/F\tBaseline\tNivolumab\tbone marrow activation\t\t\nInterim\tbone marrow activation\tSMD\t\nFinal\tbone marrow activation\tSMD\t\nP10\t54/M\tBaseline\tIpilimumab/Nivolumab\t\t\t\nInterim\t\tPMR\t\nFinal\t\tPMR\t\nP11\t20/F\tBaseline\tIpilimumab/Nivolumab\tbone marrow activation\t\t\nInterim\t\tPMD\t\nFinal\t\tPMD\t\nP12\t84/F\tBaseline\tPembrolizumab\t\t\t\nInterim\t\tSMD\t\nFinal\tmuscle uptake\tSMD\t\nP13\t53/F\tBaseline\tNivolumab\tbone marrow activation\t\t\nInterim\t\tSMD\t\nFinal\t\tSMD\t\nP14\t52/M\tBaseline\tPembrolizumab\tlaryngeal uptake\t\t\nInterim\tlaryngeal uptake\tPMR\t\nFinal\tlaryngeal uptake, radiopharmaceutical uptake in the injection site\tPMR\t\nP15\t52/M\tBaseline\tPembrolizumab\t\t\t\nInterim\t\tSMD\t\nFinal\tsigns of colitis in descending colon\tSMD\t\nP16\t71/F\tBaseline\tIpilimumab/Nivolumab\tcolon uptake\t\t\nInterim\tcolitis, sarcoid-like mediastinal lymphadenopathy\tPMD\t\nFinal\tcolitis\tPMD\t\nP17\t34/F\tBaseline\tIpilimumab/Nivolumab\t\t\t\nInterim\tbone marrow activation, colitis, muscle uptake\tCMR\t\nFinal\tbrown fat activation\tCMR\t\nP18\t78/M\tBaseline\tPembrolizumab\tradiopharmaceutical uptake in the injection site\t\t\nInterim\tarthritis\tPMD\t\nFinal\t\tPMD\t\nP19\t59/M\tBaseline\tIpilimumab/Nivolumab\t\t\t\nInterim\tsarcoid-like mediastinal lymphadenopathy, muscle uptake\tPMR\t\nFinal\tsarcoid-like mediastinal lymphadenopathy\tPMR\t\nHEALTHY CONTROLS\t\nH1\t49/M\t\t-\tmuscle uptake\t\t\nH2\t63/M\t\t-\tradiopharmaceutical uptake in the injection site\t\t\nH3\t39/M\t\t-\t-\t\t\nH4\t61/M\t\t-\t-\t\t\nH5\t52/M\t\t-\t-\t\t\nH6\t63/M\t\t-\tmuscle uptake\t\t\nH7\t69/M\t\t-\t-\t\t\nH8\t60/M\t\t-\t-\t\t\n\ncancers-13-05170-t002_Table 2 Table 2 Presentation of patient and control Fractal Dimensions (FD).\n\nPatients\tStudy\tFD\tSide Effects\tClinical Outcome\tMatching\t\nP1\tBaseline\t2.546\t\t\t\t\nInterim\t2.459\tthyroiditis\tPMD\tYES\t\nFinal\t2.558\tcolitis\tPMD\tNO\t\nP2\tBaseline\t2.523\t\t\t\t\nInterim\t2.515\tradiopharmaceutical uptake in the injection site\tSMD\tYES\t\nFinal\t2.476\tradiopharmaceutical uptake in the injection site\tCMR\tNO\t\nP3\tBaseline\t2.537\t\t\t\t\nInterim\t2.557\tradiopharmaceutical uptake in the injection site\tPMR\tYES\t\nFinal\t2.527\tthyroiditis, colitis, bone marrow activation\tPMR\tNO\t\nP4\tBaseline\t2.566\tmuscle uptake\t\t\t\nInterim\t2.543\tarthritis, muscle uptake\tSMD\tYES\t\nFinal\t2.543\tarthritis\tSMD\tYES\t\nP5\tBaseline\t2.487\tradiopharmaceutical uptake in the injection site\t\t\t\nInterim\t2.497\tduodenitis, muscle uptake\tSMD\tYES\t\nFinal\t2.448\tduodenitis, colitis\tPMD\tYES\t\nP6\tBaseline\t2.519\t\t\t\t\nInterim\t2.530\t\tSMD\tYES\t\nFinal\t2.503\t\tPMR\tNO\t\nP7\tBaseline\t2.542\t\t\t\t\nInterim\t2.544\tcolitis, bone marrow activation\tPMR\tYES\t\nFinal\t2.562\tbone marrow activation\tPMR\tYES\t\nP8\tBaseline\t2.544\tlaryngeal uptake\t\t\t\nInterim\t2.399\tbone marrow activation\tSMD\tNO\t\nFinal\t2.476\tarthritis, bone marrow activation, radiopharmaceutical uptake in the injection site, muscle uptake\tCMR\tNO\t\nP9\tBaseline\t2.524\tbone marrow activation\t\t\t\nInterim\t2.507\tbone marrow activation\tSMD\tYES\t\nFinal\t2.528\tbone marrow activation\tSMD\tYES\t\nP10\tBaseline\t2.534\t\t\t\t\nInterim\t2.562\t\tPMR\tYES\t\nFinal\t2.574\t\tPMR\tYES\t\nP11\tBaseline\t2.499\tbone marrow activation\t\t\t\nInterim\t2.398\t\tPMD\tYES\t\nFinal\t2.474\t\tPMD\tYES\t\nP12\tBaseline\t2.513\t\t\t\t\nInterim\t2.480\t\tSMD\tNO\t\nFinal\t2.537\tmuscle uptake\tSMD\tYES\t\nP13\tBaseline\t2.603\tbone marrow activation\t\t\t\nInterim\t2.596\t\tSMD\tYES\t\nFinal\t2.590\t\tSMD\tYES\t\nP14\tBaseline\t2.554\tlaryngeal uptake\t\t\t\nInterim\t2.518\tlaryngeal uptake\tPMR\tNO\t\nFinal\t2.557\tlaryngeal uptake, radiopharmaceutical uptake in the injection site\tPMR\tYES\t\nP15\tBaseline\t2.556\t\t\t\t\nInterim\t2.604\t\tSMD\tNO\t\nFinal\t2.567\tsigns of colitis in descending colon\tSMD\tYES\t\nP16\tBaseline\t2.398\tcolon uptake\t\t\t\nInterim\t2.511\tcolitis, sarcoid-like mediastinal lymphadenopathy\tPMD\tNO\t\nFinal\t2.574\tcolitis\tPMD\tNO\t\nP17\tBaseline\t2.473\t\t\t\t\nInterim\t2.518\tbone marrow activation, colitis, muscle uptake\tCMR\tYES\t\nFinal\t2.515\tbrown fat activation\tCMR\tYES\t\nP18\tBaseline\t2.541\tradiopharmaceutical uptake in the injection site\t\t\t\nInterim\t2.523\tarthritis hip\tPMD\tYES\t\nFinal\t2.539\t\tPMD\tYES\t\nP19\tBaseline\t2.549\t\t\t\t\nInterim\t2.572\tsarcoid-like mediastinal lymphadenopathy, muscle uptake\tPMR\tYES\t\nFinal\t2.580\tsarcoid-like mediastinal lymphadenopathy\tPMR\tYES\t\nHEALTHY CONTROLS\t\nH1\t\t2.544\tmuscle uptake\t\t\t\nH2\t\t2.614\tradiopharmaceutical uptake in the injection site\t\t\t\nH3\t\t2.623\t-\t\t\t\nH4\t\t2.496\t-\t\t\t\nH5\t\t2.646\t-\t\t\t\nH6\t\t2.518\tmuscle uptake\t\t\t\nH7\t\t2.581\t-\t\t\t\nH8\t\t2.589\t-\t\t\t\n\ncancers-13-05170-t003_Table 3 Table 3 Presentation of MFS and cumulative measure ΔD(j) results, for patients and healthy controls.\n\nPatients\tStudy\t<MFS>/ΔD(j)\tSide Effects\tClinical Outcome\tMatching\t\nP1\tBaseline\t2.389\t\t\t\t\nInterim\t2.178/−0.211\tthyroiditis\tPMD\tYES\t\n\tFinal\t2.460/0.071\tcolitis\tPMD\tNO\t\nP2\tBaseline\t2.314\t\t\t\t\nInterim\t2.281/−0.033\tradiopharmaceutical uptake in the injection site\tSMD\tYES\t\nFinal\t2.523/0.210\tradiopharmaceutical uptake in the injection site\tCMR\tYES\t\nP3\tBaseline\t2.341\t\t\t\t\nInterim\t2.358/0.017\tradiopharmaceutical uptake in the injection site\tPMR\tYES\t\nFinal\t2.295/−0.046\tthyroiditis, colitis, bone marrow activation\tPMR\tNO\t\nP4\tBaseline\t2.472\tmuscle uptake\t\t\t\nInterim\t2.463/−0.009\tarthritis, muscle uptake\tSMD\tYES\t\nFinal\t2.428/−0.044\tarthritis\tSMD\tYES\t\nP5\tBaseline\t2.248\tradiopharmaceutical uptake in the injection site\t\t\t\nInterim\t2.485/0.237\tduodenitis, muscle uptake\tSMD\tNO\t\nFinal\t2.202/−0.047\tduodenitis, colitis\tPMD\tYES\t\nP6\tBaseline\t2.450\t\t\t\t\nInterim\t2.399/−0.051\t\tSMD\tYES\t\nFinal\t2.252/−0.198\t\tPMR\tNO\t\nP7\tBaseline\t2.309\t\t\t\t\nInterim\t2.460/0.151\tcolitis, bone marrow activation\tPMR\tYES\t\nFinal\t2.484/0.176\tbone marrow activation\tPMR\tYES\t\nP8\tBaseline\t2.306\tlaryngeal uptake\t\t\t\nInterim\t2.154/−0.152\tbone marrow activation\tSMD\tNO\t\nFinal\t2.242/−0.064\tarthritis, bone marrow activation, radiopharmaceutical uptake in the injection site, muscle uptake\tCMR\tNO\t\nP9\tBaseline\t2.425\tbone marrow activation\t\t\t\nInterim\t2.353/−0.072\tbone marrow activation\tSMD\tYES\t\nFinal\t2.305/−0.120\tbone marrow activation\tSMD\tYES\t\nP10\tBaseline\t2.273\t\t\t\t\nInterim\t2.470/0.1907\t\tPMR\tYES\t\nFinal\t2.384/0.111\t\tPMR\tYES\t\nP11\tBaseline\t2.259\tbone marrow activation\t\t\t\nInterim\t2.145/−0.115\t\tPMD\tYES\t\nFinal\t2.237/−0.023\t\tPMD\tYES\t\nP12\tBaseline\t2.242\t\t\t\t\nInterim\t2.243/0.001\t\tSMD\tYES\t\nFinal\t2.266/0.024\tmuscle uptake\tSMD\tYES\t\nP13\tBaseline\t2.394\tbone marrow activation\t\t\t\nInterim\t2.466/0.072\t\tSMD\tYES\t\nFinal\t2.461/0.067\t\tSMD\tYES\t\nP14\tBaseline\t2.302\tlaryngeal uptake\t\t\t\nInterim\t2.511/0.209\tlaryngeal uptake\tPMR\tYES\t\nFinal\t2.310/0.008\tlaryngeal uptake, radiopharmaceutical uptake in the injection site\tPMR\tYES\t\nP15\tBaseline\t2.233\t\t\t\t\nInterim\t2.376/0.143\t\tSMD\tNO\t\nFinal\t2.253/0.020\tsigns of colitis in descending colon\tSMD\tYES\t\nP16\tBaseline\t2.155\tcolon uptake\t\t\t\nInterim\t2.261/0.106\tcolitis, sarcoid-like mediastinal lymphadenopathy\tPMD\tNO\t\nFinal\t2.378/0.223\tcolitis\tPMD\tNO\t\nP17\tBaseline\t2.192\t\t\t\t\nInterim\t2.496/0.303\tbone marrow activation, colitis, muscle uptake\tCMR\tYES\t\nFinal\t2.390/0.198\tbrown fat activation\tCMR\tYES\t\nP18\tBaseline\t2.346\tradiopharmaceutical uptake in the injection site\t\t\t\nInterim\t2.269/−0.077\tarthritis hip\tPMD\tYES\t\nFinal\t2.413/0.066\t\tPMD\tNO\t\nP19\tBaseline\t2.266\t\t\t\t\nInterim\t2.487/0.221\tsarcoid-like mediastinal lymphadenopathy, muscle uptake\tPMR\tYES\t\nFinal\t2.346/0.080\tsarcoid-like mediastinal lymphadenopathy\tPMR\tYES\t\nHEALTHY CONTROLS\t\nH1\t\t2.560\tmuscle uptake\t\t\t\nH2\t\t2.365\tradiopharmaceutical uptake in the injection site\t\t\t\nH3\t\t2.442\t-\t\t\t\nH4\t\t2.322\t-\t\t\t\nH5\t\t2.538\t-\t\t\t\nH6\t\t2.207\tmuscle uptake\t\t\t\nH7\t\t2.336\t-\t\t\t\nH8\t\t2.479\t-\t\t\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Khair D.O. Bax H.J. Mele S. Crescioli S. Pellizzari G. Khiabany A. Nakamura M. Harris R.J. French E. Hoffmann R.M. Combining immune checkpoint inhibitors: Established and emerging targets and strategies to improve outcomes in melanoma Front. Immunol. 2019 10 453 10.3389/fimmu.2019.00453 30941125\n2. Larkin J. Chiarion-Sileni V. Gonzalez R. Grob J.-J. Cowey C.L. Lao C.D. Schadendorf D. Dummer R. Smylie M. Rutkowski P. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma N. Engl. J. Med. 2015 373 23 34 10.1056/NEJMoa1504030 26027431\n3. Hodi F.S. O´Day S.J. McDermott D.F. Weber R.W. Sosman J.A. Haanen J.B. Gonzalez R. Robert C. Schadendorf D. Hassel J.C. Improved survival with ipilimumab in patients with metastatic melanoma N. Engl. J. Med. 2010 363 711 723 10.1056/NEJMoa1003466 20525992\n4. Schadendorf D. Hodi F.S. Robert C. Weber J. Margolin K. Hamid O. Patt D. Chen T.-T. Berman D.M. Wolchok J.D. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma J. Clin. Oncol. 2015 33 1889 1894 10.1200/JCO.2014.56.2736 25667295\n5. Larkin J. Chiarion-Sileni V. Gonzalez R. Grob J.-J. Rutkowski P. Lao C.D. Cowey C.L. Schadendorf D. Wagstaff J. Dummer R. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma N. Engl. J. Med. 2019 381 1535 1546 10.1056/NEJMoa1910836 31562797\n6. Dimitrakopoulou-Strauss A. Monitoring of patients with metastatic melanoma treated with immune checkpoint inhibitors using PET-CT Cancer Immunol. Immunother. 2019 68 813 822 10.1007/s00262-018-2229-6 30123922\n7. Sachpekidis C. Larribere L. Pan L. Haberkorn U. Dimitrakopoulou-Strauss A. Hassel J.C. Predictive value of early 18F-FDG PET/CT studies for treatment response evaluation to ipilimumab in metastatic melanoma: Preliminary results of an ongoing study Eur. J. Nucl. Med. Mol. Imaging 2015 42 386 396 10.1007/s00259-014-2944-y 25359635\n8. Anwar H. Sachpekidis C. Winkler J. Kopp-Schneider A. Haberkorn U. Hassel J.C. Dimitrakopoulou-Strauss A. Absolute number of new lesions on 18F-FDG PET/CT is more predictive of clinical response than SUV changes in metastatic melanoma patients receiving ipilimumab Eur. J. Nucl. Med. Mol. Imaging 2018 45 376 383 10.1007/s00259-017-3870-6 29124281\n9. Sachpekidis C. Hassel J.C. Kopp-Schneider A. Haberkorn U. Dimitrakopoulou-Strauss A. Quantitative Dynamic 18F-FDG PET/CT in Survival Prediction of Metastatic Melanoma under PD-1 Inhibitors Cancers 2021 13 1019 10.3390/cancers13051019 33804417\n10. Sachpekidis C. Kopp-Schneider A. Pan L. Papamichail D. Haberkorn U. Hassel J.C. Dimitrakopoulou-Strauss A. Interim [18F]FDG PET/CT can predict response to anti-PD-1 treatment in metastatic melanoma Eur. J. Nucl. Med. Mol. Imaging 2020 48 1932 1943 10.1007/s00259-020-05137-7 33336264\n11. Tan A.C. Emmett L. Lo S. Liu V. Kapoor R. Carlino M.S. Guminski A.D. Long G.V. Menzies A.M. FDG-PET response and outcome from anti-PD-1 therapy in metastatic melanoma Ann. Oncol. 2018 29 2115 2120 10.1093/annonc/mdy330 30137228\n12. Ito K. Teng R. Schöder H. Humm J.L. Ni A. Michaud L. Nakajima R. Yamashita R. Wolchok J.D. Weber W.A. 18F-FDG PET/CT for Monitoring of Ipilimumab Therapy in Patients with Metastatic Melanoma J. Nucl. Med. 2019 60 335 341 10.2967/jnumed.118.213652 30413661\n13. Iravani A. Osman M.M. Weppler A.M. Wallace R. Galligan A. Lasocki A. Hunter M.O. Akhurst T. Hofman M.S. Lau P.K.H. FDG PET/CT for tumoral and systemic immune response monitoring of advanced melanoma during first-line combination ipilimumab and nivolumab treatment Eur. J. Nucl. Med. Mol. Imaging 2020 47 2776 2786 10.1007/s00259-020-04815-w 32338306\n14. Dimitrakopoulou-Strauss A. Pan L. Sachpekidis C. Kinetic modeling and parametric imaging with dynamic PET for oncological applications: General considerations, current clinical applications, and future perspectives Eur. J. Nucl. Med. Mol. Imaging 2021 48 21 39 10.1007/s00259-020-04843-6 32430580\n15. Mandelbrot B. Fractal Geometry of Nature 1st ed. W.H. Freemanand Company New York, NY, USA 1982\n16. Feder J. Fractals Plenum New York, NY, USA 1988\n17. Breki C.M. Dimitrakopoulou-Strauss A. Hassel J. Theoharis T. Sachpekidis C. Pan L. Provata A. Fractal and multifractal analysis of PET/CT images of metastatic melanoma before and after treatment with ipilimumab EJNMMI Res. 2016 6 61 10.1186/s13550-016-0216-5 27473846\n18. Weibel E.R. Fractal structures in biological systems Fractals in Biology and Medicine Losa G. Merlini D. Nonnenmacher T.F. Weibel E.R. Birkhäuser-Verlag Basel, Germany 2005 Volume IV 3 16\n19. Huang W. Yen R.T. McLaurine M. Bledsoe G. Morphometry of the humanpulmonary vasculature J. Appl. Physiol. 1996 81 2123 2133 10.1152/jappl.1996.81.5.2123 8941537\n20. Helmberger M. Pienn M. Urschler M. Kullnig P. Stollberger R. Kovacs G. Olschewski A. Olschewski H. Bálint Z. Quantification of tortuosity and fractal dimension of the lung vessels in pulmonary hypertension patients PLoS ONE 2014 9 e87515 10.1371/journal.pone.0087515 24498123\n21. Gil-García J. Gimeno-Domínguez M. Murillo-Ferroll N.L. The arterial pattern and fractal dimension of the dog kidney Histol. Histopathol. 1992 7 563 574 1457978\n22. Yamaguchi H. Wyckoff J. Condeelis J. Cell migration in tumour Curr. Opin. Cell Biol. 2005 17 559 564 10.1016/j.ceb.2005.08.002 16098726\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6694",
"issue": "13(20)",
"journal": "Cancers",
"keywords": "PET-CT imaging; fractal dimensions; ipilimumab; metastatic melanoma; multifractal spectrum; nivolumab; pembrolizumab",
"medline_ta": "Cancers (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101526829",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34680319",
"pubdate": "2021-10-15",
"publication_types": "D016428:Journal Article",
"references": "32430580;33336264;33804417;29124281;31562797;8941537;25359635;30941125;20525992;30123922;27473846;25667295;24498123;30413661;1457978;16098726;26027431;32338306;30137228",
"title": "Fractal and Multifractal Analysis of PET-CT Images for Therapy Assessment of Metastatic Melanoma Patients under PD-1 Inhibitors: A Feasibility Study.",
"title_normalized": "fractal and multifractal analysis of pet ct images for therapy assessment of metastatic melanoma patients under pd 1 inhibitors a feasibility study"
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"companynumb": "GR-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-116795",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Treatment-induced neuropathy of diabetes (TIND) is an acute, painful and rare complication of intensive glycaemic control in diabetes. We present a case of a 32-year-old man with sudden onset of severe lower limb pain. It worsened progressively and was refractory to analgesic and muscle relaxant therapies. It became so severe that the patient was impossible to stand, causing a marked impact on his daily life. He had a history of type 1 diabetes, diagnosed 3 years ago, and an episode of deep vein thrombosis of the left leg, 4 years ago. While completing an extensive workup, various analgesic adjustments were made, with no improvement. After careful revision of his medical data, a significant reduction of his A1C 6 months before the appearance of symptoms was noticed. A diagnosis of TIND was made. The patient was treated with amitriptyline and showed noticeable improvement after the first month.",
"affiliations": "Internal Medicine, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal mafalda.alvesferreira@gmail.com.;Internal Medicine, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.;Internal Medicine, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.;Internal Medicine, Centro Hospitalar e Universitario de Coimbra EPE, Coimbra, Portugal.",
"authors": "Ferreira|Mafalda|M|http://orcid.org/0000-0002-7504-3385;Camoes|Guilherme|G|http://orcid.org/0000-0003-0017-6017;Gomes|João Filipe de Ferreira|JFF|http://orcid.org/0000-0002-0680-9543;Ferreira|Diana M|DM|http://orcid.org/0000-0002-2458-048X",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-241849",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "diabetes; endocrine system; peripheral nerve disease",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D003922:Diabetes Mellitus, Type 1; D003929:Diabetic Neuropathies; D006801:Humans; D008297:Male; D010146:Pain",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34016633",
"pubdate": "2021-05-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Treatment-induced diabetes neuropathy: reminder of an important clinical lesson.",
"title_normalized": "treatment induced diabetes neuropathy reminder of an important clinical lesson"
} | [
{
"companynumb": "PT-MYLANLABS-2021M1047946",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMITRIPTYLINE"
},
"drugadditional": "1",
... |
{
"abstract": "Infections with Listeria monocytogenes are uncommon but serious, with mortality rate approaching 30% in cases of systemic involvement despite first-line therapy. They are usually caused by ingestion of contaminated foods, but spontaneous infections have also been described. Listeria monocytogenes is a rare cause of peritonitis, and most of the published cases are in patients with cirrhosis and ascites. There are a few reported cases of Listeria peritonitis associated with peritoneal dialysis (PD), primarily isolated peritonitis.If detected early, Listeria peritonitis can be successfully treated with ampicillin, alone or in combination with gentamicin. Vancomycin has been listed as a second-line agent. However, it has been associated with treatment failure.In this case report, we present a patient who developed disseminated listeriosis, with peritonitis as the first manifestation of disseminated infection. This case illustrates the importance of having a high index of suspicion for L. monocytogenes if patients deteriorate despite empiric therapy for PD-associated peritonitis and serves as a further example demonstrating the inadequate coverage of vancomycin for L. monocytogenes.",
"affiliations": "Department of Medicine, The Ottawa Hospital, Affiliated with the University of Ottawa Faculty of Medicine, Ottawa, ON, Canada wbeckerleg@toh.ca.;Department of Medicine, The Ottawa Hospital, Affiliated with the University of Ottawa Faculty of Medicine, Ottawa, ON, Canada.;Department of Medicine, The Ottawa Hospital, Affiliated with the University of Ottawa Faculty of Medicine, Ottawa, ON, Canada.",
"authors": "Beckerleg|Weiwei|W|;Keskar|Vaibhav|V|;Karpinski|Jolanta|J|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": "10.3747/pdi.2016.00205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8608",
"issue": "37(2)",
"journal": "Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis",
"keywords": "Listeria monocytogenes; Peritoneal dialysis; peritonitis",
"medline_ta": "Perit Dial Int",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D018450:Disease Progression; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D008089:Listeria monocytogenes; D008088:Listeriosis; D008875:Middle Aged; D010530:Peritoneal Dialysis; D010538:Peritonitis; D018570:Risk Assessment; D012720:Severity of Illness Index",
"nlm_unique_id": "8904033",
"other_id": null,
"pages": "239-240",
"pmc": null,
"pmid": "28360372",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Peritonitis as the First Presentation of Disseminated Listeriosis in a Patient on Peritoneal Dialysis-a Case Report.",
"title_normalized": "peritonitis as the first presentation of disseminated listeriosis in a patient on peritoneal dialysis a case report"
} | [
{
"companynumb": "CA-BAUSCH-BL-2017-010740",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPICILLIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDrug-induced melanoma is a topic, concept or \"reality\" becoming more and more popular as the list of drugs considered as potential inducers of cutaneous melanoma is constantly growing. Interesting and current at the moment is the question/dilemma of \"Irbesartan induced melanomas\" and \"Valsartan induced melanomas\"! The following questions are without answers: 1) the general risk which angiotensin receptor blockers contain for potentiating the carcinogenesis and cancer development (as a whole); 2) available officialized data for withdrawal from the market of products with valsartan and irbesartan due to detected potential carcinogens-NDMA/NDEA, and 3) the missing official information on the most likely forms of cancer potentiated by these drugs. That is precisely why many questions remain open, and the inevitable assumption arises for the key, although according to some conspiratorial role of so-called \"pharmaceutical giants\" in the concept of drug-induced malignancies.\n\n\nMETHODS\nWe present a 72-year-old man with arterial hypertension in connection with which he is taking Irbesartan 300 mg (1-0-0), Amlodipine 5 mg (0-0-1) and Moxonidine 0.2 mg (0-0-1). The patient reported the presence of pigment lesion in the head area, which dates from many years and 3 years ago it was at the size of the nail plate on the index finger. Irbesartan therapy dates from 1.5-2 years, and according to the patient 1.5-2 years after the start of irbesartan therapy, the lesion grew sixfold, accompanied by sensitivity and discomfort in the area. Clinically and dermatoscopically the lesion had data on superficial spreading cutaneous melanoma. Tumour thickness ≤ 1 mm was measured preoperatively by ultrasound. The so-called one-step melanoma surgery (OSMS) was performed, and the lesion was removed by elliptical excision with an operative surgical margin of 1 cm in all directions within one operative session. The subsequent histological study (and screening staging) found that it was a superficial spreading melanoma stage IA (T1bN0M0).\n\n\nCONCLUSIONS\nPossible, but unlikely, in our opinion, is that the intake of angiotensin receptor blockers (in particular irbesartan), and the progression of benign precursor lesions to malignant do not have a direct relationship. The growing number of data in the literature for drug-induced melanoma and massive withdrawal of products with valsartan and irbesartan due to the content of probable carcinogens speaks, however in favour of the opposite, namely that it is more likely to speak about established dependence than of a sporadic association. Drug-induced melanoma-rather a reality than a myth.",
"affiliations": "Medical Institute of the Ministry of Interior, Department of Dermatology, Venereology and Dermatologic Surgery, General Skobelev Nr 79, Sofia, Bulgaria.;Medical Institute of the Ministry of Interior, Department of Dermatology, Venereology and Dermatologic Surgery, General Skobelev Nr 79, Sofia, Bulgaria.",
"authors": "Tchernev|Georgi|G|;Temelkova|Ivanka|I|",
"chemical_list": null,
"country": "North Macedonia",
"delete": false,
"doi": "10.3889/oamjms.2019.043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1857-9655",
"issue": "7(1)",
"journal": "Open access Macedonian journal of medical sciences",
"keywords": "ARB; Drug-induced melanoma; Irbesartan; Surgery; Survival benefit",
"medline_ta": "Open Access Maced J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "101662294",
"other_id": null,
"pages": "121-123",
"pmc": null,
"pmid": "30740174",
"pubdate": "2019-01-15",
"publication_types": "D002363:Case Reports",
"references": "20212233;20542468;21298300;28905299;29103328;30159073;7059943;7914430",
"title": "Irbesartan Induced Cutaneous Melanoma! Second Case in the Medical Literature!",
"title_normalized": "irbesartan induced cutaneous melanoma second case in the medical literature"
} | [
{
"companynumb": "BG-TEVA-2019-BG-1023236",
"fulfillexpeditecriteria": "1",
"occurcountry": "BG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IRBESARTAN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe extended use of an Impella LP 2.5 percutaneous left-ventricular assist device (pVAD) without a heparin-based purge solution in a patient who developed cardiogenic shock after acute myocardial infarction (AMI) is described.\n\n\nCONCLUSIONS\nA 58-year-old Asian man with no history of cardiac disease, hypertension, or diabetes mellitus had an AMI and subsequent cardiogenic shock. He was started on dopamine and norepinephrine and transferred to a tertiary care center for rescue percutaneous coronary intervention (PCI). Given that his artery was patent with Thrombolysis In Myocardial Infarction 3 flow, PCI was not attempted. He had an ejection fraction of 25% and mid-distal anteroseptal akinesis. He was transferred to the intensive care unit on intra-aortic balloon pump (IABP) support. The patient's condition continued to deteriorate, and an Impella LP 2.5 pVAD was inserted for additional hemodynamic support and as a bridge to definitive revascularization. To reduce the potential for medication error and decrease the patient's bleeding risk, the purge solution was changed to 20% dextrose injection without heparin and continued at a rate of 15 mL/hr. The patient's hemodynamic values improved, and the pVAD and IABP were continued for the next five days. The patient was successfully anticoagulated with i.v. heparin throughout the remainder of pVAD support. While the patient did develop hemolytic anemia during his device support, there were no thrombotic or bleeding complications.\n\n\nCONCLUSIONS\nAn Impella LP 2.5 pVAD was used for 75 hours with a purge solution that contained no heparin. There were no thrombotic or bleeding complications.",
"affiliations": "Cardiovascular Intensive Care Unit, Department of Pharmacy Services, Henry Ford Hospital, Detroit, MI, USA. djenninl@hfhs.org",
"authors": "Jennings|Douglas L|DL|;Nemerovski|Carrie W|CW|;Khandelwal|Akshay|A|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp100016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "67(21)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000925:Anticoagulants; D006353:Heart-Assist Devices; D006439:Hemodynamics; D006493:Heparin; D006801:Humans; D007423:Intra-Aortic Balloon Pumping; D008297:Male; D008508:Medication Errors; D008875:Middle Aged; D009203:Myocardial Infarction; D012770:Shock, Cardiogenic; D016896:Treatment Outcome",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1825-8",
"pmc": null,
"pmid": "20966145",
"pubdate": "2010-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Extended use of a percutaneous left-ventricular assist device without a heparin-based purge solution.",
"title_normalized": "extended use of a percutaneous left ventricular assist device without a heparin based purge solution"
} | [
{
"companynumb": "US-BAYER-2020-007125",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "ASPIRIN"
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{
"abstract": "Bronchiolitis Obliterans Organizing Pneumonia (BOOP) can complicate allogeneic haematopoietic stem cell transplantation. It is associated with prior graft-versus-host disease (GVHD) and the case fatality is 21%. In 22%, diagnosis is preceded by tapering the corticosteroids given as a treatment for GVHD. We report a fatal case of BOOP after tapering the corticosteroids that the patient received for a Pneumocystis jirovecii pneumonia after stem cell transplantation.",
"affiliations": "Dienst Inwendige Ziekten - Hematologie, Heilig-Hartziekenhuis Roeselare-Menen vzw, Roeselare, Belgium. DDeeren@hhr.be",
"authors": "Deeren|D|D|;Lammertijn|L|L|;Van Dorpe|J|J|",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1179/acb.2010.042",
"fulltext": null,
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"issn_linking": "1784-3286",
"issue": "65(3)",
"journal": "Acta clinica Belgica",
"keywords": null,
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000368:Aged; D018549:Cryptogenic Organizing Pneumonia; D005938:Glucocorticoids; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008775:Methylprednisolone; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "200-1",
"pmc": null,
"pmid": "20669790",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Relapsing infiltrates after pneumocystis pneumonia in stem cell transplant patients: think about BOOP!",
"title_normalized": "relapsing infiltrates after pneumocystis pneumonia in stem cell transplant patients think about boop"
} | [
{
"companynumb": "BE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-299608",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CASPOFUNGIN"
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"dru... |
{
"abstract": "AIHA is rare in the general population and associated with a mortality of 8%. In contrast, AIHA occurs in up to 12.2% of cases after intestinal transplantation and is associated with mortality up to 50%. Treatment entails a \"step-up\" approach including corticosteroids, IvIg, plasmapheresis, and rituximab. However, AIHA after transplantation often is refractory to this strategy, contributing to a poor outcome. We describe a child with microvillous inclusion disease who developed AIHA 1 year after multivisceral transplantation that was refractory to standard therapy and was subsequently treated with bortezomib.We observed remission of AIHA within 1 week after the start of bortezomib. Bortezomib was associated with transient diarrhea, leucopenia, and elevated liver enzymes. Three years later, he remains in remission without important complications. Published data on bortezomib for autoimmune cytopenias outside SOT are discussed. This is the first report to support bortezomib as an important therapeutic alternative for AIHA after SOT. The occurrence and treatment of AIHA after SOT, and specifically intestinal transplantation, should be the subject of future registry studies to collect additional experience and explore the optimal therapeutic approach.",
"affiliations": "Pediatrics (Pediatric Nephrology and Solid Organ Transplantation), University Hospitals Leuven, Leuven, Belgium.;Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium.;Pediatrics (Pediatric Nephrology and Solid Organ Transplantation), University Hospitals Leuven, Leuven, Belgium.;Pediatrics (Pediatric Nephrology and Solid Organ Transplantation), University Hospitals Leuven, Leuven, Belgium.;Pediatrics (Pediatric Nephrology and Solid Organ Transplantation), University Hospitals Leuven, Leuven, Belgium.;Abdominal Transplant Surgery, University Hospitals Leuven, Leuven, Belgium.;Pediatrics (Pediatric Hemato-Oncology), University Hospitals Leuven, Leuven, Belgium.;Hematology, University Hospitals Leuven, Leuven, Belgium.",
"authors": "Knops|Noël|N|0000-0001-5743-0966;Emonds|Marie-Paule|MP|0000-0002-2653-8656;Herman|Jean|J|0000-0002-6774-1685;Levtchenko|Elena|E|0000-0002-8352-7312;Mekahli|Djalila|D|0000-0003-0954-6088;Pirenne|Jacques|J|0000-0002-8147-8801;Van Geet|Chris|C|0000-0003-1342-6265;Dierickx|Daan|D|0000-0002-8917-022X",
"chemical_list": "D000069286:Bortezomib",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13700",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "24(4)",
"journal": "Pediatric transplantation",
"keywords": "autoimmune cytopenia; autoimmune hemolytic anemia; bortezomib; intestinal transplantation; proteasome inhibitor",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D000069286:Bortezomib; D002675:Child, Preschool; D006801:Humans; D007422:Intestines; D008297:Male; D011183:Postoperative Complications",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13700",
"pmc": null,
"pmid": "32166874",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bortezomib for autoimmune hemolytic anemia after intestinal transplantation.",
"title_normalized": "bortezomib for autoimmune hemolytic anemia after intestinal transplantation"
} | [
{
"companynumb": "BE-TAKEDA-2020TUS014913",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": null,
... |
{
"abstract": "Amebiasis is a parasitic infection caused by the protozoan Entamoeba histolytica. While most infections are asymptomatic, the disease could manifest clinically as amebic dysentery and/or extraintestinal invasion in the form of amebic liver abscess or other more rare manifestations such as pulmonary, cardiac, or brain involvement. Herein we are reporting a case of a 24-year-old male with history of Down syndrome who presented with severe right side pneumonia complicated with multicystic empyema resistant to regular medical therapy. Further investigation revealed a positive pleural fluid for E. histolytica cysts and trophozoites. The patient was diagnosed with primary pleuropulmonary amebiasis and he responded promptly to surgical drainage and metronidazole therapy. In patients from endemic areas all physicians should keep a high index of suspicion of amebiasis as a cause of pulmonary disease.",
"affiliations": "Istishari Hospital, Department of Internal Medicine, Division of Pulmonology, Amman 11183, Jordan.;Istishari Hospital, Department of Internal Medicine, Division of Pulmonology, Amman 11183, Jordan.;Istishari Hospital, Department of Internal Medicine, Division of Pulmonology, Amman 11183, Jordan.",
"authors": "Zakaria|Ali|A|0000-0003-0183-1634;Al-Share|Bayan|B|;Al Asad|Khaled|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2016/8709347",
"fulltext": "\n==== Front\nCase Rep PulmonolCase Rep PulmonolCRIPUCase Reports in Pulmonology2090-68462090-6854Hindawi Publishing Corporation 10.1155/2016/8709347Case ReportPrimary Pulmonary Amebiasis Complicated with Multicystic Empyema http://orcid.org/0000-0003-0183-1634Zakaria Ali \n*\nAl-Share Bayan Al Asad Khaled Istishari Hospital, Department of Internal Medicine, Division of Pulmonology, Amman 11183, Jordan*Ali Zakaria: alizakaria86@hotmail.comAcademic Editor: Reda E. Girgis\n\n2016 10 7 2016 2016 870934731 3 2016 16 6 2016 Copyright © 2016 Ali Zakaria et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Amebiasis is a parasitic infection caused by the protozoan Entamoeba histolytica. While most infections are asymptomatic, the disease could manifest clinically as amebic dysentery and/or extraintestinal invasion in the form of amebic liver abscess or other more rare manifestations such as pulmonary, cardiac, or brain involvement. Herein we are reporting a case of a 24-year-old male with history of Down syndrome who presented with severe right side pneumonia complicated with multicystic empyema resistant to regular medical therapy. Further investigation revealed a positive pleural fluid for E. histolytica cysts and trophozoites. The patient was diagnosed with primary pleuropulmonary amebiasis and he responded promptly to surgical drainage and metronidazole therapy. In patients from endemic areas all physicians should keep a high index of suspicion of amebiasis as a cause of pulmonary disease.\n==== Body\n1. Introduction\nAmebiasis occurs worldwide; it is estimated that approximately 40 to 50 million people develop colitis or extraintestinal disease annually with 40,000 deaths [1]. The prevalence is disproportionately increased in developing countries because of poor socioeconomic conditions and sanitation levels. In most cases the infections are asymptomatic yet; it can manifest clinically as intestinal disease or rarely as extraintestinal invasion in the form of liver abscess, pleuropulmonary, cardiac, or brain disease. The lungs are the second most common site of extraintestinal infection, with pleural invasion accounting for 2-3% of patients with invasive disease.\n\n2. Case Presentation\nThe patient is a 24-year-old male with a history of Down syndrome who was brought to our hospital from Yemen by his brother after 10 days of fever (39.5°C), productive cough, shortness of breath, and right side chest pain. He developed the symptoms after few days of being found eating a sandwich that he hid in an organic fertilized soil of his house backyard. He was brought to our hospital in Jordan after he failed a course of moxifloxacin for assumed diagnosis of community acquired pneumonia.\n\nOn presentation he was still complaining of same symptoms, and he denied any jaundice, abdominal pain, nausea, vomiting, or diarrhea. On physical examination he was alert, oriented, sweaty, and in mild respiratory distress. His vital signs were as follows: temperature 38.3°C; pulse 110 bpm; respiratory rate 26 bpm; blood pressure 90/45 mmHg; and O2% of 82% on room air. He had cracked lips, protruded tongue, erythematous, and dry mucous membranes of the oropharynx. Chest exam revealed significant decreased air entry and tactile vocal fremitus with crackles and minimal wheezes on the right side and normal heart sounds with no murmurs or rubs or gallops. His abdomen was soft and nontender with no evidence of organomegaly.\n\nHe was immediately resuscitated with IVF bolus and oxygen supplementation; his chest X-ray revealed right sided obliteration of costophrenic angle and displaced right lung (Figure 1). CT scan showed right sided pleural effusion with pocket mainly in lateral aspect and in the oblique fissure, multiple gas bubbles with air fluid levels, and partial atelectasis of right middle and lower lobes that are medially displaced (Figure 2). Abdomen ultrasound and CT scan showed no evidence of obvious gross liver pathology.\n\nHe was diagnosed with right sided pneumonia complicated with multicystic empyema, and he underwent thoracotomy with drainage, decortication, and chest tube placement. Light microscopic examination of both pleural fluid and bronchoalveolar lavage sample revealed Entamoeba cysts and trophozoites. Microbiology revealed negative acid-fast stain or fungal infection. Aerobic and anaerobic blood culture showed no growth.\n\nColonoscopy was done and biopsy revealed mixed inflammatory infiltrate suggestive of infection with no demonstrable amoeba. And stool analysis ×3 was also negative for Entamoeba cyst or trophozoites. Serological test was not done due to unavailability.\n\nThe patient was treated with metronidazole 750 mg three times daily; luminal agent was not given due to unavailability in Jordan. His clinical condition significantly improved after 48 hours of antibiotic treatment. On one-month follow-up visit he was free of symptoms, and he returned back to Yemen.\n\n3. Discussion\nAmebiasis is defined by the World Health Organization (WHO) and Pan American Health Organization (PAHO) as a parasitic infection with the protozoan Entamoeba histolytica regardless of symptomatology. It is considered the third most common parasitic infection worldwide with around 500 million infections per year and a leading cause of parasite-related mortality with over 100,000 deaths annually. This protozoal infection has an especially high prevalence in subtropical and tropical countries where poor socioeconomic and sanitary conditions predominate, while in resource-rich nations infections may be seen in travelers to and emigrants from endemic areas [2–5].\n\nThe majority of Entamoeba infections are asymptomatic. Factors that influence whether infection leads to asymptomatic or invasive disease include the E. histolytica strain and host factors such as genetic susceptibility, age, and immune status, where young age, pregnancy, corticosteroid treatment, malignancy, malnutrition, and alcoholism are considered risk factors for severe disease [4].\n\nClinical manifestation of amebiasis generally occurs in the form of intestinal involvement as acute or subacute colitis, with symptoms range from mild diarrhea to severe dysentery producing abdominal pain, diarrhea, and bloody stools, to fulminant amebic colitis. It can also present as extraintestinal disease in the form of amebic liver abscess and even more rare as pulmonary, cardiac, and brain involvement.\n\nPleuropulmonary complications (i.e., pleural effusion, lung abscess, and, rarely, pleural empyema) are the second most frequent extraintestinal complication; they occur in 7–20% of patients with amebic liver abscesses and in 2-3% of those with invasive disease [6]. The presentation of pleuropulmonary amebiasis is variable and depends on the type of pulmonary involvement whether it is primary simulating bronchopneumonia or tuberculosis or secondary to rupture giving the characteristic suppurative syndrome. The most common symptoms include pain, cough, hemoptysis, and dyspnea. The pain may be pleuritic or localized to the right upper quadrant. Cough can be nonproductive but more often is associated with expectoration of material ranging from small amounts of sputum to large amounts of amebic pus. If a hepatobronchial fistula develops, the patient may expectorate necrotic material that can include liver abscess contents; such material may have a reddish brown or “anchovy sauce” appearance [1].\n\nThe theoretical mechanisms of thoracic amebiasis are as follows. First, the infection usually spreads to the lung by direct rupture of an amoebic liver abscess through the diaphragm. Second, the infection may disseminate to the thorax directly from the primary intestinal lesion through hematogenous or lymphatic spread. And finally, inhalation of dust containing cysts of E. histolytica is also a hypothetical route (which is the most probable route in our case) [6, 7].\n\nPleuropulmonary amebiasis is easily confused with other illnesses which makes the differential diagnosis rather a complex one, involving and not limited to (1) pulmonary TB, (2) bacterial lung abscess, (3) carcinoma of the lung, and (4) in endemic areas malaria and schistosomiasis considered common causes of parasitic deaths that can present with unremitting fevers and hepatic or lung disease [8, 9].\n\nThe diagnosis of pleuropulmonary amebiasis may be supported by the clinical manifestation and radiographic imaging such as homogenous opacity or cavitating lesion most commonly involving the right lower and middle lobes, elevated right hemidiaphragm, basilar pulmonary infiltrates with areas of focal atelectasis, and pleural effusions. In the setting of suggestive findings on imaging studies, confirmatory serologic or antigenic testing should be pursued and perhaps supplemented with stool microscopy or antigenic testing of stool [10, 11].\n\nLight microscopic examination can often identify characteristic trophozoites and cysts through direct, concentrated, and/or permanently stained smears. Keeping in mind that the organisms may appear intermittently, specimens from patients with disseminated disease may not contain cysts and trophozoites despite repeated examinations [5]. Immunological tests such as indirect hemagglutination assay (IHA) and enzyme-linked immunosorbent assay (ELISA) for E. histolytica antibodies are characterized by high sensitivity. The primary disadvantage of serologic tests is that they cannot distinguish between past and current infection unless IgM is detected; IgM antibodies to E. histolytica are short-lived and rarely detected. In contrast, IgG antibodies are long-lived but highly prevalent in endemic settings. New serologic tests based on recombinant E. histolytica antigens have been developed; such assays may be especially useful in endemic areas [5, 12].\n\nIn general, amebic pleural effusions should be aspirated. Drained pleural effusions resolve rapidly with drainage and antimicrobial therapy, which consists of metronidazole (750 mg orally three times daily for 7 to 10 days) or alternatively tinidazole (2 g once daily for five days) [13]. Most patients respond to a single course of treatment with resolution of symptoms before the end of therapy. In rare cases, a second course is needed because of failure to achieve complete resolution after the initial regimen. Treatment with a luminal agent such as paromomycin (25–30 mg/kg/day orally in three divided doses for seven days), diiodohydroxyquin (650 mg orally three times daily for 20 days), or diloxanide furoate (500 mg orally three times daily for 10 days) to eliminate intraluminal cysts is also warranted.\n\nThe mortality rate of amebic pleural empyema is as high as 16%, which can increase to 42% due to the rupture of a hepatic abscess into the pleural space. Empyema requires chest tube thoracostomy and decortication to prevent recurrence and chronic infection [8, 10, 14].\n\nIn conclusion, pleuropulmonary amebiasis is the second most frequent extraintestinal complication that can be easily treated with drainage and antimicrobial therapy. Inhalation of dust containing cysts of E. histolytica is a possible route of primary infection. In patients from endemic areas all physicians should keep a high index of suspicion of amebiasis as a cause of pulmonary disease.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nFigure 1 (a) Preoperative chest X-ray shows right sided obliteration of costophrenic angle and displaced right lung. (b) Postoperative resolution of the empyema (note chest tube).\n\nFigure 2 Chest CT scan right sided pleural effusion with pocket mainly in lateral aspect and in the oblique fissure, multiple gas bubbles with air fluid levels (black arrow), and partial atelectasis of right middle and lower lobes that are medially displaced (white arrow).\n==== Refs\n1 Kennedy D. Sharma O. P. Hemoptysis in a 49-year-old man: an unusual presentation of a sporadic disease Chest 1990 98 5 1275 1278 10.1378/chest.98.5.1275 2225980 \n2 WHO/PAHO/UNESCO report. A consultation with experts on amoebiasis. Mexico City, Mexico 28-29 January, 1997 Epidemiological Bulletin 1997 18 1 13 14 \n3 Ximénez C. Morán P. Rojas L. Valadez A. Gómez A. Reassessment of the epidemiology of amebiasis: state of the art Infection, Genetics and Evolution 2009 9 6 1023 1032 10.1016/j.meegid.2009.06.008 2-s2.0-70449587557 \n4 Stanley S. L. Jr. Amoebiasis The Lancet 2003 361 9362 1025 1034 10.1016/s0140-6736(03)12830-9 2-s2.0-0037460789 \n5 Fotedar R. Stark D. Beebe N. Marriott D. Ellis J. Harkness J. Laboratory diagnostic techniques for Entamoeba species Clinical Microbiology Reviews 2007 20 3 511 532 10.1128/cmr.00004-07 2-s2.0-34547400970 17630338 \n6 Shamsuzzaman S. M. Hashiguchi Y. Thoracic amebiasis Clinics in Chest Medicine 2002 23 2 479 492 10.1016/s0272-5231(01)00008-9 12092041 \n7 Meng X.-Y. Wu J.-X. Perforated amebic liver abscess: clinical analysis of 110 cases Southern Medical Journal 1994 87 10 985 990 10.1097/00007611-199410000-00004 2-s2.0-0028088744 7939926 \n8 Shamsuzzaman S. M. Hashiguchi Y. Thoracic amebiasis Clinics in Chest Medicine 2002 23 2 479 492 10.1016/S0272-5231(01)00008-9 2-s2.0-0035985691 12092041 \n9 Salles J. M. Moraes L. A. Salles M. C. Hepatic amebiasis Brazilian Journal of Infectious Diseases 2003 7 2 96 110 2-s2.0-1542758763 12959680 \n10 Lyche K. D. Jensen W. A. Pleuropulmonary amebiasis Seminars in Respiratory Infections 1997 12 2 106 112 2-s2.0-0030947361 9195675 \n11 Pritt B. S. Graham Clark C. Amebiasis Mayo Clinic Proceedings 2008 83 10 1154 1160 10.4065/83.10.1154 2-s2.0-54049096302 18828976 \n12 Stanley S. L. Jr. Jackson T. F. Foster L. Singh S. Longitudinal study of the antibody response to recombinant Entamoeba histolytica antigens in patients with amebic liver abscess American Journal of Tropical Medicine and Hygiene 1998 58 4 414 416 2-s2.0-2642673612 9574784 \n13 Fung H. B. Doan T.-L. Tinidazole: a nitroimidazole antiprotozoal agent Clinical Therapeutics 2005 27 12 1859 1884 10.1016/j.clinthera.2005.12.012 2-s2.0-33644516605 16507373 \n14 Kubitschek K. R. Peters J. Nickeson D. Musher D. M. Amebiasis presenting as pleuropulmonary disease Western Journal of Medicine 1985 142 2 203 207 2-s2.0-0021955297 4013249\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6854",
"issue": "2016()",
"journal": "Case reports in pulmonology",
"keywords": null,
"medline_ta": "Case Rep Pulmonol",
"mesh_terms": null,
"nlm_unique_id": "101585355",
"other_id": null,
"pages": "8709347",
"pmc": null,
"pmid": "27478673",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": "16507373;12660071;12092041;19540361;7939926;18828976;9574784;12959680;17630338;9197085;9195675;4013249;2225980",
"title": "Primary Pulmonary Amebiasis Complicated with Multicystic Empyema.",
"title_normalized": "primary pulmonary amebiasis complicated with multicystic empyema"
} | [
{
"companynumb": "JO-BAYER-2016-156136",
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"actiondrug": null,
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"activesubstancename": "MOXIFLOXACIN"
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... |
{
"abstract": "Massive pulmonary hemorrhage during pulmonary thromboendarterectomy (PTE) can be managed by a conservative approach with mechanical ventilatory support, positive end-expiratory pressure, lung isolation, reversal of heparin, and correct of coagulopathy. We present three challenging cases that developed intrapulmonary hemorrhage during/after PTE and managed successfully. The first patient had bleeding from the bronchial artery and right internal mammary collaterals, which was managed by coil-embolization. The second patient had a breach in the blood airway barrier in the right upper lobar segment of the lung, and the repair was done using a surgical absorbable hemostat. The third patient developed reperfusion injury, he was instituted on veno-venous extracorporeal membranous oxygenation, a week later, the patient recovered completely. An algorithm was adopted and modified to our requirements; all the 3 challenging intrapulmonary hemorrhage cases were successfully managed. This algorithm can be used for satisfactory outcomes in patients who suffer intrapulmonary hemorrhage during PTE.",
"affiliations": "Department of Anaesthesiology and Intensive Care, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India.;Department of Anaesthesiology and Intensive Care, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India.;Department of Anaesthesiology and Intensive Care, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India.;Department of Cardiac Surgery, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India.;Department of Cardiac Surgery, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India.;Department of Anaesthesiology and Intensive Care, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India.;Department of Cardiac Surgery, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India.;Department of Anaesthesiology, University of Minnesota, Minneapolis, MN, United States of America.",
"authors": "Kanchi|Muralidhar|M|;Nair|Hema C|HC|;Natarajan|Pooja|P|;Punnen|Julius|J|;Shetty|Varun|V|;Patangi|Sanjay Orathi|SO|;Shetty|Deviprasad|D|;Belani|Kumar|K|",
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"doi": "10.4103/aca.ACA_191_20",
"fulltext": "\n==== Front\nAnn Card Anaesth\nAnn Card Anaesth\nACA\nAnnals of Cardiac Anaesthesia\n0971-9784\n0974-5181\nWolters Kluwer - Medknow India\n\n34269276\nACA-24-384\n10.4103/aca.ACA_191_20\nCase Report\nManagement of intrapulmonary hemorrhage in patients undergoing pulmonary thrombo-endarterectomy\nKanchi Muralidhar\nNair Hema C\nNatarajan Pooja\nPunnen Julius 1\nShetty Varun 1\nPatangi Sanjay Orathi\nShetty Deviprasad 1\nBelani Kumar 2\nDepartment of Anaesthesiology and Intensive Care, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India\n1 Department of Cardiac Surgery, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore, Karnataka, India\n2 Department of Anaesthesiology, University of Minnesota, Minneapolis, MN, United States of America\nAddress for correspondence: Dr. Muralidhar Kanchi, Anaesthesia and Intensive Care, #258/A, Bommasandra Industrial Area, Anekal Taluk, Bangalore - 560 099, Karnataka, India. E-mail: muralidhar.kanchi.dr@narayanahealth.org\nJul-Sep 2021\n09 7 2021\n24 3 384388\n31 7 2020\n20 9 2020\n24 9 2020\nCopyright: © 2021 Annals of Cardiac Anaesthesia\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.\nMassive pulmonary hemorrhage during pulmonary thromboendarterectomy (PTE) can be managed by a conservative approach with mechanical ventilatory support, positive end-expiratory pressure, lung isolation, reversal of heparin, and correct of coagulopathy. We present three challenging cases that developed intrapulmonary hemorrhage during/after PTE and managed successfully. The first patient had bleeding from the bronchial artery and right internal mammary collaterals, which was managed by coil-embolization. The second patient had a breach in the blood airway barrier in the right upper lobar segment of the lung, and the repair was done using a surgical absorbable hemostat. The third patient developed reperfusion injury, he was instituted on veno-venous extracorporeal membranous oxygenation, a week later, the patient recovered completely. An algorithm was adopted and modified to our requirements; all the 3 challenging intrapulmonary hemorrhage cases were successfully managed. This algorithm can be used for satisfactory outcomes in patients who suffer intrapulmonary hemorrhage during PTE.\n\nChronic thromboembolic pulmonary hypertension\nCTEPH\npulmonary hemorrhage\npulmonary thromboendarterectomy\nPTE\n==== Body\nINTRODUCTION\n\nChronic thromboembolic pulmonary hypertension (CTEPH) is an often-undiagnosed serious illness. The World Health Organization (WHO) has classified this disease as class 4 in the categorization of pulmonary hypertension (PH).[1] Pulmonary hypertension is defined as pulmonary vascular resistance (PVR) ≥3 Wood units in pre-capillary PH associated with a mean pulmonary artery pressure (mPAP) >20 mmHg, and pulmonary artery wedge pressure (PAWP) <15 mmHg by the 6th World symposium on pulmonary hypertension (WSPH) task force.[1] Pulmonary hypertension in chronic pulmonary thromboembolic disease occurs as a result of partial or complete occlusion of the pulmonary vascular bed due to recurrent or residual thrombi. Vascular remodeling in the distal pulmonary arteries contributes to increased PVR, leading to right ventricular dysfunction. Pulmonary endarterectomy (PTE) is the only surgical treatment which is curative for patients who are suffering from CTEPH.[2] The observed survival at 3 years was 89% for operated CTEPH compared to 70% for the non-operated group (P < 0.001).[3] The surgical procedure is technically challenging, requiring a multidisciplinary approach involving careful patient selection, detailed preoperative, intraoperative, and postoperative care plans along with surgical expertise. According to recent report of Madani et al., the in-hospital mortality with the most experienced center has reduced from 4.4% to 2.2%.[4] Significant pulmonary hemorrhage occurs in 1% of PTE cases and is associated with a mortality of nearly 70%.[5] Manecke et al. reported three cases out of 600 procedures (0.5%) and suggested the friability of pulmonary vasculature, advanced age, and presence of residual pulmonary hypertension is likely to result in bleeding.[6]\n\nIn this case report, we illustrate three challenging cases who developed pulmonary bleeding during or after PTE at a tertiary care large-volume cardiac center.\n\nCASE REPORT\n\nCase 1: Systemic to pulmonary arterial collateral bleed managed with coil embolization [Figure 1a]\n\nFigure 1 (goes with case 1) Shows (a) Bronchopulmonary collateral bleed; (b) Preoperative angiogram of descending thoracic aorta showing large Broncho-pulmonary collaterals; (c) Bronchopulmonary collateral bleed coil embolized; (d) Specimen of bronchial clots retrieved with fiberoptic bronchoscope\n\nA 38-year-old female was diagnosed to suffer from CTEPH. Her transthoracic echocardiogram (TTE) showed a dilated right atrium (RA), right ventricle (RV) and main pulmonary artery (MPA), moderate tricuspid regurgitation (TR), increased pulmonary artery pressure (PAP), and reduced biventricular function. A right heart catheterization revealed a PAP of 150/40 mmHg, with an mPAP of 80 mmHg and a PVR of 16.4 Wood units. Systemic to pulmonary arterial collaterals from right internal mammary artery to right middle and upper lobe, left internal mammary artery to left middle lobe, and from the thoracic aorta to right middle and lower lobes were identified on computerized tomography of pulmonary artery (CTPA) [Figure 1b]. PTE was performed under cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). During rewarming on CPB, when the heart could eject, bleeding from the endotracheal tube (ETT) was noticed and fiberoptic bronchoscopy revealed bleeding from the right intermedius bronchus.\n\nThe single lumen ETT was exchanged for a left-sided double-lumen endotracheal tube (DLT) to isolate the right lung and to prevent the soiling of the left lung. In view of severe intrapulmonary hemorrhage, failure of ventilation, and hemodynamic instability, central veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was instituted with a vent in the pulmonary artery. Anesthesia was maintained with inhalation of isoflurane in 50% oxygen, fentanyl, and atracurium infusion. Anticoagulation with heparin was partially reversed with titrated doses of protamine sulfate so as to maintain the activated coagulation time (ACT) between 160 and 180 seconds. Emergency pulmonary angiography revealed the source of bleeding to be the bronchial artery and right internal mammary collaterals, which were successfully coil-embolized in the cardiac catheterization laboratory [Figure 1c]. On the 2nd postoperative day (POD), central VA-ECMO was converted to central veno-venous ECMO (VV-ECMO) in view improvement in cardiac function. Fiberoptic bronchoscopy was performed to retrieve clots from the airway on the 4th POD [Figure 1d]. With control of bleeding and improvement in oxygenation and radiography, the patient was weaned off ECMO on the 8th POD. The patient made an uneventful recovery thereafter. At the time of hospital discharge, the PAP to be 32/16 mmHg, with an mPAP of 23 mmHg and a PVR of 3 Wood units.\n\nCase 2: Breach in blood airway barrier\n\nA 36-year-old male with a history of deep vein thrombosis (DVT) in both lower extremities, presented with increasing shortness of breath on exertion and recurrent hemoptysis for 2 years. TTE showed dilated RV, RA, and pulmonary artery (PA) with severe TR, thrombus in MPA, and significantly reduced RV systolic function. Pre-operative PAP was 100/50 mmHg, with an mPAP of 65 mmHg and a PVR of 17.5 Wood units. CTPA revealed central hypodense filling defects in the MPA, right pulmonary artery (RPA), and left pulmonary artery (LPA) with multiple foci of calcification. The patient underwent PTE surgery on CPB with DHCA. Intraoperative findings revealed an MPA thrombus, UCSD level I disease in RPA, and UCSD level II disease in LPA [Figure 2]. The surgeon suspected a breach in the blood airway barrier in the right upper lobar segment of the lung, hence repair was performed using a surgical absorbable hemostat (Surgicel®, Ethicon, Johnson & Johnson, US).[7] Lung isolation was performed by exchanging ETT to a left-sided DLT and conservative management of bleeding was instituted. After the administration of protamine, bleeding via ETT abated. Post-operative PAP was 50/20 mmHg, with an mPAP of 35 mmHg and a PVR of 8 Wood units. The patient had an uneventful recovery and was discharged in a stable condition on the 12th POD.\n\nFigure 2 (goes with case 2): Specimen of the pulmonary clot retrieved\n\nCase 3: Reperfusion pulmonary edema (RPE) [Figure 3]\n\nFigure 3 (goes with case 3): (a) Chest X-ray showing reperfusion injury; (b) CTPA showing web-like defects in the pulmonary artery segments\n\nA 24-year-old female complained of dyspnea on exertion and was investigated to confirm a diagnosis of CTEPH. She gave a recent history of hemoptysis when she presented for surgery. Pre-operatively, she had PAP of 124/50 mmHg, with an mPAP of 74 mmHg, at an aortic pressure of 140/80 (mean; 100) mmHg and a PVR of 20 Wood units. The TTE showed dilated RA, RV, PA, moderate TR, increased PAP, and borderline left ventricular function. After PTE, the patient exhibited impaired oxygenation and a decreased partial pressure of oxygen (PaO2)/inspired oxygen (FiO2) ratio despite chest X-ray being normal. Inhaled nitric oxide at 60 parts per million was initiated because of persistent pulmonary hypertension. The patient continued to be hypoxic despite adequate ventilation with FiO2 of >0.6. On the 2nd POD, she developed pink frothy secretions from ETT, reduced compliance of lung and radiological features of pulmonary edema. Reperfusion injury was diagnosed after excluding other causes of this clinical picture. A central VV-ECMO (RA to PA) was instituted to maintain oxygenation. Patient was sedated with fentanyl and midazolam infusion. Heparin was administered to achieve anticoagulation to maintain the ACT between 160 and 180 s and activated thromboplastin time of 1.5 times the normal. After one week of ECMO, she made a complete recovery, and her PAP before hospital discharge was 34/18 mmHg, with an mPAP of 24 mmHg and a PVR of 4 Wood units.\n\nDISCUSSION\n\nPTE is a technically very demanding procedure that needs skill, precision, and expertise. An expert center should perform ≥20 PTE operations per year with a <10% mortality rate. Patients with University of California San Diego (UCSD) level IV disease previously considered inoperable now are undergoing surgery in expert centers. Three different causes of intrapulmonary hemorrhage have been highlighted in this report. (i) Bleeding due to rupture of fragile bronchopulmonary collateral: a considerable number of patients suffering from CTEPH present with hemoptysis; such patients may undergo pulmonary angiogram to identify specific collaterals for coil embolization; this can be done either in the immediate preoperative period or after surgery if the patient bleeds form the ETT. Gan et al., showed us that preoperative transcatheter occlusion of the bronchopulmonary collateral artery can reduce the incidence of reperfusion pulmonary edema and reduce ECMO usage.[8] Reesink et al., reported that 5 of 79 patients with CTEPH (6%) had moderate to severe hemoptysis due to systemic to pulmonary arterial collateral bleed, requiring medical intervention.[9] (ii) Damage to blood-airway barrier: If the surgeon suspects violation of the blood-airway barrier during endarterectomy, the surgeon attempts to locate the breach and pack it with a surgical absorbable hemostat as is described.[4] (iii) Reperfusion pulmonary edema: RPE occurs in 10 − 14% of patients following hyper-perfusion of areas of the lung that have undergone endarterectomy. RPE is a hypoxic state associated with a PaO2/FiO2 ratio <300, opacity on chest radiograph, and no alternative explanation such as pneumonia or atelectasis. Management of RPE is supportive including the use of ECMO as a bridge to recovery.[1011]\n\nThere are several other techniques that have been described in the literature techniques to help control pulmonary bleeding after endarterectomy; these use of positive end-expiratory pressure (PEEP), topical vasoconstrictors,[6] temporary overnight clamping of the culprit PA beyond the lobar branch,[12] bronchial occlusion with a Fogarty balloon catheter while on peripheral VA-ECMO.[13] With refractory bleeding, using VV and VA ECMO is lifesaving.[1114] The algorithm for these complications has been published in the textbook of cardiac anesthesia edited by Kaplan.[15] We have adapted and changed this algorithm to suit our requirements with satisfactory outcomes in patients who suffer intrapulmonary hemorrhage during PTE [Figure 4].\n\nFigure 4 Algorithm for the care of pulmonary hemorrhage during/after pulmonary thrombo-endarterectomy. (Abbreviations used in the figure: DLT, double-lumen endotracheal tube; ETT, endotracheal tube; CPB, cardiopulmonary bypass; PA, pulmonary artery; FOB, fiberoptic bronchoscopy; ECMO, extracorporeal membrane oxygenation; VV, veno-venous; VA, veno-arterial; RV, right ventricle; LV, left ventricle; OLV, one-lung ventilation; H/o, history of.)\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nEthical statement\n\nThis study was approved by the institutional review board and ethics committee.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\nAcknowledgments\n\nThe authors would like to acknowledge Dr. V. M. Annapandian (academic consultant), Narayana Hrudayalaya Foundations, for his help in editing this manuscript.\n==== Refs\nREFERENCES\n\n1 Simonneau G Montani D Celermajer DS Denton CP Gatzoulis MA Krowka M Haemodynamic definitions and updated clinical classification of pulmonary hypertension? Eur Respir J 2019 53 1801913 doi: 10.1183/13993003.01913-2018 30545968\n2 Jenkins D Pulmonary endarterectomy: The potentially curative treatment for patients with chronic thromboembolic pulmonary hypertension Eur Respir Rev 2015 24 263 71 26028638\n3 Delcroix M Lang L Pepke-Zaba J Jansa P D’Armini AM Snijder R Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: Results from an international prospective registry Circulation 2016 133 859 71 26826181\n4 Madani MM Auger WR Pretorius V Sakakibara N Kerr KM Kimet NH al. Pulmonary endarterectomy: Recent changes in a single institution’s experience of more than 2,700 patients Ann Thorac Surg 2012 94 97 103 22626752\n5 Mayer E Klepetko W Techniques, and outcomes of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension Proc Am Thorac Soc 2006 3 589 93 16963539\n6 Manecke GR Kotzur A Atkins G Fedullo PF Auger WR Kapelanski DP Massive pulmonary hemorrhage after pulmonary thromboendarterectomy Anesth Analg 2004 99 672 5 15333391\n7 Shetty DP Nair HC Shetty V Punnen J A novel treatment for pulmonary hemorrhage during thromboendarterectomy surgery Ann Thorac Surg 2015 99 e77 8 25742864\n8 Gan HL Zhang JQ Sun JC Feng L Huang XY Luet JK Preoperative transcatheter occlusion of bronchopulmonary collateral artery reduces reperfusion pulmonary edema and improves early hemodynamic function after pulmonary thromboendarterectomy J Thorac Cardiovasc Surg 2014 148 3014 9 24929804\n9 Reesink HJ van Delden OM Kloek JJ Jansen HM Reekers JA Bresseret P Embolization for hemoptysis in chronic thromboembolic pulmonary hypertension: Report of two cases and a review of the literature Cardiovasc Intervent Radiol 2007 30 136 9 17086459\n10 Kerr KM Auger WR Marsh JJ The use of cylexin (CY-1503) in prevention of reperfusion lung injury in patients undergoing pulmonary thromboendarterectomy Am J Respir Crit Care Med 2000 162 14 20 10903213\n11 Thistlethwaite PA Madani MM Kemp AD Hartley M Auger WR Jamieson SW Venovenous extracorporeal life support after pulmonary endarterectomy: Indications, techniques, and outcomes Ann Thorac Surg 2006 82 2139 46 17126125\n12 Reddy S Rajanbabu BB Sunil Kumar NK Rajani I Temporary clamping of branch pulmonary artery for pulmonary hemorrhage after endarterectomy Ann Thorac Surg 2013 96 1459 61 24088460\n13 Yildizeli B Arslan O Tas S Eldem B Aksoy E Koçak T Management of massive pulmonary hemorrhage following pulmonary endarterectomy Thorac Cardiovasc Surg 2014 62 89 91 23208844\n14 Berman M Tsui S Vuylsteke A Successful extracorporeal membrane oxygenation support after pulmonary thromboendarterectomy Ann Thorac Surg 2008 86 1261 7 18805172\n15 Banks DA Auger WR Madani MM Kaplan JA Pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension Cardiac anaesthesia for cardiac and non-cardiac surgery 2016 7th ed Philadelphia, PA Elsevier 994 1021\n\n",
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"keywords": "CTEPH; Chronic thromboembolic pulmonary hypertension; PTE; pulmonary hemorrhage; pulmonary thromboendarterectomy",
"medline_ta": "Ann Card Anaesth",
"mesh_terms": "D002908:Chronic Disease; D004691:Endarterectomy; D006470:Hemorrhage; D006801:Humans; D006976:Hypertension, Pulmonary; D007231:Infant, Newborn; D008168:Lung; D008297:Male; D011651:Pulmonary Artery; D011655:Pulmonary Embolism",
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"title": "Management of intrapulmonary hemorrhage in patients undergoing pulmonary thrombo-endarterectomy.",
"title_normalized": "management of intrapulmonary hemorrhage in patients undergoing pulmonary thrombo endarterectomy"
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"abstract": "The majority of children with FASD suffer from disruptive behaviors and most of them need medications to modify these behaviors. The objective of this review is to familiarize professionals caring for children with FASD with stimulants and other drugs for ADHD, and the second generation antipsychotic risperidone - for aggressive and defiant behaviors.",
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"mesh_terms": "D000293:Adolescent; D000294:Adolescent Behavior; D000367:Age Factors; D014150:Antipsychotic Agents; D001289:Attention Deficit Disorder with Hyperactivity; D019958:Attention Deficit and Disruptive Behavior Disorders; D000697:Central Nervous System Stimulants; D002648:Child; D002652:Child Behavior; D002675:Child, Preschool; D019955:Conduct Disorder; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders; D006801:Humans; D008297:Male; D016896:Treatment Outcome",
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"title": "Medications used in the treatment of disruptive behavior in children with FASD--a guide.",
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"abstract": "Ipilimumab, 10 mg/kg with sargramostim (GM-CSF; GM), improved overall survival (OS) and safety of patients with advanced melanoma over ipilimumab in a randomized phase II trial. The FDA-approved dose of ipilimumab of 3 mg/kg has not been assessed with GM (IPI-GM). Consecutive patients treated with IPI-GM at a single institution were reviewed. Treatment included ipilimumab every 3 weeks × 4 and GM, 250-μg s.c. injection days 1 to 14 of each ipilimumab cycle. Efficacy, clinical characteristics, toxicities, and blinded radiology review of tumor burden were evaluated. Thirty-two patients were identified with 25 (78%) having immune-related response criteria (irRC) measurable disease and 41% with central nervous system metastases. A total of 88.6% of GM doses were administered. Response rate by irRC and disease control rate at 12 weeks were 20% and 44%, respectively (median follow-up 37 weeks). Immune-related adverse events (irAE) were observed in 10 (31.3%) patients, with 3 (9.4%) grade 3 events. Patients with grade 3 irAEs had prior autoimmunity, advanced age, and poor performance status. The median OS from first dose of ipilimumab was 41 weeks. Ipi-GM treatment is feasible and in this poor-risk advanced melanoma population, efficacy appeared similar but safety appeared improved relative to historical ipilimumab alone.",
"affiliations": "Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois. jluke@medicine.bsd.uchicago.edu.;Melanoma Disease Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Radiology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Melanoma Disease Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Melanoma Disease Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Melanoma Disease Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.;Melanoma Disease Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.",
"authors": "Luke|Jason J|JJ|;Donahue|Hilary|H|;Nishino|Mizuki|M|;Giobbie-Hurder|Anita|A|;Davis|Meredith|M|;Bailey|Nancy|N|;Ott|Patrick A|PA|;Hodi|F Stephen|FS|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D011994:Recombinant Proteins; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005240:Feasibility Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D011994:Recombinant Proteins; D012189:Retrospective Studies; D016896:Treatment Outcome",
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"title": "Single Institution Experience of Ipilimumab 3 mg/kg with Sargramostim (GM-CSF) in Metastatic Melanoma.",
"title_normalized": "single institution experience of ipilimumab 3 mg kg with sargramostim gm csf in metastatic melanoma"
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"abstract": "Williams syndrome (WS) is a genetic condition characterized by a unique neurocognitive and behavioral profile, including increased incidence of attention deficit/hyperactivity disorder (ADHD). The purpose of the present study was to examine the perceived helpfulness and side effects of medications used to treat ADHD (methylphenidate class, amphetamine class, atomoxetine) in individuals with WS. This was accomplished with a survey of parents/caregivers of individuals with WS through the Williams Syndrome Association. Five-hundred twelve (512) parents/caregivers responded to the survey regarding their child's/adult child's use of ADHD medications. Twenty-seven percent (27%) of the individuals had been prescribed a medication for ADHD, most commonly a methylphenidate class medication. OROS-methylphenidate was reported as the most helpful methylphenidate class formulation, with 74% reporting it at least somewhat helpful. Survey participants reported similar side effects as typically developing controls, but to a greater degree. Irritability was the most commonly endorsed side effect of an ADHD medication (38%). Individuals reported use of stimulant medications in the presence and absence of underlying cardiac conditions, with 56% of ADHD medication users reporting supravalvular aortic stenosis, 36% pulmonary artery stenosis, and 25% systemic hypertension. Individuals taking ADHD medications were more likely to report dental problems (p=0.004). Additional studies are needed to further investigate these findings and examine short-versus long-acting stimulant medications and dosage effects.",
"affiliations": "The Nisonger Center, The Ohio State University, Columbus, OH 43210, USA. martens.22@osu.edu",
"authors": "Martens|Marilee A|MA|;Seyfer|Daisha L|DL|;Andridge|Rebecca R|RR|;Foster|Jessica E A|JE|;McClure|Kelsey E|KE|;Coury|Daniel L|DL|",
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"keywords": null,
"medline_ta": "Res Dev Disabil",
"mesh_terms": "D000293:Adolescent; D000662:Amphetamines; D001020:Aortic Stenosis, Subvalvular; D001289:Attention Deficit Disorder with Hyperactivity; D017028:Caregivers; D000697:Central Nervous System Stimulants; D002648:Child; D002675:Child, Preschool; D003625:Data Collection; D005260:Female; D006801:Humans; D006973:Hypertension; D015994:Incidence; D007223:Infant; D008297:Male; D001523:Mental Disorders; D008774:Methylphenidate; D015995:Prevalence; D011666:Pulmonary Valve Stenosis; D018980:Williams Syndrome; D055815:Young Adult",
"nlm_unique_id": "8709782",
"other_id": null,
"pages": "1700-9",
"pmc": null,
"pmid": "23500164",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Caregiver survey of pharmacotherapy to treat attention deficit/hyperactivity disorder in individuals with Williams syndrome.",
"title_normalized": "caregiver survey of pharmacotherapy to treat attention deficit hyperactivity disorder in individuals with williams syndrome"
} | [
{
"companynumb": "US-JNJFOC-20130410917",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Sleep-related breathing disruptions in children with epilepsy are common and can range from primary snoring to obstructive sleep apnea. Untreated obstructive sleep apnea can lead to significant morbidity. This study aimed to identify factors associated with its occurrence and severity in children with epilepsy. Children with epilepsy and sleep disruption were evaluated with polysomnography and diagnosed with obstructive sleep apnea or primary snoring. Statistical analyses were done to identify differences within both the groups and among the subjects in the obstructive sleep apnea group. Uncontrolled epilepsy was a risk factor for obstructive sleep apnea (80%) compared with primary snoring (47%, P = .02). Obstructive index increased with increasing number of antiepileptic drugs. In children with epilepsy and disturbed sleep, obstructive sleep apnea is associated with uncontrolled epilepsy and is more severe with polytherapy use. Children with uncontrolled seizures on antiepileptic polytherapy should be routinely screened for obstructive sleep apnea.",
"affiliations": "Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Sejal.Jain@cchmc.org",
"authors": "Jain|Sejal V|SV|;Horn|Paul S|PS|;Simakajornboon|Narong|N|;Glauser|Tracy A|TA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0883073812440326",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "28(1)",
"journal": "Journal of child neurology",
"keywords": null,
"medline_ta": "J Child Neurol",
"mesh_terms": "D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D017286:Polysomnography; D012189:Retrospective Studies; D020181:Sleep Apnea, Obstructive; D012913:Snoring; D013223:Statistics as Topic",
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "77-82",
"pmc": null,
"pmid": "22580903",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Obstructive sleep apnea and primary snoring in children with epilepsy.",
"title_normalized": "obstructive sleep apnea and primary snoring in children with epilepsy"
} | [
{
"companynumb": "US-UCBSA-2020000440",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
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