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"abstract": "Bisphosphonates have been commonly used for the treatment of osteoporosis. However, there have been recent case reports of atypical fractures citing their long-term use, which inhibits the turnover of bone components. A 64-year-old woman visited the outpatient clinic with pain in her right thigh and ambulation difficulty. We found fractures at both pedicles of L4 vertebra. subtrochanteric region of right femur, and left femoral shaft upon a radiologic examination. She had taken intravenous ibandronic sodium for osteoporosis over 3 years. We changed the bishophonates to a parathyroid hormone because it was suspected that the multiple fractures were caused by the medication. Further, rehabilitation, including progressive weight bearing, was started. After 3 months of the conservative treatment, she was able to walk independently. In conclusion, it is necessary to evaluate the possibility of atypical fractures in osteoporotic patients when they complain of lower extremity pain and to consider alternative treatments instead of bisphosphonates.",
"affiliations": "From the Department of Physical and Rehabilitation Medicine (H-SK, H-yJ, M-OK, K-LJ, S-YK, C-HK); and Department of Radiology (YJK), School of Medicine, Inha University, Incheon, Republic of Korea.",
"authors": "Kim|Hyo-Sang|HS|;Jung|Han Young|HY|;Kim|Myeong-Ok|MO|;Joa|Kyung-Lim|KL|;Kim|Yeo Ju|YJ|;Kwon|Su-Yeon|SY|;Kim|Chang-Hwan|CH|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D000077557:Ibandronic Acid",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2565438010.1097/MD.0000000000000446004466900ArticleClinical Case ReportSuccessful Conservative Treatment: Multiple Atypical Fractures in Osteoporotic Patients After Bisphosphate Medication A Unique Case ReportKim Hyo-Sang MDJung Han Young MDKim Myeong-Ok MDJoa Kyung-Lim MDKim Yeo Ju MDKwon Su-Yeon MDKim Chang-Hwan MDSinha. Partha From the Department of Physical and Rehabilitation Medicine (H-SK, H-yJ, M-OK, K-LJ, S-YK, C-HK); and Department of Radiology (YJK), School of Medicine, Inha University, Incheon, Republic of Korea.Correspondence: Chang-Hwan Kim, Department of Physical and Rehabilitation Medicine, Inha University School of Medicine, 27 Inhang-ro, Jung-gu, Incheon 400-711, Republic of Korea (e-mail: jacob.kim@inha.ac.kr).2 2015 06 2 2015 94 5 e44622 10 2014 7 12 2014 16 12 2014 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nBisphosphonates have been commonly used for the treatment of osteoporosis. However, there have been recent case reports of atypical fractures citing their long-term use, which inhibits the turnover of bone components.\n\nA 64-year-old woman visited the outpatient clinic with pain in her right thigh and ambulation difficulty. We found fractures at both pedicles of L4 vertebra. subtrochanteric region of right femur, and left femoral shaft upon a radiologic examination. She had taken intravenous ibandronic sodium for osteoporosis over 3 years.\n\nWe changed the bishophonates to a parathyroid hormone because it was suspected that the multiple fractures were caused by the medication. Further, rehabilitation, including progressive weight bearing, was started. After 3 months of the conservative treatment, she was able to walk independently.\n\nIn conclusion, it is necessary to evaluate the possibility of atypical fractures in osteoporotic patients when they complain of lower extremity pain and to consider alternative treatments instead of bisphosphonates.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nBisphosphonates have been widely prescribed for the treatment of osteoporosis, and their therapeutic effects have been proved.1,2 Bisphosphonates are considered safe, but recent cases have shown that their long-term use may precipitate atypical femoral fractures such as subtrochanteric and diaphyseal femoral fractures.3–5\n\nThis case was about an osteoporotic patient who had suffered atypical fractures on both femurs and the pedicles of the lumbar spine after treatment with intravenous ibandronic sodium, 13 times, over 3 years.\n\nAccordingly, we tried to find correlations between the atypical fractures and bisphosphonates through clinical presentations and radiologic evaluations. Unlike this case, most of the patients with atypical fractures had a medical history of long-term use of bisphosphonate for >5 years, and they usually received surgical fracture treatment.6,7\n\nWe report this rare case of multiple atypical fractures after bisphosphonate therapy. The patient had a successful recovery through conservative treatment.\n\nCase\nA 64-year-old woman visited our clinic in the department of physical medicine and rehabilitation complaining of right thigh pain and both lower extremity weakness. The patient had a limping gait due to the pain in her right thigh, which had persisted for 4 months without direct traumatic episodes. It had aggravated 3 months previously due to slipping in her bathroom. Motor weakness of her right thigh was apparent. The sensation of her lower extremities was normal. Her deep tendon reflexes seemed to be hypoactive, and there was no muscular atrophy.\n\nWe initially assumed that the weakness of her lower extremities was due to inflammatory neuropathy or lumbar herniated nucleus pulposi. However, neurophysiologic studies yielded normal results. We thus suspected a hip joint problem and a consequent magnetic resonance imaging (MRI) scan was conducted. Surprisingly, a linear fracture at the right subtrochanteric cortex and a stress fracture with bone marrow edema at the left femur shaft were observed in the hip joint MRI (Figure 1). We had not suspected fractures to be the cause of the symptoms. The patient also had a hybrid single-photon emission computed tomography (SPECT)-computed tomography (CT) scan 2 weeks later, and it revealed atypical fractures on both femurs and a bilateral fracture of the L4 pedicles as it appeared as a hot uptake (Figure 2). These fractures were found on bone scan in 2013 (Figure 3B). The patient had a hip x-ray 1 month later, and the linear fracture at the right subtrochanteric cortex was aggravated and crossed not only the cortex but also the bone marrow. We thus concluded that the pain and weakness of her lower extremities were due to atypical fractures of both femurs.\n\nFIGURE 1 Hip MRI reveals a right femur subtrochanteric fracture (arrows). MRI = magnetic resonance imaging.\n\nFIGURE 2 Hybrid SPECT–CT scan was conducted. (A) The SPECT-CT demonstrates the bilateral pedicle fracture through L4 (arrows). (B) The SPECT-CT parasagittal reconstruction image confirms L4 pedicle fractures (arrows). SPECT–CT = single-photon emission computed tomography–computed tomography.\n\nFIGURE 3 (A) Bone scan taken in 2011 shows no fractures. (B) Bone scan in 2013 shows multiple fractures including both a femur fracture and a bilateral pedicle (arrows).\n\nShe had been diagnosed with osteoporosis 3 years before by a rheumatologist. Since then, she had received intravenous ibandronic sodium (Bonviva (Roche, Switzerland) injection), a derivative of the bisphosphonates, for osteoporosis starting in 2010, at 3 mg every 3 months, 13 times in total. Bone mineral density (BMD) by dual energy x-ray absorptiometry (DEXA) in 2010 showed the L-spine (T-score −3.0) and the femur (T-score −1.3) without fractures on a bone scan (Figure 3A). Also, she was undergoing cryotherapy and daily nisolone at 2.5 mg weekly and MTX at 5 mg for psoriatic arthritis diagnosed 2 years before for skin lesions and pain in her fingers.\n\nA follow-up study of her BMD by a DEXA in February 2013 showed her L-spine (T-score −3.4) and her femur (T-score −1.6) at the time of the fracture diagnosis. Blood chemical tests revealed a low bone specific alkaline phosphatase of 7.5 (normal 15–41.3) μg/L and osteocalcin of 3.80 (normal 4.00–12.00) ng/mL.\n\nThe patient preferred conservative treatments to surgical management for the multiple fractures. We changed the medication to a monthly subcutaneous injection of a parathyroid hormone and provided her with 3-month rehabilitation programs for partial weight bearing and gait with assistive devices. The follow-up image studies showed an improved union of her femur bone fractures (Figure 4B) compared with the initial image (Figure 4A). After 3 months of the conservative treatment, she was able to walk as an improved union was observed in the x-rays without any adverse medication effects.\n\nFIGURE 4 (A) Femur x-ray was conducted at the time of diagnosis (arrows). (B) Femur x-ray was conducted after conservative management (arrows).\n\nDISCUSSION\nBisphosphonates inhibit bone resorption, and are widely prescribed as a treatment for osteoporosis.1,2 Its mechanism includes inhibiting osteoclasts and inducing their apoptosis, which eventually increases bone density as bone resorption decreases.8,9 Although bisphosphonates are the standardized prevention choice for osteoporosis and fractures,10–12 they may also reduce the bony turnover and cause atypical fractures.3–5\n\nTo date, the most severe known complications of bisphosphonate use is jaw necrosis, and there is a consensus of diagnosis and treatment.13 However, there are no treatment and diagnostic guidelines for atypical fractures despite an increase in the number of incidences.4,14 The incidences of atypical fractures increase as the treatment is prolonged, especially for regiments lasting >5 years.6,7 If an atypical fracture occurred over short-term use, as in this case, contributing factors must be investigated.\n\nWe also need to consider the correlations between the isolated fracture of the bilateral L4 pedicles and the use of bisphosphonates. The fracture at the posterior element of a vertebra may be a malignant pathologic fracture, so it is important to differentiate this from osteoporotic fractures.15 There have been some reports that fractures at pedicles may coincide with osteoporosis, whereas others say they do not.16,17 A previous case demonstrated that patients using the medication, risedronate, longer than 10 years had an isolated fracture of the bilateral L5 pedicles.18 Therefore, further studies may be necessary to find spinal fractures that have occurred as an atypical fracture or as an osteoporotic fracture.\n\nWe observed not only femur fractures but also pedicle fractures on bone SPECT CTs, which was different from previous case reports. Bone scans or SPECT CTs may be helpful to find incidental fractures in different body parts. It is known that a HYBRID bone SPECT CT has a high diagnostic validity in finding jaw necrosis and in differentiating other fractures, which are hard to distinguish in other simple radiologic images.19,20\n\nLastly, the application of an alternative medication, which acts on the osteoblast such as parathyroid hormone, should be considered. In this case, we changed the intravenous bisphosphonates to a parathyroid hormone, expecting that the bone turnover treatment would positively affect the bony union of the right subtrochanteric fractures. Refraining from weight bearing and the use of alternative medication resulted in a successful bony union, as observed on image studies 3 months later. Further, a large-group study is essential to validate conservative treatment for atypical fractures and establish it as a therapeutic guideline.\n\nCONCLUSION\nBisphosphonates are the first line of treatment for osteoporosis, and they are widely used in the world. However, there still are controversies regarding its duration of use and maintenance regiments notwithstanding their adverse effects. Physicians and patients should be aware of the symptoms, which bisphosphonates may cause such as jaw necrosis or atypical fractures. At the same time, it is important to consider not only surgery but also alternative conservative treatments for atypical fractures and establish therapeutic guidelines.\n\nAbbreviations: BMD = bone mineral density, CT = computed tomography, DEXA = dual energy x-ray absorptiometry, MRI = magnetic resonance imaging, SPECT = single-photon emission computed tomography.\n\nWritten informed consent was obtained from the patients for publication of this case report. And the ethical approval was obtained from the Inha review board system (Inha University Hospital Institutional Review Board approval No. 2014-0247).\n\nThis work was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2010-0022109), and an Inha University Research Grant.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Liberman UA Weiss SR Bröll J \nEffect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group . N Engl J Med \n1995 ; 333 :1437 –1443 .7477143 \n2. Lyles KW Colón-Emeric CS Magaziner JS \nHORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture . N Engl J Med \n2007 ; 1 :1799 –1809 .17878149 \n3. Isaacs JD Shidiak L Harris IA \nFemoral insufficiency fractures associated with prolonged bisphosphonate therapy . Clin Orthop Relat Res \n2010 ; 468 :3384 –3392 .20809164 \n4. Schilcher J Michaëlsson K Aspenberg P \nBisphosphonate use and atypical fractures of the femoral shaft . N Engl J Med \n2011 ; 364 :1728 –1737 .21542743 \n5. Bauer DC \nAtypical femoral fracture risk in patients treated with bisphosphonates . Arch Intern Med \n2012 ; 172 :936 –937 .22732750 \n6. Lenart BA Neviaser AS Lyman S \nAssociation of low-energy femoral fractures with prolonged bisphosphonate use: a case control study . Osteoporos Int \n2009 ; 20 :1353 –1362 .19066707 \n7. Park-Wyllie LY Mamdani MM Juurlink DN \nBisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women . JAMA \n2011 ; 305 :783 –789 .21343577 \n8. Reszka AA Rodan GA \nBisphosphonate mechanism of action . Cur Rheu Rep \n2003 ; 5 :65 –74 .\n9. Drake MT Clarke BL Khosla S \nBisphosphonates: mechanism of action and role in clinical practice . Mayo Clin Proc \n2008 ; 83 :1032 –1045 .18775204 \n10. Papaioannou A Morin S Cheung AM \nScientific Advisory Council of Osteoporosis Canada . 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary . CMAJ \n2010 ; 182 :1864 –1873 .20940232 \n11. Qaseem A Snow V Shekelle P \nClinical Efficacy Assessment Subcommittee of the American College of Physicians . Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians . Ann Intern Med \n2008 ; 149 :404 –415 .18794560 \n12. Watts NB Bilezikian JP Camacho PM \nAACE Osteoporosis Task Force . American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis . Endocr Pract \n2010 ; (16 suppl 3) :1 –37 .21224201 \n13. Khan AA Sándor GK Dore E \nCanadian Association of Oral and Maxillofacial Surgeons . Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw . J Rheumatol \n2008 ; 35 :1391 –1397 .18528958 \n14. Schilcher J Aspenberg P \nIncidence of stress fractures of the femoral shaft in women treated with bisphosphonate . Acta Orthop \n2009 ; 80 :413 –415 .19568963 \n15. Cuenod CA Laredo JD Chevret S \nAcute vertebral collapse due to osteoporosis or malignancy: appearance on unenhanced and gadolinium-enhanced MR images . Radiology \n1996 ; 199 :541 –549 .8668809 \n16. Ishiyama M Fuwa S Numaguchi Y \nPedicle involvement on MR imaging is common in osteoporotic compression fractures . Am J Neuroradiol \n2010 ; 31 :668 –673 .20019106 \n17. Doita M Ando Y Hirata S \nBilateral pedicle stress fracture in a patient with osteoporotic compression fracture . Eur Spine J \n2009 ; 18 \nsuppl 2 :206 –209 .19005693 \n18. Rachkidi RE Sari-Leret ML Wolff S \nAtypical bilateral pedicle fracture in long-term bisphosphonate therapy . Spine \n2011 ; 36 :E1769 –1773 .21415813 \n19. Fabbricini R Catalano L Pace L \nBone scintigraphy and SPECT/CT in bisphosphonate-induced osteonecrosis of the jaw . J Nucl Med \n2009 ; 50 :1385 .19617329 \n20. Probst S Rakheja R Stern J \nAtypical bisphosphonate-associated subtrochanteric and femoral shaft stress fractures: diagnostic features on bone scan . Clin Nucl Med \n2013 ; 38 :397 –399 .23478849\n\n",
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"mesh_terms": "D015519:Bone Density; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D005269:Femur; D050723:Fractures, Bone; D006801:Humans; D000077557:Ibandronic Acid; D008159:Lumbar Vertebrae; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal",
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"title": "Successful conservative treatment: multiple atypical fractures in osteoporotic patients after bisphosphate medication: a unique case report.",
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"abstract": "Immune checkpoint inhibitory (ICI) therapy represents a novel approach in a variety of cancers, with impressive survival benefit. With ICIs, however, a new spectrum of immune related adverse events (irAE) including life threatening hypohysitis has emerged. This autopsy study aimed to investigate inflammatory cells, PD-1 and PD-L1 expression in cases of patients who developed hypophysitis and involvement of other organs. We analysed 6 patients, who were treated with ICIs and developed hypophysitis. Two received an additional MAP-kinase inhibitor, MEK-inhibitor and cytotoxic chemotherapy. Besides the pituitary gland, all investigated adrenal glands (5/5) were affected; three cases had other organs involved (liver (2/6), thyroid (2/6), lung (1/6), myocardium (1/6), colon (1/6). The inflammatory cells of involved organs were further specified and PD1 and PDL-1 expression was analyzed using immunohistochemistry. We observed that patients treated with ICIs alone showed T-cell predominant lymphocytic infiltrates, whereas patients receiving additional therapies demonstrated an increase in B- and T-lymphocytes. Surprisingly, the dominant inflammatory population was not T-cell, but type 2 macrophages. CD25 positive T-regs were sparse or absent. Our study suggests that T cell activation is only partially responsible for irAE. ICI therapy interaction with CTLA-4, PD-1 and PDL-1 in type 2 macrophages appears to result in disturbance of their control. Furthermore, depletion of T-regs seems to contribute significantly. Our findings with simultaneous pituitary and adrenal gland involvement underlines the systemic involvement as well as the importance of monitoring cortisol levels to avoid potentially life threatening hypocortisolism.",
"affiliations": "Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland. Electronic address: Daniela.mihic@usz.ch.;Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.;Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.;Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.;Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.;Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.;Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.;Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.;Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.",
"authors": "Mihic-Probst|Daniela|D|;Reinehr|Michael|M|;Dettwiler|Susanne|S|;Kolm|Isabel|I|;Britschgi|Christian|C|;Kudura|Ken|K|;Maggio|Ewerton Marques|EM|;Lenggenhager|Daniela|D|;Rushing|Elisabeth J|EJ|",
"chemical_list": "D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000082082:Immune Checkpoint Inhibitors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor",
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"title": "The role of macrophages type 2 and T-regs in immune checkpoint inhibitor related adverse events.",
"title_normalized": "the role of macrophages type 2 and t regs in immune checkpoint inhibitor related adverse events"
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"abstract": "BACKGROUND\nAortic thrombi in the ascending aorta or aortic arch are rare but are associated with a relevant risk of major stroke or distal embolization. Although stent grafting is commonly used as a treatment option in the descending aorta, only a few case reports discuss stenting of the aortic arch for the treatment of a thrombus. The use of bare metal stents in this setting has not yet been described.\n\n\nMETHODS\nWe report two cases of ascending and aortic arch thrombus that were treated by covering the thrombus with an uncovered stent. Both procedures were performed under local anesthesia via a femoral approach. A femoral cutdown was used in one case, and a total percutaneous insertion was possible in the second case.\n\n\nRESULTS\nBoth procedures were successfully performed without any periprocedural complications. Postoperative recovery was uneventful. In both cases, no late complications or recurrent embolization occurred at midterm follow-up, and control CT angiography at 1 respectively 10 months revealed no stent migration, freely perfused supra-aortic branches, and no thrombus recurrence.\n\n\nCONCLUSIONS\nTreating symptomatic thrombi in the ascending aorta or aortic arch with a bare metal stent is feasible. This technique could constitute a minimally invasive alternative to a surgical intervention or complex endovascular therapy with fenestrated or branched stent grafts.",
"affiliations": "Department of Diagnostic Radiology, University Hospital Giessen and Marburg, Philipps University of Marburg, Baldingerstrasse, 35033, Marburg, Germany. mahnken@med.uni-marburg.de",
"authors": "Mahnken|Andreas H|AH|;Hoffman|Andras|A|;Autschbach|Rüdiger|R|;Damberg|Anneke L M|AL|",
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"mesh_terms": "D001013:Aorta, Thoracic; D001027:Aortography; D001157:Arterial Occlusive Diseases; D019917:Blood Vessel Prosthesis Implantation; D057510:Endovascular Procedures; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008670:Metals; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D061214:Patient Safety; D011474:Prosthesis Design; D018570:Risk Assessment; D012494:Sampling Studies; D015607:Stents; D013927:Thrombosis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
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"title": "Bare metal stenting for endovascular exclusion of aortic arch thrombi.",
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"abstract": "BACKGROUND\nLong-term immunosuppression is associated with an increased risk of cancer. Especially, the immunosuppression in pancreas transplantation is more intensive than that in other organ transplantation because of its strong immunogenicity. Therefore, it suggests that the risk of post-transplant de novo malignancy might increase in pancreas transplantation. However, there have been few studies of de novo malignancy after pancreas transplantation. The aim of this study was to analyze the incidence of de novo malignancy after pancreas transplantation in Japan.\n\n\nMETHODS\nPost-transplant patients with de novo malignancy were surveyed and characterized in Japan.\n\n\nRESULTS\nAmong 107 cases receiving pancreas transplantation in Japan between 2001 and 2010, de novo malignancy developed in 9 cases (8.4%): post-transplant lymphoproliferative disorders in 6 cases, colon cancer in 1 case, renal cancer in 1 case, and brain tumor in 1 case.\n\n\nCONCLUSIONS\nWe clarified the incidence of de novo malignancy after pancreas transplantation in Japan.",
"affiliations": "Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan; Department of Complementary and Alternative Medicine, Osaka University, Graduate School of Medicine, Osaka, Japan; The Japan Registry of Pancreas Transplantation, The Japan Society for Pancreas and Islet Transplantation, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan; The Japan Registry of Pancreas Transplantation, The Japan Society for Pancreas and Islet Transplantation, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan.;Department of Surgery, Osaka University, Graduate School of Medicine, Osaka, Japan. Electronic address: hnagano@gesurg.med.osaka-u.ac.jp.",
"authors": "Tomimaru|Y|Y|;Ito|T|T|;Marubashi|S|S|;Kawamoto|K|K|;Tomokuni|A|A|;Asaoka|T|T|;Wada|H|H|;Eguchi|H|H|;Mori|M|M|;Doki|Y|Y|;Nagano|H|H|",
"chemical_list": null,
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"delete": false,
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"issue": "47(3)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D001932:Brain Neoplasms; D002292:Carcinoma, Renal Cell; D003110:Colonic Neoplasms; D005260:Female; D005909:Glioblastoma; D006801:Humans; D015994:Incidence; D007564:Japan; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D016035:Pancreas Transplantation; D011183:Postoperative Complications; D012306:Risk",
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"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "De novo malignancy after pancreas transplantation in Japan.",
"title_normalized": "de novo malignancy after pancreas transplantation in japan"
} | [
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"abstract": "Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.",
"affiliations": "Hôpitaux universitaires Paris Ouest, hôpital européen Georges-Pompidou, service de biochimie, pôle biologie-pathologie-PUI-hygiène, 20, rue Leblanc, 75015 Paris, France.;Département de data-management, fédération francophone de cancérologie digestive, 7, boulevard Jeanne-d'Arc, BP 87900, 21079 Dijon, France.;Département de statistique, fédération francophone de cancérologie digestive, 7, boulevard Jeanne-d'Arc, BP 87900, 21079 Dijon, France.;Département de statistique, fédération francophone de cancérologie digestive, 7, boulevard Jeanne-d'Arc, BP 87900, 21079 Dijon, France.;Centre hospitalier universitaire de la Timone, service d'hépato-gastroentérologie et d'oncologie médicale, 264, rue Saint-Pierre, 13385 Marseille, France.;Centre hospitalier universitaire Charles-Nicolle, service d'oncologie, 1, rue Germont, 76031 Rouen, France.;Centre hospitalier régional, service d'hépato-gastroentérologie et oncologie digestive, 14, avenue de l'Hôpital, 45100 Orléans, France.;Centre hospitalier universitaire Robert-Debré, service d'hépato-gastroentérologie et cancérologie digestive, avenue du Général-Koenig, 51092 Reims, France.;AP-HP, hôpital Saint-Antoine, Sorbonne université, département d'oncologie médicale, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France.;Centre hospitalier départemental (CHD) Vendée, service d'hépato-gastroentérologie, boulevard Stéphane-Moreau, 85925 La Roche-sur-Yon, France.;Service d'oncologie médicale, Gustave-Roussy, 114, rue Edouard-Vaillant, 94805 Villejuif, France.;Université Paris-Saclay, centre Gustave-Roussy, département de médecine oncologique, 114, rue Edouard-Vaillant, 94805 Villejuif, France.;Centre Antoine-Lacassagne, département d'oncologie médicale, 33, avenue de Valombrose, 06189 Nice cedex 2, France.;Centre François-Baclesse-ARCHADE, département de radiothérapie, 3, avenue du général-Harris, 14000 Caen, France.;Institut Claudius-Regaud IUCT-Oncopole, et CRCT Inserm 1037, laboratoire de biologie médicale oncologique, 1, avenue Irène-Joliot-Curie, 31100 Toulouse, France.;CHU Bretonneau, laboratoire de biochimie et biologie moléculaire, 2, boulevard Tonnellé, 37000 Tours, France.;AP-HM, hôpital La Timone, laboratoire de pharmacocinétique et toxicologie, 264, rue Saint-Pierre, 13005 Marseille, France.;CHU Carémeau, laboratoire de biochimie et biologie moléculaire, rue du Professeur-Debré, 30900 Nîmes, France.;Laboratoire d'oncopharmacologie, centre Antoine-Lacassagne, 33, avenue de Valombrose, 06189 Nice cedex 2, France. Electronic address: marie-christine.etienne@nice.unicancer.fr.",
"authors": "Loriot|Marie-Anne|MA|;Masskouri|Fadil|F|;Carni|Paolo|P|;Le Malicot|Karine|K|;Seitz|Jean-François|JF|;Michel|Pierre|P|;Legoux|Jean-Louis|JL|;Bouché|Olivier|O|;André|Thierry|T|;Faroux|Roger|R|;Delaloge|Suzette|S|;Malka|David|D|;Guigay|Joel|J|;Thariat|Juliette|J|;Thomas|Fabienne|F|;Barin-Le-Guellec|Chantal|C|;Ciccolini|Joseph|J|;Boyer|Jean-Christophe|JC|;Étienne-Grimaldi|Marie-Christine|MC|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D011743:Pyrimidines; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "France",
"delete": false,
"doi": "10.1016/j.bulcan.2019.04.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-4551",
"issue": "106(9)",
"journal": "Bulletin du cancer",
"keywords": "DPD; Dihydropyrimidine dehydrogenase; Dihydropyrimidine déshydrogénase; Dépistage; Enquête; Fluoropyrimidine; Screening; Surveys; Toxicity; Toxicité",
"medline_ta": "Bull Cancer",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001695:Biology; D035843:Biomedical Research; D001943:Breast Neoplasms; D000069287:Capecitabine; D004067:Digestive System Neoplasms; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D005260:Female; D005472:Fluorouracil; D005602:France; D005838:Genotype; D019538:Health Care Surveys; D006801:Humans; D000072103:Oncologists; D010039:Otorhinolaryngologic Neoplasms; D060735:Pharmacovigilance; D017410:Practice Guidelines as Topic; D011743:Pyrimidines; D012051:Reimbursement Mechanisms",
"nlm_unique_id": "0072416",
"other_id": null,
"pages": "759-775",
"pmc": null,
"pmid": "31253356",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists.",
"title_normalized": "dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine results of two national practice surveys addressed to clinicians and biologists"
} | [
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"companynumb": "CH-ORION CORPORATION ORION PHARMA-21_00015638",
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"activesubstancename": "METHOTREXATE"
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"abstract": "SARS-CoV-2 has wreaked havoc globally and has claimed innumerable lives all over the world. Apart from the characteristic respiratory illness, this disease has been associated with florid extrapulmonary manifestations and complications. A 59-year-old female healthcare worker presented with features of acute-onset non-compressive myelopathy with a sensory level at T10 segment along with high-grade fever for 4 days. MRI of dorsal spine was suggestive of myelitis at T7 vertebral level. She was initiated on injectable steroids and did show some initial signs of recovery. A day later, she developed an acute-onset respiratory failure but could not be revived despite our best efforts. Her nasopharyngeal and oropharyngeal swab turned out to be positive for SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR). We hereby report a case of acute transverse myelitis with COVID-19 as a probable aetiology.",
"affiliations": "Internal Medicine, R G Kar Medical College and Hospital, Kolkata, India.;Internal Medicine, R G Kar Medical College and Hospital, Kolkata, India chandraatanu123@gmail.com.;Internal Medicine, R G Kar Medical College and Hospital, Kolkata, India.;Internal Medicine, R G Kar Medical College and Hospital, Kolkata, India.",
"authors": "Chakraborty|Uddalak|U|;Chandra|Atanu|A|http://orcid.org/0000-0002-3809-8926;Ray|Aritra Kumar|AK|;Biswas|Purbasha|P|",
"chemical_list": "D005938:Glucocorticoids; D008775:Methylprednisolone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238668",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(8)",
"journal": "BMJ case reports",
"keywords": "infectious diseases; spinal cord",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D008775:Methylprednisolone; D008875:Middle Aged; D009188:Myelitis, Transverse; D058873:Pandemics; D011024:Pneumonia, Viral; D012131:Respiratory Insufficiency; D000086402:SARS-CoV-2; D013904:Thoracic Vertebrae",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32843475",
"pubdate": "2020-08-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32104915;32238976;31978945;32312872;23186897;32835294;32294339;32275288;32409215;32458198",
"title": "COVID-19-associated acute transverse myelitis: a rare entity.",
"title_normalized": "covid 19 associated acute transverse myelitis a rare entity"
} | [
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"companynumb": "IN-SGP-000008",
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"activesubstancename": "METHYLPREDNISOLONE"
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{
"abstract": "Although non-small-cell lung cancer occasionally presents as cavitary lesions, it is rare for small-cell lung cancer (SCLC) to present or progress in such a manner. If a cavitary lesion is seen in the setting of small-cell lung carcinoma, infectious etiologies must be excluded first. We present the case of a 43-year-old man with refractory SCLC that progressed despite two lines of therapy, and who was ultimately found to have recurrent adenopathy and numerous widespread cavitary lung nodules. Fine-needle aspiration of a hilar lymph node revealed extensively necrotic SCLC, while bronchoalveolar cultures grew Aspergillus fumigatus and Candida albicans. The patient was subsequently treated with voriconazole; however, despite these measures, his overall clinical course deteriorated and the patient ultimately succumbed to his illness. Aspergillosis is a major cause of cavitary lung lesions, especially in immunocompromised patients. Our patient with refractory stage four SCLC was found to have several cavitary lung lesions. Before assuming that cavitary lesions are neoplastic, evaluation for aspergillosis should be conducted, particularly in SCLC patients. Although invasive fungal infections are often missed, it may be prudent to conduct such testing because aspergillosis is a treatable condition and the treatment can improve a patient's hospitalization and overall clinical course.",
"affiliations": "Department of Internal Medicine, Roger Williams Medical Center, Providence, USA.;Division of Hematology/Oncology, Roger Williams Medical Center, Providence, USA.;Division of Hematology/Oncology, University of California, Irvine School of Medicine, Irvine, USA.",
"authors": "Tannous|Toufic|T|;Mak|Andrew|A|;Keating|Matthew|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.13691",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13691\nInternal Medicine\nInfectious Disease\nOncology\nSmall-Cell Lung Cancer Cavities: Primary or Secondary?\nMuacevic Alexander\nAdler John R\nTannous Toufic 1\nMak Andrew 2\nKeating Matthew 3\n1 Department of Internal Medicine, Roger Williams Medical Center, Providence, USA\n2 Division of Hematology/Oncology, Roger Williams Medical Center, Providence, USA\n3 Division of Hematology/Oncology, University of California, Irvine School of Medicine, Irvine, USA\nToufic Tannous 2fictannous@gmail.com\n4 3 2021\n3 2021\n13 3 e136914 3 2021\nCopyright © 2021, Tannous et al.\n2021\nTannous et al.\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/53417-small-cell-lung-cancer-cavities-primary-or-secondary\nAlthough non-small-cell lung cancer occasionally presents as cavitary lesions, it is rare for small-cell lung cancer (SCLC) to present or progress in such a manner. If a cavitary lesion is seen in the setting of small-cell lung carcinoma, infectious etiologies must be excluded first. We present the case of a 43-year-old man with refractory SCLC that progressed despite two lines of therapy, and who was ultimately found to have recurrent adenopathy and numerous widespread cavitary lung nodules. Fine-needle aspiration of a hilar lymph node revealed extensively necrotic SCLC, while bronchoalveolar cultures grew Aspergillus fumigatus and Candida albicans. The patient was subsequently treated with voriconazole; however, despite these measures, his overall clinical course deteriorated and the patient ultimately succumbed to his illness. Aspergillosis is a major cause of cavitary lung lesions, especially in immunocompromised patients. Our patient with refractory stage four SCLC was found to have several cavitary lung lesions. Before assuming that cavitary lesions are neoplastic, evaluation for aspergillosis should be conducted, particularly in SCLC patients. Although invasive fungal infections are often missed, it may be prudent to conduct such testing because aspergillosis is a treatable condition and the treatment can improve a patient’s hospitalization and overall clinical course.\n\nsmall-cell lung cancer\ncavitary lesions\naspergillus\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nA cavitary lung lesion is a gas-filled space within a zone of pulmonary consolidation, mass, or nodule. It is produced by the expulsion of a necrotic part of the lesion via the bronchial tree. The etiology of the cavity can be either infectious or non-infectious. Prominent infectious agents can be bacterial (e.g., Staphylococcus aureus, Klebsiella pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, mycobacterial organisms), fungal (e.g., Aspergillus), or parasitic (e.g., Echinococcus). Non-infectious etiologies include primary lung tumors, most commonly squamous cell carcinoma or metastatic disease, and on rare occasions, pulmonary emboli [1].\n\nA. fumigatus can affect the lung in the following ways: allergic bronchopulmonary aspergillosis, which afflicts patients with long-standing asthma; aspergilloma, which can be found in patients with preexisting lung cavities; chronic necrotizing aspergillosis, affecting patients with chronic lung disease; and invasive aspergillosis, more commonly seen in immunocompromised and critically ill hosts [2]. Lung cancer patients are especially at risk given the high incidence of chemotherapy-induced neutropenia and a compromised immune system.\n\nRegarding primary lung malignancies, non-small-cell lung cancers (NSCLC) have the potential to form cavitary lung lesions or progress in that form. In fact, squamous cell carcinoma is the most common type of NSCLC described that cavitates. In some of these NSCLC cases, aspergilloma is found to be occupying these cavities, and the co-existence of Aspergillus and NSCLC is a frequently reported incident [3,4]. However, cases of small-cell lung cancer (SCLC) with concurrent Aspergillus and cavitary lesions have only been described previously in rare instances [5].\n\nWe describe a patient with extensive-stage refractory SCLC who failed two lines of chemotherapy, progressing to form multiple cavitary lesions. According to our literature search, SCLC does not commonly present or progress as cavitary lung lesions. This anomaly led us to further investigate the nature of these lung lesions and discover a co-existing Aspergillus infection.\n\nCase presentation\n\nA 43-year-old man presented with hoarseness in his voice for five months, fatigue, weakness, and 30-pound weight loss. He had a medical history of essential hypertension treated with beta blockers. He was a 30-pack-year smoker and a chronic alcohol drinker. His family history was pertinent for essential hypertension and diabetes mellitus. A computed tomography (CT) of the chest revealed bulky left mediastinal adenopathy. Subsequent bronchoscopy and transbronchial biopsy of the lesion confirmed the diagnosis of SCLC with thyroid transcription factor 1, synaptophysin, and Ki-67 positive stains. Head CT showed a left paracentral cerebellar mass. The patient initially underwent six cycles of carboplatin and etoposide, and a significant response was seen. He was then given whole-brain radiation and 10 fractions of thoracic radiation.\n\nRepeat CT of the chest/abdomen/pelvis showed a new right paratracheal node and an increase in left hilar adenopathy and a new left adrenal nodule. He was then started on second-line chemotherapy for relapsed/refractory disease with six cycles of irinotecan. Follow-up imaging showed a new cerebellar metastasis and a new right frontal lobe metastasis, as well as an increase in the adrenal nodule size. Due to the cerebral edema seen on imaging, he was started on dexamethasone. After his fatigue improved, his steroids were tapered off and discontinued. He was then scheduled to start third-line therapy with nivolumab, but it was delayed for a few weeks as he developed cholecystitis requiring a cholecystectomy. After the surgery, the patient was recovering well and felt better for a couple of weeks until he started to feel dyspneic again. He was sent to the hospital where a CT chest/abdomen/pelvis showed significant adenopathy and several widespread cavitary lung nodules (Figure 1).\n\nFigure 1 CT scan of the chest without contrast showing pulmonary cavities in a patient with SCLC.\n\nCT, computed tomography; SCLC, small cell lung cancer\n\nWorkup for the cavitary lung lesions included Epstein-Barr virus polymerase chain reaction, anti-streptolysin O antibody titers, anti-DNAse level, and a serum beta-D-glucan level. All results came back within normal limits except for an elevated beta-D-glucan result with a level above 500 pg/mL (reference range: 0-60 pg/mL). A bronchoscopy with a bronchoalveolar lavage (BAL) was performed for all lung lobes. The BAL fluid was sent for gram stain and culture, fungal culture, acid-fast bacilli (AFB), Legionella, Pneumocystis jirovecii, fluid galactomannan, and cytology. All fungal cultures came back positive for A. fumigatus and Candida albicans. The left lobe fluid galactomannan yielded a positive result with an index of 2.7 (normal index: <0.5). Brushing of the left hilar mass (Figure 2) came back positive for SCLC with extensive necrosis. The patient was then treated with voriconazole. Unfortunately, due to the patient’s extensive disease and poor prognosis, his overall condition continued to deteriorate despite treatment. He and his family opted for hospice care, and he eventually succumbed to his illness.\n\nFigure 2 Arrow showing the 4 × 4.2 cm hilar mass that was brushed.\n\nDiscussion\n\nThis case describes a patient with extensive-stage SCLC who eventually progressed through two lines of chemotherapy and radiotherapy. During his final hospitalization, he was found to have multiple cavitary lung masses and nodules. As it was difficult to elucidate the exact nature of these nodules, bronchoscopy was performed to sample the nearby tissue. Unexpectedly, in the setting of multiple cavitary lesions, the cytology from the left hilar mass showed SCLC with extensive necrosis. As previously mentioned, a cavity is formed after the central necrotic part within a mass is expelled. This is a particularly interesting finding because rare, if any, cases of SCLC with cavities have been reported [1,4]. A few reports have mentioned the cavitation of SCLC lesions, but this was mostly seen after treatment with anti-angiogenic agents, which was not the case here [6]. Moreover, BAL cultures grew A. fumigatus, and BAL fluid was positive for galactomannan. This also confounds the clinical scenario as the origin of these nodules could be small-cell tumors, invasive aspergillosis, or a combination of both with small-cell lung cavitations containing aspergillomas. It is very difficult to distinguish invasive aspergillosis solely based on imaging [3].\n\nMost cases of primary cavitary lung lesions are non-small cell in origin, mainly squamous cell carcinoma and adenocarcinoma [4]. These cavitating NSCLC lesions tend to overexpress the epidermal growth factor receptor marker [5]. The reason behind this characteristic association could be secondary to the tumor type itself or due to previous therapy [7]. In fact, around 19% of NSCLC lesions are thought to cavitate after treatment with anti-angiogenic therapy [8]. It was previously considered that cavitary lesions represent chemo-resistant lesions and may carry a worse outcome than non-cavitary lesions [9]. So far, the prognostic significance of such a presentation remains to be seen. Multiple studies have been performed to elucidate any prognostic implications, but none has yielded results thus far [10,11]. Other studies tried to associate wall thickness with outcome and chemo-responsiveness [12]. To date, the clinical relevance and prognostic implications remain unknown.\n\nA. fumigatus is one of the several infectious causes of lung cavities and can present in the lung in various ways depending on the patient’s underlying pulmonary disease, presence of organ failure, and current immune status on or off immunosuppressive agents [13]. Invasive aspergillosis is seen in patients with a compromised immune system, causing cavitary lung lesions. It can mimic metastatic lung disease [14], or it can coexist within the primary lung cancer [15]. In many cases, this phenomenon has also been seen after NSCLC treatment, including chemotherapy or surgery [16,17]. Some studies have shown that surface binding proteins such as E-cadherins may play a role in the affinity between non-small-cell tumor cells and the Aspergillus species [18].\n\nThe association between aspergillosis and SCLC has not been documented extensively, and the presence of Aspergillus in our patient may appear to be an unusual finding. However, it is quite possible that Aspergillus infections are frequently overlooked in SCLC versus NSCLC patients. There are nearly six-fold as many cases of NSCLC as there are of SCLC in the United States [19]. SCLC almost invariably recurs and is such a threat to mortality that it is easy to ignore how other causes contribute to a patient’s decline. We would argue that, given the data available and cases like ours, a heightened awareness of Aspergillus in SCLC is indicated, particularly when ambiguous cavitating lesions are present.\n\nBased on NSCLC’s predilection for cavitation, one might assume that there would be a higher incidence of Aspergillus infections in NSCLC versus SCLC patients. However, a retrospective study discredits this assumption, and we would like to draw attention to this study to emphasize the importance of increased awareness for Aspergillus infections in SCLC patients. In a retrospective analysis of 1,711 lung cancer patients, 2.63% were found to have developed invasive pulmonary aspergillosis. NSCLC patients greatly outnumbered SCLC patients in the study. However, when the aspergillosis infection rate was broken down by lung cancer subtype, the results were comparable in NSCLC versus SCLC, with no significant difference between the two groups (2.51% in NSCLC versus 3.28% in SCLC) [16].\n\nConsidering the high incidence of chemotherapy-induced neutropenia and prolonged steroid use in SCLC, it is not a surprise that bacterial, viral, and/or fungal infections can complicate treatment. Furthermore, with the rise of immunotherapy use in extended-stage SCLC, high-dose steroids often provide the antidote to immunotherapy side effects but also predispose patients to more infections. This raises the question of prophylactic antifungal therapy in these patients. Antifungal therapy is the mainstay for prophylaxis against invasive fungal infections in post-transplant leukemia/lymphoma patients. For practical purposes, any cancer patient on prolonged steroids and chemotherapy can be considered for antifungal prophylaxis. Both prolonged steroids and chemotherapy administration in the month preceding infection are significant risk factors for invasive pulmonary aspergillosis in lung cancer patients [16]. However, several trials have failed to show a mortality benefit for antifungal prophylaxis in non-transplant patients [20]. Without a strict guideline for antifungal prophylaxis in solid tumor patients, this puts an even greater emphasis on the importance of expedient detection and treatment of invasive fungal infections.\n\nConclusions\n\nTesting cavitary lesions for the presence of A. fumigatus in the setting of SCLC or NSCLC is not routinely done but should be performed if such lesions emerge in these patients. Infectious etiologies should be considered in addition to disease recurrence. Treatment for aspergillosis is widely available and can greatly improve a patient’s clinical outcome if implemented early. Nearly all SCLC patients eventually have disease relapse, but forgoing further workup for abundant cavitary lesions can do the patient a great disservice.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Cavitary pulmonary disease Clin Microbiol Rev Gadkowski LB Stout JE 305 333 21 2008 18400799\n2 Pulmonary aspergillosis: imaging findings with pathologic correlation AJR Am J Roentgenol Aquino SL Kee ST Warnock ML Gamsu G 811 815 163 1994 8092014\n3 Fungal diseases mimicking primary lung cancer: radiologic-pathologic correlation Mycoses Gazzoni FF Severo LC Marchiori E 197 208 57 2014 24147761\n4 Lung adenocarcinoma presenting with enlarged and multiloculated cystic lesions over 2 years Respir Care Yoshida T Harada T Fuke S 1522 1524 49 2004 http://rc.rcjournal.com/content/49/12/1522.short 15571644\n5 Tumor cavitation in stage I non-small cell lung cancer: epidermal growth factor receptor expression and prediction of poor outcome Radiology Onn A Choe DH Herbst RS 342 347 237 2005 16183941\n6 Prognostic value of tumor cavitation in extensive-stage small-cell lung cancer patients treated with anlotinib J Cancer Res Clin Oncol Chen D Xu J Zhao Y 401 406 146 2020 31691871\n7 Tumor cavitation in patients with stage III non-small-cell lung cancer undergoing concurrent chemoradiotherapy: incidence and outcomes J Thorac Oncol Phernambucq ECJ Hartemink KJ Smit EF Paul MA Postmus PE Comans EFI Senan S 1271 1275 7 2012 22659960\n8 Tumor cavitation: impact on objective response evaluation in trials of angiogenesis inhibitors in non-small-cell lung cancer J Clin Oncol Crabb SJ Patsios D Sauerbrei E 404 410 27 2009 19047292\n9 Cavitating squamous cell lung carcinoma-distinct entity or not? Analysis of radiologic, histologic, and clinical features Lung Cancer Pentheroudakis G Kostadima L Fountzilas G Kalogera-Fountzila A Klouvas G Kalofonos C Pavlidis N 349 355 45 2004 15301875\n10 18F-fluoro-2-deoxy-D-glucose standardized uptake value in cavitating non-small-cell lung carcinoma Nucl Med Commun Coffey JP Hill JC 1040 1045 29 2008 18987523\n11 Tumor cavitation during therapy with antiangiogenesis agents in patients with lung cancer J Thorac Oncol Marom EM Martinez CH Truong MT 351 357 3 2008 18379352\n12 Cavity wall thickness in solitary cavitary lung adenocarcinomas is a prognostic indicator Ann Thorac Surg WatanabeY WatanabeY Kusumoto M Yoshida A Shiraishi K Suzuki K Watanabe SI Tsuta K 1863 1871 102 2016 27663793\n13 Clinical characteristics of 45 patients with invasive pulmonary aspergillosis: retrospective analysis of 1711 lung cancer cases Cancer Yan X Li M Jiang M Z L-Q Luo F Jiang Y 5018 5025 115 2009 19637340\n14 Invasive aspergillosis mimicking metastatic lung cancer Front Oncol Vanfleteren MJEGW Dingemans AMC Surmont VF 188 8 2018 29922593\n15 Localized Aspergillus infestation in primary lung carcinoma: clinical and pathological contrasts with post-tuberculous intracavitary aspergilloma Chest Smith FB Beneck D 554 556 100 1991 1864137\n16 Invasive aspergillosis in a patient with stage III (or 3a or 3b) non-small-cell lung cancer treated with durvalumab Case Rep Oncol Med Gupta A Tun A Ticona K Baqui A Guevara E 2178925 2019 2019 31534809\n17 Pulmonary aspergillosis as a late complication after surgery for locally advanced non-small cell lung cancer treated with induction chemoradiotherapy Surg Today Sugimoto S Soh J Suzawa K 863 871 50 2020 31965262\n18 E-cadherin mediates adhesion of Aspergillus fumigatus to non-small cell lung cancer cells Tumor Biol Yan T Han J Yu X 15593 15599 37 2016\n19 The effect of advances in lung-cancer treatment on population mortality N Engl J Med Howlader N Forjaz G Mooradian MJ 640 649 383 2020 32786189\n20 Prophylaxis of invasive fungal infections in patients with hematological malignancies and solid tumors--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) Ann Hematol Cornely OA Böhme A Buchheidt D 186 200 82 2003 12634955\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "13(3)",
"journal": "Cureus",
"keywords": "aspergillus; cavitary lesions; small-cell lung cancer",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e13691",
"pmc": null,
"pmid": "33824833",
"pubdate": "2021-03-04",
"publication_types": "D002363:Case Reports",
"references": "13680164;32786189;26472726;31691871;27663793;18400799;19047292;31534809;15301875;19637340;31965262;16183941;22659960;24147761;1864137;18379352;18987523;29922593;15571644;8092014",
"title": "Small-Cell Lung Cancer Cavities: Primary or Secondary?",
"title_normalized": "small cell lung cancer cavities primary or secondary"
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditio... |
{
"abstract": "Kounis syndrome (KS) consists of an association between hypersensitivity reactions triggered by various environmental and pharmacological factors and acute coronary syndromes. Blood supply may be compromised by either vasospasm (type I), native plaque destabilization (type II) or stent thrombosis (type III). Although the prognosis is generally favorable, treatment should include aggressive anti-thrombotic and anti-allergic therapies. A case compatible with type III KS, manifested as a macular rash followed by two episodes of stent thrombosis after primary angioplasty (PCI) of the right coronary artery is presented, and complemented by a review on the topic.",
"affiliations": "Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil; Federal University of Rio de Janeiro, Edson Saad Heart Institute, Rua Rodolpho Paulo Rocco 255, Ilha do Fundão, Rio de Janeiro, RJ 21941-913, Brazil. Electronic address: betomf@terra.com.br.;Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil; Federal University of Rio de Janeiro, Edson Saad Heart Institute, Rua Rodolpho Paulo Rocco 255, Ilha do Fundão, Rio de Janeiro, RJ 21941-913, Brazil.;Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil; Federal University of Rio de Janeiro, Edson Saad Heart Institute, Rua Rodolpho Paulo Rocco 255, Ilha do Fundão, Rio de Janeiro, RJ 21941-913, Brazil.;Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil.;Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil.;Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil.;Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil.;Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil.;Samaritano Hospital, Cardiology Department, Rua Bambina 98, Botafogo, Rio de Janeiro, RJ 22251-050, Brazil.",
"authors": "Ferreira|Roberto M|RM|;Villela|Paolo B|PB|;Almeida|Juliano C G|JCG|;Sampaio|Pedro Paulo N|PPN|;Albuquerque|Felipe N|FN|;Pinheiro|Fernanda M C|FMC|;França Filho|William|W|;Salles|José Ary B E|JABE|;Mansur Filho|João|J|",
"chemical_list": "D018926:Anti-Allergic Agents; D005343:Fibrinolytic Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.carrev.2018.03.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-0938",
"issue": "19(7 Pt B)",
"journal": "Cardiovascular revascularization medicine : including molecular interventions",
"keywords": "Allergy; Cardiovascular disease; Stent Thrombosis",
"medline_ta": "Cardiovasc Revasc Med",
"mesh_terms": "D018926:Anti-Allergic Agents; D017023:Coronary Angiography; D003328:Coronary Thrombosis; D004562:Electrocardiography; D005343:Fibrinolytic Agents; D006801:Humans; D000074962:Kounis Syndrome; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D012008:Recurrence; D015607:Stents; D016896:Treatment Outcome",
"nlm_unique_id": "101238551",
"other_id": null,
"pages": "890-895",
"pmc": null,
"pmid": "29576520",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Allergic recurrent coronary stent thrombosis: A mini-review of Kounis syndrome.",
"title_normalized": "allergic recurrent coronary stent thrombosis a mini review of kounis syndrome"
} | [
{
"companynumb": "BR-BAYER-2018-071773",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,... |
{
"abstract": "The importance of early thrombolysis in acute myocardial infarction has been highlighted in several large trials. The clinical decision is often taken by physicians who need to take a rapid action with the risk of misdiagnosing non-coronary events that mimic myocardial infarction. Here we describe a case of acute pericarditis in a 37-year-old man whom received thrombolysis and developed a sudden hemorrhagic pericardial effusion that evolved rapidly into a cardiac tamponade. These errors leading to lethal thrombolysis complications have been surprisingly rare; but a correct diagnosis of aortic dissection or hemorrhagic pericarditis needs to be stressed because even after obtaining the correct diagnosis, the prolonged disturbance of hemostasis prevents a rapid therapy being instigated.",
"affiliations": "Division of Cardiology, Woodhull Medical Center , Brooklyn, New York , USA.",
"authors": "Irivbogbe|Osereme|O|;Mirrer|Brooks|B|;Loarte|Pablo|P|;Gale|Michael|M|;Cohen|Ronny|R|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": "10.3109/17482941.2014.902470",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1748-2941",
"issue": "16(2)",
"journal": "Acute cardiac care",
"keywords": null,
"medline_ta": "Acute Card Care",
"mesh_terms": "D000328:Adult; D002305:Cardiac Tamponade; D003951:Diagnostic Errors; D004562:Electrocardiography; D005343:Fibrinolytic Agents; D006470:Hemorrhage; D006801:Humans; D008297:Male; D009203:Myocardial Infarction; D010490:Pericardial Effusion; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "101276603",
"other_id": null,
"pages": "83-7",
"pmc": null,
"pmid": "24749992",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Thrombolytic-related complication in a case of misdiagnosed myocardial infarction.",
"title_normalized": "thrombolytic related complication in a case of misdiagnosed myocardial infarction"
} | [
{
"companynumb": "US-ROCHE-1410063",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"druga... |
{
"abstract": "We describe a case of a 48-year-old woman who presented with acute respiratory failure due to diffuse alveolar haemorrhage and acute renal failure due to pauci-immune glomerulonephritis consistent with a new diagnosis of microscopic polyangiitis (MPA). The patient had a recent SARS-CoV-2 infection 6 weeks before MPA diagnosis and had stopped immunosuppression for her rheumatoid arthritis (RA) at that time. The patient was treated with pulse intravenous steroids, plasma exchange therapy and rituximab, which induced remission of her illness. This case highlights a timely dilemma of holding immunosuppression in a RA patient with low disease activity on combination therapy with SARS-CoV-2 infection, and the potential risk of developing an additional autoimmune disease, such as vasculitis, given their existing autoimmunity due to RA.",
"affiliations": "Division of Rheumatology, Department of Medicine, UF Health Jacksonville, Jacksonville, Florida, USA sukhraj.singh@jax.ufl.edu.;Division of Rheumatology, Department of Medicine, UF Health Jacksonville, Jacksonville, Florida, USA.;Division of Rheumatology, Department of Medicine, UF Health Jacksonville, Jacksonville, Florida, USA.;Division of Rheumatology, Department of Medicine, UF Health Jacksonville, Jacksonville, Florida, USA.",
"authors": "Singh|Sukhraj|S|http://orcid.org/0000-0002-9968-6625;Vaghaiwalla|Zareen|Z|;Thway|Myint|M|;Kaeley|Gurjit Singh|GS|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-241125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(4)",
"journal": "BMJ case reports",
"keywords": "COVID-19; acute renal failure; biological agents; rheumatoid arthritis; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D001172:Arthritis, Rheumatoid; D000086382:COVID-19; D003937:Diagnosis, Differential; D005260:Female; D005921:Glomerulonephritis; D006470:Hemorrhage; D006801:Humans; D007166:Immunosuppressive Agents; D008171:Lung Diseases; D055953:Microscopic Polyangiitis; D008875:Middle Aged; D010951:Plasma Exchange; D012074:Remission Induction; D012128:Respiratory Distress Syndrome; D000069283:Rituximab; D014657:Vasculitis; D028761:Withholding Treatment",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33846189",
"pubdate": "2021-04-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32892311;32506699;32968761;32205186;25664229;32299776;32546603;32892516;33277981;23678356;32475830;28619978;28960869;21288960;10939757;32309814;21860391;32406001;32410760",
"title": "Does withdrawal of immunosuppression in rheumatoid arthritis after SARS-CoV-2 infection increase the risk of vasculitis?",
"title_normalized": "does withdrawal of immunosuppression in rheumatoid arthritis after sars cov 2 infection increase the risk of vasculitis"
} | [
{
"companynumb": "US-MYLANLABS-2021M1043232",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
... |
{
"abstract": "Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ.",
"affiliations": "Departments of Clinical and Experimental Oncology Familial Cancer Clinic and Oncoendocrinology.;Medical Oncology 1.;Medical Oncology 1.;Operative Unit of Endocrinology, Bentivoglio Hospital, Bologna, Italy.;Immunology and Molecular Oncology Unit.;Department of Radiological Sciences and Medical Physics, Radiology Unit.;Departments of Clinical and Experimental Oncology Familial Cancer Clinic and Oncoendocrinology.;Department of Surgery, Oncology and Gastroenterology, Endocrine Surgery Unit, University of Padua, Padua.;Department of Medicine, Scientific Direction, Veneto Institute of Oncology IOV-IRCCS.;Medical Oncology 1.;Departments of Clinical and Experimental Oncology Familial Cancer Clinic and Oncoendocrinology.",
"authors": "Ferrara|Alfonso M|AM|;Lombardi|Giuseppe|G|;Pambuku|Ardi|A|;Meringolo|Domenico|D|;Bertorelle|Roberta|R|;Nardin|Margherita|M|;Schiavi|Francesca|F|;Iacobone|Maurizio|M|;Opocher|Giuseppe|G|;Zagonel|Vittorina|V|;Zovato|Stefania|S|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human; D003606:Dacarbazine; D000077204:Temozolomide",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000570",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "29(1)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D018906:Antineoplastic Agents, Alkylating; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D003606:Dacarbazine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma; D010673:Pheochromocytoma; D000077204:Temozolomide",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "102-105",
"pmc": null,
"pmid": "29099418",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma.",
"title_normalized": "temozolomide treatment of a malignant pheochromocytoma and an unresectable max related paraganglioma"
} | [
{
"companynumb": "IT-009507513-1804ITA004011",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXAZOSIN MESYLATE"
},
"drugadditional": nu... |
{
"abstract": "Pyoderma gangrenosum is a rare ulcerative dermatosis. It may be caused by some drugs, including small molecule tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the reported evidence of pyoderma gangrenosum associated with the use of these drugs. A systematic electronic literature search of PubMed and Embase was conducted. In these databases, search terms describing pyoderma gangrenosum were combined with TKIs. Fifteen case reports (eight cases associated with sunitinib, two with imatinib, two with ibrutinib, one with gefitinib, one with pazopanib, and one with dabrafenib and trametinib) were identified over the 14 years. The average Naranjo score of these cases is 6.6, which indicates a probable adverse drug reaction. Pyoderma gangrenosum is a probable and reversible drug reaction associated with some TKIs. Detailed medical history can help to prompt diagnosis of drug-induced pyoderma gangrenosum. Clinicians should be aware of TKI-associated pyoderma gangrenosum when caring for the skin of oncologic patients undergoing therapy with kinase inhibitors.",
"affiliations": "Department of Clinical Pharmacy, Faculty of Pharmacy Breast Disease Research Center (BDRC), Tehran University of Medical Sciences, Tehran, Iran, Tehran, Iran.",
"authors": "Khoshnam-Rad|Niloofar|N|;Gheymati|Azin|A|;Jahangard-Rafsanjani|Zahra|Z|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000001140",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": null,
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": null,
"nlm_unique_id": "9100823",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34282745",
"pubdate": "2021-07-19",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Tyrosine kinase inhibitors-associated pyoderma gangrenosum, a systematic review of published case reports.",
"title_normalized": "tyrosine kinase inhibitors associated pyoderma gangrenosum a systematic review of published case reports"
} | [
{
"companynumb": "IR-AMNEAL PHARMACEUTICALS-2022-AMRX-00747",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugad... |
{
"abstract": "To introduce the prenatal regenerative medicine service at Mayo Clinic for fetal endoscopic tracheal occlusion (FETO) care for severe congenital diaphragmatic hernia (CDH).\n\n\n\nTwo cases of prenatal management of severe CDH with FETO between January and August 2017 are reported. Per protocol, FETO was offered for life-threatening severe CDH at between 26 and 29 weeks' gestation. Regenerative outcome end point was fetal lung growth. Gestational age at procedure and maternal and perinatal outcomes were additional monitored parameters.\n\n\n\nDiagnosis by ultrasonography of severe CDH was based on extremely reduced lung size (observed-to-expected lung area to head circumference ratio [o/e-LHR], eg, o/e-LHR of 20.3% for fetus 1 and 23.0% for fetus 2) along with greater than one-third of the liver herniated into the chest in both fetuses. Both patients underwent successful FETO at 28 weeks. At the time of intervention, no maternal or fetal complications were observed. Postintervention, fetal lung growth was observed in both fetuses, reaching an o/e-LHR of 62.7% at 36 weeks in fetus 1 and 52.4% at 32 weeks in fetus 2. The balloons were removed successfully at 35 weeks and 4 days by ultrasound-guided puncture in the first patient and at 32 weeks and 3 days by ex utero intrapartum therapy-to-airway procedure in the second patient. Postnatal management followed standard of care with patch CDH therapy. At discharge, one patient was breathing normally, whereas the other required minimal nasal cannula oxygen support.\n\n\n\nThe successful launch of the first fetoscopic therapy for CDH at Mayo Clinic reveals its feasibility and safety, with early signs of benefit documented by fetal lung growth and reversal of severe pulmonary hypoplasia.\n\n\n\nclinicaltrials.gov Identifier: G170062.",
"affiliations": "Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN; Center for Regenerative Medicine, Mayo Clinic, Rochester, MN. Electronic address: ruano.rodrigo@mayo.edu.;Division of Pediatric Surgery, Department of Surgery, Mayo Clinic, Rochester, MN.;Department of Otorhinolaryngology, Mayo Clinic, Rochester, MN.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN.;Division of Pediatric Surgery, Department of Surgery, Mayo Clinic, Rochester, MN.;Division of Neonatal Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.;Division of Neonatal Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.;Department of Radiology, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN.;Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN.;Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, MN.;Center for Regenerative Medicine, Mayo Clinic, Rochester, MN.",
"authors": "Ruano|Rodrigo|R|;Klinkner|Denise B|DB|;Balakrishnan|Karthik|K|;Novoa Y Novoa|Victoria A|VA|;Davies|Norman|N|;Potter|Dean D|DD|;Carey|William A|WA|;Colby|Christopher E|CE|;Kolbe|Amy B|AB|;Arendt|Katherine W|KW|;Segura|Leal|L|;Sviggum|Hans P|HP|;Lemens|Maureen A|MA|;Famuyide|Abimbola|A|;Terzic|Andre|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.mayocp.2018.02.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "93(6)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000328:Adult; D005260:Female; D005332:Fetoscopy; D005865:Gestational Age; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D011247:Pregnancy; D055815:Young Adult",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "693-700",
"pmc": null,
"pmid": "29803315",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Fetoscopic Therapy for Severe Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A First in Prenatal Regenerative Medicine at Mayo Clinic.",
"title_normalized": "fetoscopic therapy for severe pulmonary hypoplasia in congenital diaphragmatic hernia a first in prenatal regenerative medicine at mayo clinic"
} | [
{
"companynumb": "US-009507513-1806USA002814",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE ACETATE\\BETAMETHASONE SODIUM PHOSPHATE"
... |
{
"abstract": "BACKGROUND\nHigh-grade spindle cell sarcomas are a subtype of rare, undifferentiated pleomorphic sarcomas (UPSs) for which diagnosis is difficult and no specific treatment strategies have been established. The limited published data on UPSs suggest an aggressive clinical course, high rates of local recurrence and distant metastasis, and poor prognosis.\n\n\nMETHODS\nHere we present the unusual case of a 45-year-old male patient with a lumbosacral UPS extending into the sacrum. An initial diagnosis of a low-grade malignant spindle cell tumor was based on a tumor core biopsy. After complete extensive resection, the diagnosis of an UPS of the lumbosacral region was confirmed by excluding other types of cancers. Despite treatment with neoadjuvant radiotherapy, extensive resection, and adjuvant chemotherapy, the patient presented with multiple pulmonary metastases 3 months after surgery. The patient then began treatment with crizotinib at an oral dose of 450 mg per day, based on the detection of a LMNA-NTRK1 fusion gene in the tumor by next-generation sequencing. Over 18 months of follow-up through July 2018, the patient maintained a near-complete clinical response to crizotinib.\n\n\nCONCLUSIONS\nThe LMNA-NTRK1 fusion was likely the molecular driver of tumorigenesis and metastasis in this patient, and the observed effectiveness of crizotinib treatment provides clinical validation of this molecular target. Molecular and cytogenetic evaluations are critical to accurate prognosis and treatment planning in cases of UPS, especially when treatment options are limited or otherwise exhausted. Molecularly targeted therapy of these rare but aggressive lesions represents a novel treatment option that may lead to fewer toxic side effects and better clinical outcomes.",
"affiliations": "Department of Abdominal Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, People's Republic of China.;Comprehensive Cancer Center, Charité Universitätsmedizin Berlin, Charitéplatz 1, D-10117, Berlin, Germany.;Department of Bone and Soft-tissue Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, People's Republic of China.;Department of Integration of Traditional Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, People's Republic of China.;Department of Abdominal Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, 310022, People's Republic of China. liuly@zjcc.org.cn.",
"authors": "Zhou|Ning|N|;Schäfer|Reinhold|R|;Li|Tao|T|;Fang|Meiyu|M|;Liu|Luying|L|http://orcid.org/0000-0001-6325-1518",
"chemical_list": "C494847:LMNA protein, human; D034904:Lamin Type A; D015514:Oncogene Proteins, Fusion; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D020917:Receptor, trkA",
"country": "England",
"delete": false,
"doi": "10.1186/s12885-018-4749-z",
"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 474910.1186/s12885-018-4749-zCase ReportA primary undifferentiated pleomorphic sarcoma of the lumbosacral region harboring a LMNA-NTRK1 gene fusion with durable clinical response to crizotinib: a case report Zhou Ning zhouning@zjcc.org.cn 12Schäfer Reinhold reinhold.schaefer@charite.de 2Li Tao litao@zjcc.org.cn 3Fang Meiyu fangmy@zjcc.org.cn 4http://orcid.org/0000-0001-6325-1518Liu Luying liuly@zjcc.org.cn 11 0000 0004 1808 0985grid.417397.fDepartment of Abdominal Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022 People’s Republic of China 2 0000 0001 2218 4662grid.6363.0Comprehensive Cancer Center, Charité Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany 3 0000 0004 1808 0985grid.417397.fDepartment of Bone and Soft-tissue Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022 People’s Republic of China 4 0000 0004 1808 0985grid.417397.fDepartment of Integration of Traditional Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022 People’s Republic of China 22 8 2018 22 8 2018 2018 18 84221 3 2018 14 8 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\nHigh-grade spindle cell sarcomas are a subtype of rare, undifferentiated pleomorphic sarcomas (UPSs) for which diagnosis is difficult and no specific treatment strategies have been established. The limited published data on UPSs suggest an aggressive clinical course, high rates of local recurrence and distant metastasis, and poor prognosis.\n\nCase presentation\nHere we present the unusual case of a 45-year-old male patient with a lumbosacral UPS extending into the sacrum. An initial diagnosis of a low-grade malignant spindle cell tumor was based on a tumor core biopsy. After complete extensive resection, the diagnosis of an UPS of the lumbosacral region was confirmed by excluding other types of cancers. Despite treatment with neoadjuvant radiotherapy, extensive resection, and adjuvant chemotherapy, the patient presented with multiple pulmonary metastases 3 months after surgery. The patient then began treatment with crizotinib at an oral dose of 450 mg per day, based on the detection of a LMNA-NTRK1 fusion gene in the tumor by next-generation sequencing. Over 18 months of follow-up through July 2018, the patient maintained a near-complete clinical response to crizotinib.\n\nConclusions\nThe LMNA-NTRK1 fusion was likely the molecular driver of tumorigenesis and metastasis in this patient, and the observed effectiveness of crizotinib treatment provides clinical validation of this molecular target. Molecular and cytogenetic evaluations are critical to accurate prognosis and treatment planning in cases of UPS, especially when treatment options are limited or otherwise exhausted. Molecularly targeted therapy of these rare but aggressive lesions represents a novel treatment option that may lead to fewer toxic side effects and better clinical outcomes.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12885-018-4749-z) contains supplementary material, which is available to authorized users.\n\nKeywords\nUndifferentiated pleomorphic sarcomaSpindle cellsLumbosacralLMNA-NTRK1 gene fusionCrizotinib therapyissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nUndifferentiated pleomorphic sarcoma (UPS), which is also referred to as malignant fibrous histiocytoma (MFH) according to the 2002 World Health Organization classification, is a rare and aggressive type of mesenchymal malignancy with no definitive cell of origin or specific recurrent genetic hallmarks. Extensive immunohistochemical characterization is required to differentiate UPS from other tumors. While UPS can occur throughout the body, these tumors are commonly found in the extremities and in the retroperitoneum [1, 2], and superficial lesions (subcutaneous) are rare. High-grade spindle cell sarcomas are one subtype of UPSs that is particularly challenging to accurately diagnose and effectively treat. The current 5-year overall survival rate for patients with UPSs is only 65–70%, highlighting the need for more effective treatment options [3].\n\nAt present, UPSs should be treated according to current guidelines for soft tissue sarcoma (STS), because no standard treatment strategy specific for UPSs has been established. Extensive excision and radiotherapy remain the cornerstones of treatment for non-metastatic tumors. With the majority of these tumors being high grade at diagnosis, localized treatments commonly result in poor local control and poor survival. Perioperative chemotherapy was recently reported to be beneficial in terms of overall survival [4], and doxorubicin as a single agent or in combination with ifosfamide is the first choice of chemotherapy in cases of UPS metastasis. A more complete understanding of the molecular characteristics and cytogenetics of these tumors will aid in the differentiation of sarcoma subtypes and development of specifically targeted therapies. Here we report a rare case of UPS in the lumbrosacral region and review the diagnostic procedures applied in this case as well as the treatment decisions and outcomes.\n\nCase presentation\nA 45-year-old male patient presented with a complaint of progressive pain and soreness in the lumbosacral region persisting for more than 3 months. The pain radiated to the left thigh and perineum but did not affect walking. Magnetic resonance imaging (MRI) and computed tomography (CT) scans with and without intravenous contrast showed a tumor mass adjacent to the left side of the fifth lumbar spinous process. The tumor was located in the lower left part of the erector spinae and extended onto the fifth lumbar vertebra, the first sacral vertebra, and the iliac wing. Positron emission tomography with CT (PET/CT) showed a hypermetabolic lesion in the erector spinae adjacent to the left side of the fifth lumbar spinous process. No sites of regional or distant metastases were found. A core biopsy of the tumor mass revealed spindle-shaped cells with infiltrating inflammatory cells. Together the morphological and immunohistochemical features indicated a low-grade inflammatory myofibroblastic tumor. The expression profile based on immunostaining was as follows: overall positive for vimentin, CD34, ALK (SP8), and p53; focally positive for smooth muscle actin (SMA); sporadically positive for S-100; partially positive for CD68; and negative for cytokeratin (CK) (AE1/AE3), desmin, and CD117. The Ki-67 nuclear labeling index was 10%.\n\nThe patient reported no other symptoms. Physical examinations revealed no neuro-pathological signs or symptoms. He denied smoking, alcohol, or illicit drug usage. He also denied recent radiation or toxin exposure. He had no history of unintentional weight loss, fever, or chills. He had no family history of malignant or other chronic diseases, with the exception of a sister who had breast cancer.\n\nThe treatment plan of the case was discussed by our multi-disciplinary team including experts from orthopedics, neurosurgery, chemotherapy, radiotherapy, pathology, and radiology. Considering that the boundary of the tumor was unclear and involved the sacrum, a complete resection would be difficult. Therefore, we administered neoadjuvant radiotherapy to the affected area at a dose of DT 5000 cGy in 25 fractions to the planning target volume (PTV). After shrinkage of the tumor volume, the patient underwent complete extensive resection at 1 month after radiotherapy. Postoperative pathology confirmed that resection of a lesion measuring 7.5 cm × 4 cm × 3.5 cm achieved negative histological margins and indicated a classification of the specimen as a mesenchymal-derived malignant tumor involving the sacrum. Histologic examination of the resected tumor revealed undifferentiated pleomorphic spindle cells surrounding an area of geographic necrosis with frequent atypical mitosis. Microscopically, the morphology conformed to that of a high-grade spindle cell sarcoma consistent with UPS. The result from MDM2 amplification using fluorescence in situ hybridization was negative, and thus, lipogenesis on histology could be excluded (Additional file 1). The expression profile of the UPS tissue is described in Table 1, and representative images of staining tumor tissue are presented in Fig. 1.Table 1 Expression profile of UPS tumor based on immunohistochemical staining of surgically resected tumor tissue\n\nPositive\tINI-1 (+), vimentin (+), S-100 (focally+), p53 (partially+), Bcl-2 (partially+), CD99 (+), calponin (sporadically+), Ki-67 (+, 15%), transducin-like enhancer of Split 1 (TLE1+), melan-A (focally weak+).\t\nNegative\tAE1/AE3 (−), desmin (−), CD31 (−), caldesmon (−), CK (−), EMA (−), ALK (−), SMA (−), CD117\\c-kit (−), CD34 (−), MyoD1 (−), myogenin (−), CK/LMW (−), CK5/6 (−), 34βE12 (−), CAM5.2 (−), HMB45 (−), SOX10 (−), MITF (−).\t\nFig. 1 Histopathological staining of surgically resected tumor tissue. Pathology revealed high-grade spindle cell sarcoma consistent with UPS. a Hematoxylin and eosin (H&E); magnification, 100×. b H&E, 400×. c H&E, 400×. d Ki-67, 200×. Brown nuclear staining for this proliferation marker is seen in many tumor cells\n\n\n\nA postsurgical MRI scan obtained 1 month after surgery showed postoperative changes and no obvious mass in the surgical area. The patient underwent adjuvant chemotherapy with liposomal doxorubicin and ifosfamide but had to discontinue chemotherapy after 2 cycles due to intolerance of grade 3 fatigue and grade 2 nausea. At 3 months after surgery, three new lesions were discovered in the bilateral pulmonary region on a routine follow-up CT scan (Fig. 2a). Further radiographic imaging with PET/CT showed hypermetabolic metastases involving the erector spinae of the left posterior sacral, fifth lumbar spine, sacrum, left ilium, and twelfth thoracic vertebra, accompanied by multiple lung lesions and a suspected metastasis adjacent to the spleen (Fig. 3a). At this stage, the patient refused further chemotherapy.Fig. 2 Chest CT images. (a) Follow-up chest CT images taken 3 months after surgery on January 10, 2017 demonstrated three new lesions (arrows) in the bilateral pulmonary region, before treatment with cizotinib. b Follow-up chest CT images taken on February 20, 2017 at 4 weeks after the initiation of oral crizotinib administration indicated improvement\n\nFig. 3 PET-CT images showing visible regression of the multiple metastases after 16 weeks of crizotinib monocherapy. a Follow-up PET-CT image taken on January 10, 2017 at 3 months after surgery showed hypermetabolic metastases in multiple regions, before the start of cizotinib treatment. b Follow-up PET-CT images taken on May 19, 2017 at 4 months after initiation of crizotinib showed near-CCR\n\n\n\nWith the standard therapeutic options exhausted, primary tumor tissue was subjected to DNA sequencing via next-generation sequencing (NGS) with an ILLUMINA Nextseq 500 (3DMedicines, Inc.). The MasterView 381 cancer-gene panel covered 4557 exons of 365 cancer-related genes and 47 introns of 25 genes frequently rearranged in 381 cancer-related genes (Additional file 2). The genomic DNA was extracted with the QIAamp DNA formalin-fixed paraffin-embedded tissue kit (Qiagen) following the manufacturer’s protocol and quantified with the Qubit™ dsDNA HS Assay kit (Invitrogen). Bioinformatics analyses involved analyzing the clipped reads, which can be extracted by the tag information of bam files, which mapped the individual reads to the reference human genome (hg19) with bwa aligner v0.7.12. Candidate reads that were discordant or aligned in the same direction were filtered. Read pairs with reads mapped to separate chromosomes or separated by a distance of over 2 kb on the same chromosome were kept for fusion detection at the probe level. Output rearrangements contained translocation, inversion, long deletion, etc. [5]. Through this profiling, a LMNA-NTRK1 gene fusion encoding exons 1–2 of lamin A/C and exons 11–17 of the NTRK1 gene was identified (Fig. 4), and the other unlisted genes were all wild-type. The sequencing results for the LMNA-NTRK1 gene fusion are presented in Additional files 3 and 4.Fig. 4 Schematic presentation of the LMNA–NTRK1 gene fusion. The fusion consisted of LMNA exons 1–2 followed by NTRK1 exons 11–17\n\n\n\nAfter extensive discussion and consultation with the patient and his family, we initiated crizotinib therapy per os at 450 mg per day on January 23, 2017. One month later, chest CT scanning showed that all lesions in the bilateral lungs had almost disappeared, and the patient had achieved a near-complete clinical response (CCR, Fig. 2b). PET/CT imaging was repeated after 4 months of treatment and continued to show the same response to crizotinib therapy. PET/CT revealed that local FDG metabolism was slightly increased at the lesions of the fifth lumbar spine, sacrum, left ilium and left paraspinal muscle. However, with crizotinib treatment, the FDG metabolism was significantly reduced in comparison with that seen in the first PET-CT examination. The bilateral pulmonary nodules had disappeared, and the twelfth vertebra, which had shown osteolytic bone destruction, now showed signs of healing, with an increased density and a lower FDG metabolism. The volume of the left front nodule of the spleen was significantly reduced after treatment (Fig. 3b). A timeline of the treatment course is presented in Fig. 5. As of July 2018, clinical assessments in this patient showed an ongoing near-CCR of 18 months. In general, the side effects of oral administration of crizotinib at 450 mg per day were tolerable for the patient. During the course of treatment, the patient experienced grade 3 myelosuppression and grade 2 weakness, but myelosuppression could be alleviated with granulocyte colony-stimulating factor (G-CSF)-based supportive treatment.Fig. 5 Timeline of the patient’s clinical course\n\n\n\nDiscussion and conclusions\nApproximately 5–15% of STS lesions cannot be differentiated by current molecular technologies or immunohistochemical criteria and are therefore classified as UPSs in an exclusion-based diagnosis [6]. The morphology of the primary tumor in the present case showed an ordered storiform pattern on hematoxylin and eosin (H&E) staining and progressively dedifferentiated to a highly pleomorphic tumor without definite true histiocytic differentiation. In addition, the tumor cells were mainly spindly with elongated, tapering nuclei. Considering also the findings on immunohistochemical staining after surgery, we finally confirmed a diagnosis of high-grade spindle cell UPS. The main pathology-based differential diagnosis among different potential histological entities was based on morphology as well as the expression profile of a panel of immunocytochemical markers. Before rendering the diagnosis of UPSs, the differential diagnoses that must be excluded include dedifferentiated liposarcoma, pleomorphic liposarcoma, pleomorphic leiomyosarcoma, pleomorphic rhabdomyosarcoma, high grade and epithelioid variant of myxofibrosarcoma, poorly differentiated carcinoma, and melanoma [7]. The diagnosis of primary UPS is made easier by extensive tumor sampling, evaluation of the overall morphologic pattern, careful searching for the best-differentiated area, and determination of the specific immunophenotype to evaluate a particular lineage of differentiation. In the present case, the initial diagnostic classification was difficult.\n\nCurrent knowledge on UPSs suggests an aggressive clinical course, high incidence of recurrence and metastasis compared with other histologic STS subtypes [8]. Treatment with surgery only leads to poor rates of local control and even survival. To date, the clinical benefit of adjuvant chemotherapy and radiation remains unclear. More recently, genetic studies have contributed to an increased understanding of sarcomas and provided possible therapeutic advancements by identifying genetic markers of patients most likely to respond. In the present case, we identified a LMNA-NTRK1 fusion gene comprising exons 11–17 of the NKRT1 gene and exons 1–2 of LMNA gene in the patient’s tumor. The NTRK1 gene encodes tropomyosin receptor kinase A (TrkA), which is a membrane-bound receptor that, upon neurotrophin binding, undergoes autophosphorylation and activates members of the mitogen activated protein kinase (MAPK) pathway [9, 10]. The LMNA gene (localized at chromosome 1q22) encodes a key component of the nuclear lamina that is involved in nuclear assembly and chromatin organization. TrkA does not appear to be an oncogene, but gene fusions involving NTRK1 have been shown to be oncogenic, resulting in constitutive TrkA activation [11]. Activation of this receptor initiates several key downstream signal transduction cascades, including the MAPK, phosphatidylinositol 3-kinase (PI3K), and phospholipase C-γ (PLC-γ) pathways [12] as well as promotes phosphorylation of the AKT, ERK, and PLC-γ1 fusion proteins in vitro. Strong activation of the MAPK, PLC-γ1 and PI3K pathways can be inhibited by the NTRK1 inhibitor AZ-23 [13].\n\nAt present, no direct kinase inhibitors with NTRK1 fusions have been approved by the U.S. Food and Drug Administration. Doebele et al. [14] reported the case of a 41-year-old woman with an undifferentiated soft tissue sarcoma and lung metastasis harboring a LMNA-NTRK1 gene fusion who consented to treatment with the Trk inhibitor LOXO-101. Her tumors underwent rapid and substantial regression, with improvements in pulmonary dyspnea, oxygen saturation and reductions in plasma tumor markers. In another case of congenital infantile fibrosarcoma harboring a LMNA-NTRK1 gene fusion, a complete response to crizotinib therapy over 12 weeks was reported [15]. Crizotinib is a multi-active kinase inhibitor that blocks TrkA autophosphorylation and cell growth in cells expressing NTRK1 fusion proteins [11]. Notably, targeted crizotinib therapy is superior to standard chemotherapy in lung cancer patients with ALK fusions [16]. Based on the report of a minor response to crizotinib in a case of non-small cell lung cancer harboring a NTRK1 fusion as well as preclinical data [11], we started oral administration of crizotinib (450 mg QD) in the UPS patient described in this report. Over the follow-up period, the patient did not experience intolerable adverse effects from treatment and continued crizotinib monotherapy with no evidence of disease for more than 18 months as of July 2018. To our knowledge, this is the first case of UPS with a LMNA-NTRK1 gene fusion showing a durable response to crizotinib.\n\nAfter screening a total of 1272 soft tissue sarcomas, Doebele et al. [14] identified five cases with a NTRK1 gene fusion, including three pediatric cases aged < 5 years and two adults. Thus, the detection rate for NTRK1 fusions in STS was less than 1% in their study. Haller et al [17] also reported four cases of sarcomas harboring NTRK1 gene fusions. The patients were two children aged 11 months and 2 years and two adults aged 51 and 80 years. The histomorphology in these cases was also described as characteristic spindle cell features, corresponing well to observations in the present case. These findings highlight the importance of further large research series with genetic testing of any sarcomatous neoplasm with similar histomorphology features for NTRK1 gene fusion and the application of such testing in the routine clinical diagnostic setting. The tumor regression and clinical response observed in the present case establishes that this LMNA-NTRK1 fusion may be a molecular driver of carcinogenesis in this patient and provides clinical validation of a molecular target in oncology. The oncogene driver may be the dominant factor in determining the response to targeted therapy, rather than the histologic subtype. We will continue following the clinical course of the patient to monitor the duration of the response, investigate how crizotinib has impacted the tumor, and track the potential development of treatment resistance.\n\nIn summary, this case provides robust evidence for the importance of molecular evaluation in cases of these rare but aggressive lesions and stresses the need for the development of drugs for better molecularly targeted STS treatment, especially when standard-of-care options have been exhausted or treatment options are unavailable.\n\nAdditional files\n\nAdditional file 1: FISH result of MDM2 amplification. (PDF 299 kb)\n\n \nAdditional file 2: The MasterView 381 cancer-gene panel. (PDF 77 kb)\n\n \nAdditional file 3: LMNA BLAST. (PDF 42 kb)\n\n \nAdditional file 4: NTRK1 BLAST. (PDF 47 kb)\n\n \n\n\nAbbreviations\nCCRComplete clinical response\n\nCKCytokeratin\n\nCTComputed tomography\n\nG-CSFGranulocyte colony-stimulating factor\n\nH&EHematoxylin and eosin\n\nMAPKMitogen-activated protein kinase\n\nMFHMalignant fibrous histiocytoma\n\nMRIMagnetic resonance imaging\n\nNGSNext-generation sequencing\n\nPET/CTPositron emission tomography−computed tomography\n\nPI3KPhosphatidylinositol 3-kinase\n\nPLC-γPhospholipase C-γ\n\nPTVPlanning target volume\n\nSMASmooth muscle actin\n\nSTSSoft tissue sarcoma\n\nTrkATropomyosin receptor kinase A\n\nUPSUndifferentiated pleomorphic sarcoma\n\nThe first author is an MD candidate in Charité Universitätsmedizin Berlin and is sponsored by Zhejiang Cancer Hospital.\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.\n\nAuthors’ contributions\nNZ treated the patient and participated in study conception, acquisition of data and drafting the article. RS participated in drafting and revising the article. TL performed the surgery. MYF provided treatment advice. LYL is responsible for the patient’s entire management, treatment, participation in conception, critical review and supervision. All the authors read and approved the final paper.\n\nEthics approval and consent to participate\nInformed consent as documented by signature was obtained from this patient.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of the Case Report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Inoue R Aoki M Matsumoto Y Haraoka S Kazekawa K Nabeshima K Prolactin-producing pituitary adenoma with atypical spindle cell morphology: a case report World J Surg Oncol 2015 13 229 10.1186/s12957-015-0655-x 26228535 \n2. Mahore A Ramdasi R Dange N Epari S Malignant fibrous histiocytoma of the skull base: a neurosurgical nuance Asian J Neurosurg 2015 10 2 135 138 10.4103/1793-5482.154981 25972949 \n3. Goldblum JR An approach to pleomorphic sarcomas: can we subclassify, and does it matter? Mod Pathol 2014 27 Suppl 1 S39 S46 10.1038/modpathol.2013.174 24384852 \n4. Gronchi A Ferrari S Quagliuolo V Broto JM Pousa AL Grignani G Basso U Blay J-Y Tendero O Beveridge RD Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial Lancet Oncol 2017 18 6 812 822 10.1016/S1470-2045(17)30334-0 28499583 \n5. Su D Zhang D Chen K Lu J Wu J Cao X Ying L Jin Q Ye Y Xie Z High performance of targeted next generation sequencing on variance detection in clinical tumor specimens in comparison with current conventional methods J Exp Clin Cancer Res 2017 36 1 121 10.1186/s13046-017-0591-4 28882180 \n6. Brennan MF Antonescu CR Moraco N Singer S Lessons learned from the study of 10,000 patients with soft tissue sarcoma Ann Surg 2014 260 3 416 422 10.1097/SLA.0000000000000869 25115417 \n7. Liegl-Atzwanger B Hofmann G Leithner A Beham A Undifferentiated high-grade pleomorphic sarcoma (UHPS): diagnostic criteria, differential diagnosis, and treatment. An attempt to erasure the misnomer “MFH” Eur Surg 2009 41 4 143 149 10.1007/s10353-009-0474-9 \n8. Savina M Le Cesne A Blay JY Ray-Coquard I Mir O Toulmonde M Cousin S Terrier P Ranchere-Vince D Meeus P Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study BMC Med 2017 15 1 78 10.1186/s12916-017-0831-7 28391775 \n9. Nakagawara A Trk receptor tyrosine kinases: a bridge between cancer and neural development Cancer Lett 2001 169 2 107 114 10.1016/S0304-3835(01)00530-4 11431098 \n10. Sossin WS Tracing the evolution and function of the Trk superfamily of receptor tyrosine kinases Brain Behav Evol 2006 68 3 145 156 10.1159/000094084 16912468 \n11. Vaishnavi A Capelletti M Le AT Kako S Butaney M Ercan D Mahale S Davies KD Aisner DL Pilling AB Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer Nat Med 2013 19 11 1469 1472 10.1038/nm.3352 24162815 \n12. Alberti L Carniti C Miranda C Roccato E Pierotti MA RET and NTRK1 proto-oncogenes in human diseases J Cell Physiol 2003 195 2 168 186 10.1002/jcp.10252 12652644 \n13. Wiesner T He J Yelensky R Esteve-Puig R Botton T Yeh I Lipson D Otto G Brennan K Murali R Kinase fusions are frequent in Spitz tumours and spitzoid melanomas Nat Commun 2014 5 3116 10.1038/ncomms4116 24445538 \n14. Doebele RC Davis LE Vaishnavi A Le AT Estrada-Bernal A Keysar S Jimeno A Varella-Garcia M Aisner DL Li Y An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101 Cancer Discov 2015 5 10 1049 1057 10.1158/2159-8290.CD-15-0443 26216294 \n15. Wong V, Pavlick D, Brennan T, Yelensky R, Crawford J, Ross JS, Miller VA, Malicki D, Stephens PJ, Ali SM, et al. Evaluation of a congenital infantile Fibrosarcoma by comprehensive genomic profiling reveals an LMNA-NTRK1 gene fusion responsive to Crizotinib. J Natl Cancer Inst. 2016;108(1):307–10.\n16. Shaw AT Kim DW Nakagawa K Seto T Crino L Ahn MJ De Pas T Besse B Solomon BJ Blackhall F Crizotinib versus chemotherapy in advanced ALK-positive lung cancer N Engl J Med 2013 368 25 2385 2394 10.1056/NEJMoa1214886 23724913 \n17. Haller F Knopf J Ackermann A Bieg M Kleinheinz K Schlesner M Moskalev EA Will R Satir AA Abdelmagid IE Paediatric and adult soft tissue sarcomas with NTRK1 gene fusions: a subset of spindle cell sarcomas unified by a prominent myopericytic/haemangiopericytic pattern J Pathol 2016 238 5 700 710 10.1002/path.4701 26863915\n\n",
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"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Crizotinib therapy; LMNA-NTRK1 gene fusion; Lumbosacral; Spindle cells; Undifferentiated pleomorphic sarcoma",
"medline_ta": "BMC Cancer",
"mesh_terms": "D063646:Carcinogenesis; D000077547:Crizotinib; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D034904:Lamin Type A; D008080:Liposarcoma; D008161:Lumbosacral Region; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion; D011379:Prognosis; D011720:Pyrazoles; D011725:Pyridines; D020917:Receptor, trkA; D012447:Sacrum; D012509:Sarcoma",
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"title": "A primary undifferentiated pleomorphic sarcoma of the lumbosacral region harboring a LMNA-NTRK1 gene fusion with durable clinical response to crizotinib: a case report.",
"title_normalized": "a primary undifferentiated pleomorphic sarcoma of the lumbosacral region harboring a lmna ntrk1 gene fusion with durable clinical response to crizotinib a case report"
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"abstract": "OBJECTIVE\nA new condition, gadolinium-associated plaques (GAP), is reported in 2 patients. It is related to a particular type of gadolinium (gadodiamide) used for contrast-enhanced radiologic studies.\n\n\nMETHODS\nErythematous plaques, 0.5 to 2.5 cm in diameter, were pruritic in one case and asymptomatic in a second case. Findings from the histopathologic examination revealed eosinophilic, collagenous, round or ovoid bodies (sclerotic bodies) in various stages of calcification. Previously, these sclerotic bodies were thought to be pathognomonic for nephrogenic systemic fibrosis (NSF) in the setting of chronic renal disease with associated gadolinium exposure. Neither patient had NSF, while only 1 of these patients had renal disease. The patient who did not have renal disease received high doses of gadolinium.\n\n\nCONCLUSIONS\nPhysicians should be aware that GAP can occur without NSF or renal disease and is associated with the use of radiologic dyes. Sclerotic bodies have been reported only in association with gadolinium exposure (eg, gadodiamide) either in the sclerotic skin in NSF or in GAP.",
"affiliations": "University of Mississippi Medical Center, Jackson.;Department of Pathology, University of Mississippi Medical Center, Jackson.;WCP Laboratories Inc, St Louis, Missouri.;Department of Dermatology, University of Mississippi Medical Center, Jackson5Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, New York.",
"authors": "Gathings|Robert M|RM|;Reddy|Raveena|R|;Santa Cruz|Daniel|D|;Brodell|Robert T|RT|",
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"title": "Gadolinium-associated plaques: a new, distinctive clinical entity.",
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{
"abstract": "The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled \"Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction\" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.",
"affiliations": "Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: priya.kishnani@duke.edu.;Division of Medical Genetics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90505-2006, USA. Electronic address: pdickson@labiomed.org.;Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: laurie.muldowney@fda.hhs.gov.;Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: jessica.j.lee@fda.hhs.gov.;Division of Therapeutic Proteins, Office of Biotechnology Products, CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: amy.rosenberg@fda.hhs.gov.;Shire, Lexington, MA 02421, USA. Electronic address: rabichan@shire.com.;Diabetes Center, University of California, San Francisco, San Francisco, CA 94143-0540, USA. Electronic address: jeff.bluestone@ucsf.edu.;Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital, Chicago, IL 60611, USA. Electronic address: bburton@luriechildrens.org.;Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: maureen.dewey@fda.hhs.gov.;National Organization for Rare Disorders, Washington, DC 20036, USA. Electronic address: afreitas@rarediseases.org.;National Organization for Rare Disorders, Washington, DC 20036, USA. Electronic address: dgavin@rarediseases.org.;Division of Gastroenterology and Inborn Errors of Metabolism Products, Office of New Drugs, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD 20993-0002, USA. Electronic address: donna.griebel@fda.hhs.gov.;Saving Case & Friends, Inc., a Hunter Syndrome Research Foundation, Thompson's Station, TN 37179, USA. Electronic address: melissa@savingcase.com.;National MPS Society, Durham, NC 27709, USA. Electronic address: steve.holland@thomsonreuters.com.;Children's National Medical Center, Washington, DC 20010, USA. Electronic address: ptanpaib@childrensnational.org.;Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA. Electronic address: lturka@partners.org.;University of Minnesota, Masonic Children's Hospital, Minneapolis, MN 55455, USA. Electronic address: utz002@umn.edu.;Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences (OTS), CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: yowming.wang@fda.hhs.gov.;University of Minnesota, Masonic Children's Hospital, Minneapolis, MN 55455, USA. Electronic address: whitley@umn.edu.;Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: zoheb.kazi@dm.duke.edu.;OTS, CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address: anne.pariser@fda.hhs.gov.",
"authors": "Kishnani|Priya S|PS|;Dickson|Patricia I|PI|;Muldowney|Laurie|L|;Lee|Jessica J|JJ|;Rosenberg|Amy|A|;Abichandani|Rekha|R|;Bluestone|Jeffrey A|JA|;Burton|Barbara K|BK|;Dewey|Maureen|M|;Freitas|Alexandra|A|;Gavin|Derek|D|;Griebel|Donna|D|;Hogan|Melissa|M|;Holland|Stephen|S|;Tanpaiboon|Pranoot|P|;Turka|Laurence A|LA|;Utz|Jeanine J|JJ|;Wang|Yow-Ming|YM|;Whitley|Chester B|CB|;Kazi|Zoheb B|ZB|;Pariser|Anne R|AR|",
"chemical_list": "D011994:Recombinant Proteins; D006867:Hydrolases",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1096-7192",
"issue": "117(2)",
"journal": "Molecular genetics and metabolism",
"keywords": "Enzyme replacement therapy; Immune tolerance; Inborn errors of metabolism; Lysosomal storage diseases; Neutralizing antibodies; Orphan drugs; Rare diseases",
"medline_ta": "Mol Genet Metab",
"mesh_terms": "D000818:Animals; D056947:Enzyme Replacement Therapy; D006801:Humans; D006867:Hydrolases; D007108:Immune Tolerance; D016464:Lysosomal Storage Diseases; D011994:Recombinant Proteins",
"nlm_unique_id": "9805456",
"other_id": null,
"pages": "66-83",
"pmc": null,
"pmid": "26597321",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.",
"title_normalized": "immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction"
} | [
{
"companynumb": "US-MYLANLABS-2017M1038827",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDURSULFASE"
},
"drugadditional": "3",
... |
{
"abstract": "Amphetamine toxicity typically presents with hypertension and tachycardia. Conversely, clonidine acts as an agonist at central α2 and imidazoline receptors, which may cause brief initial hypertension followed by hypotension and bradycardia in overdose. We report a case of mixed ingestion resulting in posterior reversible encephalopathy syndrome (PRES) successfully treated with phentolamine.A 17-year-old male adolescent presented to the emergency department 2 hours after ingesting up to 25 each of clonidine 0.1-mg tablets and dextroamphetamine 10 mg extended-release capsules. He reported nausea and fatigue with initial blood pressure (BP) 145/95 mm Hg and heart rate (HR) 52 beats per minute (bpm). Nine hours postingestion (HPI), the patient developed headache, photophobia, and confusion with BP 182/111 mm Hg and HR 48 bpm. A computed tomography scan of the head revealed generalized fullness of the cerebellum, upward bulging of the tentorial leaflets, effacement of the fourth ventricle, and crowding of the foramen magnum, suspicious for an atypical presentation of PRES. The patient's systolic BP rose over 200 mm Hg and treated with 2 mg of intravenous phentolamine at 14 HPI. Blood pressure decreased to 133/82 mm Hg, and HR increased to 56 bpm with improvements in headache. Following repeat doses of phentolamine, nicardipine was initiated and increased to 2.5 mg/h for 12 hours. The patient was stable with normal vital signs at 36 HPI.The delayed presentation of hypertensive emergency with PRES may have been due to the actions of extended-release dextroamphetamine and the α2-agonistic effects of clonidine. Phentolamine was chosen for its α1-antagonism and was effective in managing symptoms.",
"affiliations": "From the Departments of Pharmacy.;Imaging Sciences, University of Rochester Medical Center, Rochester, NY.;Emergency Medicine, and.",
"authors": "Minhaj|Faisal Syed|FS|;Schult|Rachel F|RF|;Dvorak|Peter|P|;Nacca|Nicholas|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000001819",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": null,
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": null,
"nlm_unique_id": "8507560",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30973502",
"pubdate": "2019-04-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Amphetamine and Clonidine Toxicity Resulting in Posterior Reversible Encephalopathy Syndrome.",
"title_normalized": "amphetamine and clonidine toxicity resulting in posterior reversible encephalopathy syndrome"
} | [
{
"companynumb": "US-NOVEN PHARMACEUTICALS, INC.-2022-NOV-US000285",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXTROAMPHETAMINE"
},
... |
{
"abstract": "OBJECTIVE\nThromboembolic or hemorrhagic complications related to atrial fibrillation (AF) ablation are rare, and thus, it is difficult to compare their frequency across different direct oral anticoagulants (DOACs). We aimed to compare the intra-ablation blood coagulability and post-procedural hemoglobin fall as alternatives to those complications across 4 DOACs.\n\n\nMETHODS\nWe enrolled AF patients younger than 65 years old in 3 cardiovascular centers who skipped a single dose of apixaban, dabigatran, edoxaban, and rivaroxaban, prior to the ablation. Endpoints included the activated clotting time (ACT), heparin requirement during the ablation, and drop in the hemoglobin level 24 h after the procedure.\n\n\nRESULTS\nThe time-course curves of the ACT differed significantly across the patients with apixaban (N = 113), dabigatran (N = 130), edoxaban (N = 144), and rivaroxaban (N = 81), with its highest level in the dabigatran group (P < 0.001). The average ACT was greater in the dabigatran group than in the other groups (312.3 ± 34, 334.4 ± 44, 308.1 ± 41, and 305.8 ± 34.7 s; P < 0.001). A significant difference was noted in total heparin requirement across the patient groups (3990.2 ± 1167.9, 3890.4 ± 955.3, 4423.8 ± 1051.6, and 3972 ± 978.7 U/m2/h; P < 0.001), with its greatest amount in the edoxaban group. The reduction in the hemoglobin level was similar (- 0.93 ± 0.92, - 0.88 ± 0.79, - 0.89 ± 0.97, - 0.95 ± 1.23 g/dL; P = 0.94). No inter-group difference was noted in the rate of major or minor bleedings (0.9%, 2.3%, 1.4%, and 3.7%; P = 0.51), and no thromboembolic events were encountered.\n\n\nCONCLUSIONS\nA difference in DOACs may have an impact on intra-ablation anticoagulation; however, it may not be on the procedural blood loss in the setting of a single skip.",
"affiliations": "Department of Cardiology, Cardiovascular Center, Onomichi General Hospital, Onomichi, Japan. rjrgw059@ybb.ne.jp.;Department of Cardiology, Cardiovascular Center, Onomichi General Hospital, Onomichi, Japan.;Department of Cardiology, Cardiovascular Center, Onomichi General Hospital, Onomichi, Japan.;Department of Cardiology, Cardiovascular Center, Onomichi General Hospital, Onomichi, Japan.;Department of Cardiology, Cardiovascular Center, Onomichi General Hospital, Onomichi, Japan.;Department of Cardiology, Cardiovascular Center, Hiroshima General Hospital, Hatsukaichi, Japan.;Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.",
"authors": "Sairaku|Akinori|A|;Morishima|Nobuyuki|N|;Matsumura|Hiroya|H|;Amioka|Michitaka|M|;Maeda|Junji|J|;Watanabe|Yoshikazu|Y|;Nakano|Yukiko|Y|",
"chemical_list": "D000925:Anticoagulants; D006454:Hemoglobins; D004364:Pharmaceutical Preparations; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10840-020-00851-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1383-875X",
"issue": "61(3)",
"journal": "Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing",
"keywords": "Activated clotting time; Atrial fibrillation ablation; Direct oral anticoagulants; Hemoglobin fall",
"medline_ta": "J Interv Card Electrophysiol",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D000069604:Dabigatran; D006454:Hemoglobins; D006801:Humans; D004364:Pharmaceutical Preparations; D000069552:Rivaroxaban",
"nlm_unique_id": "9708966",
"other_id": null,
"pages": "551-557",
"pmc": null,
"pmid": "32808083",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": "26424865",
"title": "Intra-procedural anticoagulation and post-procedural hemoglobin fall in atrial fibrillation ablation with minimally interrupted direct oral anticoagulants: comparisons across 4 drugs.",
"title_normalized": "intra procedural anticoagulation and post procedural hemoglobin fall in atrial fibrillation ablation with minimally interrupted direct oral anticoagulants comparisons across 4 drugs"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-043636",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
... |
{
"abstract": "We report the first case of a ganciclovir-resistant cytomegalovirus (CMV) involving the gastrointestinal tract that was successfully treated with high-dose valganciclovir. A kidney transplant recipient developed drug-resistant CMV colitis which was initially treated with valganciclovir, but his CMV was found to have major resistance to ganciclovir and cidofovir due to UL97 and UL54 mutations. The patient was switched to intravenous foscarnet 40 mg/kg given every twelve hours. However, foscarnet had to be discontinued after 4 days of treatment due to acute kidney injury. Patient was restarted on valganciclovir at a higher target dose of 1800 mg twice a day based on the creatinine clearance. CMV became undetectable 2 weeks after valganciclovir treatment was completed. High-dose valganciclovir along with immune suppression reduction may be a treatment option for CMV colitis with ganciclovir resistance due to dual UL97 and UL54 gene mutations.",
"affiliations": "Division of Nephrology, University of Oklahoma, Tulsa, Oklahoma. Electronic address: Krishna-Baradhi@ouhsc.edu.;Division of Nephrology, University of Oklahoma, Tulsa, Oklahoma.;Kidney and Transplant Division, Baptist Integris Nazih Zuhdi Transplant Institute, Oklahoma City, Oklahoma.",
"authors": "Baradhi|K M|KM|;Aure|R L|RL|;El-Amm|J-M|JM|",
"chemical_list": "D000998:Antiviral Agents; D063065:Organophosphonates; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; D017245:Foscarnet; D003596:Cytosine; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D004259:DNA-Directed DNA Polymerase; D000077562:Valganciclovir; D000077404:Cidofovir; D015774:Ganciclovir",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2017.11.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D000077404:Cidofovir; D003092:Colitis; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D003596:Cytosine; D004259:DNA-Directed DNA Polymerase; D024882:Drug Resistance, Viral; D017245:Foscarnet; D015774:Ganciclovir; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D009154:Mutation; D063065:Organophosphonates; D017853:Phosphotransferases (Alcohol Group Acceptor); D000077562:Valganciclovir; D014764:Viral Proteins",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "142-144",
"pmc": null,
"pmid": "29407298",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "High-dose Valganciclovir Treatment for Resistant Cytomegalovirus Colitis due to UL97 and UL54 Mutations.",
"title_normalized": "high dose valganciclovir treatment for resistant cytomegalovirus colitis due to ul97 and ul54 mutations"
} | [
{
"companynumb": "US-ASTELLAS-2018US011099",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo report 2 cases in which point-of-care international normalized ratios (POC-INRs) measured using a Hemochron Jr. Signature Elite device (International Technidyne Corporation) were inaccurate in rivaroxaban-treated patients.\n\n\nMETHODS\nTherapy in an 86-year-old man with atrial fibrillation was converted from warfarin to rivaroxaban 15 mg twice daily because of a deep venous thrombotic event despite an INR of 2.4, which was within the therapeutic range. One week later a POC-INR was inadvertently measured, which was 6.3. In light of the POC-INR being markedly elevated, a laboratory test for INR was performed, which gave a result of 2.74. Therapy in a 66-year-old man was converted from war-farin to rivaroxaban 15 mg twice daily because of unstable INRs and a pulmonary embolism despite a therapeutic INR. Seven days after rivaroxaban was started, the patient's POC-INR was 9.2; simultaneously measured laboratory-determined INR was 2.0. For both patients, coagulation tests performed on follow-up visits revealed continued discordance between the POC and laboratory assays.\n\n\nCONCLUSIONS\nRivaroxaban is an oral factor Xa inhibitor with a predictable pharmacokinetic profile, allowing for a fixed-dose regimen without the need for coagulation monitoring. When patients' therapy is switched from rivaroxaban to warfarin, it is recommended that the drugs be given concurrently until the INR is 2.0 or higher, to ensure adequate anticoagulation during this well-recognized vulnerable period for stroke. POC testing is a common method of INR assessment in clinical practice. During ROCKET-AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), POC-INRs were measured exclusively with the INRatio device (Hemosense), and values above 4 were seen very rarely (0.25%), which indicates that the values determined in our patients were highly unusual.\n\n\nCONCLUSIONS\nOur 2 patients receiving rivaroxaban had POC-INRs elevated beyond what was expected; these measurements were discordant from INRs simultaneously measured via the laboratory. A prospective evaluation assessing the accuracy of other commonly used POC-INR devices in patients receiving rivaroxaban would determine whether our findings extend to other devices. Until that time, laboratory measurement of INR or POC-INR using an INRatio device is recommended when patients' therapy is transitioned from rivaroxaban to warfarin.",
"affiliations": "Medical Program, James J Peters VA Medical Center, Bronx, NY.",
"authors": "Baruch|Lawrence|L|;Sherman|Olga|O|",
"chemical_list": "D000925:Anticoagulants; D009025:Morpholines; D013876:Thiophenes; D000069552:Rivaroxaban",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028013503129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "47(9)",
"journal": "The Annals of pharmacotherapy",
"keywords": "INR; anticoagulation; deep vein thrombosis; factor Xa inhibitor; point-of-care INR; rivaroxaban",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D009025:Morpholines; D019095:Point-of-Care Systems; D011655:Pulmonary Embolism; D000069552:Rivaroxaban; D013876:Thiophenes; D020246:Venous Thrombosis",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1210-2",
"pmc": null,
"pmid": "24259738",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Inaccuracy of point-of-care international normalized ratio in rivaroxaban-treated patients.",
"title_normalized": "inaccuracy of point of care international normalized ratio in rivaroxaban treated patients"
} | [
{
"companynumb": "US-CIPLA LTD.-2021US05795",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
... |
{
"abstract": "We report on a case of seriously hampered tubal repair 6 months after local MTX treatment. Histopathological examination showed destruction of tubal mucosa and remnants of the EP.",
"affiliations": "Department of Obstetrics and Gynecology, University Hospital Dijkzigt, Rotterdam, The Netherlands.",
"authors": "Klinkert|J|J|;van Geldorp|H J|HJ|;Chadha-Ajwani|S|S|;Huikeshoven|F J|FJ|",
"chemical_list": "D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1016/s0015-0282(16)55884-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0015-0282",
"issue": "59(4)",
"journal": "Fertility and sterility",
"keywords": null,
"medline_ta": "Fertil Steril",
"mesh_terms": "D000328:Adult; D005187:Fallopian Tubes; D005260:Female; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D011274:Pregnancy, Tubal",
"nlm_unique_id": "0372772",
"other_id": null,
"pages": "926-7",
"pmc": null,
"pmid": "8458517",
"pubdate": "1993-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tubal damage after intratubal methotrexate treatment.",
"title_normalized": "tubal damage after intratubal methotrexate treatment"
} | [
{
"companynumb": "NL-PFIZER INC-2021362825",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": "3",... |
{
"abstract": "Thirty-five patients with Ph+ CML aged more than 60 years were treated with imatinib. Twenty-four patients (group A) were in late chronic phase (CP) and eleven patients (group B) were in accelerated/blastic phase (AP/BP). In group A, complete haematological response (CHR) was achieved by all patients; seventeen patients (70.8%) attained a complete cytogenetic response (CCR), one (4.1%) attained a partial CR, one (4.1%) a minor CR (Ph+ 70%) and five (21%) were resistant (Ph+ 100%), toxicity was mild: seven patients had a transient cytopenia, three a skin reaction, one a moderate oedema and one muscular pain. After a median follow-up of 15 months, 1 patient died in progression and 23 patients are alive (2 in BP and 21 in persisting response). In group B, one patient died after 3 months in aplastic phase from sepsis, three patients were resistant and seven patients (63.7%) achieved CHR; of these, four obtained CCR. After a median follow-up of 17 months, 4 patients have died from progressive disease, 6 are alive; 1 in AP and 5 in CHR (4 of them being in CCR). Present data indicate that imatinib is safe also in elderly with clinical results as good as in younger patients.",
"affiliations": "Dipartimento di Biotecnologie Umane ed Ematologia, Università \"La Sapienza\" di Roma, Via Benevento 6-00161, Rome, Italy. rob.lati@libero.it",
"authors": "Latagliata|Roberto|R|;Roberto|Latagliata|L|;Breccia|Massimo|M|;Massimo|Breccia|B|;Carmosino|Ida|I|;Ida|Carmosino|C|;Sarlo|Chiara|C|;Chiara|Sarlo|S|;Montefusco|Enrico|E|;Enrico|Montefusco|M|;Mancini|Marco|M|;Marco|Mancini|M|;Natalino|Fiammetta|F|;Fiammetta|Natalino|N|;Chistolini|Antonio|A|;Antonio|Chistolini|C|;De Cuia|Rosa|R|;Rosa|De Cuia|de C|;Russo|Eleonora|E|;Eleonora|Russo|R|;Morano|Giacomo Salvatore|GS|;Giacomo|Morano Salvatore|MS|;Biondo|Francesca|F|;Francesca|Biondo|B|;Spadea|Antonio|A|;Antonio|Spadea|S|;Mandelli|Franco|F|;Franco|Mandelli|M|;Alimena|Giuliana|G|;Giuliana|Alimena|A|",
"chemical_list": "D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "England",
"delete": false,
"doi": "10.1016/j.leukres.2004.08.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-2126",
"issue": "29(3)",
"journal": "Leukemia research",
"keywords": null,
"medline_ta": "Leuk Res",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D001549:Benzamides; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016896:Treatment Outcome",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "287-91",
"pmc": null,
"pmid": "15661264",
"pubdate": "2005-03",
"publication_types": "D016430:Clinical Trial; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Elderly patients with Ph+ chronic myelogenous leukemia (CML): results of imatinib mesylate treatment.",
"title_normalized": "elderly patients with ph chronic myelogenous leukemia cml results of imatinib mesylate treatment"
} | [
{
"companynumb": "PHHY2019IT150341",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study is to determine the incidence of febrile neutropenia (FN) among women receiving FEC-D (flurouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for three cycles followed by docetaxel 100 mg/m(2) every 3 weeks for three cycles) chemotherapy for early stage breast cancer (ESBC) and the impact of primary granulocyte colony-stimulating factor (G-CSF) prophylaxis in a non-clinical trial setting.\n\n\nMETHODS\nA retrospective chart review of women referred for ESBC to The Moncton Hospital between 2005 and 2010 evaluated patient and disease characteristics, adjuvant chemotherapy receipt, G-CSF usage, FN incidence, hospital admission rates, and length of stay. Association of variables with FN was examined, and exploratory multivariable logistic regression modeling examined the impact of baseline variables on risk of FN.\n\n\nRESULTS\nOf 520 patients enrolled in the database, 251 (48.3 %) received adjuvant chemotherapy for ESBC. Most (66.9 %) received FEC-D. Overall, 55 (21.9 %) patients developed FN. Forty-four (26.2 %) patients on FEC-D developed FN. Forty of 129 (31.0 %) FEC-D patients who did not receive primary G-CSF prophylaxis developed FN, versus 4 of 39 (10.3 %) receiving G-CSF. Receipt of FEC-D or TC (docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks for four or six cycles) was associated with odds ratios of 6.5 or 6.77, respectively, for the development of FN. Receipt of trastuzumab with chemotherapy was associated with an odds ratio of 3.48 for developing FN versus no trastuzumab. Primary G-CSF prophylaxis led to a 63 % reduction in the odds ratio of developing FN.\n\n\nCONCLUSIONS\nIncidence of FN with FEC-D treatment is considerably higher in clinical practice than reported in phase III trials. Consistent with ASCO guidelines, prophylactic G-CSF should be considered for all ESBC patients receiving adjuvant FEC-D.",
"affiliations": "Division of Medical Oncology, The Moncton Hospital, 135 MacBeath Ave., Moncton, New Brunswick, E1C 6Z8, Canada, hazemassi@gmail.com.",
"authors": "Assi|Hazem|H|;Murray|Joshua|J|;Boyle|Laura|L|;Rayson|Daniel|D|",
"chemical_list": "D000277:Adjuvants, Pharmaceutic; D000970:Antineoplastic Agents; D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-014-2318-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "22(12)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": null,
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000277:Adjuvants, Pharmaceutic; D000368:Aged; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D002170:Canada; D018890:Chemoprevention; D017024:Chemotherapy, Adjuvant; D064146:Chemotherapy-Induced Febrile Neutropenia; D003520:Cyclophosphamide; D000077143:Docetaxel; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies; D012307:Risk Factors; D043823:Taxoids",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "3227-34",
"pmc": null,
"pmid": "24996828",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": "16682719;21095116;17686164;21119031;21655158;20016741;20808559;21149659;22670112;22252548;21784637;7877646;17116941;16236738;21991949",
"title": "Incidence of febrile neutropenia in early stage breast cancer patients receiving adjuvant FEC-D treatment.",
"title_normalized": "incidence of febrile neutropenia in early stage breast cancer patients receiving adjuvant fec d treatment"
} | [
{
"companynumb": "CA-BAUSCH-BL-2015-014203",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EPIRUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Blastomycosis is an endemic mycosis in the United States known to primarily cause pneumonia. However, dissemination to different organs including the musculoskeletal system has been described.\nWe report a case of mandibular blastomycosis in a healthy patient with no evidence of lung involvement. A 28 year-old female presented with recurrent right mandibular osteomyelitis despite courses of antibiotics and surgical debridement. She eventually underwent right hemimandibulectomy. Budding yeasts visualized on Gomori Methenamine-Silver (GMS) and Periodic acid-Schiff (PAS) were morphologically consistent with Blastomyces dermatitidis, and intra-operative cultures showed growth of mold identified as B. dermatitidis by DNA probe. She was placed on a prolonged course of itraconazole with clinical improvement. We also reviewed the literature and found 5 cases of similar presentation which we briefly summarized in this present case report.\nBlastomycosis should be considered in patients with recurrent or persistent mandibular osteomyelitis even in immunocompetent individuals.",
"affiliations": "MD, Division of Infectious Diseases, Loyola University Medical Center, 2160 S. 1st Ave., Maywood, IL 60153, USA.;DO, Carle Foundation Hospital, 611 W. Park Street, Urbana, IL 61801, USA.;BDS, MB ChB, FRCS, FACS, Division of Oral and Maxillofacial Surgery, Loyola University Medical Center, 2160 S. 1st Ave., Maywood, IL 60153, USA.",
"authors": "Albarillo|Fritzie S|FS|;Varma|Gotam T|GT|;MacLeod|Stephen P R|SPR|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.18683/germs.2018.1148",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2248-2997",
"issue": "8(4)",
"journal": "Germs",
"keywords": "Blastomycosis; mandibular blastomycosis.; mandibular osteomyelitis",
"medline_ta": "Germs",
"mesh_terms": null,
"nlm_unique_id": "101596099",
"other_id": null,
"pages": "207-213",
"pmc": null,
"pmid": "30775340",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports",
"references": "1420675;15472368;15610667;16238219;17097778;17364352;17591310;18462107;20318753;20375357;21801047;24486126;25339251;3864096;4160724;507527;5260665;6956819;8722836;9313293",
"title": "Mandibular blastomycosis: A case report and review of the literature.",
"title_normalized": "mandibular blastomycosis a case report and review of the literature"
} | [
{
"companynumb": "US-BAYER-2019-107316",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nChemotherapy has been associated with a theoretical risk of hepatitis C virus (HCV) reactivation. However, little is known about the amplitude of viral replication and the incidence of subsequent hepatic exacerbation.\n\n\nMETHODS\nWe aimed to describe the occurrence of hepatitis flare and HCV reactivation at our center. We included, over a period of 5 years, adult patients with chronic HCV receiving intravenous chemotherapy. We excluded patients with undetectable HCV RNA, hepatocellular carcinoma, liver metastases or other etiologies of hepatic disease. The primary objective was to identify hepatic flares (elevation of alanine aminotransferase 3 times above the upper limit of normal). Secondary objectives were to assess viral reactivation (HCVr, HCV-RNA ≥1 log10 IU/mL when compared to baseline value), hepatic decompensation, mortality and the impact on the chemotherapy. Descriptive statistics were used.\n\n\nRESULTS\nA total of 11 patients with chronic HCV were identified among the 5761 oncology patients. Five patients experienced a hepatic flare with median maximal ALT value of 139 U/L (IQR 133-237). Only 2 patients met criteria for HCVr with a median RNA increase of 1.16 log IU/mL (IQR 1.1-1.2). One patient presented with both HCVr and a hepatic flare. Only one patient required chemotherapy discontinuation following hepatic flare. No hepatic decompensation or related mortality were observed.\n\n\nCONCLUSIONS\nWe identified a very small number of HCV cases among our population. We observed HCVr and hepatic flares, but only one consequence on cancer treatment. Nonetheless, HCV screening is encouraged among patients undergoing chemotherapy to allow close follow-up of hepatic function.",
"affiliations": "Department of Microbiology, Infectious diseases and Immunology of the University of Montreal, Montreal, Canada.;Department of Pharmacy, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Canada.;Department of Pharmacy, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Canada.;CHUM Research Center, Montreal, Canada.;Department of Microbiology, Infectious diseases and Immunology of the University of Montreal, Montreal, Canada.",
"authors": "Boutin|Catherine-Audrey|CA|https://orcid.org/0000-0001-7661-0882;Adam|Jean-Philippe|JP|https://orcid.org/0000-0002-7938-0944;Martel|Dominic|D|;Doucet|Stéphane|S|;Martel-Laferrière|Valérie|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1078155220969797",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": null,
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Hepatitis C virus; chemotherapy; hepatic decompensation; hepatic flare; viral replication",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": null,
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "1078155220969797",
"pmc": null,
"pmid": "33131449",
"pubdate": "2020-11-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risks of hepatitis C virus reactivation in a real-life population of oncology patients treated in an academic center.",
"title_normalized": "risks of hepatitis c virus reactivation in a real life population of oncology patients treated in an academic center"
} | [
{
"companynumb": "CA-009507513-2203CAN002375",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Central giant cell granuloma (CGCG) is a relatively rare non-neoplastic, intraosseous lesion that exhibits a wide spectrum of clinical behavior, and its management can be particularly challenging even for experienced clinicians. The etiopathogenesis of this disease process remains unclear, although factors such as trauma, inflammatory foci, and a genetic predisposition have been implicated. Although multiple treatment modalities have been used with varying degrees of success, there is no accepted algorithm for therapeutic intervention and little is known about the reasons for success or failure of a given treatment. This article reviews the epidemiology, presentation, classification, and currently used therapies for CGCG while describing the clinical course and successful therapeutic outcome of a young female patient with an aggressive CGCG of the mandible.",
"affiliations": "Resident, Wright State University Plastic Surgery Residency Program, Dayton, OH. Electronic address: david.jerkins@gmail.com.;Resident, Wright State University Plastic Surgery Residency Program, Dayton, OH.;Private Practitioner, Clinical Faculty, Wright State University Plastic Surgery Residency Program, Dayton, OH.;Faculty Physician, Pediatric Hematology and Oncology, Dayton Children's Hospital, Dayton, OH.",
"authors": "Jerkins|David|D|;Malotky|Maximilian|M|;Miremadi|Reza|R|;Dole|Mukund|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "74(8)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D001706:Biopsy; D002648:Child; D003131:Combined Modality Therapy; D005260:Female; D006101:Granuloma, Giant Cell; D006801:Humans; D008336:Mandibular Diseases; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "1596-607",
"pmc": null,
"pmid": "27000410",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Central Giant Cell Granuloma of the Mandible Requiring Multiple Treatment Modalities: A Case Report.",
"title_normalized": "central giant cell granuloma of the mandible requiring multiple treatment modalities a case report"
} | [
{
"companynumb": "US-MYLANLABS-2017M1021103",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCITONIN SALMON"
},
"drugadditional": "3",
... |
{
"abstract": "Warfarin is a widely used anticoagulant for the prevention and treatment of thromboembolism. We conducted a retrospective review to determine the causes and management of warfarin toxicity of patients admitted to Tygerberg hospital between June 2014 and June 2015.\n\n\n\nWe identified and evaluated 126 patients who met the inclusion criteria. The cause of warfarin toxicity was identified and addressed in only 14.3% (18/126) of patients. Where the cause was identified, 56% (10/18) was due to dosing errors and 17% (3/18) drug-drug interaction (DDI). However, 77% (97/126) of patients were retrospectively identified as receiving concomitant medicines known to interact with warfarin at the time of admission. Twenty-eight percent (35/126) of patients presented with major bleeding, which included seven cases of intracranial haemorrhage. Patients were admitted for a median of eight days at an average treatment cost of R10 578.\n\n\n\nWe found that warfarin toxicity carries significant mortality and cost, but little attention is paid to the causes of toxicity.",
"affiliations": "Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa. Email: annemariejacobs15@gmail.com.;Division of Haematology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.;Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.",
"authors": "Jacobs|Annemarie|A|;Bassa|Fatima|F|;Decloedt|Eric H|EH|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "South Africa",
"delete": false,
"doi": "10.5830/CVJA-2017-029",
"fulltext": "\n==== Front\nCardiovasc J AfrCardiovasc J AfrTBCCardiovascular Journal of Africa1995-18921680-0745Clinics Cardive Publishing 2865619310.5830/CVJA-2017-029Cardiovascular TopicsA preliminary review of warfarin toxicity in a tertiary hospital in Cape Town, South Africa Jacobs, Annemarie MB ChBannemariejacobs15@gmail.comFaculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South AfricaH Decloedt Eric MB ChB, BSc Hons (Pharmacology), MMed (Clin Pharm), FCCP (SA)Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South AfricaBassa Fatima MB ChB, FCPath (Haem), MMed (Haem)Division of Haematology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South AfricaNov-Dec 2017 28 6 346 349 www.cvja.co.za01 3 2017 16 5 2017 Copyright © 2015 Clinics Cardive Publishing2016This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Summary\nAim:\nWarfarin is a widely used anticoagulant for the prevention and treatment of thromboembolism. We conducted a retrospective review to determine the causes and management of warfarin toxicity of patients admitted to Tygerberg hospital between June 2014 and June 2015.\n\nResults:\nWe identified and evaluated 126 patients who met the inclusion criteria. The cause of warfarin toxicity was identified and addressed in only 14.3% (18/126) of patients. Where the cause was identified, 56% (10/18) was due to dosing errors and 17% (3/18) drug–drug interaction (DDI). However, 77% (97/126) of patients were retrospectively identified as receiving concomitant medicines known to interact with warfarin at the time of admission. Twenty-eight per cent (35/126) of patients presented with major bleeding, which included seven cases of intracranial haemorrhage. Patients were admitted for a median of eight days at an average treatment cost of R10 578.\n\nConclusion:\nWe found that warfarin toxicity carries significant mortality and cost, but little attention is paid to the causes of toxicity.\n\nwarfarintoxicitybleedingtreatmentcost\n==== Body\nIntroduction\nWarfarin is a widely used anticoagulant indicated for the prevention and treatment of thromboembolism in patients with atrial fibrillation, prosthetic heart valves and deep-vein thrombosis. However, warfarin therapy is challenging. Sonuga et al.1 reported in a study done at Victoria Hospital, Cape Town, that a therapeutic international normalised ratio (INR) outcome was achieved in only 48.5% of patients. The warfarin dose–response curve is not predictable and requires regular INR monitoring to optimise efficacy and minimise toxicity.2\n\nCytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genetic polymorphisms contribute to clinically significant variability in warfarin exposure and efficacy.2,3 Genetic polymorphisms in the CYP2C9 and VKORC1 enzymes account for 10 to 15% and 20 to 35% of inter-individual variance in warfarin dosing, respectively, with an increase in genetic polymorphisms found in Caucasian populations in comparison to African populations.3,4 Genetic polymorphisms are associated with decreased metabolism of or increased sensitivity to warfarin, as well as increased risk for bleeding events.3\n\nThere is a direct relationship between increased INR and risk of bleeding, with an INR > 4.0 associated with a high bleeding risk.5 Various risk factors predispose patients with therapeutic INRs to develop warfarin toxicity: dosing errors, drug–drug interactions, acute illnesses (diarrhoea, cardiac failure, hepatic impairment, fever) and dietary changes influencing vitamin K intake.6,7 Bleeding associated with warfarin toxicity carries a significant rate of morbidity and mortality. Risk factors for warfarin-associated bleeding mortality are advanced age, concomitant antiplatelet use, INR ≥ 4 at presentation, the use of vitamin K during hospitalisation, and intracerebral haemorrhage as a complication.8\n\nManagement of warfarin toxicity is determined by the degree of INR elevation with or without bleeding, and in the event of bleeding, the severity. Patients with an elevated INR and no evidence of bleeding can be managed with vitamin K, with or without omission of the next warfarin dose. Minor bleeding can be managed in a similar manner. The presence of major bleeding warrants immediate reversal of coagulopathy with the administration of vitamin K in conjunction with fresh frozen plasma (FFP) or 4-factor prothrombin complex concentrate (PCC). FFP and 4-factor PCC are considered to have a similar efficacy.7\n\nThere are no published data evaluating the causes, management and treatment costs of warfarin toxicity in South African healthcare facilities. The aim of this study was to provide an overview of warfarin toxicity, the management thereof and cost implications to treat a patient with warfarin toxicity in an academic hospital in South Africa.\n\nMethods\nEthical approval for the study was obtained from the Human Research Ethics Committee of the Faculty of Medicine and Health Sciences of the University of Stellenbosch (U15/09/002).\n\nWe conducted a retrospective review of adult patients (18 years or older) admitted to Tygerberg hospital (TBH), Cape Town, with warfarin toxicity during a one-year period from June 2014 to June 2015. Only patients known to be on established warfarin therapy were eligible for inclusion. Patients who were initiated on warfarin therapy during admission were excluded. Patients admitted more than once during the study period were recorded separately for each admission. We used National Health Laboratory Service (NHLS) records to identify patients with raised INRs and reviewed clinical notes, laboratory investigations and prescription data.\n\nWe collected demographic information, admission and discharge dates, INR measurements, the presence or absence of bleeding, sites and complications of bleeding, management, presumed cause of warfarin toxicity as recorded in the clinical notes, and whether it was addressed prior to discharge, as well as concomitant medicine use at time of admission. The cause of warfarin toxicity was recorded as not identified if a cause was not recorded in the clinical records. In the presence of bleeding, we classified it as major or non-major bleeding. Major bleeding was regarded as life- or limb-threatening bleeding, whereas all other cases where regarded as non-major bleeding.\n\nWe included patients presenting with warfarin toxicity, as defined by an admission INR value greater than 5. Patients included required at least one additional in-patient INR measurement to capture only in-patients. We excluded patients with an elevated INR who were not using warfarin and presented with elevated INRs due to other pathology such as liver impairment and sepsis. Patients with one elevated INR reading but who died prior to an additional INR measurement being done were not eligible for inclusion.\n\nWe calculated the warfarin toxicity treatment cost using the procurement cost of blood and blood products from the Western Cape Blood Transfusion Service, procurement cost of medicines from the TBH pharmacy, and cost to the hospital to admit a patient in a general ward in TBH using 2015 financial year costing. The general ward admission cost included personnel cost, clinical consumables, maintenance and engineering, equipment, services and overhead costs.\n\nWe used DRUG-REAX® Interactive Drug Interactions database (Truven Health Analytics Inc, Micromedex® Healthcare Series)8 to identify possible drug–drug interactions (DDI) between warfarin and drugs used by patients at the time of admission.\n\nStatistical analysis\nNo sample size was calculated and all patients identified during the study period were included. Data were entered into Microsoft Excel® and analysed using Stata version 11.0 (StataCorp, College Station, TX, USA). We assessed the normality of the data visually and using the Shapiro–Wilk test. Normally distributed data are described using the mean and standard deviation (SD) while non-normally distributed data are described using median and interquartile ranges (IQR). We explored statistical significance using appropriate tests for categorical, normal numerical and non-normal numerical data.\n\nResults\nWe identified 474 raised INR measurements (467 patients), of which 126 (122 patients) met our inclusion criteria for warfarintoxicity admissions (Fig. 1). Four patients presented with two admissions for warfarin toxicity during the study period and each admission was recorded. For clarity we will refer to the 126 warfarin-toxicity admissions as patients.\n\nFig. 1. Study sample selection.\n\nSixty per cent (76/126) of patients were female and 40% (50/126) were male, with a median (IQR) age of 61 (48–70) years. Fifteen per cent (19/126) of patients died before discharge, although we could not attribute with certainty cause of death to warfarin toxicity. Patients were admitted for a median (IQR) of eight (5–16) days. The most common indications for the usage of warfarin were atrial fibrillation (AF) (57 patients), deep-vein thrombosis (DVT) (24 patients) and heart valve replacements (29 patients) (Table 1).\n\nTable 1 Indications for warfarin therapy\nIndication\tNumber of patients\tPercentage\t\nAF\t48\t38\t\nHeart valve replacements\t24\t19\t\nDVT\t21\t17\t\nOther\t21\t17\t\nMultiple indications (including, but not limited to AF, heart valve replacements and DVT)\t9\t7\t\nUnknown\t3\t2\t\nTotal\t126\t\t\nAF = atrial fibrillation, DVT = deep-vein thrombosis.\n\nThe median (IQR) admission INR was 8.49 (6.38–10) with the median (IQR) discharge INR 1.98 (1.28–2.82). The cause of warfarin toxicity was identified and addressed in 14.3% (18/126) of patients. Where the cause was identified, 55.6% (10/18) were due to dosing errors, 16.7% (3/18) DDIs, 11.1% (2/18) acute illnesses and 11.1% (2/18) due to inability to control INR despite best effort.\n\nIn cases of dosing errors, seven were due to physician error, two were due to patient error, and one was due to both physician and patient error. Physician error was due to a too-aggressive increase in warfarin dosage in response to previously sub-therapeutic episodes, and patient error was ascribed to incorrect and/or inconsistent usage of warfarin. In 85.7% of patients with warfarin toxicity, the cause was not identified (Table 2).\n\nTable 2 Causes of warfarin toxicity\nCauses\tNo of patients\tPercentage\t\nCause identified\t18\t14.3\t\nDosing error\t10\t7.9\t\nPhysician\t7\t5.6\t\nPatient\t2\t1.6\t\nBoth\t1\t0.8\t\nDrug–drug interaction\t3\t2.4\t\nAcute illness\t2\t1.6\t\nInability to control INR despite best effort\t2\t1.6\t\nOther (liver injury)\t1\t0.8\t\nCause not identified\t108\t85.7\t\nTotal\t126\t\t\nEighty-five per cent (107/126) of patients were using concomitant medication on admission with 77% (97/126) of patients using one or more medicines with a known DDI with warfarin. The median (IQR) number of possible DDIs was two (one to three) per patient. The potential number of DDIs with warfarin per patient were: one DDI 18% (23/126), two DDIs 25% (31/126), three DDIs 18% (23/126), four DDIs 10% (13/126), five DDIs 4% (5/126), six DDIs 1% (1/126), and seven DDIs 1% (1/126). The most frequent drugs used found to have a DDI with warfarin were simvastatin (57 patients), aspirin (33 patients) and atenolol (29 patients). Table 3 reports on all major DDIs with warfarin.\n\nTable 3 Major DDIs with warfarin\nDrug\tNumber of patients using drug\tQuality of evidence of interaction\t\nCardiovascular medicines\t\t\t\nSimvastatin\t57\tExcellent\t\nAspirin\t33\tFair\t\nClopidogrel\t4\tFair\t\nAmiodarone\t3\tExcellent\t\nAntimicrobial, including antiretroviral medicines\t\t\t\nEfavirenz\t6\tFair\t\nAmoxicillin\t1\tGood\t\nAmoxicillin/clavulanic acid\t1\tGood\t\nCiprofloxacin\t1\tGood\t\nCotrimoxazole\t1\tExcellent\t\nMoxifloxacin\t1\tExcellent\t\nMetronidazole\t1\tGood\t\nCentral nervous system medicines\t\t\t\nFluoxetine\t4\tGood\t\nCitalopram\t1\tGood\t\nMirtazapine\t1\tExcellent\t\nValproic acid\t1\tGood\t\nTwenty-eight per cent (35/126) of patients presented with major bleeding, 18% (23/126) with non-major bleeding and 54% (68/126) without bleeding. The most frequent sites of bleeding were upper gastrointestinal tract (31%, 18/58), haemoptysis (19%, 11/58) and epistaxis (17%, 10/58). Seven cases (12%, 7/58) of intracranial haemorrhage were reported. The median INRs for the major bleeding, non-major bleeding and non-bleeding groups were not significantly different (p = 0.05) at 10, 7.59 and 7.65, respectively.\n\nWe found no statistically significant relationship between the presence of DDIs and the occurrence of bleeding. Furthermore, although 36 patients were using concomitant antiplatelet medicines, no statistically significant relationships were found between the concomitant usage of antiplatelet medicines together with warfarin and the occurrence of bleeding (see Table 4).\n\nTable 4 Bleeding versus antiplatelet medicines\nBleeding\tAspirin\tClopidogrel\tAspirin and clopidogrel\t\nMajor bleeding (n)\t8\t1\t0\t\nNon-major bleeding (n)\t4\t0\t0\t\nNo bleeding (n)\t20\t2\t1\t\nThe median number of treatment interventions was two, with 33.3% (42/126) of patients not receiving any interventions and 35.7% (45/126) and 23.8% (30/126) of patients receiving one and two treatment interventions, respectively. Nine (7.14%) patients received three or more interventions. Five per cent (6/126) of patients received three, 2% (2/126) received four and 1% (1/126) received five interventions, respectively.\n\nThe most frequently used interventions were vitamin K (45 patients), FFP (43 patients) and packed red blood cells (RBC) (34 patients). Factor PCC (Haemosolvex®) was administered in eight patients. Other interventions used were cryoprecipitate (one patient), tranexamic acid (two patients) and platelet products (three patients). See Table 5 for median (IQR) total dose given for the most frequently used interventions.\n\nTable 5 Most frequent interventions given\nIntervention\tMedian total dose given (IQR)\t\nVitamin K (oral/IV) (mg)\t10 (5–20)\t\nFFP (IU)\t3 (2–4)\t\nPacked RBC (IU)\t2.5 (2–5)\t\n4-factor PCC (IU)\t1 250 (1 000–2 000)\t\nIQR = interquartile range, IV = intravenous, FFP = fresh frozen plasma, RBC =red blood cells, IU = international units, PCC = prothrombin complex concentrate.\n\nThe average cost to treat a patient with warfarin toxicity was calculated at R10 578. The largest contributors to treatment costs were cost to be admitted and the use of blood and blood products when required (see Table 6).\n\nTable 6 Component\tCost average\tTotal range\t\nHospital stay\tR 7 464\t(R 627 – R70 224)\t\nVitamin K\tR 21\t(R 1 – R 81)\t\nFFP\tR 3 948\t(R 1 193 – R 10 737)\t\nPacked RBC\tR 4 617\t(R 2 434 –R 15 821)\t\n4-factor PCC\tR 4 312\t(R 1 568 – R 6 273)\t\nTotal cost to treat\tR 10 578\t(R 627 – R 79 762)\t\nFFP = fresh frozen plasma, RBC = red blood cells, PCC = prothrombin complex concentrate.\n\nDiscussion\nTo the best of our knowledge, this is the first review of warfarin toxicity in South Africa looking at causes, management and treatment cost implications. We found that the cause of warfarin toxicity was not identified in the majority of patients. DDIs were identified to be the cause of warfarin toxicity in only three cases, while we identified that 77% (97/126) of patients were using concomitant medication known to have a DDI with warfarin. The most frequently prescribed interacting medicines were cardiovascular medicines. Major DDIs with antimicrobial, antiretroviral and central nervous system medicines were also identified.\n\nOur patients presented with significant morbidity, with nearly half of the patients presenting with bleeding, while 28% presented with major bleeding. Although many unrecorded DDIs with warfarin were identified, we could not prove a statistically significant relationship for the presence of DDIs and the occurrence of bleeding. Furthermore we could not prove a statistically significant relationship between the usage of antiplatelet medicines together with warfarin and the occurrence of bleeding.\n\nPatients were admitted for a median of eight days and the average total cost to treat a patient with warfarin toxicity was estimated at R10 578. Of concern is that some patients were treated with high-cost interventions, which do not address the pathophysiology of warfarin toxicity. We also recognised a significant mortality rate associated with warfarin toxicity as 15% of patients died, although the final cause of death could not be attributed with certainty to warfarin toxicity.\n\nThe low pick-up rate for the cause of warfarin toxicity could be explained by physicians not documenting the cause of warfarin toxicity, however this is unlikely. Furthermore, it could be postulated that physicians are not aware of or unable to determine all the drug interactions with warfarin. Medicines found to have major DDIs with warfarin are used over a variety of disciplines and within a tertiary setting could result in the addition of medications to a patient’s treatment regime without adequate knowledge of already prescribed medication by other disciplines. Difficulty in dose adjustment could be explained by the availability of only 5-mg oral tablets in the public sector, limiting physicians in the degree that they can adjust warfarin dosage.\n\nOur study has a number of limitations. Firstly, this was a retrospective study and relied on the availability of clinical records and the quality of available records. We were unable to obtain access to the clinical records of 55 raised INR measurements. Secondly, it is possible that we excluded patients presenting with warfarin toxicity complicated by major bleeding using our inclusion criteria. We identified 19 patients who died with only one INR measurement having been done, but who were excluded from our analysis due to insufficient clinical information and our inclusion criteria.\n\nThirdly, we were unable to determine the impact of genetics on warfarin toxicity. However, genotype-guided dosing is only of value when initiating warfarin therapy.10 Fourthly, INR measurements are reported up to 10 with values above 10 being reported as > 10 by the NHLS. For statistical analysis, values greater than 10 were processed as 10, and underestimated the association between INR and bleeding severity of warfarin toxicity. Lastly, we were not able to determine prolonged admission to hospital for concomitant medical or surgical conditions after correction of warfarin toxicity.\n\nConclusion\nWe found that the cause of warfarin toxicity is frequently not identified by physicians and is therefore rarely addressed. We found that warfarin toxicity carries a significant morbidity rate and significant resources to treat. Future prospective research should study the causes of patients who are stable on warfarin treatment and present with warfarin toxicity, and target interventions to address this.\n==== Refs\nReferences\n1 Sonuga BO Hellenberg DA Cupido CS Jaeger C Profile and anticoagulation outcomes of patients on warfarin therapy in an urban hospital in Cape Town, South Africa. Afr J Prim Health Care Fam Med 2016 8 1 a1032 a1032 \n2 Rossiter D (ed) South African Medicines Formulary. Cape Town: Health and Medical Publishing Group of the South African Medical Association 2014 102 103 \n3 Jonas DE McLeod HL Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci 2009 30 7 375 386 19540002 \n4 Limdi NA Wadelius M Cavallari L Eriksson N Crawford DC Lee MM et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood 2010 115 18 3827 3834 20203262 \n5 Westaway K Cruickshank M Roberts GW Esterman AJ Factors influencing over-anticoagulation and bleeding warfarin therapy during the initial five months of treatment. Austr Nursing J 2010 17 10 28 31 \n6 Gage BF Fihn SD White RH and dosing of warfarin therapy. Am J Med 2000 109 481 485 11042238 \n7 Hull RD Garcia DA Correcting excess anticoagulation after warfarin [Online] 2015 [access 2015, April 23] Available: http://www.uptodate.com/contents/correcting-excess-anticoagulation-after-warfarin \n8 Mezin J Hoesche J Friedman M Nichols C Bergman C Crowther M et al. Failure to correct international normalized ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records. J Thromb Haemostasis 2012 10 596 605 22257107 \n9 DRUG-REAX® Interactive Drug Interactions database (Truven Health Analytics Inc. Micromedex® Healthcare Series) 2016. [Online]. Available: http://www.micromedexsolutions.com/micromedex2/librarian/CS/C70D18/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/9DCF96/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.FindDrugI [2016, July] \n10 Primohamed M Burnside G Eriksson N Jorgensen AL Hock Toh C Nicholson T et al. A randomized trial of genotype-guided dosing of warfarin. New Engl J Med 2013 369 24 2294 2303 24251363\n\n",
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"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001777:Blood Coagulation; D016527:Drug Costs; D004347:Drug Interactions; D005260:Female; D006470:Hemorrhage; D017721:Hospital Costs; D006801:Humans; D019934:International Normalized Ratio; D007902:Length of Stay; D008297:Male; D008508:Medication Errors; D008875:Middle Aged; D019338:Polypharmacy; D000074286:Preliminary Data; D012189:Retrospective Studies; D012307:Risk Factors; D013019:South Africa; D062606:Tertiary Care Centers; D013997:Time Factors; D016896:Treatment Outcome; D014859:Warfarin",
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"title": "A preliminary review of warfarin toxicity in a tertiary hospital in Cape Town, South Africa.",
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"abstract": "Prognosis of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph-ALL) relapsing after allogeneic hematopoietic stem cell transplantation (HSCT) is extremely poor. Therefore, effective alternative therapeutic measures are urgently needed. Recently, the use of antigen receptor-modified T cells holds great promise for relapsed and refractory ALL treatment. Prior to chimeric antigen receptor T-cell (CAR-T) infusion conditioning chemotherapy is used routinely to establish a favorable in vivo environment for CAR-T expansion, which has mostly involved fludarabine and cyclophosphamide. We report on a patient presented with extreme fatigue and anemia and was diagnosed with relapsed and refractory acute lymphoblastic leukemia (ALL) harbored T315I-BCR-ABL mutation, who had undergone allogeneic HSCT and multiple reinducing chemotherapy, but achieved complete hematologic remission (CHR) with CAR -T infusion as a later salvage treatment. Prior to CAR-T infusion there was no conditioning chemotherapy, but a bone marrow suppression period induced by ponatinib. CAR-T cell infusion was well tolerated and the patient achieved a CHR and maintained it for three months. At present, there is no relevant report on the use of tyrosine kinase inhibitors (TKI) as preconditioning protocols before CAR-T cells infusion. Our case indicated ponatinib not only reduces tumor burden but may also serve as a conditioning regimen for CAR-T therapy in the treatment of relapsed and refractory Ph-ALL.",
"affiliations": "Department of Hematology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; First School of Clinical Medicine, Hospital of Nanjing University of Chinese Medicine, Nanjing, China.;First School of Clinical Medicine, Hospital of Nanjing University of Chinese Medicine, Nanjing, China; Research Center of TCM, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.;Department of Hematology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; First School of Clinical Medicine, Hospital of Nanjing University of Chinese Medicine, Nanjing, China.;Department of Hematology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; First School of Clinical Medicine, Hospital of Nanjing University of Chinese Medicine, Nanjing, China.;Department of Hematology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; First School of Clinical Medicine, Hospital of Nanjing University of Chinese Medicine, Nanjing, China.;Department of Hematology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; First School of Clinical Medicine, Hospital of Nanjing University of Chinese Medicine, Nanjing, China.;Department of Hematology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China; First School of Clinical Medicine, Hospital of Nanjing University of Chinese Medicine, Nanjing, China. Email: Zhuxj2@sina.com.",
"authors": "Dai|Xingbin|X|;Tian|Fang|F|;Xu|Zuqiong|Z|;Kong|Xiangtu|X|;Jiang|Pengjun|P|;Xia|Wen|W|;Zhu|Xuejun|X|",
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"journal": "Annals of palliative medicine",
"keywords": "Tyrosine kinase inhibitor (TKI); acute lymphoblastic leukemia (ALL); case report; chimeric antigen receptor T-cell (CAR-T); conditioning regimen",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016879:Salvage Therapy",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Philadelphia chromosome-positive acute lymphoblastic leukemia: a case report.",
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"abstract": "Kounis syndrome is an acute coronary syndrome concurrently occurs with allergic or hypersensitivity reactions. In patient with this syndrome, inflammatory mediators released due to an allergic reaction implicate to induce coronary artery spasm and atheromatous plaque rupture. We describe a patient with coronary artery disease who developed acute perioperative myocardial infarction leading to cardiac arrest after the anaphylactic reaction to cisatracurium, which led to a suspicion of Kounis syndrome. Anesthesiologists should be aware that anaphylaxis or allergic reactions can progress to acute coronary syndrome, thereby significantly change the course of the disease.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.",
"authors": "Yoon|Syn-Hae|SH|;Bang|Ji-Yeon|JY|;Seo|Hyungseok|H|;Song|Jun-Gol|JG|",
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"country": "Korea (South)",
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"doi": "10.4097/kjae.2014.67.6.412",
"fulltext": "\n==== Front\nKorean J AnesthesiolKorean J AnesthesiolKJAEKorean Journal of Anesthesiology2005-64192005-7563The Korean Society of Anesthesiologists 10.4097/kjae.2014.67.6.412Case ReportSudden cardiovascular collapse caused by severe anaphylaxis after cisatracurium use: a case report Yoon Syn-Hae Bang Ji-Yeon Seo Hyungseok Song Jun-Gol Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.Corresponding author: Hyungseok Seo, M.D., Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. Tel: 82-2-3010-3868, Fax: 82-2-470-1363, seohyungseok@gmail.com12 2014 29 12 2014 67 6 412 415 10 10 2013 19 11 2013 27 11 2013 Copyright © the Korean Society of Anesthesiologists, 20142014This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Kounis syndrome is an acute coronary syndrome concurrently occurs with allergic or hypersensitivity reactions. In patient with this syndrome, inflammatory mediators released due to an allergic reaction implicate to induce coronary artery spasm and atheromatous plaque rupture. We describe a patient with coronary artery disease who developed acute perioperative myocardial infarction leading to cardiac arrest after the anaphylactic reaction to cisatracurium, which led to a suspicion of Kounis syndrome. Anesthesiologists should be aware that anaphylaxis or allergic reactions can progress to acute coronary syndrome, thereby significantly change the course of the disease.\n\nAnaphylaxisCisatracuriumKounis syndromeMyocardial infarction\n==== Body\nIntroduction\nAnaphylaxis is of great concern due to its potential of life-threatening nature. During anaphylaxis or allergic reactions, various inflammatory mediators are released that could progress to acute coronary syndromes. This is termed as \"allergic myocardial infarction (MI),\" or Kounis syndrome [1]. Although it is not frequently well known and most of the information comes from case reports, coronary artery involvement after allergic reactions are being increasingly reported [1,2]. Various drugs, animals and insect bites associated with allergic reaction have been reported to develop Kounis syndrome [1]. We report a case of acute perioperative MI concurrently occurred with anaphylaxis after cisatracurium administration during general anesthesia.\n\nCase Report\nA 66-year-old man a past smoker with a medical history of acute myocardial infarction on the inferior wall due to coronary artery spasm 8 years ago (weight, 67.2 kg; height, 163.5 cm; American Society of Anesthesiologists physical status classification II) was scheduled to undergo laparoscopy-assisted distal gastrectomy with gastroduodenostomy. His functional capacity was higher than 4 metabolic equivalents and he had no previous experience of general anesthesia. Preoperative evaluation showed a normal electrocardiogram (ECG) and no specific lung lesion was found by chest radiography. There was no abnormal finding in a pulmonary function test or in conventional laboratory exams. Preoperative thallium single photon emission computerized tomography (SPECT) detected a perfusion defect on the inferior wall, and transthoracic echocardiography (TTE) showed a moderate degree of akinesia on the inferior wall. Both of these findings in thallium SPECT and TTE were detected for 8 years after the previous attack with no development of new ischemic lesions.\n\nWhen the patient arrived in the operation room, his blood pressure (BP; systolic/diastolic), heart rate, and peripheral oxygen saturation (SpO2) were 166/94 mmHg, 76 beats/min, and 99% respectively. Preoxygenation with 80% oxygen was performed followed by intravenous administration of midazolam 2 mg and lidocaine 20 mg. Induction was started with a target controlled infusion (TCI; Asan Pump, version 2.0, BionetCo., Seoul, Korea) of propofol and remifentanil at 2 µg/ml and 3 ng/ml, respectively. Cisatracurium (12 mg) was administered and mask-valve ventilation was started after the patient lost his spontaneous breathing. During mask ventilation, a depression in ST segment of more than 3 mm was detected in ECG, and difficulty in manual ventilation was noted. Propofol and remifentanil infusion were immediately stopped, and the patient was promptly intubated followed by ventilation with 100% oxygen. A few minutes later, SpO2 rapidly decreased and his BP, initially 128/78 mmHg, dropped to 64/42 mmHg. Although vasoactive drugs including phenylephrine and epinephrine were administered, the BP continued to decrease to an undetectable level by a noninvasive BP cuff. Direct arterial pressure was monitored, and a central venous catheter was inserted to maintain fluid therapy and continuous drug administration. The patient quickly developed ventricular fibrillation and we thus initiated a sequential algorithm of cardiopulmonary cerebral resuscitation (CPCR). Immediate defibrillation (200J) followed by manual chest compression was performed with repeated intravenous administration of atropine (0.5 mg) and epinephrine (1 mg). A portable transesophageal echocardiography (TEE) was obtained 20 minutes after CPCR was initiated, which showed global hypokinesia in the myocardial wall with akinesia in the inferior wall. However, the patient had not return of spontaneous circulation for 40 minutes, and the patient showed repeated ventricular fibrillation refractory to defibrillation. An emergent consultation of cardiac surgeons was requested to apply veno-arterial type extracorporeal membrane oxygenation (ECMO) to substitute cardiac function. The patient was transferred to the intensive care unit (ICU) and remained intubated during the application of ECMO. In the ICU, sequential laboratory tests including cardiac enzymes were performed. Upon arrival in the ICU, the patient's serum troponin-I and creatine kinase-MB (CK-MB) levels were 6.292 ng/ml and 34.6 ng/ml respectively, and within 5 hours they were increased to 44.099 ng/ml and 107.3 ng/ml. After 8 hours of ICU admission, 12-lead ECG showed normal sinus rhythm with right bundle branch block. On the same day, the patient had return of drowsy consciousness level from comatose state. After showing improvement on serial ECG and the hemodynamic status of the patient, the ECMO circuit was successfully weaned on the following day. He was remain intubated and sedated for three more days to continue conventional therapies for recovery and discharged to the general ward on the day of extubation. Cardiac enzymes levels were normalized (troponin-I, 1.5 ng/ml;CK-MB, 3.7 ng/ml) 5 days after the incidence had occurred.\n\nOn suspicion of anaphylactic reaction as a cause of perioperative MI, serum tryptase level was measured and an intradermal skin test was performed to all anesthetic drugs that had been used during the induction period. The level of serum tryptase was detected on the day of the incidence occurred. Serum tryptase level was 28.6 µg/L, which was higher than normal value (13.5 µg/L). Three days after the incidence, an intradermal skin test was performed and a positive reaction was only seen in cisatracurium at a 1 : 100 dilution. All other drugs rendered negative results.\n\nDiscussion\nWe presented a case of life-threatening anaphylactic reaction to cisatracurium, which concurrently developed with MI. The patient developed ventricular arrhythmia followed by cardiac arrest very rapidly, but no classical features of anaphylaxis or hypersensitivity reactions were detected. However, we had previously experienced several cases of sudden cardiovascular collapse and respiratory failure caused by anaphylaxis due to cisatracurium, thereby prompt management targeting anaphylaxis along with sequential resuscitation process was possible [3].\n\nPerioperative acute coronary syndrome is difficult to be detected during general anesthesia. Instead of classical physical symptoms such as chest pain and dyspnea, ST segment changes on ECG and an elevation in serum cardiac enzymes levels such as troponin-I are considered to be useful measures [4,5]. In the present case, ST depression on ECG and marked elevation of serum troponin-I and CK-MB levels were detected, suggesting acute coronary syndrome. However, perioperative TEE could not find any new lesion that could cause sudden acute coronary involvement, suggesting that such an acute coronary syndrome must have been triggered from an another event. Anaphylaxis was suspected to be a possible reason for the sudden cardiovascular collapse.\n\nNeuromuscular blocking agents (NMBA) account for the most causative agents for anaphylaxis during anesthesia [6]. Cisatracurium is known to have low potency of activating non-specific mast cell and basophil that are responsible for hypersensitivity reaction compared with other NMBAs such as rocuronium or succinylcholine [7]. However, serial case reports of anaphylactic reaction to cisatracurium with a variety of severe clinical manifestations have been reported [3,8]. The diagnosis of anaphylaxis is routinely made by estimating the serum tryptase level and by an intradermal skin test [6]. In the present case, we investigated the serum tryptase level and performed a skin test for all of the drugs used in general anesthesia. Although epinephrine is known to cause Kounis syndrome and is involved in various allergic responses [9], we did not include it in allergic testing since it was used only after hemodynamic instability had occurred. We found that the serum tryptase level was elevated and the skin test showed a positive result for cisatracurium, while all other drugs rendered negative results.\n\nDuring hypersensitivity reactions, inflammatory mediators including histamine and tryptase are released into the circulation [10]. Once released, tryptase can activate metalloproteinases, leading to plaque disruption or rupture [11]. Histamine is able to implicate platelet activation, thickening of intima, coronary vasoconstriction, platelet activation and tissue factor expression [12]. In fact, tissue factors activated by histamine are frequently elevated in patients with unstable angina [13]. Tryptase has also been proposed for its therapeutic efficacy as a biomarker of coronary artery disease in asymptomatic patients, since its levels were significantly elevated in non-allergic patients with severe coronary artery disease [14]. The recruitment of these inflammatory mediators is now widely accepted as a cause of acute coronary syndromes [10].\n\nVarious coronary syndromes, including Kounis syndrome, have been described during anaphylaxis. Kounis syndrome describes one of the mechanisms that could possibly take place under circumstances where there are concurrent occurrence of acute coronary syndrome and allergic reaction, resulting in a sudden cardiovascular collapse [1]. There are two variants of this syndrome. Type I variant includes subjects with normal coronary arteries without cardiac morbidities, while type II variant includes subjects with previous coronary artery disease in whom acute allergic events manifest into plaque rupture leading to acute coronary artery spasm or acute MI [1]. The syndrome suggests that coronary artery spasm or atheromatous plaque rupture is related to the release of allergic mediators [1]. Not only anesthetic drugs, but also epinephrine may be an important causative agent for Kounis syndrome. In addition, various drugs, animals, and insect bites have been reported to develop Kounis syndrome [9].\n\nIn our present case, the patient likely suffered from the type II variant of Kounis syndrome due to his preexisting coronary disease. Although newly formed wall motion abnormality was not observed, myocardial ischemia or coronary artery spasm were suspected from ST segment changes on ECG, global hypokinesia in TEE, and elevated cardiac enzymes levels. It is also possible that sudden cardiovascular collapse may not have been associated with newly developed MI, but with allergic mediators from anaphylaxis, resulting in an acute coronary syndrome suggesting Kounis syndrome or hypotension due to anaphylactic shock that further decompensated blood flow to coronary arteries affected by previous coronary disease.\n\nHypersensitivity reactions can progress to acute coronary involvement and sudden cardiovascular collapse [1]. Cases of anaphylactic or allergic reactions associated with coronary events are frequently encountered in clinical practice. It is therefore crucial to suspect the possibility of individual hypersensitivity reactions especially in patients who develop coronary events [15]. Lack of understanding and awareness of the association between allergic reactions and acute coronary syndrome could lead to inappropriate management and under-reporting. In addition to immediate and appropriate clinical management of hemodynamic instability, acute coronary syndrome with allergic symptoms should raise suspicion for the possibility of Kounis syndrome.\n==== Refs\n1 Kounis NG Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006 110 7 14 16249041 \n2 Cevik C Nugent K Shome GP Kounis NG Treatment of Kounis syndrome Int J Cardiol 2010 143 223 226 20206392 \n3 Yoon Y Lee B Seo HS Bang J Ha SI Song JG Anaphylactic reactions after cisatracurium administration in two patients -a report of two cases Korean J Anesthsiol 2013 65 147 150 \n4 Augoustides JG Neuman MD Al-Ghofaily L Silvay G Preoperative cardiac risk assessment for noncardiac surgery: defining costs and risks J Cardiothorac Vasc Anesth 2013 27 395 399 23620898 \n5 Beattie WS Wijeysundera DN Perioperative cardiac biomarkers: the utility and timing Curr Opin Crit Care 2013 19 334 341 23823311 \n6 Hepner DL Castells MC Anaphylaxis during the perioperative period Anesth Analg 2003 97 1381 1395 14570656 \n7 Mertes PM Aimone-Gastin I Gueant-Rodriguez RM Mouton-Faivre C Audibert G O'Brien J Hypersensitivity reactions to neuromuscular blocking agents Curr Pharm Des 2008 14 2809 2825 18991700 \n8 Krombach J Hunzelmann N Koster F Bischoff A Hoffmann-Menzel H Buzello W Anaphylactoid reactions after cisatracurium administration in six patients Anesth Analg 2001 93 1257 1259 11682408 \n9 Kounis N Kounis G Anaphylactic cardiovascular collapse during anesthesia: the Kounis acute hypersensitivity syndrome seems to be the most likely cause J Korean Med Sci 2013 28 638 639 23580866 \n10 Laine P Naukkarinen A Heikkilä L Penttilä A Kovanen PT Adventitial mast cells connect with sensory nerve fibers in atherosclerotic coronary arteries Circulation 2000 101 1665 1669 10758048 \n11 Johnson JL Jackson CL Angelini GD George SJ Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques Arterioscler Thromb Vasc Biol 1998 18 1707 1715 9812908 \n12 Sakata Y Komamura K Hirayama A Nanto S Kitakaze M Hori M Elevation of the plasma histamine concentration in the coronary circulation in patients with variant angina Am J Cardiol 1996 77 1121 1126 8644672 \n13 Moons AH Levi M Peters RJ Tissue factor and coronary artery disease Cardiovasc Res 2002 53 313 325 11827681 \n14 Deliargyris EN Upadhya B Sane DC Dehmer GJ Pye J Smith SC Jr Mast cell tryptase: a new biomarker in patients with stable coronary artery disease Atherosclerosis 2005 178 381 386 15694948 \n15 Kumar A Berko NS Gothwal R Tamarin F Jesmajian SS Kounis syndrome secondary to ibuprofen use Int J Cardiol 2009 137 e79 e80 19482364\n\n",
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"issue": "67(6)",
"journal": "Korean journal of anesthesiology",
"keywords": "Anaphylaxis; Cisatracurium; Kounis syndrome; Myocardial infarction",
"medline_ta": "Korean J Anesthesiol",
"mesh_terms": null,
"nlm_unique_id": "101502451",
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"references": "20206392;23823311;24023998;8644672;11682408;23620898;11827681;14570656;19482364;10758048;15694948;16249041;23580866;9812908;18991700",
"title": "Sudden cardiovascular collapse caused by severe anaphylaxis after cisatracurium use: a case report.",
"title_normalized": "sudden cardiovascular collapse caused by severe anaphylaxis after cisatracurium use a case report"
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"abstract": "Early-onset inflammatory bowel diseases can result from a wide spectrum of rare mendelian disorders. Early molecular diagnosis is crucial in defining treatment and in improving life expectancy. Herein we aimed at defining the mechanism of an immunodeficiency-polyendrocrinopathy and enteropathy-X-linked (IPEX)-like disease combined with a severe immunodeficiency in 2 siblings born from distantly related parents.\n\n\n\nWhole exome sequencing was performed on blood-extracted genomic DNA from the 2 affected children and their parents on the genomic platform of Institut IMAGINE. Candidate gene mutation was identified using the in-house software PolyWeb and confirmed by Sanger sequencing. Protein expression was determined by western blot. Flow cytometry was used to assess consequences of the mutation on lymphocyte phenotype and nuclear factor-kappa B (NF-κB) activation at diagnosis and after treatment by hematopoietic stem cell transplantation.\n\n\n\nWe identified a homozygous missense mutation in mucosa-associated lymphoid tissue lymphoma translocation 1 gene (MALT1), which precluded protein expression. In keeping with the known function of MALT1, NF-κB-dependent lymphocyte activation was severely impaired. Moreover, there was a drastic reduction in Forkhead box P3 (FOXP3) regulatory T cells accounting for the IPEX-like phenotype. Following identification of the mutation, both children received hematopoietic stem cell transplantation, which permitted full clinical recovery. Immunological workup at 6 and 12 months after transplantation showed normal NF-κB activation and correction of regulatory T cells frequency.\n\n\n\nAlong with FOXP3, interleukin 2 receptor alpha chain (IL2RA), and cytotoxic T-lymphocyte protein 4 precursor (CTLA-4) mutations, MALT1 deficiency should now be considered as a possible cause of IPEX-like syndrome associated with immunodeficiency that can be cured by hematopoietic stem cell transplantation.",
"affiliations": "*INSERM, UMR1163, Laboratory of Intestinal Immunity †Université Paris Descartes-Sorbonne Paris Cité and Institut IMAGINE ‡Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Department of Pediatric Gastroenterology, Paris §GENIUS Group (GENetically and/or ImmUne mediated enteropathieS) From ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) ||Department of Allergology, Rheumatology and Clinical Immunology ¶Department of Haemato-oncology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia #Institut de Minéralogie, de Physique des Matériaux, et de Cosmochimie, Sorbonne Universités-UMR CNRS 7590, UPMC Université Paris 6, Muséum National d'Histoire Naturelle, IRD UMR 206, IUC **Bioinformatics Platform, Université Paris-Descartes-Paris Sorbonne Centre and Institut IMAGINE ††Genomic platform, Institut IMAGINE, Paris, France ‡‡Department of Gastroenterology, Hepatology and Nutrition, University Children's Hospital §§Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia ||||INSERM, UMR1163, Immunogenetics of Pediatric Autoimmunity, Paris, France.",
"authors": "Charbit-Henrion|Fabienne|F|;Jeverica|Anja K|AK|;Bègue|Bernadette|B|;Markelj|Gasper|G|;Parlato|Marianna|M|;Avčin|Simona Lucija|SL|;Callebaut|Isabelle|I|;Bras|Marc|M|;Parisot|Mélanie|M|;Jazbec|Janez|J|;Homan|Matjaz|M|;Ihan|Alojz|A|;Rieux-Laucat|Frédéric|F|;Stolzenberg|Marie-Claude|MC|;Ruemmele|Frank M|FM|;Avčin|Tadej|T|;Cerf-Bensussan|Nadine|N|;|||",
"chemical_list": "D005819:Genetic Markers; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein",
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"issue": "64(3)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1; D003967:Diarrhea; D005260:Female; D040181:Genetic Diseases, X-Linked; D005819:Genetic Markers; D006720:Homozygote; D006801:Humans; D007154:Immune System Diseases; D008297:Male; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D020125:Mutation, Missense; D035781:Siblings",
"nlm_unique_id": "8211545",
"other_id": null,
"pages": "378-384",
"pmc": null,
"pmid": "27253662",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Deficiency in Mucosa-associated Lymphoid Tissue Lymphoma Translocation 1: A Novel Cause of IPEX-Like Syndrome.",
"title_normalized": "deficiency in mucosa associated lymphoid tissue lymphoma translocation 1 a novel cause of ipex like syndrome"
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"abstract": "Psoriatic skin lesions associated with anti-tumor necrosis factor (TNF) agents are well-described in the medical literature. However, the etiology and optimal management of this condition remain unclear. Vedolizumab is a novel, gut-specific, anti-integrin agent used for the treatment of inflammatory bowel disease (IBD). We report a case of infliximab-associated psoriasiform lesions in an ulcerative colitis patient. Transition to vedolizumab resulted in resolution of the cutaneous lesions without recurrence and remission of his ulcerative colitis.",
"affiliations": "Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, IL.;Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, IL ; Section of Gastroenterology, Hepatology and Nutrition, The University of Chicago Medicine, Chicago, IL.;Section of Gastroenterology, Hepatology and Nutrition, The University of Chicago Medicine, Chicago, IL.;Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, IL ; Section of Gastroenterology, Hepatology and Nutrition, The University of Chicago Medicine, Chicago, IL.",
"authors": "Hirsch|Ayal|A|;Colman|Ruben J|RJ|;Lang|Gabriel D|GD|;Rubin|David T|DT|",
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"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2015.7010.14309/crj.2015.70Case ReportInflammatory Bowel DiseaseSuccessful Treatment of Ulcerative Colitis With Vedolizumab in a Patient With an Infliximab-Associated Psoriasiform Rash Hirsch Ayal MD1Colman Ruben J. MD12Lang Gabriel D. MD2Rubin David T. MD121 Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, IL2 Section of Gastroenterology, Hepatology and Nutrition, The University of Chicago Medicine, Chicago, ILCorrespondence: Ruben J. Colman, University of Chicago Medicine, Inflammatory Bowel Disease Center, 5841 S. Maryland Ave., Chicago, IL 60637 (rcolman@medicine.bsd.uchicago.edu; colman.rj@gmail.com).7 2015 09 7 2015 2 4 236 238 15 1 2015 31 5 2015 Copyright © Hirsch et al.2015This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Psoriatic skin lesions associated with anti-tumor necrosis factor (TNF) agents are well-described in the medical literature. However, the etiology and optimal management of this condition remain unclear. Vedolizumab is a novel, gut-specific, anti-integrin agent used for the treatment of inflammatory bowel disease (IBD). We report a case of infliximab-associated psoriasiform lesions in an ulcerative colitis patient. Transition to vedolizumab resulted in resolution of the cutaneous lesions without recurrence and remission of his ulcerative colitis.\n==== Body\nIntroduction\nApproximately one-third of patients with inflammatory bowel disease (IBD) experience disease-related skin lesions at some point in their disease process.1 These lesions are often the result of extra-intestinal inflammatory manifestations, nutritional deficiencies, infections, or drug-related side effects.1 Cutaneous symptoms occur in 20% of patients on anti-tumor necrosis factor (TNF) therapy and most commonly include psoriasiform rash and/or eczema.2,3 Despite their prevalence, there are no evidence-based management or treatment strategies. Topical and/or methotrexate-based therapies are largely ineffective and approximately 25% of patients treated with a change of anti-TNF therapy experience cutaneous recurrence.2,4\n\nCase Report\nA 50-year-old man was diagnosed with left-sided ulcerative colitis (UC) in 2006. His medical history was significant for mild asthma, gastroesophageal reflux disease, and hypertension. He had no current or prior nicotine use. His family's medical history was negative for IBD, psoriasis, and allergic reactions. He was treated with mesalamine with no improvement, then azathioprine that was stopped secondary to thiopurine-associated pancreatitis. In June 2006, he started infliximab, an anti-TNF agent, at 5 mg/kg and achieved prompt clinical remission.\n\nIn October 2007, the patient was noted to have thick psoriatic plaques on his palms and feet after completing 12 infliximab infusions (Figure 1). Psoriasis was confirmed by skin biopsy, and the patient was prescribed topical steroid-based therapies for his skin lesions. This regimen was ineffective and the patient continued to experience cutaneous eruptions. Infliximab was discontinued, and he had significant improvement of his psoriasiform rash, but his colitis relapsed and endoscopic examination demonstrated significant inflammation. The patient was enrolled into a randomized, placebo-controlled, double-blind, phase III trial with a different class of biologic medication, an anti-α4β7 integrin agent (vedolizumab). At 8 months post-induction, endoscopic assessment demonstrated complete mucosal healing (Figure 2), and he had near complete resolution of his rash (Figure 3). One year later, at the end of the clinical trial, unblinding confirmed that the patient indeed had received vedolizumab 300 mg every 4 weeks per study protocol.5 He agreed to participate in the open label phase of the trial and has been enrolled for over 4 years. He is doing well and remains in sustained clinical, endoscopic, and histological remission, and has not experienced a relapse of a psoriasiform rash.\n\nFigure 1 Psoriasiform plaques on the patient's palms during infliximab treatment.\n\nFigure 2 Endoscopic images of the sigmoid colon (A) before vedolizumab, (B) at week 6 of treatment, (C) at week 52 of treatment, and (D) at 4.5 years of treatment. Endoscopic images of the rectum (E) before vedolizumab, (F) at week 6 of treatment, (G) at week 52 of treatment, and (H) at 4.5 years of treatment.\n\nFigure 3 Patient's palm after infliximab discontinuation and treatment with vedolizumab.\n\nDiscussion\nPsoriasiform rash and eczema are the most common anti-TNF–associated skin lesions, and are estimated to occur in 1.62–8.8% of all anti-TNF–treated IBD patients.3,4,6,7 Palmoplantar psoriasis, involving the palms and plants, affects 15–20% of patients with psoriasis, but is found in more than 30% of IBD patients with anti-TNF–associated psoriasis.7,8 Several studies and case reports report the median time of onset of psoriasis to be between the third and fourth infusion of anti-TNF exposure, but vary between 2 weeks to several years.8,9\n\nAnti-TNF–associated psoriasiform lesions are unrelated to type of IBD, gender, treatment duration, smoking status, disease activity, location, phenotype, or concomitant immunosuppressive therapy.7,10,11 This psoriasis is considered paradoxical inflammation—development of inflammatory lesions in patients with immune-mediated inflammatory disorders after initiation of anti-inflammatory agents (such as anti-TNF).12 The underlying pathogenic mechanism is poorly understood.\n\nManagement of IBD patients who experience anti-TNF–associated psoriasis is complex and complicated by many factors, including a typically poor response to topical medication (while maintaining anti-TNF therapy) and cross-reactivity upon switching anti-TNF therapy. Case studies and case series show high rates of recurrence—between 33% and 100%— after commencing a second anti-TNF agent.2,7,8 These data suggests a class effect and confirms a poor prognostic response to alternative anti-TNF therapy. Anti-TNF withdrawal occurs in 40% of these patients, and is the most effective treatment strategy when combined with topical therapy4; however, withdrawal of biologic therapy elevates the risk of IBD relapse.2,4 Concomitant treatment (anti-TNF agent with immunomodulators) has demonstrated minimal efficacy.\n\nA few case studies have demonstrated newer therapeutic options that utilize alternative biologic classes. One small case series found that 9 patients with Crohn's disease (CD) and psoriatic lesions who were treated with another monoclonal antibody, ustekinumab (anti-IL12/IL-23), demonstrated a robust cutaneous response and clearance of their lesions. Unfortunately, the patients' CD did not respond to ustekinumab therapy.13 Another case report described aggravation of pre-existing psoriasis in a patient with multiple sclerosis during treatment with natalizumab (anti-α4-integrin) treatment.14 Vedolizumab is a novel drug that has been FDA-approved for the induction and maintenance of remission in patients with UC and CD.5,15 This is a monoclonal antibody that blocks the α4β7 integrin, inhibiting lymphocyte migration from the blood stream and resulting in gut-specific, anti-inflammatory activity.\n\nDisclosures\nAuthor contributions: A. Hirsch and RJ Colman conceptualized the case report, reviewed the literature, drafted the manuscript, and share first authorship. GD Lang conceptualized the case report and drafted the initial manuscript. DT Rubin supervised and conceptualized the case report, drafted the manuscript, and is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n\nDisclaimer: DT Rubin is a consultant and received grant support from Takeda Pharmaceuticals.\n==== Refs\nReferences\n1 \nPellicer Z , Santiago JM , Rodriguez A , et al \nManagement of cutaneous disorders related to inflammatory bowel disease . Ann Gastroenterol . 2012 ;25 (1 ):21 –6 .24713996 \n2 \nTorres J , Buche S , Delaporte E , Colombel JF \nSkin side effects of inflammatory bowel disease therapy . Inflamm Bowel Dis . 2013 ;19 (5 ):1086 –98 .23474780 \n3 \nCleynen I , Van Moekercke M , Juergens M , et al \nAnti-TNF induced cutaneous lesions in IBD patients: Characterization and search for predisposing factors . Gut . 2010 ;59 (suppl 3 ):A1 .\n4 \nAfzali A , Wheat CL , Hu JK , et al \nThe association of psoriasiform rash with anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease: A single academic center case series . J Crohns Colitis . 2014 ;8 (6 ):480 –8 .24268978 \n5 \nFeagan BG , Rutgeerts P , Sands BE , et al \nVedolizumab as induction and maintenance therapy for ulcerative colitis . New Engl J Med . 2013 ;369 (8 ):699 –710 .23964932 \n6 \nGuerra I , Algaba A , Pérez-Calle JL , et al \nInduction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease: A report of 21 cases . J Crohns Colitis . 2012 ;6 (5 ):518 –23 .22398059 \n7 \nRahier JF , Buche S , Peyrin-Biroulet L , et al \nSevere skin lesions cause patients with inflammatory bowel disease to discontinue anti-tumor necrosis factor therapy . Clin Gastroenterol Hepatol . 2010 ;8 (12 ):1048 –55 .20728573 \n8 \nCullen G , Kroshinsky D , Cheifetz AS , Korzenik JR \nPsoriasis associated with anti-tumor necrosis factor therapy in inflammatory bowel disease: A new series and a review of 120 cases from the literature . Aliment Pharmacol Ther . 2011 ;34 (11–12 ):1318 –27 .21957906 \n9 \nFiorino G , Allez M , Malesci A , Danese S \nReview article: Anti TNF-alpha induced psoriasis in patients with inflammatory bowel disease . Aliment Pharmacol Ther . 2009 ;29 (9 ):921 –7 .19210297 \n10 \nVan der Heide F , Dijkstra A , Weersma RK \nEffect of active and passive smoking on disease course of Crohn's disease and ulcerative colitis . Inflamm Bowel Dis . 2009 ;15 (8 ):1199 –207 .19170191 \n11 \nSteinwurz F , Denadai R , Saad-Hossne R , et al \nInfliximab-induced psoriasis during therapy for Crohn's disease . J Crohns Colitis . 2012 ;6 (5 ):610 –6 .22398095 \n12 \nChowers Y , Sturm A , Sans M \nReport of the ECCO workshop on anti-TNF therapy failures in inflammatory bowel disease: Biological roles and effects of TNF and TNF antagonists . J Crohns Colitis . 2010 ;4 (4 ):367 –76 .21122531 \n13 \nTillack C , Ehmann LM , Friedrich M , et al \nAnti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-gamma-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment . Gut . 2014 ;63 (4 ):567 –77 .23468464 \n14 \nMillan-Pascual J , Turpin-Fenoll L , Del Saz-Saucedo P , et al \nPsoriasis during natalizumab treatment for multiple sclerosis . J Neurol . 2012 ;259 (12 ):2758 –60 .23096069 \n15 \nSandborn WJ , Feagan BG , Rutgeerts P , et al \nVedolizumab as induction and maintenance therapy for Crohn's disease . New Engl J Med . 2013 ;369 (8 ):711 –21 .23964933\n\n",
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"title": "Successful Treatment of Ulcerative Colitis With Vedolizumab in a Patient With an Infliximab-Associated Psoriasiform Rash.",
"title_normalized": "successful treatment of ulcerative colitis with vedolizumab in a patient with an infliximab associated psoriasiform rash"
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"abstract": "The 21-year-old male patient was admitted to the Department of Rheumatology and Immunology at Peking Union Medical College Hospital with chief complaints of \"skin rash for 1 year and edema for 2 months\". He was diagnosed with systemic lupus erythematosus (SLE) with renal, cardiac and hematological involvement. Remission was not achieved after glucocorticoid pulse treatment. The patient experienced oliguria, malignant hypertension, accompanied by thrombocytopenia and low serum complements, and elevated lactate dehydrogenase and serum creatinine. Schistocytes were seen in the peripheral blood smear. Thrombotic microangiopathy (TMA) secondary to SLE was diagnosed. Though plasma exchange was partially effective, TMA could not be controlled yet. The activity of serum von Willebrand factor -cleaving protease (ADAMTS 13) was 100%, and ADAMTS 13 inhibitor was negative. Finally, remission of the disease was achieved after second glucocorticoid pulse therapy and rituximab treatment. At the 3-month follow-up, the patient's condition was stable with mild anemia and normal platelet count. Patients with TMA secondary to SLE are heterogenous, while normal ADAMT 13 activity indicates poor prognosis. Early and aggressive treatment is important for disease control, and plasma exchange is helpful as a supportive care.",
"affiliations": "Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.",
"authors": "Zhou|Y Z|YZ|;Zhao|J L|JL|;Cao|X Y|XY|;Zheng|K|K|;Wu|Q J|QJ|;Zeng|X F|XF|",
"chemical_list": "D005938:Glucocorticoids; D000069283:Rituximab; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human",
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"issue": "59(3)",
"journal": "Zhonghua nei ke za zhi",
"keywords": "Lupus erythematosus, systemic; Thrombotic microangiopathy; von Willebrand factor-cleaving protease",
"medline_ta": "Zhonghua Nei Ke Za Zhi",
"mesh_terms": "D000071120:ADAMTS13 Protein; D000740:Anemia; D004487:Edema; D005076:Exanthema; D005938:Glucocorticoids; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008297:Male; D010951:Plasma Exchange; D000069283:Rituximab; D057049:Thrombotic Microangiopathies; D055815:Young Adult",
"nlm_unique_id": "16210490R",
"other_id": null,
"pages": "250-252",
"pmc": null,
"pmid": "32146758",
"pubdate": "2020-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The 476th case: skin rash, edema, thrombocytopenia and anemia.",
"title_normalized": "the 476th case skin rash edema thrombocytopenia and anemia"
} | [
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"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-246241",
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"abstract": "OBJECTIVE\nHepatic arterial infusion (HAI) of cytotoxic chemotherapy is a strategy to deliver high dose of anticancer therapy to liver metastases that derive their blood supply from the hepatic artery. Metastatic melanoma (MM) has a high incidence of liver metastases, with uveal subtype in particular exhibiting a predilection for liver dissemination. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated efficacy in MM and first-pass hepatic metabolism. Therefore, we hypothesized that HAI of nab-paclitaxel would deliver an effective dose of drug to the end organ of interest, with minimal systemic exposure.\n\n\nMETHODS\nWe performed a single-institution open-label phase I/II study of HAI of nab-paclitaxel in MM patients with liver metastasis. Patients received treatment every 21 days at 4 different dose levels. The primary objective of the phase I portion of the study was safety and determination of the maximum-tolerated dose. The primary objective of the phase II portion of the study was overall response rate per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0.\n\n\nRESULTS\nA total of 30 patients were treated between 2009 and 2013, 16 of whom had uveal melanoma. The maximum-tolerated dose was 220 mg/m and 19 patients were treated at this dose. There was 1 patient (5%) with a partial response at this dose, and 8 patients (42%) with stable disease at this dose.\n\n\nCONCLUSIONS\nHAI nab-paclitaxel demonstrates rare objective responses in melanoma patients with liver metastases. This treatment should be studied in combination with checkpoint blockade or other novel treatments to enhance meaningful responses but should not be considered effective monotherapy.",
"affiliations": "Departments of *Melanoma Medical Oncology †Biostatistics ‡General Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.",
"authors": "Vera-Aguilera|Jesus|J|;Bedikian|Agop Y|AY|;Bassett|Roland L|RL|;Hwu|Wen-Jen|WJ|;Kim|Kevin B|KB|;Qin|Yong|Y|;Cain|Suzanne|S|;Washington|Edwina W|EW|;Davies|Michael A|MA|;Patel|Sunil M|SM|;Homsi|Jade|J|;Papadopoulos|Nicholas E|NE|;Hwu|Patrick|P|;Patel|Sapna P|SP|",
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"medline_ta": "Am J Clin Oncol",
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"nlm_unique_id": "8207754",
"other_id": null,
"pages": "1132-1136",
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"pmid": "29509591",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article",
"references": "20941597;24500702;20881508;12777987;24436516;24634931;10655437;24251080;26410620;28233802;13197542;18594000;15195788;25667295;25559415;15930349;16258082;11745194;24122445;23494131;22792102;16258106;21571911;19277228",
"title": "Phase I/II Study of Hepatic Arterial Infusion of Nab-paclitaxel in Patients With Metastatic Melanoma to the Liver.",
"title_normalized": "phase i ii study of hepatic arterial infusion of nab paclitaxel in patients with metastatic melanoma to the liver"
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{
"companynumb": "US-CELGENEUS-USA-20180304728",
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"abstract": "Double primary breast and esophageal cancer have been no reported cases in which treatment methods other than surgery were selected because of multiple metastasis or advanced cancer. The patient was a 52-year-old woman who had received left pectoral muscle-preserving mastectomy and axillary lymph node dissection (level 2) 7 years prior, following the diagnosis of left breast cancer. The postoperative diagnosis was pT2 N3a M0 stage IIIC and luminal human epidermal growth factor receptor 2 (HER2) phenotype. After the surgery, six courses of triple chemotherapy with 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide and four courses of docetaxel (DTX) were administered, and letrozole was administered for 5 years. Seven years after the surgery, swelling of her left axillary, supra-, and subclavicular lymph nodes, and sternum osteolysis were observed on computed tomography (CT). Radioisotope uptake was observed in the esophagus on positron emission tomography. An esophageal cancer was observed in the upper thoracic esophagus on esophagogastroscopy. The patient was administered a local treatment for esophageal cancer and systemic chemotherapy for both cancers. As a primary therapy, double chemotherapy with 5-FU and cisplatin (FP) (two courses) + radiotherapy on the esophagus and left supraclavicular lymph nodes (total target dose of radiotherapy was 60 Gy /30 fractions) was performed with the concomitant use of trastuzumab and zoledronate. Marked shrinkage [complete response (CR)] of the esophageal cancer was observed on esophagogastroscopy and shrinkage (partial response) of the left axillary and supra- and subclavicular lymph nodes were observed on CT. The secondary treatment included pertuzumab + trastuzumab + DTX. Bilateral pleural effusions were observed in the eighth course; therefore, DTX was withdrawn and the treatment was continued with only the molecularly targeted drugs. Two years have passed since the initiation of treatment. The individual lymph node metastatic foci have disappeared or markedly shrunk (CR) on CT scans and the sternal metastases have remained hard without change. In addition, CR for esophageal cancer has been maintained. We report a case of double primary recurrent HER2-positive breast cancer and esophageal cancer that responded well to radiotherapy and chemotherapy.",
"affiliations": "1First Department of Surgery, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Shimoaiduki, Matsuoka, Eiheiji-cho, Fukui 910-1193 Japan.;1First Department of Surgery, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Shimoaiduki, Matsuoka, Eiheiji-cho, Fukui 910-1193 Japan.;1First Department of Surgery, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Shimoaiduki, Matsuoka, Eiheiji-cho, Fukui 910-1193 Japan.;Surgery, Tsuruga Medical Center, 33-1 Sakuragaoka-cho, Tsuruga, 914-0195 Japan.;Surgery, Tsuruga Medical Center, 33-1 Sakuragaoka-cho, Tsuruga, 914-0195 Japan.;1First Department of Surgery, School of Medicine, Faculty of Medical Sciences, University of Fukui, 23 Shimoaiduki, Matsuoka, Eiheiji-cho, Fukui 910-1193 Japan.",
"authors": "Yokoi|Shigehiro|S|0000-0002-0470-0560;Maeda|Hiroyuki|H|;Nishino|Takuma|T|;Togawa|Tamotsu|T|;Iida|Atsushi|A|;Goi|Takanori|T|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-018-0347-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "8(1)",
"journal": "International cancer conference journal",
"keywords": "Chemoradiation therapy (CRT); Double primary cancer; Esophageal cancer; HER2-positive breast cancer; Triple chemotherapy with pertuzumab, trastuzumab, and docetaxel",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "17-23",
"pmc": null,
"pmid": "31149541",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports",
"references": "16000588;16410755;16446058;17553821;19151581;20525235;20932658;22202238;23152024;25693012;26943418;28111535;7123674;8211676",
"title": "Double primary recurrent human epidermal growth factor receptor 2-positive breast cancer and esophageal cancer that responded well to chemotherapy.",
"title_normalized": "double primary recurrent human epidermal growth factor receptor 2 positive breast cancer and esophageal cancer that responded well to chemotherapy"
} | [
{
"companynumb": "JP-ACCORD-104261",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
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"abstract": "SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently recognized entity with undifferentiated rhabdoid morphology and mutations in the switch/sucrose nonfermenting BRG1-associated factors complex. Patients are typically males in their fifth decade with a history of smoking who present with rapidly progressive intrathoracic disease and follow an aggressive clinical course. Metastatic disease is reported in up to 77% of cases; however, to our knowledge, cutaneous metastasis has not been reported nor has it been reported as the initial manifestation of the disease. Recognizing SMARCA4-DTS from other types of epithelioid tumors that involve the skin is clinically relevant, as targeted therapies for SMARC-deficient tumors are currently being investigated and early clinical trial data show therapeutic benefit.",
"affiliations": "Division of Dermatopathology, Department of Pathology, Duke University Medical Center, Durham, North Carolina.;Division of Dermatopathology, Department of Pathology, Duke University Medical Center, Durham, North Carolina.;Division of Dermatopathology, Department of Pathology, Duke University Medical Center, Durham, North Carolina.",
"authors": "Leckey|Bruce D|BD|https://orcid.org/0000-0001-8051-0657;Selim|M Angelica|MA|;Al-Rohil|Rami N|RN|https://orcid.org/0000-0002-9431-0530",
"chemical_list": "D018952:Antigens, CD34; D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases",
"country": "United States",
"delete": false,
"doi": "10.1111/cup.13652",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": "47(6)",
"journal": "Journal of cutaneous pathology",
"keywords": "SMARCA4; epithelioid; sarcoma",
"medline_ta": "J Cutan Pathol",
"mesh_terms": "D018952:Antigens, CD34; D004265:DNA Helicases; D018450:Disease Progression; D004358:Drug Therapy; D015622:Epithelioid Cells; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins; D012509:Sarcoma; D012878:Skin Neoplasms; D012907:Smoking; D012983:Soft Tissue Neoplasms; D013899:Thoracic Neoplasms; D014157:Transcription Factors",
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "561-565",
"pmc": null,
"pmid": "31995235",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cutaneous metastasis of SMARCA4-deficient thoracic sarcoma: A diagnostic dilemma with therapeutic implications.",
"title_normalized": "cutaneous metastasis of smarca4 deficient thoracic sarcoma a diagnostic dilemma with therapeutic implications"
} | [
{
"companynumb": "NVSC2020US142587",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
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"drugadditional": null,
"dru... |
{
"abstract": "OBJECTIVE\nThe aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy (NAC) using oxaliplatin plus capecitabine (CapOX) for patients with operable locally advanced colon cancer (CC).\n\n\nMETHODS\nPatients with computed tomography-defined T4 or lymph node-positive CCs were enrolled. After radiological staging, patients were treated with at least 2 cycles of NAC consisting of 130 mg/m2 oxaliplatin on d 1, plus 1,000 mg/m2 capecitabine twice daily for 14 d every 3 weeks, followed by surgery, and then with the rest cycles of adjuvant chemotherapy. Radiological response was evaluated after 2 cycles of NAC. Tumor response, treatment toxicity, and surgical complications were recorded. The pathological response to therapy was evaluated according to the tumor regression grade (TRG) score. The primary endpoint was pathologic tumor response. This trial is registered in ClinicalTrials.gov (No: NCT02415829).\n\n\nRESULTS\nForty-seven patients were enrolled in the study. Forty-two patients completed the planned treatments. The total radiological response rate was 68% (32/47), including complete and partial response rates of 2% (1/47) and 66% (31/47), respectively. Stable disease was observed in 32% (15/47) and progressive disease was observed in none. Complete pathologic response, major regression, and at least moderate regression were achieved in 1 (2%), 2 (4%), and 29 (62%) patients, respectively. Four patients developed grade 3 treatment toxicities. One patient with wound infection occurred after operation (1/47, 2%). There was no treatment-related death.\n\n\nCONCLUSIONS\nOur results suggest that NAC with CapOX is an effective and safe treatment option for patients with locally advanced CCs.",
"affiliations": "Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Clinical Statistics Center, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.",
"authors": "Liu|Fangqi|F|;Yang|Li|L|;Wu|Yuchen|Y|;Li|Cong|C|;Zhao|Jiang|J|;Keranmu|Adili|A|;Zheng|Hongtu|H|;Huang|Dan|D|;Wang|Lei|L|;Tong|Tong|T|;Xu|Junyan|J|;Zhu|Ji|J|;Cai|Sanjun|S|;Xu|Ye|Y|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21147/j.issn.1000-9604.2016.06.05",
"fulltext": "\n==== Front\nChin J Cancer ResChin. J. Cancer ResCJCRChinese Journal of Cancer Research1000-96041993-0631AME Publishing Company cjcr-28-6-xuye10.21147/j.issn.1000-9604.2016.06.05Original ArticleCapOX as neoadjuvant chemotherapy for locally advanced operable colon cancer patients: a prospective single-arm phase II trial Liu Fangqi 12*Yang Li 12*Wu Yuchen 12Li Cong 12Zhao Jiang 12Keranmu Adili 12Zheng Hongtu 12Huang Dan 23Wang Lei 24Tong Tong 24Xu Junyan 25Zhu Ji 267Cai Sanjun crc_surgery@163.com12*Xu Ye xuye021@163.com12*1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China4 Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China5 Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China6 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China7 Clinical Statistics Center, Fudan University Shanghai Cancer Center, Shanghai 200032, ChinaYe Xu. Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China. Email: xuye021@163.comSanjun Cai. Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China. Email: crc_surgery@163.com*These authors contributed equally to this work.\n\n12 2016 28 6 589 597 26 8 2016 19 11 2016 Copyright © 2016 Chinese Journal of Cancer Research. All rights reserved.2016This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Objective\nThe aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy (NAC) using oxaliplatin plus capecitabine (CapOX) for patients with operable locally advanced colon cancer (CC).\n\nMethods\nPatients with computed tomography-defined T4 or lymph node-positive CCs were enrolled. After radiological staging, patients were treated with at least 2 cycles of NAC consisting of 130 mg/m2 oxaliplatin on d 1, plus 1,000 mg/m2 capecitabine twice daily for 14 d every 3 weeks, followed by surgery, and then with the rest cycles of adjuvant chemotherapy. Radiological response was evaluated after 2 cycles of NAC. Tumor response, treatment toxicity, and surgical complications were recorded. The pathological response to therapy was evaluated according to the tumor regression grade (TRG) score. The primary endpoint was pathologic tumor response. This trial is registered in ClinicalTrials.gov (No: NCT02415829).\n\nResults\nForty-seven patients were enrolled in the study. Forty-two patients completed the planned treatments. The total radiological response rate was 68% (32/47), including complete and partial response rates of 2% (1/47) and 66% (31/47), respectively. Stable disease was observed in 32% (15/47) and progressive disease was observed in none. Complete pathologic response, major regression, and at least moderate regression were achieved in 1 (2%), 2 (4%), and 29 (62%) patients, respectively. Four patients developed grade 3 treatment toxicities. One patient with wound infection occurred after operation (1/47, 2%). There was no treatment-related death.\n\nConclusions\nOur results suggest that NAC with CapOX is an effective and safe treatment option for patients with locally advanced CCs.\n\nColon cancerneoadjuvant chemotherapyphase II trialsurgery\n==== Body\nIntroduction\nColon cancer (CC) is one of the most common malignancies worldwide and the leading cause of cancer death in women and men worldwide (1). In western countries, CC is the second leading cause of cancer death (2). Recent reports from the World Health Organization (WHO) show that the incidence of colon cancer is rising rapidly in many Asian countries (3). In China, combined with rectal cancer (RC), CC is the fifth leading cause of cancer-associated mortality and the proportion is even higher in much more developed cities such as Shanghai (4).\n\nDespite recent development in treatment, locally advanced CC (LACC) represents a major therapeutic challenge (5,6), which is defined as tumors in T3 stage with ≥5 mm invasion beyond the muscularis propria or T4 (penetration within adjacent organs) staging by computed tomography (CT) scan (7,8). Further in ECKINOXE trial conducted by Karoui et al., LACC was defined as high-risk T3 (disruption of muscle wall and extension into pericolic fat with more than 5 mm protrusion into adjacent mesenteric fat)–T4 (penetration within adjacent organs) and/or N2 (more than 3 clustered lymph nodes above 1 cm in shortest diameter) (9). Radical surgery followed by adjuvant chemotherapy is recommended for the patients with LACCs (10). However, 20%–30% of patients with stage II/III CCs developed local or distant recurrences, which indicates the ineffectiveness of the treatment in eradicating regional spread and distant micrometastases.\n\nRecently several studies showed that neoadjuvant chemotherapy (NAC) is an effective treatment option for aggressive solid tumors including resectable and unre-sectable tumors, such as gastroesophageal cancer, gastric cancer and breast cancer (11-14). It is thought to confer an advantage over other treatment regiments through the eradication of potential micrometastases or circulating tumor cells; reduction of surgical tumor cell shedding; improvement of complete resection rate owing to primary tumor regression; maintenance of chemotherapy intensity; evaluation of chemotherapy safety and chemosensitivity, thereby contributing to the assessment of the need for postoperative chemotherapy or selection of the appropriate chemotherapy regimen; and the circumvention of delayed postoperative chemotherapy owing to surgical compli-cations (14-17).\n\nOn the other hand, the potential disadvantages associated with NAC include the risk of overtreatment due to inaccurate radiological staging, leading to severe toxicity in low-risk patients; risk of bowel obstruction or perfo-ration caused by the primary tumor during preoperative treatment, resulting in emergency but not radical surgery; increased risk of perioperative complications; prolonged hospital stay and increased fees; delayed adjuvant chemo-therapy; and tumor progression during NAC.\n\nTo date, NAC has not been routinely administered in patients with operable LACCs. There were only two prospective studies about oxaliplatin plus capecitabine (CapOX) without target treatment as NAC regimen for LACCs (NCT01675999-Paris and NCT02572141-Guangzhou) in progress and no results were available. The latest published study about NAC applied to the LACCs was a retrospective study and the result showed that NAC for operable LACC patients was safe and able to induce major tumor regression (18).\n\nBased on the situations above, the efficacy and safety of CapOX as NAC regimen for LACCs were needed to identify. The primary objective of this phase II study was to evaluate the efficacy and safety of CapOX as a neoadjuvant treatment for patients with operable LACCs.\n\nMaterials and methods\nThe study was a prospective single-arm phase II study conducted in a single center in China. We evaluated the safety and efficacy of preoperative CapOX regimen in patients with locally advanced CCs. This study was approved by the Institutional Review Board of Fudan University Shanghai Cancer Center and written informed consent was obtained from all participants. The trial is registered in ClinicalTrials.gov (No. NCT02415829). The trial protocol is shown in Figure 1.\n\n1 Trial protocol (Study design).\n\nPatients\nInclusion criteria\nThe inclusion criteria were: 1) pathologically confirmed colon carcinoma; 2) CT-defined T4 or lymph node-positive resectable CC; 3) no history of previous treatment; 4) obstructive CC treated with defunctional stoma or exploratory laparotomy; 5) age ≥18 years and ≤75 years; 6) Eastern Cooperative Oncology Group (ECOG) perfor-mance status 0–1; 7) no prior chemotherapy or abdominal or pelvic irradiation; 8) life expectancy ≥3 months; 9) no history of CRC; and 10) laboratory analysis showing leukocytes ≥3×109/L with neutrophils ≥1.5×109/L, platelets ≥100×109/L, hemoglobin ≥9 g/dL (5–6 mmol/L), total bilirubin ≤1.5×upper limit of normal (ULN), aspartate aminotransterase (ASAT) and alanine aminotransferase (ALAT) ≤2.5×ULN, alkaline phosphatase ≤1.5×ULN, and serum creatinine ≤1.5×ULN.\n\nExclusion criteria\nThe exclusion criteria were: 1) tumors within 15 cm of the anal verge determined by sigmoidoscopy, or below the sacral promontory determined by imaging; 2) evidence of distant metastases or peritoneal carcinomatosis by CT scan; 3) colonic obstruction without prior defunctional stroma or stent treatment, or 4) serious medical comorbidity that might hinder neoadjuvant therapy and/or surgery.\n\nTreatment\nThe NAC consisted of 3 cycles of CapOX (130 mg/m2 of intravenous oxaliplatin on d 1, plus 1, 000 mg/m2 of oral capecitabine twice daily on d 1–14, repeated at 3 week intervals). Dose reduction and up to 4 weeks of delay were allowed in case of reversible toxicity.\n\nCT scan assessed tumor regression after 2 cycles of NAC. If progressive or stable disease was detected, surgery was scheduled immediately. Otherwise, surgery was scheduled after additional 1–2 cycles of chemotherapy. All the patients’ conditions were assessed by multiple disciplinary teams (MDT). In order to reduce perioperative morbidity, surgery must be performed at least 1 week after the completion of preoperative chemotherapy. Both laparoscopic and open surgeries were considered. Following surgery, the rest cycles of chemotherapy were administered using a schedule identical to that of NAC, and each patient received 8 cycles of chemotherapy in all.\n\nEfficacy and safety assessment\nClinical response assessment\nThe initial evaluation included medical history, clinical examination, complete laboratory analysis, metastatic evaluation [(by chest CT, abdominal and pelvic enhanced CT or magnetic resonance imaging (MRI)], colonoscopy and tumor biopsy. The response to treatment was assessed by physical examination after the completion of 2 cycles of CapOX treatment. The clinical responses following CapOX treatment were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 guideline (RECIST version 1.1).\n\nHistological response assessment\nPathologic response to chemotherapy was determined by examination of the primary tumor and lymph node specimens collected during surgery by two independent pathologists. The pathological response of each primary tumor was scored according to the American Joint Committee on Cancer staging criteria. This scoring determined the tumor regression grade (TRG) depending on the presence of residual tumor cells and the extent of fibrosis. The definitions for TRG 0–3 were no residual tumor cells, single cells or small group of cells, residual cancer with desmoplastic response and minimal evidence of tumor response, respectively (19).\n\nSafety assessment\nToxicity and adverse events (AEs) were described according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.02 (CTCAE version 4.02).\n\nEndpoints\nThe primary endpoint of the study was pathological response indicated by TRG. The secondary endpoints were the frequency, severity, and attribution of AEs associated with neoadjuvant treatment, technical difficulty of surgery using both subjective (e.g., perceived technical difficulty of the operation by the surgeon on an arbitrary scale) and objective (e.g., estimated blood loss, time of operation, and intraoperative complications) criteria, and the frequency and severity of surgical complications. The primary and secondary endpoints were measured within the 30-d postoperative period.\n\nThe patients were followed up every 3 months in the first two years. From the third year, follow-up was scheduled every 6 months.\n\nResults\nPatient characteristics\nIn total, 47 patients were enrolled between February 2015 and June 2016. All patients were eligible for study inclusion and were treated with curative intent. Patients’ characteristics are summarized in Table 1.\n\n1 Patients’ characteristics and treatment details (N=47)\n\nCharacteristics\tn (%)\t\nNAC, neoadjuvant chemotherapy.\t\nAge (year)\t\t\nMedian (range)\t52 (25–73)\t\nGender\t\t\nMale\t36 (77)\t\nFemale\t11 (23)\t\nTumor location\t\t\nAscending colon\t14 (30)\t\nTransverse colon\t8 (17)\t\nDescending colon\t1 (2)\t\nSigmoid colon\t24 (51)\t\nRadiological T-stage\t\t\nT3\t12 (26)\t\nT4a\t17 (36)\t\nT4b\t18 (38)\t\nRadiological N-stage\t\t\nN0\t16 (34)\t\nN1\t21 (45)\t\nN2\t10 (21)\t\nNAC course\t\t\n1 cycle\t5 (11)\t\n2 cycles\t14 (30)\t\n3 cycles\t19 (40)\t\n4 cycles\t9 (19)\t\nMean (cycles)\t2.7\t\nEmergency after NAC\t\t\nBowel obstruction\t2 (4)\t\nBowel perforation\t1 (2)\t\nBowel obstruction and perforation\t1 (2)\t\nSurgery after NAC\t\t\nEmergency surgery\t1 (2)\t\nPlanned surgery\t46 (98)\t\nAcute abdominal condition\t\t\nYes\t4 (9)\t\nNo\t43 (91)\t\nTreatment toxicities ≥ grade 3\t4 (9)\t\nGrade 3 neutropenia\t3 (6)\t\nGrade 3 thrombopenia\t1 (2)\t\nChemotherapy\nForty-two patients completed the planned treatments. The mean NAC course was 2.7 cycles. Five patients only received 1 cycle of NAC. Four of them opted for surgery immediately and another one developed perforation after NAC.\n\nNAC-related AEs\nThe AEs associated with NAC were few and well tolerated. Only 4 patients developed grade 3 hematological adverse reactions after chemotherapy including grade 3 neutropenia (n=3) and grade 3 thrombopenia (n=1). There was no chemotherapy-induced grade 4 AE. In addition, most AEs, such as gastrointestinal discomfort and myelosuppression, were mild and treated for symptoms. There was no treatment-related death.\n\nAcute abdominal conditions developed in 4 (4/47, 9%) patients after NAC including bowel obstruction and perforation. Only one patient did not complete the NAC and received emergency surgery. The first patient showed symptoms of bowel obstruction after 2 cycles of NAC and another 1 cycle of NAC was given after treated with conservative treatment. The TRG was 2. The second patient was admitted to hospital after 4 cycles of NAC and surgery was prepared according to the treatment plan. But Bowel obstruction followed by perforation occurred in the planned preoperative preparation stage. The TRG was 3. The third patient developed incomplete obstruction after 2 cycles of NAC and was admitted to hospital for surgery. The TRG was 2. Bowel perforation occurred in the fourth patient after 1 cycle of NAC and surgery was immediately scheduled for her. The TRG was 2. No postoperative complications occurred in all the patients above (Table 2).\n\n2 Characteristics of patients with acute abdominal conditions\n\nCharacteristics\tPatient 1\tPatient 2\tPatient 3\tPatient 4\t\nNAC, neoadjuvant chemotherapy; SD, stable disease; TRG, tumor regression grade.\t\nAge (year)\t60\t34\t62\t48\t\nGender\tMale\tMale\tMale\tFemale\t\nTumor location\tSigmoid colon\tSigmoid colon\tSigmoid colon\tSplenic flexure colon cancer\t\nCourse of NAC\t3\t4\t2\t1\t\nAcute abdominal conditions\tIncomplete bowel obstruction\tBowel obstruction followed by perforation\tIncomplete bowel obstruction\tBowel perforation\t\nTime of acute abdominal conditions\t2 cycles of NAC\t4 cycles of NAC and perioperative period\t2 cycles of NAC\t1 cycle of NAC\t\nStage before NAC\tT4aN1M0\tT4bN1M0\tT4bN0M0\tT4bN2M0\t\nImage assessment for tumor regression\tSD\tSD\tSD\tSD\t\nTreatment for acute abdominal conditions\tConservative treatment\tEmergency surgery\tPlanned surgery\tEmergency surgery\t\nTRG\t2\t3\t2\t2\t\nSurgery\nAll patients underwent surgery including planned surgery and acute surgery (46 vs. 1, respectively). All patients who underwent surgery achieved pathological complete resection (R0 resection). Postoperative complications were observed in 1 patient with wound infection (1/47, 2%). The mean postoperative stay in the hospital was 9.4 d and there was no 30-d operative mortality. All of the patients received planned post-operative adjuvant chemotherapy.\n\nClinical response and pathological results\nAll the patients received both clinical and pathological assessment of tumor regression after NAC. Planned treatment was completed by 89% of patients (42/47). The total response rate was 68% (32/47), including complete and partial response rates of 2% (1/47) and 66% (31/47), respectively. Stable disease was observed in 32% (15/47) of the patients and progressive disease was observed in none. The tumor regression assessed by CT scan for one of the patients is shown in Figure 2.\n\n2 Clinical response evaluated by CT scan. (A) Before neoadjuvant chemotherapy; (B) After neoadjuvant chemotherapy.\n\nThe TRG score assessed the total pathological response rate. Complete pathologic response (TRG 0), major regression (TRG 1), and at least moderate regression (TRG 2) were achieved in 1 (2%), 2 (4%), and 29 (62%) patients, respectively (Table 3).\n\n3 Clinical and pathological findings in patients who underwent NAC (N=47)\n\nFactors\tn (%)\t\n NAC, neoadjuvant chemotherapy; TRG, tumor regression grade; *, the tumor was totally regressed by NAC. The histology of biopsy tissue for the patient was adenocarcinoma before treatment. \t\nPathological tumor response rate\t\t\nTRG 0\t1 (2)\t\nTRG 1\t2 (4)\t\nTRG 2\t29 (62)\t\nTRG 3\t15 (32)\t\nHistology\t\t\nAdenocarcinoma\t39 (83)\t\nMucinous\t7 (15)\t\nSignet ring cell\t0 (0)\t\nUnknown*\t1 (2)\t\nSurgical margins\t\t\nNegative\t47 (100)\t\nPositive\t0 (0)\t\nR classification\t\t\nR0\t47 (100)\t\nR1\t0 (0)\t\nR2\t0 (0)\t\nypT factor-depth of tumor invasion\t\t\nT0\t1 (2)\t\nT1\t0 (0)\t\nT2\t1 (2)\t\nT3\t15 (32)\t\nT4a\t13 (28)\t\nT4b\t17 (36)\t\nypN factor-lymph node metastasis\t\t\nN0\t29 (62)\t\nN1\t10 (21)\t\nN2\t8 (17)\t\nypStage\t\t\nStage I\t0 (0)\t\nStage II\t28 (60)\t\nStage III\t18 (38)\t\nStage IV\t0 (0)\t\nNo tumor\t1 (2)\t\nNeural invasion\t4 (9)\t\nVenous invasion\t10 (21)\t\nTumor deposit\t\t\nYes\t6 (13)\t\nNo\t41 (87)\t\nDiscussion\nPresently, the standard therapeutic approach for non-metastatic CC is surgery and/or adjuvant chemotherapy. By contrast, more treatment strategies are available for rectal cancer, particularly for locally advanced rectal cancer. For example, NAC for rectal cancer improved local control and might influence long-term survival of patients with rectal cancer (20).\n\nNeoadjuvant treatment has been effective in the treatment of several malignant tumors and is part of the standard treatment for breast, esophageal, and gastric cancers (11-14,21). In locally advanced disease, preoperative chemotherapy might reduce tumor size, eradicate micrometastases, and improve operability and surgical downstaging (14-17).\n\nNAC has recently received considerable attention as a treatment strategy most likely improving survival outcomes of patients with advanced CRCs. The FOxTROT trial was the first to evaluate the effectiveness of preoperative chemotherapy in locally advanced CC (8). Patients were randomly assigned to preoperative chemotherapy followed by surgery and a further nine cycles of OxMdG or standard surgery followed by postoperative chemotherapy. Patients with KRAS wild-type tumors were randomly assigned to receive panitumumab or not. The results of the FOxTROT study showed that preoperative chemotherapy for locally advanced operable primary CC is feasible, with tolerable toxicity and perioperative morbidity. On the basis of these promising findings from the pilot phase, the FOxTROT phase III study is ongoing to investigate the long-term oncological outcomes.\n\nAnother study with available results was conducted by Jakobsen et al. and published in 2015 (15). The NAC regimen of the study was neoadjuvant chemotherapy followed by surgery and the postoperative chemotherapy was chosen according to the pathological result. Patients with KRAS wild-type tumors received chemotherapy combined with panitumumab. Conversion rate expressed as the fraction of patients not fulfilling the criteria for adjuvant chemotherapy was the primary endpoint. The results showed that the conversion rates in wild-type and mutated (including unknown) patients were 42% and 51%, respectively. The study showed that NAC in colon cancer was feasible and the results indicated that a major part of the patients can be spared adjuvant chemotherapy. A multicenter randomized phase III trial was conducted and the NAC regimen was CapOX followed by surgery or standard surgery (NCT01918527). To date, there were no available results about the trial.\n\nIn addition, there were another two clinical trials about NAC of CC (NCT01675999-Paris and NCT02572141-Guangzhou). The two studies were still in progress without available results.\n\nThe latest research on NAC of CC was published in August 2016 (18). It was a retrospective study conducted by Arredondo et al. Sixty-five LACC patients were included and the results showed that NAC in LACC patients was safe and able to induce major tumor regression. However, it was a retrospective study and further research was warranted.\n\nAlthough there are several studies about NAC for CC, several issues around the use of NAC for CC still remain. One of the concerns is the choice of the NAC regimen. We can know from the above studies that there was no standard regimen for NAC and the optimal preoperative chemotherapy strategy was still unknown. OxMdG+/–panitumumab, CapOX+/–panitumumab and FOLFOX+/–C225 were chosen in clinical trials respectively (8,9,15,18).\n\nCapOX and FOLFOX are the standard treatment for high-risk stage II and stage III CC, and the first-line chemotherapy in patients with stage IV CCs (10,16,22-24). Due to lower frequency than FOLOFX and easier use except for efficacy, the CapOX regimen was widely used for adjuvant chemotherapy in non-metastasis CRC patients. For targeted therapy, there was no enough evidence to confirm the efficacy for non-metastasis CCs. The current results showed that there were no signs of increased conversion rate in the patients receiving NAC and panitumumab than patients receiving NAC only (15). In addition, in China, not every patient with LACCs could receive the targeted therapy due to the cost of expensive medical bills paid by patients themselves.\n\nBased on the situations above, the CapOX regimen potentially became the ideal treatment choice of NAC for LACCs in China. The primary objective of this phase II study was to evaluate the efficacy and safety of CapOX as a neoadjuvant treatment for patients with locally advanced CCs.\n\nOur study is a prospective phase II trial with available results investigating the efficacy and safety of CapOX regimen as NAC without targeted therapy for patients with LACCs, and demonstrated that CapOX as NAC regimen was safe, effective and well completed for patients with LACCs. The completion rate was 89%. The most frequently observed toxicities in the present study were hematological toxicities and gastrointestinal discomfort. Only 4 patients developed grade 3 hematological adverse reactions after chemotherapy. There were no severe AEs during NAC. All of the toxicities that developed were well tolerable and manageable.\n\nIn this study, all the patients with bowel obstruction were not caused by tumor progression. All the tumors presented some degree of regression which was assessed by the postoperative pathological tumor regression score. There were some interpretations for bowel obstruction as follows: bowel contraction was caused by tumor regression after NAC and a large number of stool accumulations during the preoperative bowel preparation. During the operation, the tumor specimen with scar can be found and it indirectly identified that the tumor regression with scar was the reason for bowel obstruction.\n\nIn our study, both clinical and pathological responses were assessed. The clinical response rate was 68%, which was consistent with pathological response rate. The results identified the efficacy of NAC with CapOX. Further, these observations confirmed the importance of clinical assessment and suggested that careful abdominal enhanced CT could be a relatively reliable pathological response predictor for NAC.\n\nThe accuracy of clinical staging via imaging before surgery is crucial to ensuring that patients without the requirement of NAC do not get over-treated. Recent advances in radiology permit better prediction of tumor stage (wall penetration and nodal involvement) before surgery (25). The features of stage T4 cancer on CT include nodular penetration of the tumor through the peritonealized areas of the muscle coat, or an advancing edge of the tumor penetrating adjacent organs. Peritoneal infiltration identified by CT can be used in the classification of patients as stage T4 and high risk.\n\nIn addition, some studies indicated that NAC could be associated with the survival outcome of patients, and the achievement of pathological complete remission (pCR) using NAC correlated with disease-free survival. This is considered as an early indicator of a novel regimen with good efficacy (26). Although the main purpose of the present study was to assess the efficacy and safety of CapOX as NAC in the treatment of CC and the prognosis was not the aim of the study, we still followed up the patients’ prognosis. Our results could not identify whether the curative effect of NAC is better than that of traditional surgery because it was a single arm phase II study. However, the outcome of patients was inspiring, and data on long-term survival will be collected in the future research.\n\nConclusions\nIn conclusion, the present study demonstrated that the CapOX regimen showed high R0 resection rate and high response rate (clinical and pathological) in the treatment of locally advanced CC. Thus, CapOX was proved to be a safety and efficacious treatment strategy with moderate toxicity. Nevertheless, the long-term follow-up is required to translate these findings to improve local control and overall survival. We plan to confirm the result of this study in a future phase III trial.\n\nAcknowledgements\nWe thank the patients and all investigators.\n\nFunding: This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81472620); Shanghai Science and Technology Planning Fund (No. 13140902100); Shanghai Combination Study Project for Major Diseases (No. 2014ZYJB0101); and Shanghai Health and Family Planning Commission (No. JGY1404).\n\nFootnote\nConflicts of Interest: The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 Siegel RL Miller KD Jemal A Cancer statistics, 2015 CA Cancer J Clin 2015 65 5 29 25559415 \n2 Belot A Grosclaude P Bossard N Cancer incidence and mortality in France over the period 1980-2005 Rev Epidemiol Sante Publique 2008 56 159 75 18547762 \n3 Ng SC Wong SH Colorectal cancer screening in Asia Br Med Bull 2013 105 29 42 23299409 \n4 Chen W Zheng R Zeng H Annual report on status of cancer in China, 2011 Chin J Cancer Res 2015 27 2 12 25717220 \n5 Hohenberger W Weber K Matzel K Standardized surgery for colonic cancer: complete mesocolic excision and central ligation——technical notes and outcome Colorectal Dis 2009 11 354 64; discussion 364-5 19016817 \n6 Kontovounisios C, Tan E, Pawa N, et al. Selection process can improve the outcome in locally advanced and recurrent colorectal cancer: activity and results of a dedicated multidisciplinary colorectal cancer centre. Colorectal Dis 2016. [Epub ahead of print]\n\n\n\n7 Smith NJ Bees N Barbachano Y Preoperative computed tomography staging of nonmetastatic colon cancer predicts outcome: implications for clinical trials Br J Cancer 2007 96 1030 6 17353925 \n8 Foxtrot Collaborative Group Feasibility of preoperative chemotherapy for locally advanced, operable colon cancer: the pilot phase of a randomised controlled trial Lancet Oncol 2012 13 1152 60 23017669 \n9 Karoui M Rullier A Luciani A Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial——the PRODIGE 22——ECKINOXE trial BMC Cancer 2015 15 511 26156156 \n10 Varghese A Chemotherapy for Stage II Colon Cancer Clin Colon Rectal Surg 2015 28 256 61 26648796 \n11 Lerebours F Rivera S Mouret-Reynier MA Randomized phase 2 neoadjuvant trial evaluating anastrozole and fulvestrant efficacy for postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients: Results of the UNICANCER CARMINA 02 French trial (UCBG 0609) Cancer 2016 122 3032 40 27315583 \n12 Samalin E Ychou M Neoadjuvant therapy for gastroesophageal adenocarcinoma World J Clin Oncol 2016 7 284 92 27298768 \n13 Yoshikawa T Morita S Tanabe K Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer Eur J Cancer 2016 62 103 11 27244537 \n14 Wang X Zhao L Liu H A phase II study of a modified FOLFOX6 regimen as neoadjuvant chemotherapy for locally advanced gastric cancer Br J Cancer 2016 114 1326 33 27172250 \n15 Neoadjuvant chemotherapy in locally advanced colon cancer A phase II trial. Acta Oncol 2015 54 1747 53 25920359 \n16 Suenaga M Fujimoto Y Matsusaka S Perioperative FOLFOX4 plus bevacizumab for initially unresectable advanced colorectal cancer (NAVIGATE-CRC-01) Onco Targets Ther 2015 8 1111 8 26056475 \n17 Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? Cancer 2011 117 2364 70 24048783 \n18 Arredondo J, Baixauli J, Pastor C, et al. Mid-term oncologic outcome of a novel approach for locally advanced colon cancer with neoadjuvant chemotherapy and surgery. Clin Transl Oncol 2016.[Epub ahead print]\n\n\n19 Trakarnsanga A, Gönen M, Shia J, et al. Comparison of tumor regression grade systems for locally advanced rectal cancer after multimodality treatment. J Natl Cancer Inst 2014; 106. pii: dju248.\n\n\n20 Dueland S Ree AH Grøholt KK Oxaliplatin-containing preoperative therapy in locally advanced rectal cancer: local response, toxicity and long-term outcome Clin Oncol (R Coll Radiol) 2016 28 532 9 26888115 \n21 Cunningham D Allum WH Stenning SP Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N Engl J Med 2006 355 11 20 16822992 \n22 André T de Gramont A Vernerey D Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study J Clin Oncol 2015 33 4176 87 26527776 \n23 Biagi JJ Raphael MJ Mackillop WJ Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis JAMA 2011 305 2335 42 21642686 \n24 André T Boni C Mounedji-Boudiaf L Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer N Engl J Med 2004 350 2343 51 15175436 \n25 Burton S Brown G Bees N Accuracy of CT prediction of poor prognostic features in colonic cancer Br J Radiol 2008 81 10 9 17967848 \n26 von Minckwitz G Untch M Blohmer JU Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes J Clin Oncol 2012 30 1796 804 22508812\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "1000-9604",
"issue": "28(6)",
"journal": "Chinese journal of cancer research = Chung-kuo yen cheng yen chiu",
"keywords": "Colon cancer; neoadjuvant chemotherapy; phase II trial; surgery",
"medline_ta": "Chin J Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "9315242",
"other_id": null,
"pages": "589-597",
"pmc": null,
"pmid": "28174487",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "27244537;18547762;26056475;25920359;27315583;26156156;25717220;17353925;23017669;26888115;26648796;27172250;27298768;26527776;19016817;21642686;25559415;17967848;22508812;24048783;16822992;23299409;15175436",
"title": "CapOX as neoadjuvant chemotherapy for locally advanced operable colon cancer patients: a prospective single-arm phase II trial.",
"title_normalized": "capox as neoadjuvant chemotherapy for locally advanced operable colon cancer patients a prospective single arm phase ii trial"
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"abstract": "OBJECTIVE\nThe aim of the present study was to analyze a single-center experience with hepatic arterial infusion (HAI) in patients with unknown or uncertain primary or tumors not usually treated with HAI.\n\n\nMETHODS\nA retrospective analysis of 14 patients treated between 1996 and 2003 for liver tumors of unknown, uncertain or unusual primary was performed.\n\n\nRESULTS\nAll patients were treated with HAI combination regimens based on 5-fluorouracil and folinic acid. The response was not evaluable in most patients, predominantly because of only a single course of therapy could be administered and no cases of partial or complete response were noted. The median survival of all patients was 6.6 months (5-year survival 14%).\n\n\nCONCLUSIONS\nThe present data demonstrate limited efficacy of HAI in patients with liver tumors of unknown, uncertain or unusual primary. HAI should not be offered to these patients.",
"affiliations": "Fourth Department of Medicine, Charles University Medical School Teaching Hospital, Hradec Kralove, Czech Republic.",
"authors": "Melichar|Bohuslav|B|;Dvorak|Josef|J|;Kamaradova|Katerina|K|;Krajina|Antonín|A|;Studentova|Hana|H|",
"chemical_list": "D002955:Leucovorin; D005472:Fluorouracil",
"country": "Cyprus",
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"issue": "24(1)",
"journal": "Journal of B.U.ON. : official journal of the Balkan Union of Oncology",
"keywords": null,
"medline_ta": "J BUON",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006499:Hepatic Artery; D006801:Humans; D007261:Infusions, Intra-Arterial; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "100883428",
"other_id": null,
"pages": "143-149",
"pmc": null,
"pmid": "30941963",
"pubdate": "2019",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Hepatic arterial infusion in liver tumors of unknown, uncertain or unusual primary: single-center experience.",
"title_normalized": "hepatic arterial infusion in liver tumors of unknown uncertain or unusual primary single center experience"
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"companynumb": "CZ-SA-2019SA096552",
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"abstract": "BACKGROUND\nEffective anticoagulation routinely precludes patients from receiving intravenous thrombolysis with recombinant tissue plasminogen activator to reverse severe symptoms of ischemic stroke. We report what we believe to be the first case of ischemic stroke successfully treated with recombinant tissue plasminogen activator after antagonizing dabigatran with the monoclonal antibody idarucizumab, recently approved worldwide.\n\n\nMETHODS\nA 75-year-old Caucasian man presented to our hospital with severe aphasia and mild hemiparesis. After providing written consent, he received two doses of 2.5 g of idarucizumab over 20 minutes followed by standard protocol in-label recombinant tissue plasminogen activator application. All symptoms resolved within 1 h.\n\n\nCONCLUSIONS\nApplying a recombinant tissue plasminogen activator after antagonizing dabigatran with idarucizumab is feasible and easy to manage in an emergency room or stroke unit. Thus, idarucizumab represents a new therapeutic option for patients receiving dabigatran treatment, reestablishing their eligibility for recombinant tissue plasminogen activator thrombolysis.",
"affiliations": "Department of Neurology, Nordwest-Krankenhaus Sanderbusch GmbH, Am Gut Sanderbusch 1, 26452, Sande, Germany.;Department of Neurology, Nordwest-Krankenhaus Sanderbusch GmbH, Am Gut Sanderbusch 1, 26452, Sande, Germany.;Department of Neurology, Nordwest-Krankenhaus Sanderbusch GmbH, Am Gut Sanderbusch 1, 26452, Sande, Germany.;Department of Neurology, Nordwest-Krankenhaus Sanderbusch GmbH, Am Gut Sanderbusch 1, 26452, Sande, Germany.;Department of Neurology, Nordwest-Krankenhaus Sanderbusch GmbH, Am Gut Sanderbusch 1, 26452, Sande, Germany. pkermer@gwdg.de.",
"authors": "Gawehn|Annemarie|A|;Ayari|Yassine|Y|;Heuschkel|Christian|C|;Kaste|Matthias|M|;Kermer|Pawel|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13256-016-1050-0",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 105010.1186/s13256-016-1050-0Case ReportSuccessful thrombolysis with recombinant tissue plasminogen activator after antagonizing dabigatran by idarucizumab: a case report Gawehn Annemarie a.gawehn@sanderbusch.de 12Ayari Yassine yassine_ayari@hotmail.com 12Heuschkel Christian c.heuschkel@sanderbusch.de 12Kaste Matthias m.kaste@sanderbusch.de 12Kermer Pawel +49-4422-801401pkermer@gwdg.de 121 Department of Neurology, Nordwest-Krankenhaus Sanderbusch GmbH, Am Gut Sanderbusch 1, 26452 Sande, Germany 2 Academic Clinical Department, University Medical Center Gottingen, Gottingen, Germany 29 9 2016 29 9 2016 2016 10 26926 3 2016 30 8 2016 © The Author(s). 2016\nOpen 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\nEffective anticoagulation routinely precludes patients from receiving intravenous thrombolysis with recombinant tissue plasminogen activator to reverse severe symptoms of ischemic stroke. We report what we believe to be the first case of ischemic stroke successfully treated with recombinant tissue plasminogen activator after antagonizing dabigatran with the monoclonal antibody idarucizumab, recently approved worldwide.\n\nCase presentation\nA 75-year-old Caucasian man presented to our hospital with severe aphasia and mild hemiparesis. After providing written consent, he received two doses of 2.5 g of idarucizumab over 20 minutes followed by standard protocol in-label recombinant tissue plasminogen activator application. All symptoms resolved within 1 h.\n\nConclusions\nApplying a recombinant tissue plasminogen activator after antagonizing dabigatran with idarucizumab is feasible and easy to manage in an emergency room or stroke unit. Thus, idarucizumab represents a new therapeutic option for patients receiving dabigatran treatment, reestablishing their eligibility for recombinant tissue plasminogen activator thrombolysis.\n\nKeywords\nIschemic strokeThrombolysisDabigatranIdarucizumabrecombinant tissue plasminogen activatorissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nNeurologists have used dabigatran mostly for secondary prevention of cardioembolic stroke in patients with atrial fibrillation since the phase III RE-LY trial [1] showed positive results for the prevention of stroke or systemic embolism as compared with warfarin. Besides dabigatran, three additional non-vitamin-K-dependent oral anticoagulants (NOACs) [2–4] are currently available. Substantially decreased rates of bleeding complications in comparison with warfarin, especially when considering intracerebral hemorrhage, are an advantage of NOAC therapy. However, one major concern was the lack of specific antidotes. With the approval of idarucizumab, a novel monoclonal antibody fragment with a high potency to reverse the anticoagulant effects of dabigatran within minutes [5, 6], the question arose if recombinant tissue plasminogen activator (rt-PA) could be used after reversal of dabigatran with idarucizumab in individuals with newly occurring ischemic stroke. Since the introduction of NOAC therapy, these patients have frequently been excluded from thrombolytic therapy, owing to the unpredictable risk of bleeding.\n\nCase presentation\nA 75-year-old, right-handed Caucasian man with a history of embolic stroke and atrial fibrillation was admitted on 30 January 2016 to the stroke unit of our primary care hospital for severe aphasia and right-sided hemiparesis with sudden onset of symptoms about 1 h before presentation. He was receiving NOAC therapy with dabigatran 110 mg twice daily. His CHA2DS2-VASc score was 6 points (on scale representing congestive heart failure [or left ventricular systolic dysfunction] 1 point, hypertension [blood pressure consistently above 140/90 mmHg or treated hypertension on medication] 1 point, age ≥75 years 2 points, diabetes mellitus 1 point, prior stroke or transient ischemic attack or thromboembolism 2 points, vascular disease [e.g., peripheral artery disease, myocardial infarction, aortic plaque] 1 point, age 65–74 years 1 point, sex category [female sex] 1 point), and his HAS-BLED score was 3 points (with scale representing hypertension, abnormal renal and liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol). Correct dabigatran therapy of 110 mg twice daily could be verified by the accompanying spouse with last intake on the same morning approximately 9.5 h before. Besides cardioembolic stroke, the patient’s medical history consisted of structural epilepsy based on middle cerebral artery ischemia in March 2015 treated with levetiracetam 500 mg twice daily and arterial hypertension treated with amlodipine, metoprolol, and torasemide.\n\nThe patient’s impairment of production and comprehension of speech was severe. It was possible for him to communicate, but only to a very limited extent. His hemiparesis was rather mild. His initial National Institutes of Health Stroke Scale (NIHSS) score was 5. No convulsions or lack of consciousness was reported or noticed. According to the patient’s spouse, his symptoms were not comparable to prior seizure symptomatology displayed by sudden loss of consciousness and generalized tonic-clonic convulsions. As a residual of his prior stroke, the patient had a slight outer rotation of his right foot without gait impairment.\n\nLaboratory examinations done upon admission revealed a slight coagulation disorder (international normalized ratio 1.01, activated partial thromboplastin time [aPTT] 39.0 seconds [upper limit of normal 42 seconds], thrombin time 66.8 seconds [upper limit of normal 22 seconds]). Besides a defect zone arising from ischemic stroke in May 2015, computed tomographic (CT) scans (Fig. 1) displayed no early signs of acute stroke. Taking into account the patient’s NIHSS score of 5, no CT angiography or perfusion protocol was performed, in accordance with effective stroke guidelines. Except for the existing oral dabigatran anticoagulation therapy, the patient’s history did not reveal any contraindications against systemic thrombolytic therapy. After the patient provided written consent, we applied two doses of 2.5 g idarucizumab according to the current product characteristics and prescribing information within 20 minutes to antagonize dabigatran. Another blood sample showing normalized coagulation parameters preceded immediate weight-adapted intravenous rt-PA therapy. Within 1 h, all symptoms resolved to baseline levels.Fig. 1 Computed tomographic scan taken upon admission shows no early signs of acute stroke, but displays the residuals of a cardioembolic stroke in the left hemisphere that had occurred in May 2015\n\n\n\nA clinical examination done the next day revealed fluent speech with hardly noticeable word-finding difficulties in an aphasia assessment. Detailed conversation was possible again, and the patient reported subjective well-being. Because the patient’s symptoms resolved within 1 h and because of the lack of therapeutic consequences, we abstained from follow-up magnetic resonance imaging scans as part of the stroke workup. The patient’s electroencephalogram was free of any epileptic discharges. Echocardiography revealed no evidence of intracardial thrombotic material, and an ultrasound of the brain-supplying arteries did not reveal relevant stenoses. With the patient’s low-density lipoprotein cholesterol values being elevated (160 mg/dl), we initiated therapy with simvastatin 20 mg. Dabigatran therapy was reestablished after 24 h. However, on the basis of the patient’s age and normal renal function, we chose an increased dose of 150 mg twice daily according to the effective prescribing information. During idarucizumab application and throughout the entire hospital stay, no thrombotic or bleeding complications occurred. The patient’s laboratory examination results remained normal, and he was released to home in good health.\n\nDiscussion\nIntravenous rt-PA thrombolysis in acute ischemic stroke is considered an emergency intervention allowing an in-label application of idarucizumab. Interestingly, in our patient, thrombin time was the only clearly pathologic coagulation parameter 9.5 h after the last medication intake. aPTT was somehow prolonged but still within normal range. A second laboratory examination done immediately after idarucizumab application showed normal coagulation parameters. This allowed in-label use of rt-PA, which is prohibited when anticoagulation therapy is in effect. However, we did not wait for the results, but rather infused rt-PA in order not to lose time to reperfusion of ischemic brain regions. In cases where the second laboratory examinations still show prolonged thrombin time, we suggest immediate termination of rt-PA infusion. However, according to the available idarucizumab data, dabigatran anticoagulation should be abrogated in more than 98 % of patients [6]. Besides our patient, two similar cases [7, 8] have recently been reported. In both cases, rt-PA could be administered successfully after reversing anticoagulation effects of dabigatran by using the specific antidote idarucizumab. As for our patient, no adverse events such as thromboembolism or bleeding occurred in these two cases. Still, large registries on the use of idarucizumab should be established with special emphasis on unfavorable outcomes such as thrombotic events, bleeding, and mortality to further explore potential concerns regarding safety and efficacy.\n\nConclusions\nTo our knowledge, and according to available supplier information, we report the first case worldwide of ischemic stroke successfully treated with rt-PA after antagonizing dabigatran with idarucizumab. In line with two other recent German cases, in which the procedure appeared to be feasible, easy to manage, and without severe adverse events, this novel therapeutic option should be considered in individuals presenting with ischemic stroke who are receiving dabigatran therapy. However, further evidence concerning safety and efficacy is needed before this therapeutic regimen can be generally recommended.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding available.\n\nAvailability of data and material\nAll data generated or analyzed during this study are included in this published article and its supplementary information files.\n\nAuthors’ contributions\nAG was responsible for data acquisition and manuscript preparation. YA was responsible for data acquisition. CH was responsible for data acquisition and critical revision of the manuscript. MK was responsible for data acquisition and critical revision of the manuscript. PK was responsible for data acquisition and manuscript preparation. All authors read and approved the final manuscript.\n\nCompeting interests\nMK reports receiving speaker’s honoraria from Boehringer Ingelheim. PK reports receiving speaker’s honoraria and compensation for service on advisory boards from Boehringer Ingelheim. The other authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Connolly SJ Ezekowitz MD Yusuf S Eikelboom J Oldgren J Parekh A Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med. 2009 361 1139 51 10.1056/NEJMoa0905561 19717844 \n2. Patel MR Mahaffey KW Garg J Pan G Singer DE Hacke W Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med. 2011 365 883 91 10.1056/NEJMoa1009638 21830957 \n3. Granger CB Alexander JH McMurray JJ Lopes RD Hylek EM Hanna M Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med. 2011 365 981 92 10.1056/NEJMoa1107039 21870978 \n4. Giugliano RP Ruff CT Braunwald E Murphy SA Wiviott SD Halperin JL Edoxaban versus warfarin in patients with atrial fibrillation N Engl J Med. 2013 369 2093 104 10.1056/NEJMoa1310907 24251359 \n5. Glund S Stangier J Schmohl M Gansser D Norris S van Ryn J Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial Lancet. 2015 386 680 90 10.1016/S0140-6736(15)60732-2 26088268 \n6. Pollack CV Jr Reilly PA Eikelboom J Glund S Verhamme P Bernstein RA Idarucizumab for dabigatran reversal N Engl J Med. 2015 373 511 20 10.1056/NEJMoa1502000 26095746 \n7. Schäfer N Müller A Wüllner U Systemic thrombolysis for ischemic stroke after antagonizing dabigatran with idarucizumab—a case report J Stroke Cerebrovasc Dis. 2016 25 e126 7 10.1016/j.jstrokecerebrovasdis.2016.05.006 27236361 \n8. Berrouschot J Stoll A Hogh T Eschenfelder CC Intravenous thrombolysis with recombinant tissue-type plasminogen activator in a stroke patient receiving dabigatran anticoagulant after antagonization with idarucizumab Stroke. 2016 47 1936 8 10.1161/STROKEAHA.116.013550 27301937\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "10(1)",
"journal": "Journal of medical case reports",
"keywords": "Dabigatran; Idarucizumab; Ischemic stroke; Thrombolysis; recombinant tissue plasminogen activator",
"medline_ta": "J Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "269",
"pmc": null,
"pmid": "27686252",
"pubdate": "2016-09-29",
"publication_types": "D016428:Journal Article",
"references": "24251359;26095746;27301937;26088268;19717844;21870978;27236361;21830957",
"title": "Successful thrombolysis with recombinant tissue plasminogen activator after antagonizing dabigatran by idarucizumab: a case report.",
"title_normalized": "successful thrombolysis with recombinant tissue plasminogen activator after antagonizing dabigatran by idarucizumab a case report"
} | [
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... |
{
"abstract": "The introduction of novel antimyeloma therapies, including thalidomide, lenalidomide and bortezomib, has expanded treatment options for patients with multiple myeloma. These compounds alter the natural history of multiple myeloma and help improve outcomes, but have different and specific toxicity profiles. The major adverse events associated with these treatments are somnolence (thalidomide), venous thromboembolism (thalidomide and lenalidomide), myelosuppression (lenalidomide and bortezomib), gastrointestinal disturbance, and peripheral neuropathy (thalidomide and bortezomib). These adverse events are predictable, consistent, and manageable with patient monitoring, supportive care, and dose reduction and interruption where appropriate. Herein we evaluate the incidence of treatment-related adverse events associated with each of these compounds. We further review the management of these adverse events with a view to delivering optimal therapeutic outcomes in patients with newly diagnosed and relapsed and/or refractory multiple myeloma.",
"affiliations": "Haematology Department, University Hospital of Salamanca, Salamanca, Spain. mvmateos@usal.es",
"authors": "Mateos|María-Victoria|MV|",
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"nlm_unique_id": "7502030",
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"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Management of treatment-related adverse events in patients with multiple myeloma.",
"title_normalized": "management of treatment related adverse events in patients with multiple myeloma"
} | [
{
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... |
{
"abstract": "This study assessed the relationship between pharmacological regimens at hospital discharge and hospital readmission among schizophrenia patients. The records reviewed were all consecutive admissions (N=720) from a specific catchment area during the period 1991-2005. Two main groups were selected for analysis: the first group (N=537) included patients discharged with first-generation antipsychotics (FGA), and the second group (N=183) included patients with second-generation antipsychotics (SGA). Data on clinical and demographic characteristics at discharge, including a brief psychiatric rating scale and pharmacological treatment, were collected. The rate of readmission within 12 months was analyzed in relation to the specific pharmacological treatment at discharge. There was no significant difference in the risk of readmission in patients treated with SGA compared with FGA. Adjuvant psychotropic medications to either FGA or SGA did not attenuate the risk of readmission. The readmission rate in patients treated with clozapine (N=74) was significantly lower in comparison with depot FGA (N=293) medications (P=0.016). There was no advantage of SGA over FGA, with or without adjuvant psychotropic treatment, with regard to rehospitalization risk during the 12-month follow-up. Clozapine was found to reduce the risk for readmission in comparison with depot FGA.",
"affiliations": "The Geha Mental Health Center bFelsenstein Medical Research Center, Beilinson Campus, Petah Tiqva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. valevski@gmail.com",
"authors": "Valevski|Avi|A|;Gilat|Yaron|Y|;Olfson|Mark|M|;Benaroya-Milshtein|Noa|N|;Weizman|Abraham|A|",
"chemical_list": "D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D011619:Psychotropic Drugs; D003024:Clozapine",
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"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D003692:Delayed-Action Preparations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007557:Israel; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010351:Patient Discharge; D010359:Patient Readmission; D016016:Proportional Hazards Models; D011569:Psychiatric Status Rating Scales; D011619:Psychotropic Drugs; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8609061",
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"publication_types": "D016428:Journal Article",
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"title": "Antipsychotic monotherapy and adjuvant psychotropic therapies in schizophrenia patients: effect on time to readmission.",
"title_normalized": "antipsychotic monotherapy and adjuvant psychotropic therapies in schizophrenia patients effect on time to readmission"
} | [
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... |
{
"abstract": "Although upper-extremity deep vein thrombosis (UEDVT) is considered rare, its prevalence appears to be increasing, and this may be related to expanding indications for catheter-based interventions. In contrast, few cases have been reported related to strenuous exercise, especially in healthy young adults with thoracic outlet syndrome (Paget-Schroetter syndrome). In contrast to lower-extremity DVT, optimal treatment strategies for UEDVT have not been robustly studied. In this report, we describe a 56-year-old man with primary UEDVT presenting with left arm swelling, paresthesia, and visible collateral veins around the shoulder. Venography revealed thrombotic occlusion of the left subclavian vein. Emergent pharmaco-mechanical catheter-directed thrombolysis (PCDT) was performed, and his left subclavian vein was recanalized. A novel oral anticoagulant was initiated to prevent reclosure. The patient's symptoms subsided without major bleeding complications and at six months, he has no disability for daily activities. Follow-up ultrasonography revealed almost complete patency of the left subclavian vein, after which anticoagulation therapy was terminated. We discuss the role of PCDT in the management of primary UEDVT from the perspective of efficacy and contribution to quality of life. <Learning objective: UEDVT is relatively rare and has not been examined as extensively as lower-extremity DVT. Nonetheless, patients may have a variety of unpleasant symptoms that substantially decrease quality of life. Pharmaco-mechanical catheter-directed thrombolysis may be effective to reduce clot burden and mitigate the risk of post-thrombotic syndrome. Although there is no current consensus about exact indications for UEDVT patients, the procedure may be more useful than the standard anticoagulant therapy.>.",
"affiliations": "Division of Cardiology, Joetsu General Hospital, Joetsu, Niigata, Japan.;Division of Cardiology, Joetsu General Hospital, Joetsu, Niigata, Japan.;Division of Cardiology, Joetsu General Hospital, Joetsu, Niigata, Japan.",
"authors": "Hasegawa|Tomoya|T|;Tabata|Hiroaki|H|;Kagoshima|Mitsuru|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
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"journal": "Journal of cardiology cases",
"keywords": "Catheter-directed thrombolysis/Pharmaco-mechanical catheter-directed thrombolysis; Effort-related thrombosis (Paget-Schroetter syndrome); Venous thoracic outlet syndrome",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "194-198",
"pmc": null,
"pmid": "30279833",
"pubdate": "2017-12",
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"references": "23537968;21366477;26867832;22172244;22545895;16002126;22577443;22869858;25246013;20237328;18445117;17574105",
"title": "A case of upper extremity deep vein thrombosis with long-term patency using pharmaco-mechanical catheter-directed thrombolysis in the acute phase.",
"title_normalized": "a case of upper extremity deep vein thrombosis with long term patency using pharmaco mechanical catheter directed thrombolysis in the acute phase"
} | [
{
"companynumb": "JP-TEVA-2017-JP-842310",
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{
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"activesubstancename": "HEPARIN SODIUM"
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... |
{
"abstract": "Neonatal abstinence syndrome (NAS) due to prenatally exposure to citalopram can develop during the first days of life even with low dose of drug exposure. Supportive management is the first choice but phenobarbital can be used in treatment of this syndrome. Breastfeeding should not be interrupted. These neonates should be followed both for NAS and neurodevelopmental outcome. In this article, we reported a newborn with NAS due to citalopram exposure with a lower dose than previously reported in the literature, during the last six months of pregnancy. Phenobarbital was used because of non-pharmacological treatment failure.",
"affiliations": "Neonatology, Etlik Zubey de Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey. sarasurmeli@gmail.com.;Neonatology, Etlik Zubey de Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey.;Neonatology, Etlik Zubey de Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey.;Neonatology, Etlik Zubey de Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey.;Neonatology, Etlik Zubey de Hanim Women's Health Teaching and Research Hospital, Ankara, Turkey.",
"authors": "Erol|Sara|S|;Ozcan|Beyza|B|;Celik|Istemi H|IH|;Bas|Ahmet Y|AY|;Demirel|Nihal|N|",
"chemical_list": "D000927:Anticonvulsants; D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D010634:Phenobarbital",
"country": "Argentina",
"delete": false,
"doi": "10.5546/aap.2017.eng.e424",
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"issue": "115(6)",
"journal": "Archivos argentinos de pediatria",
"keywords": "Phenobarbital; citalopram; neonatal abstinence syndrome",
"medline_ta": "Arch Argent Pediatr",
"mesh_terms": "D000927:Anticonvulsants; D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D003865:Depressive Disorder, Major; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009357:Neonatal Abstinence Syndrome; D010634:Phenobarbital; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects",
"nlm_unique_id": "0372460",
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"pages": "e424-e427",
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"pmid": "29087127",
"pubdate": "2017-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neonatal abstinence syndrome due to prenatally citalopram exposure: A case report.",
"title_normalized": "neonatal abstinence syndrome due to prenatally citalopram exposure a case report"
} | [
{
"companynumb": "SE-CIPLA LTD.-2017SE23382",
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{
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"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"drugadditional":... |
{
"abstract": "Heparin-induced thrombocytopenia (HIT) may be a critical condition in intensive care patients. Diagnosis of HIT is often difficult, and management too, as physicians have usually a limited experience with alternative anticoagulants. A 36-year-old man was admitted for orthopaedic surgery after a trauma causing a fracture of the sacrum and right ankle. Anticoagulant prophylaxis was made by nadroparin (3800 IU/day). But the patient developed less than 10 days after nadroparin exposure a significant drop in platelet count. The diagnosis of HIT was based on the pretest clinical score and demonstration of platelet factor 4 and heparin antibodies. Fondaparinux was transiently administered but was replaced 3 days later by rivaroxaban (15 mg twice a day during 21 days then 20 mg/day), after the demonstration of an acute thrombosis of the left radial artery. Platelet count returned to normal range and a partial recanalization of arterial thrombosis was noted. The use of rivaroxaban in this indication is of theoretical interest but requires further experience.",
"affiliations": "aDepartment of Intensive Care bDivision of Hematology, Université catholique de Louvain, Cliniques St-Luc, Brussels, Belgium.",
"authors": "Hantson|Philippe|P|;Lambert|Catherine|C|;Hermans|Cédric|C|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D006493:Heparin; D000069552:Rivaroxaban",
"country": "England",
"delete": false,
"doi": "10.1097/MBC.0000000000000205",
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"issn_linking": "0957-5235",
"issue": "26(2)",
"journal": "Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis",
"keywords": null,
"medline_ta": "Blood Coagul Fibrinolysis",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D006493:Heparin; D006801:Humans; D008297:Male; D009025:Morpholines; D000069552:Rivaroxaban; D013876:Thiophenes; D013921:Thrombocytopenia; D013927:Thrombosis",
"nlm_unique_id": "9102551",
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"pmc": null,
"pmid": "25255239",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rivaroxaban for arterial thrombosis related to heparin-induced thrombocytopenia.",
"title_normalized": "rivaroxaban for arterial thrombosis related to heparin induced thrombocytopenia"
} | [
{
"companynumb": "BE-MYLANLABS-2015M1022764",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FONDAPARINUX"
},
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... |
{
"abstract": "The objective of the study was to describe a very rare complication of foam ultrasound-guided sclerotherapy (FUGS). An unusual case of persisting chest discomfort following FUGS in a 61-year-old woman led to a diagnosis of non-ST-elevation myocardial infarction. The patient was found to have a patent foramen ovale (PFO). The differential diagnoses of paradoxical embolism, gas embolism or vasospasm are discussed, with reference to relevant literature. A hypothesis of post sclerotherapy release of endothelin-1 (in a patient with a known PFO) leading to sustained coronary artery spasm causing sufficient myocardial damage to be reflected in elevated troponin levels is suggested. Any episode of chest tightness or pain following FUGS should be considered as possibly cardiac in origin. Sustained symptoms warrant admission to hospital for troponin monitoring and ECG assessment.",
"affiliations": "Palm Clinic, Auckland, New Zealand rowanstephens@orcon.net.nz.;Palm Clinic, Auckland, New Zealand.",
"authors": "Stephens|R|R|;Dunn|S|S|",
"chemical_list": "D012597:Sclerosing Solutions",
"country": "England",
"delete": false,
"doi": "10.1177/0268355513481765",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3555",
"issue": "29(7)",
"journal": "Phlebology",
"keywords": "foam; non-ST-elevation myocardial infarction; patent foramen ovale; sclerotherapy",
"medline_ta": "Phlebology",
"mesh_terms": "D019320:Embolism, Paradoxical; D005260:Female; D054092:Foramen Ovale, Patent; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction; D012307:Risk Factors; D012597:Sclerosing Solutions; D015911:Sclerotherapy; D018084:Ultrasonography, Interventional; D014689:Venous Insufficiency",
"nlm_unique_id": "9012921",
"other_id": null,
"pages": "488-90",
"pmc": null,
"pmid": "23563647",
"pubdate": "2014-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Non-ST-elevation myocardial infarction following foam ultrasound-guided sclerotherapy.",
"title_normalized": "non st elevation myocardial infarction following foam ultrasound guided sclerotherapy"
} | [
{
"companynumb": "NZ-MYLANLABS-2016M1005316",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SODIUM TETRADECYL SULFATE"
},
"drugadditional... |
{
"abstract": "Sclerosing peritonitis is a complication described in different clinical situations, such as patients that underwent prolonged peritoneal dialysis or renal transplantation with previous history of peritoneal dialysis. The origin of this entity is unclear so far and it is believed that several mechanisms may contribute to its development. The hallmark of sclerosing peritonitis is the continuous accumulation of fibrocollagenous deposits in the intestinal wall and mesenteries causing progressive adhesion of the intestinal loops and mesenteric retraction resulting in intestinal obstruction. Also, it has been described as a rare complication after intestinal transplant that might lead to graft failure. In this report, we describe a case of sclerosing peritonitis after intestinal transplantation that was successfully treated with modifications in the immunosuppressive regime allowing restitution of gastrointestinal transit and intestinal autonomy.",
"affiliations": "Instituto de Trasplante Multiorgánico (ITMO), Hospital Universitario Fundación Favaloro, Buenos Aires, Argentina. crumbo@ffavaloro.org",
"authors": "Rumbo|Carolina|C|;Zambernardi|Agustina|A|;Cabanne|Ana|A|;Rumbo|Martin|M|;Gondolesi|Gabriel|G|",
"chemical_list": "D007166:Immunosuppressive Agents; D007073:Immunoglobulin E",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12110",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "17(5)",
"journal": "Pediatric transplantation",
"keywords": "fibrosis; rejection; sclerosing peritonitis; small bowel; transplant",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001706:Biopsy; D002648:Child; D006627:Hirschsprung Disease; D006801:Humans; D007073:Immunoglobulin E; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007415:Intestinal Obstruction; D007422:Intestines; D008297:Male; D010538:Peritonitis; D011183:Postoperative Complications; D012598:Sclerosis; D014180:Transplantation; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E125-9",
"pmc": null,
"pmid": "23902605",
"pubdate": "2013-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sclerosing peritonitis, a rare complication after intestinal transplant. Report of one case successfully treated with adjustment of immunosuppression.",
"title_normalized": "sclerosing peritonitis a rare complication after intestinal transplant report of one case successfully treated with adjustment of immunosuppression"
} | [
{
"companynumb": "AR-ASTELLAS-2017US035600",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Four cases of pancytopenia related to low-dose weekly pulse methotrexate therapy for rheumatoid arthritis are described. All patients were aged above 60 years and had renal impairment. In every case marrow recovery followed withdrawal of methotrexate. However, one patient developed pneumonitis and died. Cholangitis, respiratory infection and increase in methotrexate dose were precipitating factors. Pharmacokinetic data indicated prolonged tissue drug exposure in two cases studied; dose-related toxicity was further supported by successful resumption of methotrexate in reduced dosage in two cases. It is possible that methotrexate dose should be modified during intercurrent illness in patients older than 60 years who have renal impairment.",
"affiliations": "Flinders Medical Centre, Bedford Park, SA.",
"authors": "Kevat|S G|SG|;Hill|W R|WR|;McCarthy|P J|PJ|;Ahern|M J|MJ|",
"chemical_list": "D008727:Methotrexate",
"country": "Australia",
"delete": false,
"doi": "10.1111/j.1445-5994.1988.tb00155.x",
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"issn_linking": "0004-8291",
"issue": "18(5)",
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"keywords": null,
"medline_ta": "Aust N Z J Med",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate; D010198:Pancytopenia; D012307:Risk Factors",
"nlm_unique_id": "1264322",
"other_id": null,
"pages": "697-700",
"pmc": null,
"pmid": "3245825",
"pubdate": "1988-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pancytopenia induced by low-dose methotrexate for rheumatoid arthritis.",
"title_normalized": "pancytopenia induced by low dose methotrexate for rheumatoid arthritis"
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"companynumb": "AU-ORION CORPORATION ORION PHARMA-TREX2016-2332",
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"abstract": "Hitherto, no study has yielded important information on whether the scales of frailty may improve the ability to discriminate the risk of haemorrhages in older adults admitted to hospital for acute coronary syndrome (ACS). The aim of this study is to investigate whether frailty scales would predict the 1-year occurrence of haemorrhagic events and if they confer a significant incremental prognostic value over the bleeding risk scores.\n\n\n\nThe present study involved 346 ACS patients aged ≥ 70 years enrolled in the FRASER study. Seven different scales of frailty and PARIS, PRECISE-DAPT and BleeMACS bleeding risk scores were available for each patient. The outcomes were the 1-year BARC 3-5 and 2 bleeding events.\n\n\n\nAdherence to antiplatelet treatment at 1, 6 and 12 months was 98%, 87% and 78%, respectively. At 1-year, 14 (4%) and 30 (9%) patients presented BARC 3-5 and 2 bleedings, respectively. Bleeding risk scores and four scales of frailty (namely Short Physical Performance Battery, Columbia, Edmonton and Clinical Frailty Scale) significantly discriminated the occurrence of BARC 3-5 events. The addition of the scales of frailty to bleeding risk scores did not lead to a significant improvement in the ability to predict BARC 3-5 bleedings. Neither the bleeding risk scores nor the scales of frailty predicted BARC 2 bleedings.\n\n\n\nBoth the bleeding risk scores and the scales of frailty predicted BARC 3-5 haemorrhages. However, integrating the scales of frailty with the bleeding risk scores did not improve their discriminative ability.\n\n\n\nwww.clinicaltrials.gov: NCT02386124.",
"affiliations": "Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Unità Operativa di Cardiologia, Ospedale GB Morgagni, Forlì, Italy.;Department of Emergency, Division of Cardiology, Delta Hospital, Azienda Unità Sanitaria Locale di Ferrara, Ferrara, Italy.;Division of Cardiology, S. Maria Delle Croci Hospital, Ravenna, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy.;Department of Medical Science, University of Ferrara, Ferrara, Italy.;Cardiovascular Institute, Azienda Ospedaliero-Universitaria di Ferrara, Via Aldo Moro 8, 44124, Cona, Fe, Italy. cmpglc@unife.it.",
"authors": "Pavasini|Rita|R|;Maietti|Elisa|E|;Tonet|Elisabetta|E|;Bugani|Giulia|G|;Tebaldi|Matteo|M|;Biscaglia|Simone|S|;Cimaglia|Paolo|P|;Serenelli|Matteo|M|;Ruggiero|Rossella|R|;Vitali|Francesco|F|;Galvani|Marcello|M|;Minarelli|Monica|M|;Rubboli|Andrea|A|;Bernucci|Davide|D|;Volpato|Stefano|S|;Campo|Gianluca|G|0000-0002-5150-188X",
"chemical_list": "D010975:Platelet Aggregation Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1007/s10557-019-06911-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0920-3206",
"issue": "33(5)",
"journal": "Cardiovascular drugs and therapy",
"keywords": "Acute coronary syndrome; Bleeding; Elderly; Frailty; PARIS; PRECISE-DAPT",
"medline_ta": "Cardiovasc Drugs Ther",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D003661:Decision Support Techniques; D005260:Female; D000073496:Frailty; D015577:Geriatric Assessment; D006470:Hemorrhage; D006801:Humans; D007558:Italy; D008297:Male; D055118:Medication Adherence; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "8712220",
"other_id": null,
"pages": "523-532",
"pmc": null,
"pmid": "31549262",
"pubdate": "2019-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Bleeding Risk Scores and Scales of Frailty for the Prediction of Haemorrhagic Events in Older Adults with Acute Coronary Syndrome: Insights from the FRASER study.",
"title_normalized": "bleeding risk scores and scales of frailty for the prediction of haemorrhagic events in older adults with acute coronary syndrome insights from the fraser study"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1027178",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRASUGREL"
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"abstract": "Several drugs have a QTc-prolonging effect and are metabolized by CYP3A4. The combination of QTc-prolonging drugs may act additive of the QTc interval. The risk increases additionally by co-administration of a CYP3A4-inhibiting substrate. This case report describes an incident with QTc prolongation which was probably caused by an interaction induced by a combination of amiodarone, clarithromycin and the CYP3A4-inhibitor fluconazole.",
"affiliations": "buch.tinabuch@gmail.com.",
"authors": "Buch|Tina|T|;Andersen|Stig Ejdrup|SE|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D015725:Fluconazole; D017291:Clarithromycin; D000638:Amiodarone",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "177(41)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D017291:Clarithromycin; D003131:Combined Modality Therapy; D004347:Drug Interactions; D004562:Electrocardiography; D015725:Fluconazole; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome; D008297:Male",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": "V04150371",
"pmc": null,
"pmid": "26471025",
"pubdate": "2015-10-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Combination therapy with fluconazole and other QTc-prolonging drugs increase the QTc interval.",
"title_normalized": "combination therapy with fluconazole and other qtc prolonging drugs increase the qtc interval"
} | [
{
"companynumb": "DK-GLENMARK PHARMACEUTICALS-2017GMK027390",
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"occurcountry": "DK",
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"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
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{
"abstract": "BACKGROUND\nImmunosuppressive therapy, prolonged antibiotic use, and intrathecal injections are known risk factors for the development of invasive aspergillosis. Central nervous system (CNS) aspergillosis can manifest in many forms, including mycotic aneurysm formation. The majority of the mycotic aneurysms presents with subarachnoid hemorrhage after rupture and are associated with high mortality. Only 3 cases of true mycotic aneurysms have been reported following trans-sphenoidal surgery.\n\n\nMETHODS\nA 38-year-old man was admitted with nonfunctioning pituitary adenoma for which he underwent trans-sphenoidal surgery. Three weeks later, he presented with cerebrospinal fluid (CSF) rhinorrhea and meningitis. He was treated with intrathecal and intravenous antibiotics, stress dose of glucocorticoids, and lumbar drain. The defect in the sphenoid bone was closed endoscopically. After 3 weeks of therapy, he suddenly became unresponsive, and computed tomography of the head showed subarachnoid hemorrhage. He succumbed to illness on the next day, and a limited autopsy of the brain was performed. The autopsy revealed extensive subarachnoid hemorrhage and aneurysmal dilatation, thrombosis of the basilar artery (BA), multiple hemorrhagic infarcts in the midbrain, and pons. Histopathology of the BA revealed the loss of internal elastic lamina and septate hyphae with an acute angle branching on Grocott's methenamine silver stain, conforming to the morphology of Aspergillus.\n\n\nCONCLUSIONS\nThe possibility of intracranial fungal infection should be strongly considered in any patient receiving intrathecal antibiotics who fails to improve in 1-2 weeks, and frequent CSF culture for fungi should be performed to confirm the diagnosis. Since CSF culture has poor sensitivity in the diagnosis of fungal infections of CNS; empirical institution of antifungal therapy may be considered in this scenario.",
"affiliations": "Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Radiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Radotra|Bishan Das|BD|;Salunke|Praveen|P|;Parthan|Girish|G|;Dutta|Pinaki|P|;Vyas|Sameer|S|;Mukherjee|Kanchan K|KK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/2152-7806.172697",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-6-19310.4103/2152-7806.172697Case ReportTrue mycotic aneurysm in a patient with gonadotropinoma after trans-sphenoidal surgery Radotra Bishan Das radotra.bishan@pgimer.edu.inSalunke Praveen drpravin_salunke@yahoo.co.uk1Parthan Girish girishparthan@gmail.com2Dutta Pinaki pinaki_dutta@hotmail.com2Vyas Sameer drsameervyas@gmail.com3Mukherjee Kanchan K. kk_mukherjee@hotmail.com1*Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India1 Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India2 Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India3 Department of Radiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India* Corresponding author\n2015 28 12 2015 6 19325 4 2015 27 8 2015 Copyright: © 2015 Surgical Neurology International2015This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nImmunosuppressive therapy, prolonged antibiotic use, and intrathecal injections are known risk factors for the development of invasive aspergillosis. Central nervous system (CNS) aspergillosis can manifest in many forms, including mycotic aneurysm formation. The majority of the mycotic aneurysms presents with subarachnoid hemorrhage after rupture and are associated with high mortality. Only 3 cases of true mycotic aneurysms have been reported following trans-sphenoidal surgery.\n\nCase Description:\nA 38-year-old man was admitted with nonfunctioning pituitary adenoma for which he underwent trans-sphenoidal surgery. Three weeks later, he presented with cerebrospinal fluid (CSF) rhinorrhea and meningitis. He was treated with intrathecal and intravenous antibiotics, stress dose of glucocorticoids, and lumbar drain. The defect in the sphenoid bone was closed endoscopically. After 3 weeks of therapy, he suddenly became unresponsive, and computed tomography of the head showed subarachnoid hemorrhage. He succumbed to illness on the next day, and a limited autopsy of the brain was performed. The autopsy revealed extensive subarachnoid hemorrhage and aneurysmal dilatation, thrombosis of the basilar artery (BA), multiple hemorrhagic infarcts in the midbrain, and pons. Histopathology of the BA revealed the loss of internal elastic lamina and septate hyphae with an acute angle branching on Grocott's methenamine silver stain, conforming to the morphology of Aspergillus.\n\nConclusion:\nThe possibility of intracranial fungal infection should be strongly considered in any patient receiving intrathecal antibiotics who fails to improve in 1–2 weeks, and frequent CSF culture for fungi should be performed to confirm the diagnosis. Since CSF culture has poor sensitivity in the diagnosis of fungal infections of CNS; empirical institution of antifungal therapy may be considered in this scenario.\n\nAspergillosisbasilar arterymycotic aneurysmpituitary adenomasubarachnoid hemorrhagetrans-sphenoidal surgery\n==== Body\nINTRODUCTION\nAspergillosis of central nervous system (CNS) is an uncommon entity; however, the number of reported cases has increased in the past few years, possibly due to the widespread use of antibiotics, corticosteroids, and other immunosuppressants.[8] Cerebral aneurysms caused by aspergillosis are very rare and until date, 40 odd cases have been described in the English literature.\n\nCLINICAL PRESENTATION\nA 38-year-old male presented with an episode of giddiness and uneasiness that lasted for 2 days. There was no history of dyspnea or palpitation. He did not have any comorbid illness. Clinical examination revealed bitemporal hemianopia and biochemical evaluation showed hyponatremia, hypocortisolism, and hypothyroidism, with elevated follicle-stimulating hormone, luteinizing hormone, and testosterone [Supplementary file, Table 1]. Magnetic resonance imaging (MRI) brain revealed a sellar-supra-sellar mass [Figure 1]. After hormone supplementation and correction of electrolytes, he underwent gross total excision of the tumor through endonasal trans-sphenoidal route. During the perioperative period, he was given hydrocortisone infusion at 4 mg/h and during the immediate postoperative period, he was given hydrocortisone 50 mg intravenously 8th hourly. The intraoperative and immediate postoperative period was uneventful, and he was discharged on glucocorticoid (oral hydrocortisone 10 mg/m2 /day) and thyroxine replacement. Histopathology and immunohistochemistry showed a gonadotropin secreting pituitary adenoma. The dura and bone was free of tumor, and the sphenoid sinus mucosa was normal.\n\nFigure 1 Coronal T1-weighted magnetic resonance image of the sella showing a pituitary macroadenoma with supra-sellar extension\n\nSupplementary Table 1 Preoperative hormonal profile of the patient\n\nClick here for additional data file.\n\n Three weeks later, he presented with intermittent fever and cerebrospinal fluid (CSF) rhinorrhea of 5 days duration. On examination, he had terminal neck rigidity. CSF studies were suggestive of pyogenic meningitis, CSF culture showed Enterobacter species, and he was started on appropriate antibiotics. The computed tomography (CT) scan showed pneumocephalus. Endoscopic repair of the defect was done after the infection was apparently controlled, and CSF was diverted through an external lumbar drain, to aid healing. Despite the repair, CSF rhinorrhea persisted, and CT scan showed the progression of pneumocephalus. Repeat CSF culture after a week grew Staphylococcus and he was started on intravenous Vancomycin and Meropenem with intrathecal Vancomycin. His preoperative total leukocyte count was 8700 mm3 with neutrophils 71%, lymphocytes 22%, monocytes 5%, and eosinophils 2%. At present admission, his total leukocyte count was 15,800 with neutrophils 82%, lymphocytes 14%, and monocytes 4%. His serum albumin and globulin were 4.5 g/dl and 3.5 g/dl, respectively. Serology for HIV was negative. The serial CSF reports of the patient are given in the Supplementary file, Table 2. Throughout the course, he was on therapy with injectable hydrocortisone 50 mg every 8th hourly and thyroxine 100 μg, and required subcutaneous desmopressin intermittently for diabetes insipidus. After 3 weeks of hospital stay, he suddenly became unresponsive and CT scan showed a subarachnoid hemorrhage with intraventricular extension [Figure 2]. The patient expired a day later, despite the external ventricular drainage.\n\nSupplementary Table 2 Serial CSF analysis of the patient\n\nClick here for additional data file.\n\n Figure 2 Axial noncontrast computed tomography scan of head showing subarachnoid hemorrhage with intra-ventricular extension\n\nThe cause of death was speculated to be due to rupture of an intracranial aneurysm. This may have been an association with pituitary macroadenoma (although it is seen often with functioning pituitary macroadenoma), or due to the weakening of vessel wall due to inflammatory exudates. The third possibility could be an inadvertent intraoperative injury such as snapping of a perforator from a distal vessel, resulting in pseudoaneurysm formation. To confirm the cause of death, a limited brain autopsy was performed, which revealed extensive subarachnoid hemorrhage and aneurysmal dilatation and thrombosis of the basilar artery (BA) [Figure 3]. There were multiple hemorrhagic infarcts in the midbrain and pons. Histopathology of the BA revealed the loss of internal elastic lamina and septate hyphae with an acute angle branching on Grocott's methenamine silver stain, conforming to the morphology of Aspergillus [Figure 4a–d].\n\nFigure 3 Cut section of brain showing extensive subarachnoid hemorrhage and ruptured basilar artery aneurysm\n\nFigure 4 Low power photo micrographs taken through the wall of the basilar artery at the site of aneurysm. (a) H and E staining showing dilated and destroyed arterial wall. (b) Elastic Van Gieson staining is showing the loss of internal elastic lamina on the upper part. (c) Gomorri methenamine silver staining is showing an invasive fungal elements from outer to the inner side in the aneurysmal wall. (d) High power photo micrograph showing numerous filamentary infiltrates with an acute angle branching confirming to the morphology of Aspergillus species\n\nDISCUSSION\nThe common fungi associated with CNS infections include yeasts (Candida, Cryptococcus), moniliaceous molds (Aspergillus spp. and Fusarium spp.), dimorphic fungi (Blastomyces, Coccidioides, and Histoplasma), zygomycetes (Mucor spp., Rhizopus spp.), and dematiaceous fungi (Scedosporium spp.).[17] Fungal infections of the CNS can be endemic mycoses or opportunistic mycoses. Fungi such as Blastomyces, Coccidioides, and Histoplasma are not part of the normal human microbiota and are acquired from the environment; these agents cause endemic mycoses. Other fungi such as Candida, Cryptococcus, Aspergillus, and Mucor are commensals in the human body and cause opportunistic mycoses, in an immunodeficient individual.[6] Fungi may enter into the CNS through hematogenous route, infection from adjacent structures such as paranasal sinuses and orbit or direct inoculation as a result of trauma or surgery.[12] Fungal infections of the CNS are associated with various clinical syndromes; meningitis, intracranial mass lesions, skull base syndromes, rhinocerebral form, stroke syndrome, or spinal syndrome. Meningitis and meningoencephalitis are common presenting clinical syndrome with most of the yeasts, whereas rhinocerebral form is usually caused by zygomycetes. Intracranial mass lesions can be caused by Aspergillus, zygomycetes, dematiaceous fungi, and Candida; the skull base syndromes are associated with Aspergillus infections.[15]\n\nAspergillus is a ubiquitous fungus, and more than 180 species of Aspergillus have been described. Aspergillus fumigatus is the most common pathogen responsible for invasive Aspergillosis; although Aspergillus flavus, Aspergillus terreus, Aspergillus niger, and Aspergillus nidulans can also cause invasive disease.[20] The risk factors for the development of invasive aspergillosis include prolonged severe neutropenia, hematopoietic stem cell and solid organ transplantation, advanced AIDS, and chronic granulomatous disease. Although the sinopulmonary disease is the most common form of Aspergillosis, it can virtually affect any organ.[19] CNS can be infected by Aspergillus as a result of hematogenous dissemination from a pulmonary focus, direct extension from paranasal sinuses, middle ear or after head injury, brain surgery, or lumbar puncture.[5] The diagnosis of CNS aspergillosis requires a high index of suspicion because the clinical features are nonspecific and CT and MRI findings, although helpful are also nondiagnostic.[18] The CNS aspergillosis can present as meningitis, meningoencephalitis, abscess, granuloma, vasculitis, and myelitis.[1418] Vasculitis may result in thrombosis, hemorrhage, or aneurysm formation.\n\nMycotic aneurysms account for 0.7–5.4% of all intracranial aneurysms and is most commonly caused by bacteria; fungi are a rare cause of mycotic aneurysm.[1] Aneurysms caused by bacteria tend to be multiple, spherical, and typically arise from the peripheral cortical arteries, especially middle and anterior cerebral arteries. They are commonly caused by Staphylococcus and Streptococcus. In contrast, aneurysms caused by fungi are usually single, fusiform, and involve internal carotid, or BA.[11] Mycotic aneurysms can result from infective emboli, occlusion of the vasa vasorum, invasion of the arterial wall from within, extension from an infection of neighboring structures, or vascular injury due to immune complexes.[2] Aspergillus species accounts for approximately 65% of mycotic aneurysms caused by fungi, while the rest by Candida and Mucorale (zygomycetes, Penicillium).[3] Aspergillus is an angioinvasive fungus and this is due to its ability to produce the enzyme elastase, which destroys elastin present in blood vessels. Aneurysm formation is due to the proliferation of fungi within the internal elastic lamina, dissecting it away from media, aided by hydrostatic pulsation, and thrust against the infected arterial wall.[416] The other mechanism postulated is the weakening of vessel wall due to bathing of vessels in the inflammatory exudates collected in basal cisterns.\n\nPostoperative mycotic aneurysms of the CNS are rare.[4] Only 3 cases of true mycotic aneurysms have been reported following pituitary surgery [Table 1]. One patient had aneurysm of basilar artery, one had aneurysm of internal carotid artery while the third patient had aneurysms of both basilar and internal carotid artery. All three patients succumbed to the disease, and diagnosis could be made only at autopsy. Our patient presented with meningitis 3 weeks after surgery and died 24 h after the onset of subarachnoid hemorrhage. The probable cause of death was infarction of vital structures in the brain stem.\n\nTable 1 Summary of the cases of true mycotic aneurysms caused by Aspergillus after trans-sphenoidal surgery\n\nKomatsu et al. have described the two processes of mycotic aneurysm formation; those secondary to meningitis and those secondary to sepsis. The former tend to affect the larger vessels and are a result of fungal invasion of vessels from outside, whereas the latter tend to involve peripheral vessels and are a result of the invasion of vessel wall from within.[9] The aneurysm formation in our patient probably occurred due to the direct invasion of arterial wall by fungal hyphae from outer to inner side, leading to de-novo mycotic aneurysm formation and subsequent rupture due to weakening of vessel wall [Figure 4a–d]. Infection of a preexisting aneurysm or the development following surgical trauma are unlikely as preoperative MR-angiography was normal, and the aneurysm was quite away from the surgical field. Serial angiograms performed in a previous case have shown that only a few days are required for a fungal aneurysm to develop.[23]\n\nThere are various possible portals through which the fungi would have entered into CNS. Hematogenous dissemination was unlikely as the histopathology showed that vessel was invaded from outside. The direct entry through the operative route was also unlikely, as the sphenoid mucosa showed no evidence of fungus; however, the possibility of subsequent lodgment and focal arachnoiditis due to the persistent CSF leak could not be excluded. Our patient received the intrathecal antibiotics, and this could have given the fungus access to CNS. Fungal meningitis has been reported after epidural steroids for pain.[7] Alternatively, the prolonged placement of lumbar drain could be another portal of entry leading to the deposition of fungus and exudates in the dependent part of the brain. Another possibility is that of a fungus getting in along with the air that was sucked in the cranial cavity due to the negative pressure secondary to CSF drainage. Our patient received a supraphysiological dose of glucocorticoids, which led to immunosuppression and prolonged use of antibiotics might have caused the selective growth of fungi and subsequent development of invasive aspergillosis. The absence of recurrent skin, ear, and sinopulmonary infections since childhood, negative HIV serology, and normal serum globulin is strongly against the possibility of congenital or noniatrogenic immunodeficiency; however, we do not have a CD4 count to exclude primary CD4 deficiency.\n\nAspergillus species may be found as a commensal in paranasal sinuses.[21] Aspergillus species are known to induce allergic reactions in susceptible individuation without causing infection. This commonly occurs after the repeated inhalation of spores of Aspergillus species, which induce a Type I (immunoglobulin E mediated) hypersensitivity reaction; however, Type III (immune complex mediated) and Type IV (cell-mediated) reactions have also been implicated. It has been shown that 28% of patients with asthma demonstrate hypersensitivity to Aspergillus antigens.[10]\n\nHigh index of the suspicion based on clinical, radiological, and fungal culture is essential to make a diagnosis of CNS aspergillosis, and brain biopsy is required for the definitive diagnosis, which is not feasible in most of the cases.[18] In our patient, there was no scope to diagnose the fungal disease by neuroimaging. Unfortunately, histopathology of vital structures was not possible and ultimately it could be diagnosed only at autopsy.\n\nCONCLUSION\nThe possibility of intracranial fungal infection should be strongly considered in any patient receiving intrathecal antibiotics who fails to improve in 1–2 weeks, and frequent CSF culture for fungi should be performed to confirm the diagnosis. Since CSF culture has poor sensitivity in the diagnosis of the fungal infections of CNS, the empirical institution of antifungal therapy may be considered in this scenario.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nhttp://surgicalneurologyint.com/True-mycotic-aneurysm-in-a-patient-with-gonadotropinoma-after-trans-sphenoidal-surgery/\n==== Refs\nREFERENCES\n1 Ducruet AF Hickman ZL Zacharia BE Narula R Grobelny BT Gorski J Intracranial infectious aneurysms: A comprehensive review Neurosurg Rev 2010 33 37 46 19838745 \n2 Horten BC Abbott GF Porro RS Fungal aneurysms of intracranial vessels Arch Neurol 1976 33 577 9 947319 \n3 Hot A Mazighi M Lecuit M Poirée S Viard JP Loulergue P Fungal internal carotid artery aneurysms: Successful embolization of an Aspergillus -associated case and review Clin Infect Dis 2007 45 e156 61 18190310 \n4 Hurst RW Judkins A Bolger W Chu A Loevner LA Mycotic aneurysm and cerebral infarction resulting from fungal sinusitis: Imaging and pathologic correlation AJNR Am J Neuroradiol 2001 22 858 63 11337328 \n5 Iihara K Makita Y Nabeshima S Tei T Keyaki A Nioka H Aspergillosis of the central nervous system causing subarachnoid hemorrhage from mycotic aneurysm of the basilar artery – Case report Neurol Med Chir (Tokyo) 1990 30 618 23 1703641 \n6 Kasper D Fauci A Hauser S Longo D Jameson J Loscalzo J Diagnosis and treatment of fungal infections Harrison's Principles of Internal Medicine 2015 I 19th ed New York McGraw-Hill 1239 \n7 Kleinfeld K Jones P Riebau D Beck A Paueksakon P Abel T Vascular complications of fungal meningitis attributed to injections of contaminated methylprednisolone acetate JAMA Neurol 2013 70 1173 6 23877880 \n8 Kleinschmidt-DeMasters BK Central nervous system aspergillosis: A 20-year retrospective series Hum Pathol 2002 33 116 24 11823982 \n9 Komatsu Y Narushima K Kobayashi E Tomono Y Nose T Aspergillus mycotic aneurysm – Case report Neurol Med Chir (Tokyo) 1991 31 346 50 1724300 \n10 Kousha M Tadi R Soubani AO Pulmonary aspergillosis: A clinical review Eur Respir Rev 2011 20 156 74 21881144 \n11 Masago A Fukuoka H Yoshida T Majima K Tada T Nagai H Intracranial mycotic aneurysm caused by Aspergillus – Case report Neurol Med Chir (Tokyo) 1992 32 904 7 1282683 \n12 McCarthy M Rosengart A Schuetz AN Kontoyiannis DP Walsh TJ Mold infections of the central nervous system N Engl J Med 2014 371 150 60 25006721 \n13 Mielke B Weir B Oldring D von Westarp C Fungal aneurysm: Case report and review of the literature Neurosurgery 1981 9 578 82 6895659 \n14 Mukoyama M Gimple K Poser CM Aspergillosis of the central nervous system. Report of a brain abscess due to A. fumigatus and review of the literature Neurology 1969 19 967 74 5387599 \n15 Murthy JM Fungal infections of the central nervous system: The clinical syndromes Neurol India 2007 55 221 5 17921650 \n16 Okada Y Shima T Nishida M Yamane K Yoshida A Subarachnoid hemorrhage caused by Aspergillus aneurysm as a complication of transcranial biopsy of an orbital apex lesion – Case report Neurol Med Chir (Tokyo) 1998 38 432 7 9745252 \n17 Redmond A Dancer C Woods ML Fungal infections of the central nervous system: A review of fungal pathogens and treatment Neurol India 2007 55 251 9 17921654 \n18 Ruhnke M Kofla G Otto K Schwartz S CNS aspergillosis: Recognition, diagnosis and management CNS Drugs 2007 21 659 76 17630818 \n19 Segal BH Walsh TJ Current approaches to diagnosis and treatment of invasive aspergillosis Am J Respir Crit Care Med 2006 173 707 17 16387806 \n20 Sugui JA Kwon-Chung KJ Juvvadi PR Latgé JP Steinbach WJ Aspergillus fumigatus and related species Cold Spring Harb Perspect Med 2014 5 a019786 25377144 \n21 Vennewald I Henker M Klemm E Seebacher C Fungal colonization of the paranasal sinuses Mycoses 1999 42 Suppl 2 33 6 10865901 \n22 Visudhiphan P Bunyaratavej S Khantanaphar S Cerebral aspergillosis.Report of three cases J Neurosurg 1973 38 472 6 4696195 \n23 Walsh TJ Mendelsohn G Invasive aspergillosis complicating Cushing's syndrome Arch Intern Med 1981 141 1227 8 7259386\n\n",
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"journal": "Surgical neurology international",
"keywords": "Aspergillosis; basilar artery; mycotic aneurysm; pituitary adenoma; subarachnoid hemorrhage; trans-sphenoidal surgery",
"medline_ta": "Surg Neurol Int",
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"title": "True mycotic aneurysm in a patient with gonadotropinoma after trans-sphenoidal surgery.",
"title_normalized": "true mycotic aneurysm in a patient with gonadotropinoma after trans sphenoidal surgery"
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"abstract": "OBJECTIVE\nTo compare the efficacy and safety of oral paracetamol and oral ibuprofen for the pharmacological closure of patent ductus arteriosus (PDA) in preterm infants.\n\n\nMETHODS\nThis prospective, randomized, controlled study enrolled 90 preterm infants with gestational age ≤ 30 weeks, birthweight ≤ 1250 g, and postnatal age 48 to 96 hours who had echocardiographically confirmed significant PDA. Each enrolled patient received either oral paracetamol (15 mg/kg every 6 hours for 3 days) or oral ibuprofen (initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours).\n\n\nRESULTS\nSpontaneous closure rate for the entire study group was 54%. After the first course of treatment, the PDA closed in 31 (77.5%) of the patients assigned to the oral ibuprofen group vs 29 (72.5%) of those enrolled in the oral paracetamol group (P = .6). The reopening rate was higher in the paracetamol group than in the ibuprofen group, but the reopening rates were not statistically different (24.1% [7 of 29] vs 16.1% [5 of 31]; P = .43). The cumulative closure rates after the second course of drugs were high in both groups. Only 2 patient (2.5%) in the paracetamol group and 3 patients (5%) in the ibuprofen group required surgical ligation.\n\n\nCONCLUSIONS\nThis randomized, controlled clinical study compared oral paracetamol with ibuprofen in preterm infants and demonstrated that paracetamol may be a medical alternative in the management of PDA.",
"affiliations": "Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey. Electronic address: dryekta@gmail.com.;Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey.;Division of Neonatology, Department of Pediatrics, Ankara University School of Medicine, Ankara, Turkey.;Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey.;Division of Pediatric Cardiology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey.;Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey.;Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey.;Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey; Department of Pediatrics, Yildirim Beyazit University School of Medicine, Ankara, Turkey.",
"authors": "Oncel|Mehmet Yekta|MY|;Yurttutan|Sadik|S|;Erdeve|Omer|O|;Uras|Nurdan|N|;Altug|Nahide|N|;Oguz|Serife Suna|SS|;Canpolat|Fuat Emre|FE|;Dilmen|Ugur|U|",
"chemical_list": "D016861:Cyclooxygenase Inhibitors; D000082:Acetaminophen; D007052:Ibuprofen",
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"mesh_terms": "D000082:Acetaminophen; D000284:Administration, Oral; D016861:Cyclooxygenase Inhibitors; D004374:Ductus Arteriosus, Patent; D006801:Humans; D007052:Ibuprofen; D007231:Infant, Newborn; D007234:Infant, Premature; D008026:Ligation; D011446:Prospective Studies; D014463:Ultrasonography",
"nlm_unique_id": "0375410",
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"pmid": "24359938",
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"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial.",
"title_normalized": "oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants a randomized controlled trial"
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"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP017012",
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"abstract": "Patients with unresectable metastasized osteosarcoma have a poor prognosis. Current treatment options do not offer a chance to cure the disease in this situation. Despite the fact that immunotherapy has expanded its indications continuously over previous years, its use is not yet established in osteosarcoma. There is a lack of randomized controlled studies that could show a significant benefit in this rare tumor entity. So far, efficacy of immunotherapy is only reported in individual cases as well as in mouse models. To predict a response to immunotherapy, testing for programmed death-ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB) can be useful, but status is not yet clear for most cancer entities.\nSingle case study and review of the literature.\nThis report presents the case of a 37-year-old patient with metastatic advanced osteosarcoma, who had no more established options for tumor treatment left. PD-L1 expression in the most recent tumor sample was high (tumor proportion score (TPS) 90%, combined positive score (CPS) 92%) but no MSI could be detected. In an individual therapy attempt, an ongoing and profound remission of all tumor manifestations due to four cycles of immunotherapy with ipilimumab and nivolumab was reached. Despite discontinuation of immunotherapy for 3 months due to therapy-related pneumonitis, remission of all tumor manifestations was ongoing, and no detectable relapse in restaging before onset of Nivolumab-maintenance could be observed.\nThe present case constitutes the first report of an adult patient with metastasized advanced osteosarcoma who reached a deep remission of disease by immunotherapy with ipilimumab and nivolumab, which continued even though immunotherapy had to be interrupted. To verify whether the high expression of PD-L1, as seen in this patient, is a predictive marker for response to immunotherapy in osteosarcoma, requires further investigation.",
"affiliations": "Klinik für Innere Medizin III, Universitätsklinikum Regensburg, Regensburg, Germany.;Klinik für Innere Medizin III, Universitätsklinikum Regensburg, Regensburg, Germany.;Klinik für Innere Medizin III, Universitätsklinikum Regensburg, Regensburg, Germany.;Department of Nuclear Medicine, University Medical Center Regensburg, Regensburg, Germany.;Zentrum für Neuroradiologie, Universitätsklinikum Regensburg, Regensburg, Germany.;Klinik für Innere Medizin III, Universitätsklinikum Regensburg, Regensburg, Germany.",
"authors": "Sterz|Ulrich|U|;Grube|Matthias|M|;Herr|Wolfgang|W|;Menhart|Karin|K|;Wendl|Christina|C|;Vogelhuber|Martin|M|",
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"doi": "10.3389/fonc.2021.684733",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.684733\nOncology\nCase Report\nCase Report: Dual Checkpoint Inhibition in Advanced Metastatic Osteosarcoma Results in Remission of All Tumor Manifestations—A Report of a Stunning Success in a 37-Year-Old Patient\nSterz Ulrich 1 *\n\nGrube Matthias 1\nHerr Wolfgang 1\nMenhart Karin 2\n\nWendl Christina 3\n\nVogelhuber Martin 1\n\n1Klinik für Innere Medizin III, Universitätsklinikum Regensburg, Regensburg, Germany\n2Department of Nuclear Medicine, University Medical Center Regensburg, Regensburg, Germany\n3Zentrum für Neuroradiologie, Universitätsklinikum Regensburg, Regensburg, Germany\nEdited by: Eyad Elkord, University of Salford, United Kingdom\n\nReviewed by: Simon Heeke, University of Texas MD Anderson Cancer Center, United States; Scott Moerdler, Rutgers Cancer Institute of New Jersey, United States\n\n*Correspondence: Ulrich Sterz, ulrich.sterz@ukr.de\nThis article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology\n\n06 8 2021\n2021\n11 68473323 3 2021\n12 7 2021\nCopyright © 2021 Sterz, Grube, Herr, Menhart, Wendl and Vogelhuber\n2021\nSterz, Grube, Herr, Menhart, Wendl and Vogelhuber\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground\n\nPatients with unresectable metastasized osteosarcoma have a poor prognosis. Current treatment options do not offer a chance to cure the disease in this situation. Despite the fact that immunotherapy has expanded its indications continuously over previous years, its use is not yet established in osteosarcoma. There is a lack of randomized controlled studies that could show a significant benefit in this rare tumor entity. So far, efficacy of immunotherapy is only reported in individual cases as well as in mouse models. To predict a response to immunotherapy, testing for programmed death-ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB) can be useful, but status is not yet clear for most cancer entities.\n\nMethods\n\nSingle case study and review of the literature.\n\nCase Presentation\n\nThis report presents the case of a 37-year-old patient with metastatic advanced osteosarcoma, who had no more established options for tumor treatment left. PD-L1 expression in the most recent tumor sample was high (tumor proportion score (TPS) 90%, combined positive score (CPS) 92%) but no MSI could be detected. In an individual therapy attempt, an ongoing and profound remission of all tumor manifestations due to four cycles of immunotherapy with ipilimumab and nivolumab was reached. Despite discontinuation of immunotherapy for 3 months due to therapy-related pneumonitis, remission of all tumor manifestations was ongoing, and no detectable relapse in restaging before onset of Nivolumab-maintenance could be observed.\n\nConclusion\n\nThe present case constitutes the first report of an adult patient with metastasized advanced osteosarcoma who reached a deep remission of disease by immunotherapy with ipilimumab and nivolumab, which continued even though immunotherapy had to be interrupted. To verify whether the high expression of PD-L1, as seen in this patient, is a predictive marker for response to immunotherapy in osteosarcoma, requires further investigation.\n\nimmunotherapy\nosteosarcoma\nnivolumab\nipilimumab\ndual checkpoint inhibition\n==== Body\nIntroduction\n\nOsteosarcomas are rare malignant tumors of mesenchymal origin in the bone, which occur mostly in children and adolescents younger than 20 years but are also found in adults with a second peak after the age of 65 years (1). Standard treatment includes surgery framed by neoadjuvant and adjuvant chemotherapy. Commonly used agents are methotrexate (MTX), doxorubicin, cisplatin (MAP). Alternative agents are etoposide and ifosfamide (2). If all tumor manifestations can be resected, cure of the patient can be achieved, and the 5-year OS is 54% (3).\n\nIn recurrent disease, prognosis depends on the resectability of all tumor manifestations. If complete resection is also feasible in second or third relapse, cure can still be achieved. Local relapse is more favorable than recurrence in lung or other sites. Also, good histological response to pre-operative chemotherapy correlates with a more favorable outcome in recurrence (3).\n\nHowever, patients with unresectable metastases have a poor prognosis, and there is no established treatment to achieve cure at this stage (4).\n\nIn advanced metastatic osteosarcoma, therapy with checkpoint inhibitors has not been established so far. In 2017, Tawbi et al. published the results of a multicenter phase 2 trial in which patients with advanced bone and soft tissue sarcomas were treated with pembrolizumab (5). Of the 22 patients with osteosarcoma, only one reached an objective response. In another multicenter phase 2 study, 85 heavily pretreated adult patients with various kinds of sarcoma received either a monotherapy with nivolumab or a combination therapy with nivolumab and ipilimumab. In the nivolumab plus ipilimumab group, six patients (16%) had a confirmed response to the immunotherapy, whereas in the nivolumab group, only two (5%) had a confirmed response (6).\n\nA case report of a patient with advanced osteosarcoma who reached disease-control after immunotherapy with a combination of ipilimumab and nivolumab can be found in the literature (7).\n\nSide effects of immunotherapy are frequent autoimmune phenomena of various severity, such as pneumonitis, hepatitis, or myositis (8). In the treatment of melanoma, side effects more often occur in combination therapy with CTLA-4 and PD1/PD-L1 inhibition compared with single-agent use (9). If side effects occur, discontinuation of immunotherapy and treatment with corticosteroids is required in many cases (10).\n\nCase Presentation\n\nThe present case reports a 37-year-old man suffering from metastatic osteosarcoma originating in the distal part of the left femur. In March 2018, the patient entered the hospital with pain in the left leg as the major symptom. An MRI scan showed a large tumor with extramedullary parts and an intraosseous diameter of 13 cm. The histological examination of the biopsy showed a mostly epithelioid, in part osteoblastic, high-grade osteosarcoma. In the CT scans of the thorax and abdomen, there was no metastasis detectable. Before surgery, the patient was treated with a neoadjuvant regimen analog to the EURAMOS-1 trial (11) with two cycles of doxorubicin and cisplatin and four cycles of high-dose MTX. In the intermediate staging performed by a further CT scan before surgical resection of the tumor, there was still no sign of distant metastasis. In the restaging-MRI of the left thigh the tumor showed a decrease in size. Limb saving surgical resection of the entire tumor (R0) was performed in August 2018. The tumor showed regression with 30% vital tumor cells (grade IV Salzer-Kutschnik).\n\nSurgery was followed by an adjuvant chemotherapy analog to the EURAMOS-1-protocol containing two cycles of doxorubicin and cisplatin, two further cycles of Doxorubicin and eight cycles of high-dose MTX. The start of adjuvant chemotherapy was delayed for two weeks because of a wound infection.\n\nThe final staging after the last chemotherapy cycle showed two new pulmonary metastases in the CT scan of the lung. Hence, curatively intended surgical resection was performed in April 2019.\n\nIn September 2019, the patient had a seizure and in an MRI of the brain multiple cerebral metastases became visible. A neurosurgical resection of a symptomatic metastasis was performed, followed by a total brain irradiation with a boost on parafalcial and occipital metastases.\n\nIn a systemic restaging performed by a total body FDG-PET-CT scan and an MRI of the brain, the patient then showed a rapid systemic disease-progression with metastases affecting the lung, the mediastinum, the left adrenal gland, the brain, soft tissue, bones, and the skin. (Figures 1A, 2A, 3A)\n\nFigure 1 MRI showing cerebral metastasis before (A), after three month (B) and after one year (C) of double check point inhibition with ipilimumab and nivolumab.\n\nFigure 2 FDG-PET-CT showing systemic metastasis before (A), after three months (B), and after one year (C) of double check point inhibition with ipilimumab and nivolumab.\n\nFigure 3 Tumor lesions before (A) and after 3 months (B) of double checkpoint inhibition with ipilimumab and nivolumab.\n\nIn a molecular testing of the most recent tissue sample of the resected brain metastases, the tumor showed a high expression of PD-L1 (TPS 90% CPS 92%) but microsatellite stability (MSS). The patient was still in a good performance state (ECOG 1). A salvage chemotherapy containing the in osteosarcoma therapy established drugs ifosfamide and etoposide was not performed because of an acute kidney failure in the patient’s history and a high amount of cumulative neurotoxicity after the total brain irradiation. Benefit-risk ratio was not considered being favorable for this option. Referring to the case of a patient with advanced osteosarcoma reported by Nuytemans et al. (7), who reached a stabilization of disease-progression undergoing immunotherapy with nivolumab and ipilimumab, an individual therapy attempt with the same treatment combination was conducted, as there was no further established therapy and no ongoing study available.\n\nStarting in December 2019, we exposed the patient to the immunotherapy combination of Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg every 3 weeks for four times analog to the established treatment protocol for kidney cancer. In the following restaging performed by a PET-CT scan and an MRI of the brain 3 months after starting the therapy, the patient showed a clear response to the therapy with a profound remission of all tumor lesions (Figures 1B, 2B, 3B). In some of the lesions, a minimally elevated uptake of FDG remained residually, whereas the lesions were not metrically measurable any more in the corresponding CT scan. In brain MRIs, minimal residual structures were interpreted as gliosis after total brain irradiation and immunotherapy. A definite distinction between inflammation or scar and minimal tumor residuals was not possible in PET-CT scans and MRIs.\n\nIn February 2020, the patient suffered from herpes zoster as a complication, which was treated with brivudine for 7 days.\n\nThe patient developed a mild facial palsy of the right side in March 2020, which can be considered as a side effect of the immunotherapy. In an examination of the cerebrospinal fluid, a slightly increased cell count of 9/nl could be detected but no signs of VZV encephalitis or meningeosis carcinomatosa, respectively.\n\nIn March 2020, the patient developed an immunotherapy-related pneumonitis with clinically mild symptoms but clear correlations in CT scans of the lung (Figure 4A) and noticeably reduced diffusion capacity in a subsequent lung-function examination. Therefore, immunotherapy had to be discontinued, and nivolumab maintenance could not be started according to protocol.\n\nFigure 4 (A) immunotherapy related pneumonitis after four cycles of ipilimumab and nivolumab. (B) regression of pneumonitis after discontinuation of immunotherapy and immunosuppressive treatment with tapered prednisolone.\n\nFor treatment of pneumonitis, the patient received prednisolone with an initial dose of 50 mg per day (0.5 mg/kg). Because of decreasing signs of pneumonitis in control CT scans (Figure 4B) and an improving diffusion capacity in lung function, prednisolone could be quickly tapered to 7.5 mg, and re-exposure to nivolumab was feasible in June 2020. In the actual PET-CT scan and MRI of the brain, the patient still showed a profound remission of all tumor lesions, and there was no detectable sign of a relapse (Figures 1C, 2C). Currently, prednisolone is completely tapered, and the patient undergoes nivolumab maintenance (240mg) every 2 weeks. The performance state has further improved, and the patient is starting reintegration into work.\n\nFigure 5 outlines the patient’s history.\n\nFigure 5 Timeline of the patients' history.\n\nDiscussion\n\nIn metastatic osteosarcoma, prognosis for patients is very poor if surgical resection of all metastases is not possible (4). Standard treatment with chemotherapy often provides only little benefit with a high frequency of side effects reducing the patient’s quality of life. Radiotherapy has its place only in individual cases for local tumor control. Other treatments like therapies with different agents targeting various cellular signaling pathways are still in evaluation (12).\n\nApproaches using immunotherapy already started in the 1970s. Although the use of interferon showed no benefit in the EURAMOS-1-trial (11), Mifamurtide showed a benefit in nonmetastatic osteosarcoma in combination with adjuvant chemotherapy (12). It is thought to be tumoricidal via activation of macrophages and monocytes. So far, the use of checkpoint inhibition is not an established treatment option in osteosarcoma. A phase 2 trial by Tawbi et al. treating patients with osteosarcoma with pembrolizumab showed almost no benefit (5). In addition, a pediatric phase 1/2 study testing efficacy of nivolumab in children and young adults showed no benefit in young patients with solid tumors, including osteosarcoma as well (13). A phase 1 study by Merchant, Wright et al. of Ipilimumab in pediatric patients with solid tumors, also including osteosarcoma, did not even show a partial remissions in this cohort (14). In contrast to the aforementioned results, another phase 2 trial by D’Angelo et al. in patients with mixed types of sarcomas showed a response to a combined immunotherapy with nivolumab and ipilimumab in 16% of the patients (6). Single-agent immunotherapys seems to have a limited efficacy, whereas combined immunotherapy in some patients with sarcomas leads to objective responses.\n\nPositive predictive markers for the efficacy of immunotherapy in solid tumors, for instance PD-L1 expression in tumor and tumor environment, MSI or TMB are established, but significance is not yet clear for most entities (15). Significance of PD-L1 expression is best proven in non-small-cell lung cancer (NSCLC) and melanoma, but in a lot of other entities predictive value remains doubtful (16). In the present case, expression of PD-L1 in tumor cells (TPS), also in combination with surrounding immune cells (CPS), was high with 90% and 92%, respectively, but MSI, another positive predictive marker for success in immunotherapy in solid tumors (17, 18) was not detectable, even though it is seen in about 50% of skeletal sarcomas (19).\n\nAs a salvage chemotherapy containing ifosfamide and etoposide was expected to have an unfavorable ratio of possible benefit and harming side effects in this patient with a history of acute kidney failure and a high cumulative neurotoxicity, this option was not considered. Analog to the similar reported case, treatment with ipilimumab and nivolumab was chosen as it is established for treatment of metastasized RCC (20,) (7). For this combination, there also exists preclinical evidence concerning the efficacy against metastatic osteosarcoma in mouse model (21) and objective responses were observed in sarcoma patients (6).\n\nAutoimmune diseases are a common side effect of immunotherapies. In double check point inhibition blocking, CTLA-4 and PD-1 severe side effects occur more frequently compared with monotherapy with a PD-1-agent (9). In the reported case the patient suffered from two probable side effects, i.e., facial palsy and pneumonitis. Standard treatment of autoimmune side effects is corticosteroids and discontinuation of immunotherapy (10), which were both done in this case. Despite of discontinuation of immunotherapy and immunosuppression with corticosteroids an ongoing anti-tumor effect was observed. Nevertheless, nivolumab maintenance was initiated after controlling side effects as in patients with melanoma resuming single-agent PD1/PD-L1-inhibition is described as feasible after toxicity in CTLA-4 and PD-L1 combination (22).\n\nThe fact that the reason for the exceptional good response to the combined immunotherapy in this patient remains unclarified constitutes the main limitation of the significance of this case report for the treatment of other patients with metastatic osteosarcoma. Hence, it currently does not seem possible to predict whether patients in similar situations would benefit from combined immunotherapy.\n\nConclusion\n\nThe present case constitutes an encouraging example of a patient with advanced metastasized osteosarcoma who reached a persistent remission of all tumor lesions undergoing an immunotherapy with ipilimumab and nivolumab by analogy with the treatment protocol for advanced RCC. Immunotherapy is currently not established in osteosarcoma and efficacy of dual checkpoint inhibition in osteosarcoma has only been shown in mouse model so far (21) and has been observed in some patients with mixed types of sarcoma (6). This is the first reported case in which the patient reached a profound remission of all known tumor manifestations in metastasized osteosarcoma upon immune checkpoint inhibition. The ongoing anti-tumor-effect despite required therapy discontinuation and tapered immunosuppression with prednisolone for three months is unexpected but is indicative of a durable efficacy of immunotherapy in this patient. High PD-L1 expression of tumor cells in this case and these results of immunotherapy suggest a predictive value of PD-L1 expression but to prove this hypothesis, further research in this area is needed. The main limitation is that at the moment a predication of a response to combined immunotherapy in similar patients appears not to be possible.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.\n\nAuthor Contributions\n\nUS and MV were responsible for treatment of the patient. KM was responsible for interpretation of PET scans. CW was responsible for interpretation of CT and MRI scans. US wrote the first draft of the manuscript. MG and WH wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nOpen access publication fees paid by Universität Regensburg.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAbbreviations\n\nCT scan, computed tomography scan; CPS, combined positive score; CTLA-4, cytotoxic T-lymphocyte-associated Protein 4; ECOG, Eastern Cooperative Oncology Group; EURAMOS, European and American osteosarcoma study group; FDG 18F-Fluordesoxyglucose; MRI, magnetic resonance imaging; MSI, microsatellite instability; MSS, microsatellite stability; MTX, methotrexate; OS, overall survival; PD-L1, programmed death-ligand 1; PET, positron emission tomography; RCC, renal cell carcinoma; TMB, tumor mutational burden; TPS, tumor proportion score; VZV, varicella zoster virus.\n==== Refs\nReferences\n\n1 Mirabello L Troisi RJ Savage SA . Osteosarcoma Incidence and Survival Rates From 1973 to 2004: Data From the Surveillance, Epidemiology, and End Results Program. Cancer (2009) 115 (7) :1531–43. 10.1002/cncr.24121\n2 Whelan JS Davis LE . Osteosarcoma, Chondrosarcoma, and Chordoma. J Clin Oncol (2018) 36 (2 ):188–93. 10.1200/JCO.2017.75.1743\n3 Gelderblom H Jinks RC Sydes M Bramwell VH van Glabbeke M Grimer RJ . Survival After Recurrent Osteosarcoma: Data From 3 European Osteosarcoma Intergroup (EOI) Randomized Controlled Trials. Eur J Cancer (Oxford Engl 1990) (2011) 47 (6 ):895–902. 10.1016/j.ejca.2010.11.036\n4 Ferrari S Briccoli A Mercuri M Bertoni F Picci P Tienghi A . Postrelapse Survival in Osteosarcoma of the Extremities: Prognostic Factors for Long-Term Survival. J Clin Oncol Off J Am Soc Clin Oncol (2003) 21 (4 ):710–5. 10.1200/JCO.2003.03.141\n5 Tawbi HA Burgess M Bolejack V van Tine BA Schuetze SM Hu J . Pembrolizumab in Advanced Soft-Tissue Sarcoma and Bone Sarcoma (SARC028): A Multicentre, Two-Cohort, Single-Arm, Open-Label, Phase 2 Trial. Lancet Oncol (2017) 18 (11 ):1493–501. 10.1016/S1470-2045(17)30624-1\n6 D’Angelo SP Mahoney MR van Tine BA Atkins J Milhem MM Jahagirdar BN . Nivolumab With or Without Ipilimumab Treatment for Metastatic Sarcoma (Alliance A091401): Two Open-Label, Non-Comparative, Randomised, Phase 2 Trials. Lancet Oncol (2018) 19 (3 ):416–26. 10.1016/S1470-2045(18)30006-8\n7 Nuytemans L Sys G Creytens D Lapeire L . NGS-Analysis to the Rescue: Dual Checkpoint Inhibition in Metastatic Osteosarcoma - A Case Report and Review of the Literature. Acta Clin Belgica (2019) 76 (2 ):1–6. 10.1080/17843286.2019.1683129\n8 Naidoo J Page DB Li BT Connell LC Schindler K Lacouture ME . Toxicities of the Anti-PD-1 and Anti-PD-L1 Immune Checkpoint Antibodies. Ann Oncol Off J Eur Soc Med Oncol (2015) 26 (12 ):2375–91. 10.1093/annonc/mdv383\n9 Larkin J Chiarion-Sileni V Gonzalez R Connell LC Schindler K Lacouture ME . Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med (2015) 373 (1 ):23–34. 10.1056/NEJMoa1504030 26027431\n10 Puzanov I Diab A Abdallah K Bingham CO Brogdon C Dadu R . Managing Toxicities Associated With Immune Checkpoint Inhibitors: Consensus Recommendations From the Society for Immunotherapy of Cancer (Sitc) Toxicity Management Working Group. J ImmunoTher Cancer (2017) 5 :95. 10.1186/s40425-017-0300-z 29162153\n11 Bielack SS Smeland S Whelan JS Marina N Jovic G Hook JM . Methotrexate, Doxorubicin, and Cisplatin (Map) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative Map: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial. J Clin Oncol (2015) 33 (20 ):2279–87. 10.1200/JCO.2014.60.0734\n12 Lilienthal I Herold N . Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies. Int J Mol Sci (2020) 21 (18 ):6885. 10.3390/ijms21186885\n13 Davis KL Fox E Merchant MS Marina N Jovic G Hook JM . Nivolumab in Children and Young Adults With Relapsed or Refractory Solid Tumours or Lymphoma (ADVL1412): A Multicentre, Open-Label, Single-Arm, Phase 1–2 Trial. Lancet Oncol (2020) 21 (4 ):541–50. 10.1016/S1470-2045(20)30023-1\n14 Merchant MS Wright M Baird K Wexler LH Rodriguez-Galindo C Bernstein D . Phase I Clinical Trial of Ipilimumab in Pediatric Patients With Advanced Solid Tumors. Clin Cancer Res An Off J Am Assoc Cancer Res (2016) 22 (6 ):1364–70. 10.1158/1078-0432.CCR-15-0491\n15 Shen H Yang ES-H Conry M Wexler LH Rodriguez-Galindo C Bernstein D . Predictive Biomarkers for Immune Checkpoint Blockade and Opportunities for Combination Therapies. Genes Dis (2019) 6 (3 ):232–46. 10.1016/j.gendis.2019.06.006\n16 Gibney GT Weiner LM Atkins MB . Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy. Lancet Oncol (2016) 17 (12 ):e542–51. 10.1016/S1470-2045(16)30406-5\n17 Le DT Uram JN Wang H Bartlett BR Kemberling H Eyring AD . Pd-1 Blockade in Tumors With Mismatch-Repair Deficiency. New Engl J Med (2015) 372 (26 ):2509–20. 10.1056/NEJMoa1500596\n18 Le DT Durham JN Smith KN Wang H Bartlett BR Aulakh LK . Mismatch Repair Deficiency Predicts Response of Solid Tumors to PD-1 Blockade. Science (2017) 357 (6349 ):409–13. 10.1126/science.aan6733\n19 Martin SS Hurt WG Hedges LK . Microsatellite Instability in Sarcomas. Ann Surg Oncol (1998) 5 (4 ):356–60. 10.1007/BF02303500\n20 Motzer RJ Tannir NM McDermott DF Arén Frontera O Melichar B Choueiri TK . Nivolumab Plus Ipilimumab Versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med (2018) 378 (14 ):1277–90. 10.1056/NEJMoa1712126\n21 Lussier DM Johnson JL Hingorani P Blattman JN . Combination Immunotherapy With α-CTLA-4 and α-PD-L1 Antibody Blockade Prevents Immune Escape and Leads to Complete Control of Metastatic Osteosarcoma. J ImmunoTher Cancer (2015) 3 (1 ):21. 10.1186/s40425-015-0067-z 25992292\n22 Pollack MH Betof A Dearden H Rapazzo K Valentine I Brohl AS . Safety of Resuming anti-PD-1 in Patients With Immune-Related Adverse Events (irAEs) During Combined Anti-CTLA-4 and Anti-PD1 in Metastatic Melanoma. Ann Oncol (2018) 29 (1 ):250–5. 10.1093/annonc/mdx642\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "dual checkpoint inhibition; immunotherapy; ipilimumab; nivolumab; osteosarcoma",
"medline_ta": "Front Oncol",
"mesh_terms": null,
"nlm_unique_id": "101568867",
"other_id": null,
"pages": "684733",
"pmc": null,
"pmid": "34422638",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "27924752;28988646;21216138;29370992;32192573;19197972;31635553;29562145;29220289;25992292;26371282;29045547;29162153;26027431;32042863;12586810;26028255;26033801;9641458;26534966;32961800;28596308",
"title": "Case Report: Dual Checkpoint Inhibition in Advanced Metastatic Osteosarcoma Results in Remission of All Tumor Manifestations-A Report of a Stunning Success in a 37-Year-Old Patient.",
"title_normalized": "case report dual checkpoint inhibition in advanced metastatic osteosarcoma results in remission of all tumor manifestations a report of a stunning success in a 37 year old patient"
} | [
{
"companynumb": "DE-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-086532",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Rituximab treatment may cause or exacerbate Kaposi's sarcoma (KS) in patients with human immunodeficiency virus (HIV)-associated multicentric Castleman's disease. Despite the widespread use of rituximab, rituximab-induced KS has not yet been reported in HIV-negative patients with diffuse large B cell lymphoma (DLBCL). We herein report a case of KS that developed after undergoing rituximab-containing chemotherapy in an HIV-negative patient with DLBCL. An 84-year-old man who received rituximab-containing chemotherapy for the treatment of DLBCL developed severe infection, and subsequently KS. Our observations indicate that serious infections under rituximab treatment may trigger KS. KS should therefore be considered when skin tumors appear in lymphoma patients receiving rituximab-containing chemotherapy.",
"affiliations": "Department of Internal Medicine, Karatsu Red Cross Hospital, Japan.",
"authors": "Ureshino|Hiroshi|H|;Ando|Toshihiko|T|;Kojima|Kensuke|K|;Itamura|Hidekazu|H|;Jinnai|Shunichi|S|;Doi|Kazuko|K|;Ohshima|Koichi|K|;Kurogi|Kazuya|K|;Miyahara|Masaharu|M|;Kimura|Shinya|S|",
"chemical_list": "D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.5103",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(24)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D011239:Prednisolone; D000069283:Rituximab; D012514:Sarcoma, Kaposi; D012878:Skin Neoplasms; D014750:Vincristine",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3205-8",
"pmc": null,
"pmid": "26666614",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rituximab-containing Chemotherapy (R-CHOP)-induced Kaposi's Sarcoma in an HIV-negative Patient with Diffuse Large B Cell Lymphoma.",
"title_normalized": "rituximab containing chemotherapy r chop induced kaposi s sarcoma in an hiv negative patient with diffuse large b cell lymphoma"
} | [
{
"companynumb": "JP-ACTAVIS-2015-28983",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report on the clinical course of ocular and extraocular involvement in a multidrug-resistant patient with Behçet's disease (BD).\n\n\nMETHODS\nA 22-year-old male with BD (bilateral panuveitis and retinal vasculitis, oral ulcers, erythema nodosum, arthralgia, epididymitis) was followed-up from 1999 to 2014. He was treated continuously with corticosteroids in combination with different immunosuppressive therapies (cyclosporine, azathioprine, methotrexate, interferon, infliximab, mycophenolate), which exerted numerous side-effects such as nephrotoxicity, nephrolithiasis, increase of liver enzymes, severe depression with suicidal ideation, severe leucopenia, pulmonary tuberculosis, pulmonary legionellosis, recurrent bronchopneumonia.\n\n\nRESULTS\nDespite immunosuppressive and corticosteroid therapies, the patient showed multiple relapses of uveitis and systemic BD lesions and developed severe osteoporosis with multiple vertebral fractures, bilateral cataracts and steroid-associated glaucoma until 2007. Since then he has been treated with prednisone alone, currently at low dosage, remaining free from uveitis and systemic symptoms. His final visual acuity is 9/10 in the right eye and counting fingers in the left one.\n\n\nCONCLUSIONS\nBD patients are usually responsive to immunosuppressive drugs. The possibility of a multi-drug resistance as well as of multiple drug-related side effects cannot be disregarded and continuous therapy should be given in order to preserve a useful visual acuity until the disease, either spontaneously or drug-induced, runs into remission.",
"affiliations": "Centro di Riferimento Regionale Malattia di Behçet, Azienda Policlinico Umberto I, \"Sapienza\" Università di Roma, Rome, Italy. massimo.accorinti@tiscali.it.;Centro di Riferimento Regionale Malattia di Behçet, Azienda Policlinico Umberto I, \"Sapienza\" Università di Roma, Rome, Italy.;Centro di Riferimento Regionale Malattia di Behçet, Azienda Policlinico Umberto I, \"Sapienza\" Università di Roma, Rome, Italy.;Dipartimento di Reumatologia, \"Sapienza\" Università di Roma, Rome, Italy.;Centro di Riferimento Regionale Malattia di Behçet, Azienda Policlinico Umberto I, \"Sapienza\" Università di Roma, Rome, Italy.",
"authors": "Accorinti|Massimo|M|;Pesci|Francesca Romana|FR|;Pirraglia|Maria Pia|MP|;Priori|Roberta|R|;Pivetti-Pezzi|Paola|P|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "33(6 Suppl 94)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D001528:Behcet Syndrome; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D012008:Recurrence; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "S141-4",
"pmc": null,
"pmid": "25962416",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multi-drug resistance and side-effects in a patient with Behçet's disease.",
"title_normalized": "multi drug resistance and side effects in a patient with beh et s disease"
} | [
{
"companynumb": "PHHY2011IT20447",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
"dru... |
{
"abstract": "A 58 year-old woman with type 2 diabetes diagnosed 3 years before came to our clinic. Her treatment was metformin 850 mg every 12 hours and glimepiride 4 mg every 24 hours. After the initiation of glimepiride 9 months before her weight has increased 5 kg, and she suffers frequent hypoglycemias which have affected her while driving. Her BMI is 35.5 kg/m². She has a normal eye fund exam. She has hypertension treated with telmisartán and hidroclorotiazide with adequate control, and also hypercholesterolemia treated with atorvastatine 40 mg every 24 hours. Her blood test shows an HbA1c of 7.0%, normal values of microalbuminuria, total cholesterol 149 mg/dl, HDL cholesterol 52 mg/dl, LDL cholesterol 98 mg/dl and triglycerides 123 mg/dl. Her blood pressure is 129/81 mmHg, there was no orthostatic hypotension, and her peripheral neurological examination shows normal results. In summary, our case is a young woman with type 2 diabetes and obesity, without chronic complications and which has frequent hypoglycaemia. How must this woman be evaluated and treated?",
"affiliations": "Unidad de Endocrinología, Hospital General Universitario Rafael Méndez, Lorca, Murcia, España; Servicio de Endocrinología, Clínica San Pedro, Almería, España.;Unidad de Endocrinología, Nutrición y Riesgo Vascular, Complejo Hospitalario Torrecárdenas, Almería, España; Servicio de Endocrinología, Clínica San Pedro, Almería, España. Electronic address: pmr.csp@gmail.com.",
"authors": "Reyes García|R|R|;Mezquita Raya|P|P|",
"chemical_list": "D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C057619:glimepiride; D008687:Metformin",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2254-8874",
"issue": "214(4)",
"journal": "Revista clinica espanola",
"keywords": "Antidiabetics; Antidiabéticos; Diabetes tipo 2; Hipoglucemia; Hipoglycemia; Type 2 diabetes",
"medline_ta": "Rev Clin Esp (Barc)",
"mesh_terms": "D000924:Anticholesteremic Agents; D000959:Antihypertensive Agents; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia; D006973:Hypertension; D007003:Hypoglycemia; D007004:Hypoglycemic Agents; D008687:Metformin; D008875:Middle Aged; D013453:Sulfonylurea Compounds",
"nlm_unique_id": "101632437",
"other_id": null,
"pages": "202-8",
"pmc": null,
"pmid": "24468002",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "How to prevent and treat pharmacological hypoglycemias.",
"title_normalized": "how to prevent and treat pharmacological hypoglycemias"
} | [
{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2015-01457",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"... |
{
"abstract": "Extracorporeal membrane oxygenation (ECMO) is an established therapy for primary graft dysfunction (PGD) in adults after lung transplant, while venovenous (VV) ECMO is an evolving therapy that can bridge patients to lung transplantation. This report describes a case of relatively quick improvement of grade 3 PGD, based on the PaO2/FIO2 (P/F) ratio, in a 17-year-old patient with cystic fibrosis who was bridged to lung transplantation with ambulatory VV ECMO and then received support with VV ECMO as a protective strategy during the initial phases of PGD after lung transplantation.",
"affiliations": "Department of Pediatrics, The Ohio State University College of Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA, hayes.705@osu.edu.",
"authors": "Hayes|Don|D|;Galantowicz|Mark|M|;Yates|Andrew R|AR|;Preston|Thomas J|TJ|;Mansour|Heidi M|HM|;McConnell|Patrick I|PI|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s10047-013-0699-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1434-7229",
"issue": "16(3)",
"journal": "Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs",
"keywords": null,
"medline_ta": "J Artif Organs",
"mesh_terms": "D000293:Adolescent; D003550:Cystic Fibrosis; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006801:Humans; D016040:Lung Transplantation; D055031:Primary Graft Dysfunction; D016896:Treatment Outcome",
"nlm_unique_id": "9815648",
"other_id": null,
"pages": "382-5",
"pmc": null,
"pmid": "23508264",
"pubdate": "2013-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17403473;22035707;14525601;10892906;16515929;14555551;16210116;20219215;11404168;17449416;15653978;16210119;21765353;20381081;9674447;21962264",
"title": "Venovenous ECMO as a bridge to lung transplant and a protective strategy for subsequent primary graft dysfunction.",
"title_normalized": "venovenous ecmo as a bridge to lung transplant and a protective strategy for subsequent primary graft dysfunction"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-292532",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drug... |
{
"abstract": "Diclofenac is a widely used analgesic so that exposure during pregnancy may frequently occur. Most publications have evaluated the safety of NSAIDs on pregnancy outcome as a group of substances. Specific data on diclofenac are rare. This observational cohort study used the German Embryotox pharmacovigilance database to assess the risk of major birth defects and spontaneous abortion after first trimester exposure to diclofenac. A group of 260 women who took diclofenac during first trimester was compared to 778 non-exposed pregnancies. In the diclofenac exposed cohort 4 major birth defects were observed among 220 live-born infants and 25 spontaneous abortions occurred. Neither the rate of major birth defects (1.8% vs. 3.1%; OR adjusted 0.59; 95% CI 0.17-2.08) nor the risk of spontaneous abortion (HR adjusted 0.90; 95% CI 0.56-1.46) was increased. The study results do not indicate that diclofenac exposure during first trimester is associated with a teratogenic risk.",
"affiliations": "Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Augustenburger Platz 1, 13353, Berlin, Germany. Electronic address: stephanie.padberg@charite.de.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Augustenburger Platz 1, 13353, Berlin, Germany. Electronic address: tatjana.tissen-diabate@charite.de.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Augustenburger Platz 1, 13353, Berlin, Germany. Electronic address: katarina.dathe@charite.de.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Augustenburger Platz 1, 13353, Berlin, Germany. Electronic address: stefanie.hultzsch@charite.de.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Augustenburger Platz 1, 13353, Berlin, Germany. Electronic address: katja.meixner@charite.de.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Augustenburger Platz 1, 13353, Berlin, Germany. Electronic address: verena.linsenmeier@charite.de.;Beuth Hochschule für Technik - University of Applied Sciences, Department of Mathematics, Luxemburger Straße 10, 13353, Berlin, Germany. Electronic address: meister@beuth-hochschule.de.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Clinical Pharmacology and Toxicology, Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Augustenburger Platz 1, 13353, Berlin, Germany. Electronic address: christof.schaefer@charite.de.",
"authors": "Padberg|Stephanie|S|;Tissen-Diabaté|Tatjana|T|;Dathe|Katarina|K|;Hultzsch|Stefanie|S|;Meixner|Katja|K|;Linsenmeier|Verena|V|;Meister|Reinhard|R|;Schaefer|Christof|C|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac",
"country": "United States",
"delete": false,
"doi": "10.1016/j.reprotox.2018.02.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "77()",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": "Birth defect; Diclofenac; Non-steroidal anti-inflammatory drug (NSAID); Pregnancy outcome; Spontaneous abortion",
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000013:Congenital Abnormalities; D004008:Diclofenac; D005260:Female; D005858:Germany; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008431:Maternal-Fetal Exchange; D060735:Pharmacovigilance; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D011446:Prospective Studies",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "122-129",
"pmc": null,
"pmid": "29477808",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Safety of diclofenac use during early pregnancy: A prospective observational cohort study.",
"title_normalized": "safety of diclofenac use during early pregnancy a prospective observational cohort study"
} | [
{
"companynumb": "PHHY2018DE062358",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": null,
"drug... |
{
"abstract": "Therapy for the inflammatory bowel diseases increasingly includes the use of immune-modifying and biologic therapies. Recently, in young patients with IBD, an association has been noted between the use of infliximab along with concomitant purine analogues and the development of hepatosplenic T-cell lymphoma (HSTCL)-a rare and all but incurable form of non-Hodgkin's lymphoma. This report briefly reviews the issue of lymphoma and IBD therapy. Additionally, a description of HSTCL and a summary of the known cases of this apparent therapeutic complication are presented. Clinical options in light of this new information are explored.",
"affiliations": "Goryeb Children's Hospital/Atlantic Health, Morristown, New Jersey, USA. joel.rosh@atlantichealth.org",
"authors": "Rosh|Joel R|JR|;Gross|Thomas|T|;Mamula|Petar|P|;Griffiths|Anne|A|;Hyams|Jeffrey|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1002/ibd.20169",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0998",
"issue": "13(8)",
"journal": "Inflammatory bowel diseases",
"keywords": null,
"medline_ta": "Inflamm Bowel Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal; D002648:Child; D003424:Crohn Disease; D005260:Female; D006801:Humans; D000069285:Infliximab; D008113:Liver Neoplasms; D016399:Lymphoma, T-Cell; D008297:Male; D013160:Splenic Neoplasms",
"nlm_unique_id": "9508162",
"other_id": null,
"pages": "1024-30",
"pmc": null,
"pmid": "17480018",
"pubdate": "2007-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale?",
"title_normalized": "hepatosplenic t cell lymphoma in adolescents and young adults with crohn s disease a cautionary tale"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-123792",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"dru... |
{
"abstract": "An unusual case of diabetes secondary to acute pancreatitis in a boy with end-stage renal failure receiving continuous ambulatory peritoneal dialysis (CAPD) is described. A hyperglycaemic, hyperosmolar pre-coma developed, aggravated by associated hypercalcaemia. The glucose content of the dialysis fluid contributed to the hyperglycaemia, which settled as the pancreatitis resolved and lower glucose concentration dialysis fluid was used. Our experience suggests that pancreatic dysfunction should be considered where significant hyperglycaemia occurs during peritoneal dialysis.",
"affiliations": null,
"authors": "Emder|P J|PJ|;Howard|N J|NJ|;Rosenberg|A R|AR|",
"chemical_list": "D007328:Insulin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000184019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1660-8151",
"issue": "44(4)",
"journal": "Nephron",
"keywords": null,
"medline_ta": "Nephron",
"mesh_terms": "D000208:Acute Disease; D002648:Child; D003926:Diabetic Coma; D006801:Humans; D006944:Hyperglycemic Hyperosmolar Nonketotic Coma; D007328:Insulin; D007676:Kidney Failure, Chronic; D008297:Male; D010195:Pancreatitis; D010531:Peritoneal Dialysis, Continuous Ambulatory",
"nlm_unique_id": "0331777",
"other_id": null,
"pages": "355-7",
"pmc": null,
"pmid": "3540693",
"pubdate": "1986",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Non-ketotic hyperosmolar diabetic pre-coma due to pancreatitis in a boy on continuous ambulatory peritoneal dialysis.",
"title_normalized": "non ketotic hyperosmolar diabetic pre coma due to pancreatitis in a boy on continuous ambulatory peritoneal dialysis"
} | [
{
"companynumb": "AU-BAXTER-2021BAX001311",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEPHALOTHIN"
},
"drugadditional": null,
... |
{
"abstract": "Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an adverse drug reaction most commonly associated with aromatic antiepileptic agents. It is characterized by the triad of skin eruption, fever, and systemic involvement, with the latter usually manifesting as hepatitis and lymphadenopathy. Mortality is primarily due to hepatic failure and can be as high as 10%. Formerly referred to by names such as Dilantin hypersensitivity syndrome and anticonvulsant hypersensitivity syndrome, DRESS syndrome is a more precise term since this reaction pattern can be seen with other agents. DRESS syndrome has also been reported in association with sulfonamides, allopurinol, terbinafine, minocycline, azathioprine, and dapsone as well as with several antiretroviral agents such as abacavir and nevirapine. We describe a patient with HIV who developed nevirapine hypersensitivity syndrome who was successfully treated with intravenous immune globulin (IVIG).",
"affiliations": "Department of Dermatology, University of Utah, School of Medicne, Salt Lake City, UT 84132-2409, USA. katherine.fields@hsc.utah.edu",
"authors": "Fields|Katherine S|KS|;Petersen|Marta J|MJ|;Chiao|Elizabeth|E|;Tristani-Firouzi|Payam|P|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D019829:Nevirapine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "4(4)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000328:Adult; D004802:Eosinophilia; D005076:Exanthema; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D019829:Nevirapine; D013577:Syndrome",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "510-3",
"pmc": null,
"pmid": "16004028",
"pubdate": "2005",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case reports: treatment of nevirapine-associated dress syndrome with intravenous immune globulin (IVIG).",
"title_normalized": "case reports treatment of nevirapine associated dress syndrome with intravenous immune globulin ivig"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP019079",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nMultidrug-resistant Acinetobacter baumannii (MDRAB) pneumonia with severe sepsis in a patient with rheumatoid arthritis (RA), who is predisposed after treatment with tumor necrosis factor inhibitor (TNFI), is a rare severe infection and can be successfully treated with prompt antibiotics.\n\n\nMETHODS\nA 75-year-old woman was diagnosed with RA >30 years previously. After inadequate treatment responses to conventional disease-modifying antirheumatic drugs (DMARDs), she developed progressive RA, including swollen joints in both hands, and had a high disease activity score of 4.96 when presenting at our rheumatology clinic. She had started taking the TNFI, golimumab (50 mg/month), 3 years before and developed a productive cough 4 weeks before this admission. One week after admission, she developed fever, dyspnea, hypoxemia, tachycardia, and increased serum C-reactive protein level.\n\n\nMETHODS\nChest plain film (CxR) and computed tomography of the chest showed hospital-acquired pneumonia; microbial examination of the sputum showed the presence of MDRAB.\nShe was prescribed a full course of antibiotics with cefoperazone sulbactam.\n\n\nRESULTS\nCxR showed complete remission of pneumonia.\n\n\nCONCLUSIONS\nBiological DMARDs, such as TNFI, act as a double-edged sword: these drugs are used to treat autoimmune diseases, but they increase the risk of infection. The trend toward antibiotic resistance and persistent environmental survival of MDRAB is an emerging problem in countries with high rates of antibiotic abuse. TNFI may affect intestinal immunity by inducing dysbiosis, which affects T helper 17-mediated mucosal immunity and can contribute to A baumannii colonization and the development of MDRAB in frequently hospitalized patients.",
"affiliations": "Division of Rheumatology/Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei Division of Rheumatology/Immunology and Allergy, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taipei Veteran General Hospital, Taipei, Taiwan Department of Pathology, University of Washington, WA.",
"authors": "Lin|Shu-Yi|SY|;Huang|Zheng-Hao|ZH|;Chen|Hsiang-Cheng|HC|;Chang|Deh-Ming|DM|;Lu|Chun-Chi|CC|",
"chemical_list": "D000900:Anti-Bacterial Agents; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D002438:Cefoperazone; D002097:C-Reactive Protein; D013407:Sulbactam",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000011730",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30113458MD-D-18-0166810.1097/MD.0000000000011730117306900Research ArticleClinical Case ReportMultidrug-resistance Acinetobacter baumannii pneumonia in a rheumatoid arthritis patient receiving tumor necrosis factor inhibitor A case reportLin Shu-Yi BSNaHuang Zheng-Hao MDabChen Hsiang-Cheng MD PhDaChang Deh-Ming MD PhDacLu Chun-Chi MDad∗NA. a Division of Rheumatology/Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipeib Division of Rheumatology/Immunology and Allergy, Department of Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiungc Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taipei Veteran General Hospital, Taipei, Taiwand Department of Pathology, University of Washington, WA.∗ Correspondence: Chun-Chi Lu, Division of Rheumatology/Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, No. 325, Sec 2, Cheng-Gong Rd, Neihu Dist, 114, Taipei, Taiwan (e-mail: jameslutaiwan@gmail.com).8 2018 17 8 2018 97 33 e1173015 3 2018 6 7 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-nc-sa/4.0Abstract\nIntroduction:\nMultidrug-resistant Acinetobacter baumannii (MDRAB) pneumonia with severe sepsis in a patient with rheumatoid arthritis (RA), who is predisposed after treatment with tumor necrosis factor inhibitor (TNFI), is a rare severe infection and can be successfully treated with prompt antibiotics.\n\nCase presentation:\nA 75-year-old woman was diagnosed with RA >30 years previously. After inadequate treatment responses to conventional disease-modifying antirheumatic drugs (DMARDs), she developed progressive RA, including swollen joints in both hands, and had a high disease activity score of 4.96 when presenting at our rheumatology clinic. She had started taking the TNFI, golimumab (50 mg/month), 3 years before and developed a productive cough 4 weeks before this admission. One week after admission, she developed fever, dyspnea, hypoxemia, tachycardia, and increased serum C-reactive protein level.\n\nDiagnosis:\nChest plain film (CxR) and computed tomography of the chest showed hospital-acquired pneumonia; microbial examination of the sputum showed the presence of MDRAB.\n\nTherapeutics:\nShe was prescribed a full course of antibiotics with cefoperazone sulbactam.\n\nOutcomes:\nCxR showed complete remission of pneumonia.\n\nConclusion:\nBiological DMARDs, such as TNFI, act as a double-edged sword: these drugs are used to treat autoimmune diseases, but they increase the risk of infection. The trend toward antibiotic resistance and persistent environmental survival of MDRAB is an emerging problem in countries with high rates of antibiotic abuse. TNFI may affect intestinal immunity by inducing dysbiosis, which affects T helper 17–mediated mucosal immunity and can contribute to A baumannii colonization and the development of MDRAB in frequently hospitalized patients.\n\nKeywords\ndisease-modifying antirheumatic drugsmultidrug-resistance Acinetobacter baumanniirheumatoid arthritistumor necrosis factor inhibitorOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nRheumatoid arthritis (RA), a chronic inflammatory disease, is attributed to the actions of inflammatory cells and cytokines.[1,2] Patients with RA are often treated with biological disease-modifying antirheumatic drugs (bDMARDs), such as a tumor necrosis factor inhibitor (TNFI), which can decrease the risk of complications such as bone erosion and help to sustain joint function.[1] Nonetheless, bDMARDs may increase the risk of acquiring an infectious disease,[3] and TNFI slightly increases the risk of infectious diseases in patients with inflammatory bowel disease (IBD).[4] Therefore, TNFIs can act as a double-edged sword by successfully treating autoimmune diseases but at the same time increasing the risk of infection.[3]\n\nAcinetobacter baumannii (AB), a gram-negative bacterium, is commonly present in the environment and can colonize the human intestinal tract[5] and cause extensive infections, such as pneumonia, because of the patient's immunosuppressed condition.[5] Lately, multidrug-resistant AB (MDRAB) has become an emerging problem in several hospitals and health settings because of its tendency to accumulate in hospital machinery, in which it can become resistance to antibiotics and difficulty in its eradication.[5] Here, we report an unusual case of MDRAB-induced pneumonia in a patient with RA receiving a TNFI.\n\n2 Case presentation\nA 75-year-old woman with RA had been receiving conventional treatment with DMARDs, including 7 years of methotrexate (MTX), 10 years of hydroxychloroquine and prednisolone before this admission. Three years before this admission, she started taking the TNFI, golimumab (50 mg/month) in addition to MTX, hydroxychloroquine and prednisolone, because of high disease activity, including swelling and deformity of the proximal interphalangeal joints, metacarpophalangeal joints, and wrist joints on both sides, and a Disease Activity Score 28 (DAC28) of 4.96. Four weeks before this admission, she had developed a productive cough without weight loss, afternoon fever, and altered bowel habits. She visited our emergency room because of hematochezia, dizziness, nausea, vomiting, and abdominal pain. Blood sampling revealed leukopenia (white blood count, 2200/μL; absolute neutrophil count, 770/μL) and thrombocytopenia (platelet count, 29,000/μL). A chest plain film (CxR) of the chest revealed infiltration into the left lower lung and peribronchial wall thickening in the right lung. Of note, MTX had been discontinued because of bone marrow suppression, and golimumab was stopped for infection of both lungs. She received piperacillin-tazobactam for complicated pneumonia immediately after admission.\n\nOne week after admission, the patient developed fever, dyspnea, hypoxemia, tachycardia, and increased serum C-reactive protein (CRP) level. CxR showed increased interstitial and alveolar opacity in both lungs, whereas chest contrast computed tomography revealed sparse progressive consolidation in both lung fields (Fig. 1). We administered meropenem trihydrate because of suspected hospital-acquired pneumonia complicated by severe sepsis. Because of AB-A calcoaceticus complex infection, which is resistant to multiple antibiotics, including penicillin, cephalosporins, aminoglycosides, and fluoroquinolones (i.e., MDRAB), was detected in microbial examination of the sputum, the patient received a full course of cefoperazone-sulbactam. A post-treatment CxR showed resolution of consolidation, and her fever had subsided. Finally, she was discharged 3 weeks after admission. This patient experienced recurrent high disease activity of RA after discharge, including swelling and tender joints, a high DAC28, and high serum CRP and erythrocyte sedimentation rate. Infectious diseases had been excluded at the follow-up at our rheumatology clinic. Because of the previous medical history of serious adverse effects such as stomatitis and bone marrow suppression, MTX is not suitable and has not been prescribed for her. Based on treatment guideline for RA, TNFI could be resumed after total recovery from infectious diseases. Thus, the patient received half dose of golimumab to prevent reinfection of MDRAB. We have monitored and collected this patient's sputum and fecal, which did not show AB colonization.\n\nFigure 1 A high-resolution chest computed tomography scan revealed infiltration and air bronchograms in both lungs (arrow heads) and moderate pleural effusion with atelectasis of lower lobes of both lungs.\n\n3 Discussion\nRA is a chronic inflammatory disease that is characterized by joint inflammation and the devastation of cartilage and bone in multiple joints.[1,6] Inflammatory cells and cytokines, such as neutrophils, TNF-α, and interleukin-17, contribute to the synovitis and structural damage to joints.[2,7] An increased risk of infection has been reported in patients with RA.[8]\n\nTNF-α is a 26 kDa homotrimeric transmembrane protein that appears on the surface of fibroblasts, macrophages, T lymphocytes, natural killer cells, and smooth muscle cells. TNF-α is involved in the pathogenesis of autoimmune diseases, such as RA, ankylosing spondylitis, and IBD.[3] The treatment of patients with RA aims at reducing the disease activity and preventing progressive joint damage.[1] bDMARDs can reduce disease activity and delay intra-articular structural damage, especially in patients with an inadequate response to conventional DMARDs.[6] Golimumab, a human anti-TNF-α immunoglobulin G1 monoclonal antibody, is widely prescribed for patients with RA.\n\nTNFI therapy has beneficial effects on the immune system in the treatment of autoimmune diseases; however, TNF-α plays a major role in controlling infections by regulating the immune system.[8] Specifically, TNF-α released from macrophages plays an important role in the maintenance and formation of granulation tissue and in preventing invasion of intracellular organisms.[8] TNFIs affect cellular and humoral immunity, and may contribute to greater susceptibility to infection, such as invasive pneumococcal disease, granulomatous infection, new tuberculosis infection, chronic hepatitis B, varicella-zoster virus, reactivation of latent tuberculosis, and new onset of opportunistic infection by Candida or Aspergillus.[3] Old age, the presence of underlying disease in immunocompromised patients, or the combination of immunomodulatory therapy and biological therapy can impair innate immune function and increase the risk of opportunistic infections.[3] Before and during biological treatment, patients should be monitored regularly by assessment of complete blood count, biochemistry, C-reactive protein, hepatitis B, hepatitis C, tuberculosis, and CxR. Adherence to the hospital's standard infection-prevention measures can reduce the risk of acquiring hospital-acquired infections.[5]\n\nAB is commonly found in the environment.[5]AB bacteremia has become a significant public health problem and accounts for one of the most common nosocomial pathogens in healthcare centers because of accidental spreading by health caregivers or environmental contamination by patients.[9]AB can colonize the human intestinal tract and cause extensive infection, including pneumonia, peritonitis, urinary tract infection, and bacteremia.[5] Because of its tendency to develop antibiotic resistance, persistent environmental survival, and difficult eradication, MDRAB is a significant nosocomial pathogen, that often requires treatment with carbapenems.[5] MDRAB infection or colonization also increases the mortality rate.[5] Risk factors for MDRAB include cardiovascular disease, chronic obstructive lung disease, neurological impairment, and diabetes mellitus, and the risk is elevated in surgical patient groups receiving mechanical ventilation, previous antibiotic therapy, or with comorbidities, in particular multiple Acinetobacter isolates and neurological impairment.[5] A recent study reported that 88% of patients with MDRAB were infected during hospitalization and that the rest of the patients had recently visited a hospital before infection.[10] Frequent visits to the rheumatology clinic may have exposed our patient to MDRAB, which has become an emerging problem in hospitals, especially in countries with antibiotic abuse. Because of the tendency of AB to develop antibiotic resistance and difficult eradication, it is critical and very important to avoid AB colonization as much as possible. Clinicians and rheumatologists should emphasize the importance of adherence to the hospital's standard infection-prevention measures to all patients receiving TNFI and all immunosuppressants.\n\nThe chronic inflammation of RA results in pathogenic gut bacterial overgrowth or the lack of immunomodulatory commensal bacteria.[11] TNF-α agonists facilitate the regulation and eradication of intestinal pathogens and microbial-induced inflammation.[3] T helper 17 (Th17) cells in the gut mucosa help to regulate mucosal immunity and prevent AB colonization.[2] Thus, it is rational that TNFI may affect intestinal immunity by inducing dysbiosis, which affects Th17-mediated mucosal immunity and contributes to AB colonization and the development of MDRAB in this patient because she frequently visited the hospital and exposed to environmental AB.\n\nIn this case, it is reasonable that golimumab raised an additional impact on the development of MDRAB pneumonia. In the real-world practice, rheumatologists should not focus only on the therapeutic effects of bDMARDs but also be aware of possible adverse effects, such as serious infections, especially in countries with high rates of antibiotic abuse and drugs resistance. To our knowledge, this is the first case of MDRAB-induced pneumonia with severe sepsis in a patient with RA who was predisposed to infection because of TNFI treatment and was successfully treated with adequate antibiotics. We hypothesize that TNFI may affect intestinal immunity by inducing dysbiosis, which affects Th17-mediated mucosal immunity and contributes to AB colonization and the development of MDRAB in this patient. However, we still need more real-world data to prove the hypothesis. We have launched a prospective registry study to observe whether there is increased prevalence of AB colonization at gut in patients receiving TNFI or other biological agents.\n\nThis case shows that clinicians should be aware of the possibility of TNFI-related adverse effects, such as infectious disease, especially in patients exposed to a nosocomial infection environment and in countries with a high rate of antibiotic abuse.\n\nAuthor contributions\nAll authors had contributed to the patient care and had access to the data and a role in writing this manuscript.\n\nConceptualization: Shu-Yi Lin, Chun-Chi Lu.\n\nData curation: Shu-Yi Lin, Deh-Ming Chang.\n\nInvestigation: Shu-Yi Lin.\n\nProject administration: Shu-Yi Lin, Chun-Chi Lu.\n\nResources: Shu-Yi Lin, Hsiang-Cheng Chen, Deh-Ming Chang, Chun-Chi Lu.\n\nSoftware: Shu-Yi Lin, Chun-Chi Lu.\n\nSupervision: Shu-Yi Lin, Zheng-Hao Huang, Hsiang-Cheng Chen, Deh-Ming Chang, Chun-Chi Lu.\n\nValidation: Zheng-Hao Huang, Hsiang-Cheng Chen, Deh-Ming Chang.\n\nVisualization: Shu-Yi Lin.\n\nWriting – original draft: Shu-Yi Lin, Zheng-Hao Huang, Deh-Ming Chang.\n\nWriting – review and editing: Shu-Yi Lin, Chun-Chi Lu.\n\nAbbreviations: AB = Acinetobacter baumannii, bDMARD = biological disease-modifying antirheumatic drug, CRP = C-reactive protein, CxR = chest plain film, DAC28 = Disease Activity Score 28, DMARD = disease-modifying antirheumatic drug, IBD = inflammatory bowel disease, IL = interleukin, MDRAB = multidrug-resistance Acinetobacter baumannii, MTX = methotrexate, RA = rheumatoid arthritis, Th17 = T helper 17, TNFI = tumor necrosis factor inhibitor.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Ma X Xu S \nTNF inhibitor therapy for rheumatoid arthritis . Biomed Rep \n2013 ;1 :177–84 .24648915 \n[2] Yan Z Yang J Hu R \nAcinetobacter baumannii infection and IL-17 mediated immunity . Mediators Inflamm \n2016 ;2016 :9834020.26977122 \n[3] Ali T Kaitha S Mahmood S \nClinical use of anti-TNF therapy and increased risk of infections . Drug Healthc Patient Saf \n2013 ;5 :79–99 .23569399 \n[4] Hindryckx P Novak G Bonovas S \nInfection risk with biologic therapy in patients with inflammatory bowel disease . Clin Pharmacol Ther \n2017 ;102 :633–41 .28699217 \n[5] Shih MJ Lee NY Lee HC \nRisk factors of multidrug resistance in nosocomial bacteremia due to Acinetobacter baumannii: a case-control study . J Microbiol Immunol Infect \n2008 ;41 :118–23 .18473098 \n[6] Curtis JR Singh JA \nUse of biologics in rheumatoid arthritis: current and emerging paradigms of care . Clin Ther \n2011 ;33 :679–707 .21704234 \n[7] Navegantes KC De Souza Gomes R Pereira PAT \nImmune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity . J Transl Med \n2017 ;15 :36.28202039 \n[8] Galloway JB Hyrich KL Mercer LK \nAnti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly . Rheumatology \n2010 ;50 :124–31 .20675706 \n[9] Teng SO Yen MY Ou TY \nComparison of pneumonia- and non-pneumonia-related Acinetobacter baumannii bacteremia: impact on empiric therapy and antibiotic resistance . J Microbiol Immunol Infect \n2015 ;48 :525–30 .25103719 \n[10] Abbo A Navon-Venezia S Hammer-Muntz O \nMultidrug-resistant Acinetobacter baumannii . Emerg Infect Dis \n2005 ;11 :22–9 .15705318 \n[11] Zhang X Zhang D Jia H \nThe oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment . Nat Med \n2015 ;21 :895–905 .26214836\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0025-7974",
"issue": "97(33)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D040981:Acinetobacter baumannii; D000368:Aged; D000900:Anti-Bacterial Agents; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D002097:C-Reactive Protein; D002438:Cefoperazone; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D011014:Pneumonia; D011859:Radiography; D013407:Sulbactam; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e11730",
"pmc": null,
"pmid": "30113458",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26977122;28202039;21704234;20675706;23569399;26214836;28699217;25103719;24648915;18473098;15705318",
"title": "Multidrug-resistance Acinetobacter baumannii pneumonia in a rheumatoid arthritis patient receiving tumor necrosis factor inhibitor: A case report.",
"title_normalized": "multidrug resistance acinetobacter baumannii pneumonia in a rheumatoid arthritis patient receiving tumor necrosis factor inhibitor a case report"
} | [
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"companynumb": "TW-JNJFOC-20180906045",
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"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBevacizumab is a recombinant humanized monoclonal antibody that obstructs the vascular endothelial growth factor (VEGF) pathway. Despite its extensive employment in the treatment of primary tumors of the brain, experience of brain metastatic disease, a frequent complication in patients with lung cancer, is very limited. On the basis of the strong antiedemigenous effect and no risk of intracranial bleeding, we administered a bevacizumab-based chemotherapy to patients with non-small-cell lung cancer (NSCLC) and symptomatic metastatic brain lesions who were not suitable candidates for a specific local therapy.\n\n\nMETHODS\nThe patients received bevacizumab 7.5 mg/kg and cisplatin 75 mg/m(2) on day 1, and gemcitabine 1,250 mg/m(2) on days 1 and 8, every 21 days.\n\n\nRESULTS\nWe studied 13 patients with clinical and radiological progressive brain metastases; the majority had a treatment-naïve disease. Bevacizumab-based chemotherapy was found to be well tolerated and effective: progression-free survival (PFS) was 9.1 months (range: 0.9-39.2+) and overall survival (OS) was 9.6 months (range 3-41.5+).\n\n\nCONCLUSIONS\nBevacizumab-based therapy proved to be feasible and safe. The PFS and the OS data are very encouraging as well as the symptomatic benefit due to bevacizumab's high capacity to provide a long-lasting decrease of perilesional edema.",
"affiliations": "Veneto Institute of Oncology IRCCS, Padova, Italy.",
"authors": "Zustovich|Fable|F|;Ferro|Alessandra|A|;Lombardi|Giuseppe|G|;Farina|Patrizia|P|;Zagonel|Vittorina|V|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000376605",
"fulltext": null,
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"issue": "60(5-6)",
"journal": "Chemotherapy",
"keywords": null,
"medline_ta": "Chemotherapy",
"mesh_terms": "D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D001932:Brain Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged",
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"title": "Bevacizumab-Based Therapy for Patients with Brain Metastases from Non-Small-Cell Lung Cancer: Preliminary Results.",
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"abstract": "BACKGROUND\nThe use of nivolumab in the treatment of metastatic melanoma has become well established during past years. Despite its undeniable efficacy, immune-related side effects may occur, including acute liver injury. Liver toxicity caused by nivolumab is usually observed as liver enzyme elevation with mild or no symptoms; further, there is limited information regarding any histopathological findings.\n\n\nMETHODS\nWe report a case of a 38-year-old woman with metastatic melanoma who developed unusual nivolumab-induced hepatic injury after a single dose of nivolumab. A liver biopsy was performed to assess the aetiology of hepatic lesions as no other analysis concerning biochemistry, virology, autoantibodies, nor imaging studies revealed any pathology. The histopathological analysis showed an oedema in the portal fields and mixed inflammation consisting of eosinophilic and neutrophilic granulocytes. The major finding was a prominent, predominantly intracellular, cholestasis.\n\n\nCONCLUSIONS\nTo our knowledge, no such histopathological pattern of liver injury has been described in relation to nivolumab therapy elsewhere. This type of liver injury shows higher resistance to corticosteroids, which may warrant upfront high-dose corticotherapy combined with other immunosuppressive agents, including mycophenolate mofetil. This case highlights a necessary awareness regarding immunotherapy-related adverse events, which could be severe and potentially life-threatening.",
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"authors": "Kopecký|J|J|;Kubecek|O|O|;Geryk|T|T|;Podhola|M|M|;Ziaran|M|M|;Priester|P|P|;Hanisova|M|M|;Borilova|S|S|",
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"keywords": "autoimmunity; corticosteroids; hepatitis; nivolumab; toxicity",
"medline_ta": "Klin Onkol",
"mesh_terms": "D000328:Adult; D000074322:Antineoplastic Agents, Immunological; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D008545:Melanoma; D000077594:Nivolumab; D011379:Prognosis",
"nlm_unique_id": "9425213",
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"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hepatic Injury Induced by a Single Dose of Nivolumab - a Case Report and Literature Review.",
"title_normalized": "hepatic injury induced by a single dose of nivolumab a case report and literature review"
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"abstract": "BACKGROUND\nTachycardia-induced cardiomyopathy (TIC) is defined as systolic and/or diastolic dysfunction of the left ventricle resulting from prolonged elevated heart rates, completely reversible upon control of the arrhythmia. Atrioventricular reentrant tachycardia (AVRT) is one of the most frequent causes of TIC. In its incessant form, it is unlikely to be controlled by pharmacological treatment, catheter ablation being the principal therapeutic option. The coexistence of left bundle branch block (LBBB) in patients with AVRT may cause difficulties in the early diagnosis and management of tachycardia because of the wide complex morphology, making it harder to localize the accessory pathway (AP).\nA 60-year-old woman, presented incessant episodes of palpitations and shortness of breath due to a LBBB tachycardia leading to hemodynamic instability.\n\n\nMETHODS\nThe patient had a wide QRS tachycardia, with LBBB morphology and a heart rate of 160/minute. Echocardiography showed global hypokinesia with 25% left ventricular ejection fraction (LVEF). Considering the patient's clinical picture, TIC was suspected.\n\n\nMETHODS\nThe electrophysiological study revealed a left lateral accessory pathway. Catheter ablation was successfully performed at the level of the lateral mitral ring.\n\n\nRESULTS\nOne week after the ablation the patient had no signs of heart failure and the LVEF normalized to 55%. During 6-months follow-up the patient presented no more episodes of tachycardia or heart failure and the LVEF remained normal.\n\n\nCONCLUSIONS\nAVRT is rarely associated with intrinsic LBBB, being a potential cause of TIC. In these patients, it is unlikely to control the arrhythmia pharmacologically, catheter ablation being the best therapeutic option. The variation of QRS complex duration between LBBB pattern in SR and AVRT could be useful for early diagnosis of an ipsilateral AP on surface ECG.",
"affiliations": "5th Department of Internal Medicine, Cardiology-Rehabilitation, \"Iuliu Hatieganu\" Univerity of Medicine and Pharmacy Cluj-Napoca, Romania.",
"authors": "Minciuna|Ioan Alexandru|IA|;Puiu|Mihai|M|;Cismaru|Gabriel|G|;Gusetu|Gabriel|G|;Comsa|Horatiu|H|;Caloian|Bogdan|B|;Zdrenghea|Dumitru|D|;Pop|Dana|D|;Radu|Rosu|R|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31393361MD-D-18-0980610.1097/MD.0000000000016642166423400Research ArticleClinical Case ReportTachycardia-induced cardiomyopathy in a patient with left-sided accessory pathway and left bundle branch block A case reportMinciuna Ioan Alexandru MDPuiu Mihai MDCismaru Gabriel MD, PhD∗Gusetu Gabriel MD, PhDComsa Horatiu MDCaloian Bogdan MDZdrenghea Dumitru MD, PhDPop Dana MD, PhDRadu Rosu MD, PhDNA. 5th Department of Internal Medicine, Cardiology-Rehabilitation, “Iuliu Hatieganu” Univerity of Medicine and Pharmacy Cluj-Napoca, Romania.∗ Correspondence: Gabriel Cismaru, Rehabilitation Hospital, Cardiology Department, Viilor Street 46-50, Cluj-Napoca 400437, Romania(e-mail: gabi_cismaru@yahoo.com).8 2019 09 8 2019 98 32 e166421 1 2019 27 5 2019 8 7 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nTachycardia-induced cardiomyopathy (TIC) is defined as systolic and/or diastolic dysfunction of the left ventricle resulting from prolonged elevated heart rates, completely reversible upon control of the arrhythmia. Atrioventricular reentrant tachycardia (AVRT) is one of the most frequent causes of TIC. In its incessant form, it is unlikely to be controlled by pharmacological treatment, catheter ablation being the principal therapeutic option. The coexistence of left bundle branch block (LBBB) in patients with AVRT may cause difficulties in the early diagnosis and management of tachycardia because of the wide complex morphology, making it harder to localize the accessory pathway (AP).\n\nPatient concerns:\nA 60-year-old woman, presented incessant episodes of palpitations and shortness of breath due to a LBBB tachycardia leading to hemodynamic instability.\n\nDiagnosis:\nThe patient had a wide QRS tachycardia, with LBBB morphology and a heart rate of 160/minute. Echocardiography showed global hypokinesia with 25% left ventricular ejection fraction (LVEF). Considering the patient's clinical picture, TIC was suspected.\n\nInterventions:\nThe electrophysiological study revealed a left lateral accessory pathway. Catheter ablation was successfully performed at the level of the lateral mitral ring.\n\nOutcomes:\nOne week after the ablation the patient had no signs of heart failure and the LVEF normalized to 55%. During 6-months follow-up the patient presented no more episodes of tachycardia or heart failure and the LVEF remained normal.\n\nLessons:\nAVRT is rarely associated with intrinsic LBBB, being a potential cause of TIC. In these patients, it is unlikely to control the arrhythmia pharmacologically, catheter ablation being the best therapeutic option. The variation of QRS complex duration between LBBB pattern in SR and AVRT could be useful for early diagnosis of an ipsilateral AP on surface ECG.\n\nKeywords\ncatheter ablationleft bundle branch blockaccessory pathwaymitral ringOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nTachycardia-induced cardiomyopathy (TIC) was first described in 1913 in a young patient who presented with congestive heart failure (CHF) and atrial fibrillation with rapid ventricular response, which resolved by control of arrhythmia.[1,2]\n\nTIC is defined as systolic and/or diastolic ventricular dysfunction resulting from a prolonged elevated heart rate, which is reversible upon control of the arrhythmia or heart rate.[1–4]\n\nAtrioventricular reentrant tachycardia (AVRT) is most frequently paroxysmal and can rarely occur in its incessant form, being one of the most frequent causes of TIC. Once it becomes incessant, it is unlikely to be controlled by pharmacological treatment, catheter ablation being the principal therapeutic option.[1,2]\n\nThe coexistence of intrinsic left bundle branch block (LBBB) in patients with AVRT may cause difficulties in the early diagnosis of tachycardia because of the wide complex morphology,[5–7] but most importantly, it can be the cause of the incessant nature of tachycardia.[8]\n\nWe present the atypical case of a patient with incessant wide QRS complex tachycardia lasting for 4 days, with hemodynamic instability, drug resistance, which was only resolved by emergency intracardiac overdrive pacing and subsequent catheter ablation.\n\n2 Case report\nA 52 year-old Caucasian male patient, presented to the Emergency Department of a small town for palpitations. He had no medical history or past interventions. At presentation, ECG showed wide QRS tachycardia with LBBB morphology, 180/minute. The patient was given intravenous amiodarone with no effect on the arrhythmia. At 24 hour after admission, the patient showed CHF signs and symptoms with hemodynamic instability: blood pressure 80/40 mm Hg, pale fingers, dyspnea, transpirations, hepatomegaly, and edema. Electrical cardioversion was performed with conversion to sinus rhythm (SR) – also with LBBB morphology (Fig. 1), but with recurrence of tachycardia in the following minutes. Adenosine and verapamil were administered with no effect. As all therapeutic resources were exhausted without any change in arrhythmia and taking into account the progressive hemodynamic instability, the patient was transferred to a tertiary referral hospital.\n\nFigure 1 Sinus rhythms with LBBB after electrical cardioversion.\n\nThe patient underwent an electrophysiology study, which found supraventricular tachycardia with 1:1 atrioventricular conduction that was stopped by overdrive pacing, with spontaneous recurrence after a few seconds through an atrial ectopic beat. During SR, positive delta waves could be seen in leads I, II, III, aVF, with rS complex in lead V1 and QRS transition in leads V4-V6 suggesting the presence of a right accessory pathway (AP) and antidromic AVRT. A temporary stimulation catheter was left in the right ventricle, with repeated conversions through overdrive pacing in the next few hours, with a reduction of tachycardia recurrence and clinical improvement. The patient was transferred to our service for AP catheter ablation ().\n\nFigure 2 Wide complex tachycardia with LBBB morphology on admission to the regional hospital.\n\nOn admission to our department, the patient was hemodynamically and respiratorily stable, while ECG showed SR with the same LBBB morphology and preexcitation. We performed an electrophysiology study, with tachycardia recurrence at the beginning of the procedure (Fig. 3A).\n\nFigure 3 (A) Wide complex tachycardia at the beginning of the EP study. (B) During programmed atrial stimulation, a shift in QRS morphology from LBBB (second circle) to RBBB (first circle) can be observed. (C) Fusion between A and V potentials in the distal coronary sinus suggesting a left lateral AP. (D) The first two arrows show the presence of the AP – fusion between A and V potentials; the last two arrows show the disappearance of the fusion – successful ablation of the AP. Also, a wider QRS complex after ablation can be observed on surface ECG (V1-3).\n\nDuring programmed atrial stimulation, a QRS shift from LBBB to right bundle branch block morphology could be seen (Fig. 3B), suggesting the presence of a left lateral AP, which was confirmed by the fusion between atrial and ventricular potentials in the distal coronary sinus catheter (Fig. 3C). We successfully performed AP ablation (Fig. 3D). During the procedure, we noticed a wider QRS complex during AVRT compared to SR, which made us suspicious about a second, right-sided AP, with anterograde conduction and antidromic AVRT. This possibility was excluded because of the constancy in AH and HV intervals during programmed atrial pacing, at the end of the procedure. Furthermore, we observed that the QRS complex during pre-ablation SR was narrower compared to post-ablation SR (Fig. 3D). In both cases, the narrower QRS complex during preablation SR could be explained by the fusion between atrioventricular node with LBBB conduction and AP conduction (Fig. 4). After the procedure, the patient maintained SR with LBBB morphology and no preexcitation on surface ECG, while clinically and echocardiographically, 1 week after ablation, there were no signs of CHF, with the normalization of LVEF (Fig. 5).\n\nFigure 4 (A) The QRS complex in SR results from a fusion between AVN + LBBB conduction and left lateral AP conduction, which makes it narrower than in SR after ablation of the AP, and also narrower than in tachycardia. (B) Orthodromic AVRT with LBBB – the left lateral AP conducts retrogradely, so the QRS will be wider than in SR. (Adapted from[5]).\n\nFigure 5 Flow chart with the evolution of the patient before and after catheter ablation of the accessory pathway.\n\n3 Discussion and conclusion\nThe fast clinical and echocardiographic recovery after arrhythmia control in a patient without a history of structural cardiac disease confirms the diagnosis of TIC. Taking into account the reversibility of heart failure after TIC, early arrhythmia control is the cornerstone of complete recovery in these patients. The fast normalization of LVEF in our patient, 1 week after arrhythmia control, is in accordance with the current literature data[1] and could be explained by the short overall time that our patient spent in tachycardia.\n\nEven though AVRT is one of the main causes leading to TIC, the number of case reports in the literature is scarce. Catheter ablation, as performed by us in our patient, is the best therapeutic option once AVRT becomes incessant[1].\n\nThere are many algorithms for localizing APs in patients with LBBB, but most of them refer to patients with functional, not intrinsic BBB. Also, it is demonstrated that the presence of LBBB, by causing a delay in intraventricular conduction, facilitates the induction of orthodromic AVRT when a left-sided AP is present, which may be an explanation for the incessant nature of our tachycardia[8–10].\n\nThe coexistence of a left lateral AP and intrinsic LBBB is a rare finding in patients with AVRT and could be easily mistaken for antidromic AVRT with anterograde conduction via a right AP. The variation in our patient's QRS complex, narrower during pre-ablation SR compared to both tachycardia and post-ablation SR, could be explained by the fusion between LBBB pattern and left lateral AP conduction. In 1 study, the authors found that a QRS duration closer to normal during SR compared to tachycardia could be useful in diagnosing LBBB + ipsilateral AP on surface ECG. They also investigated whether fusion of LBBB pattern and AP conduction could provide physiological resynchronization in these patients. The conclusion was that even though some of them may benefit from left-sided AP conduction, the risks are higher than the advantages (i.e., malignant arrhythmias), catheter ablation being the best therapeutic option whenever possible.[11]\n\nFinally, surface ECG may still play an important role in the diagnosis of wide complex tachycardia, even in patients with intrinsic LBBB. Concomitant LBBB and left lateral AP diagnosis on surface ECG could be challenging, “but not always unattainable” if some criteria are met: rapid conduction through the AV node and/or slow conduction through the AP in SR. In the absence of either of these 2 criteria, premature conduction through the AP will tend to conceal the LBBB pattern, resulting in a normal QRS duration on surface ECG.[12] However, if either of these is present, a narrower QRS complex during LBBB pattern SR compared to orthodromic tachycardia may be useful in unfolding an ipsilateral AP.\n\n3.1 Consent\nInformed written consent was obtained from the patient for the publication of this case report and any accompanying medical images.\n\nAuthor contributions\nConceptualization: Ioan Alexandru Minciuna, Gabriel Cismaru.\n\nData curation: Gabriel Cismaru.\n\nMethodology: Ioan Alexandru Minciuna.\n\nSupervision: Gabriel Cismaru, Gabriel Gusetu, Horatiu Comsa, Dumitru Zdrenghea, Dana Pop, Rosu Radu.\n\nValidation: Mihai Puiu, Gabriel Cismaru, Gabriel Gusetu, Bogdan Caloian, Dumitru Zdrenghea, Dana Pop.\n\nVisualization: Gabriel Cismaru.\n\nWriting – original draft: Ioan Alexandru Minciuna, Mihai Puiu, Gabriel Cismaru, Horatiu Comsa, Bogdan Caloian.\n\nWriting – review & editing: Ioan Alexandru Minciuna, Mihai Puiu, Gabriel Cismaru, Gabriel Gusetu, Dumitru Zdrenghea, Dana Pop, Rosu Radu.\n\nAbbreviations: AP = accessory pathway, AVRT = atrioventricular reentrant tachycardia, CHF = congestive heart failure, LBBB= left bundle branch block, LVEF = left ventricular ejection fraction, SR = sinus rhythm, TIC = tachycardia-induced cardiomyopathy.\n\nThe authors have no conflicts of interests to disclose.\n==== Refs\nReferences\n[1] Ellis EL Josephson ME \nWhat about tachycardia-induced cardiomyopathy? \nArrhythm Electrophysiol Rev \n2013 ;2 :82–90 . 10.15420/aer.2013.2.2.82 .26835045 \n[2] Martin CA Lambiase PD \nPathophysiology, diagnosis and treatment of tachycardiomyopathy . Heart \n2017 ;103 :1543–52 . 10.1136/heartjnl -2016- 310391 .28855272 \n[3] Nakatani BT Minicucci MF Okoshi K \nTachycardia induced cardiomyopathy . BMJ Case Rep \n2012 ;1–4 . 10.1136/bcr -2012- 006587 .\n[4] Perez Silva A Merino JL \nTachycardia-induced cardiomyopathy . E-J Cardiol Pract [internet] \n2009 ;7 :16https://www.escardio orghttps://www.escardio org/Journals/E-Journal-of-Cardiology-Practice/Volume-7/Tachycardia-induced-cardiomyopathy [accessed September 10, 2018] .\n[5] Erdogan O Kepez A Atas H \nLeft bundle branch block type wide QRS tachycardia: what is the most likely diagnosis derived from the ECG? \nHeart \n2015 ;101 :384–90 . 10.1136/heartjnl-2014-306471 .25502812 \n[6] Neiger JS Trohman RG \nDifferential diagnosis of tachycardia with a typical left bundle branch block morphology . World J Cardiol \n2011 ;3 :127–34 . 10.4330/wjc.v3.i5.127 .21666813 \n[7] Littmann L Saxonhouse SJ \nRepetitive, incessant supraventricular tachycardia: noninvasive determination of the electrophysiologic mechanism . Int J Cardiol Heart Vasc \n2015 ;190 :256–9 . 10.1016/j.ijcard.2015.04.181 .\n[8] Issa ZF Miller JM Zipes DP \nAtrioventricular Reentrant Tachycardia. In Clinical Arrhythmology and Electrophysiology: A companion to Braunwald's Heart Disease: Second edition . 2012 ;Philadelphia : Elsevier Inc , 411–467 .\n[9] Haisty WK \nLeft bundle-branch block and a left-sided accessory pathway: physiologic cardiac synchronization? \nJ Electrocardiol \n2012 ;45 :525–7 . 10.1016/j.jelectrocard.2012.06.007 .22809576 \n[10] Stanke A Storti C De Ponti R \nSpontaneous incessant AV reentrant tachycardia related to left bundle branch block and concealed left-sided accessory AV pathway . J Cardiovasc Electrophysiol \n1994 ;5 :777–81 . 10.1111/j.1540-8167.1994.tb01201.x .7827717 \n[11] Kim MH Trohman RG \nLeft bundle branch block during orthodromic reciprocating tachycardia: where is the accessory pathway? \nHeartRhythm Case Rep \n2006 ;3 :610–1 . 10.1016/j.hrthm.2006.01.006 .\n[12] Chiale PA Elizari MV \nThe electrocardiographic diagnosis of intraventricular blocks coexisting with ventricular preexcitation . J Electrocardiol \n2012 ;45 :515–24 . 10.1016/j.jelectrocard.2012.04.002 .22560599\n\n",
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"mesh_terms": "D002037:Bundle-Branch Block; D009202:Cardiomyopathies; D017115:Catheter Ablation; D004452:Echocardiography; D004562:Electrocardiography; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D013318:Stroke Volume; D013611:Tachycardia, Atrioventricular Nodal Reentry",
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"title": "Tachycardia-induced cardiomyopathy in a patient with left-sided accessory pathway and left bundle branch block: A case report.",
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"abstract": "Methylenetetrahydrofolate reductase (MTHFR) genetic mutations and intra-procedural inhaled nitrous oxide (N2O) independently increase blood levels of homocysteine, a compound associated with thrombosis. Patients with MTHFR mutations who also receive N2O during ophthalmic artery chemotherapy (OAC) for retinoblastoma may have a heightened thrombotic risk.\nSingle-center retrospective review of pediatric patients with advanced retinoblastoma who received OAC and developed choroidal infarcts. Four retinoblastoma patients with advanced intraocular disease (2 males, 2 females: 13-58 months) experienced choroidal infarcts within the one-month period after OAC, in which procedural N2O induction was used (duration between 21 and 58 min). All 4 patients had MTHFR (chromosome 1p, position 36.22) genetic abnormalities: one was homozygous for the C677T mutation, one was C677T heterozygous, one was A1298C heterozygous, and one was heterozygous for both C677T and A1298C. In all 4 patients, indirect ophthalmoscopy and fundus photography showed marked disturbance of the retinal pigment epithelium and optical coherence tomography (OCT) confirmed thinning of the choroid. Follow-up time ranged from 15 to 46 months (median 21 months).\nChoroidal infarction in eyes treated with OAC developed in children who were both deficient in at least one working allele of the MTHFR gene (heterozygous or homozygous) and received N2O induction during OAC.",
"affiliations": "1Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Room A330, New York, NY 10065 USA.;2Interventional Neuroradiology, Departments of Radiology and Neurosurgery, Weill Cornell Medical Center/New York Presbyterian Hospital, New York, NY USA.;1Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Room A330, New York, NY 10065 USA.;3Department of Anesthesiology, Weill Cornell Medical Center/New York Presbyterian Hospital, New York, NY USA.;4Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA.;4Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA.;1Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Room A330, New York, NY 10065 USA.;1Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Room A330, New York, NY 10065 USA.",
"authors": "Bohm|Kelley J|KJ|;Gobin|Y Pierre|YP|;Francis|Jasmine H|JH|;McInerney|Gabrielle|G|;Dabo-Trubelja|Anahita|A|;Dalecki|Paul H|PH|;Marr|Brian P|BP|;Abramson|David H|DH|",
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"fulltext": "\n==== Front\nInt J Retina VitreousInt J Retina VitreousInternational Journal of Retina and Vitreous2056-9920BioMed Central London 11910.1186/s40942-018-0119-xCase ReportChoroidal infarction following ophthalmic artery chemotherapy Bohm Kelley J. 1Gobin Y. Pierre 2Francis Jasmine H. 1McInerney Gabrielle 3Dabo-Trubelja Anahita 4Dalecki Paul H. 4Marr Brian P. 1Abramson David H. 212-639-7232abramsod@mskcc.org 11 0000 0001 2171 9952grid.51462.34Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Room A330, New York, NY 10065 USA 2 0000 0000 8499 1112grid.413734.6Interventional Neuroradiology, Departments of Radiology and Neurosurgery, Weill Cornell Medical Center/New York Presbyterian Hospital, New York, NY USA 3 0000 0000 8499 1112grid.413734.6Department of Anesthesiology, Weill Cornell Medical Center/New York Presbyterian Hospital, New York, NY USA 4 0000 0001 2171 9952grid.51462.34Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY USA 30 4 2018 30 4 2018 2018 4 162 1 2018 30 3 2018 © The Author(s) 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nMethylenetetrahydrofolate reductase (MTHFR) genetic mutations and intra-procedural inhaled nitrous oxide (N2O) independently increase blood levels of homocysteine, a compound associated with thrombosis. Patients with MTHFR mutations who also receive N2O during ophthalmic artery chemotherapy (OAC) for retinoblastoma may have a heightened thrombotic risk.\n\nCase presentations\nSingle-center retrospective review of pediatric patients with advanced retinoblastoma who received OAC and developed choroidal infarcts. Four retinoblastoma patients with advanced intraocular disease (2 males, 2 females: 13–58 months) experienced choroidal infarcts within the one-month period after OAC, in which procedural N2O induction was used (duration between 21 and 58 min). All 4 patients had MTHFR (chromosome 1p, position 36.22) genetic abnormalities: one was homozygous for the C677T mutation, one was C677T heterozygous, one was A1298C heterozygous, and one was heterozygous for both C677T and A1298C. In all 4 patients, indirect ophthalmoscopy and fundus photography showed marked disturbance of the retinal pigment epithelium and optical coherence tomography (OCT) confirmed thinning of the choroid. Follow-up time ranged from 15 to 46 months (median 21 months).\n\nConclusions\nChoroidal infarction in eyes treated with OAC developed in children who were both deficient in at least one working allele of the MTHFR gene (heterozygous or homozygous) and received N2O induction during OAC.\n\nKeywords\nChoroidal infarctionMTHFRNitrous oxideOphthalmic artery chemotherapyRetinoblastomahttp://dx.doi.org/10.13039/100000054National Cancer InstituteGrant P30 CA008748Abramson David H. Fund for Ophthalmic Knowledge, Inc.n/aAbramson David H. issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nChoroidal blood flow can be affected by severe hypertension, inflammatory vasculopathies, and thrombophilias (inherited, developed, or iatrogenic). Though choroidal infarction typically entails a lobular and patchy distribution of ischemia, we have seen several cases of choroidal infarction covering many clock hours from the central posterior pole to the periphery after ophthalmic artery chemotherapy (OAC) delivery. In addition to their unique patterns of infarction, these patients had two other curious similarities: methylenetetrahydrofolate reductase (MTHFR) genetic mutations (both heterozygous and homozygous for mutated alleles) and intra-procedural inhaled nitrous oxide—two characteristics known to increase homocysteine in the blood (see biochemical pathway in Fig. 1) [1, 2], thus possibly increasing thrombotic risk [1]. Through this case series, we will describe our experiences and explore the etiology of the patients’ choroidal damage.Fig. 1 Homocysteine—MTHFR biochemical pathway. Increase of homocysteine can be caused by inhibition of methionine synthase by nitrous oxide and by inhibition of MTHFR by genetic polymorphisms\n\n\n\n\nCase presentations\nWe retrospectively reviewed four retinoblastoma (RB) pediatric patients with MTHFR mutations (of at least one copy of either C677T or A1298C polymorphisms of chromosome 1p at position 36.22). Out of the ten patients our institution’s RB patient cohort who suffered from choroidal infarctions, 7 patients received testing and were positive for MTHFR mutations—4 of whom received OAC and nitrous oxide that corresponded with the timing of infarction. These four patients were diagnosed with choroidal infarctions by imaging at the post-procedural follow-up visits approximately one month after OAC. All patients had been diagnosed with advanced intraocular RB (International Classification Groups D and E) and were monitored regularly at Memorial Sloan Kettering Cancer Center (median length of post-infarct follow-up 21 months, range 15–46 months) and received OAC at New York Presbyterian-Cornell in New York, NY. Prophylactic heparin (dose-adjusted to each patient’s activated clotting time) was administered at the beginning of the procedure and is standard of care for our OAC procedures. Genetic testing for known prothrombotic mutations (in genes for MTHFR, Factor V Leiden, prothrombin) was performed after infarctions were detected. Indirect ophthalmoscopy, RetCam digital photography, optical coherence tomography (OCT) and in some of the patients, fluorescein angiography was used to describe fundus findings. Characteristic findings in choroidal infarction include segmental pallor and granular fundus pigmentation on ophthalmoscopy, thinning of the choroid on OCT, and lack of choroidal perfusion on fluorescein angiography. Below, we will discuss each patient’s characteristics, treatment course, and infarct presentation.\n\nPatient one was a 52-month old male with bilateral RB at the time of infarct diagnosis in his right eye. He was homozygous for the C677T polymorphism, and experienced choroidal ischemia after his seventh dose of OAC (carboplatin, topotecan, and melphalan) to the right eye only. His prior six OAC doses were unremarkable except for vasospasm of the ophthalmic artery during the fifth dose, which limited the ability for simultaneous bilateral chemotherapy infusion. The seventh dose, however, was his first administration of nitrous oxide during the procedure; he received 24 min of nitrous oxide induction anesthesia with a maximum end tidal nitrous oxide (ET N2O) of 60.2% (higher ET N2O percentage correlates to higher nitrous oxide concentration in the blood). He experienced no intra-procedural complications. One month later, new choroidal ischemia was identified in the right eye, presumed to be due to an infarction.\n\nPatient two was a 13-month old female with bilateral RB when she experienced ischemia of her left choroid. She was heterozygous for the A1298C polymorphism and experienced an infarction after her third cycle of carboplatin OAC to the left eye only, anesthetically induced by nitrous oxide. Two prior OAC infusions were done with sevoflurane induction alone. She received 47 min of nitrous oxide, with 65.6% max ET N2O, and the procedure was without acute complications. Follow-up 1 month later revealed infarction of the lateral half of the posterior choroid.\n\nPatient three was a 25-month old male with unilateral RB when he experienced choroidal infarction in the treated eye. His infarction was diagnosed at the one-month follow-up appointment after his second dose of OAC with melphalan and carboplatin. He was heterozygous for two polymorphisms: C677T and A1298C. While he did not receive nitrous oxide during his first OAC session, he did receive 58 min of nitrous oxide with max ET N2O 31.9% during this second session of OAC.\n\nPatient four was a 58-month old female when her right eye experienced a choroidal infarction following OAC for her bilateral RB. Her genetic testing showed heterozygosity for the C677T polymorphisim. The infarct occurred after her eighth dose of OAC with carboplatin, topotecan, and melphalan to the right eye (tenth treatment of OAC for this patient, two treatments only to left eye). This was her first time receiving nitrous oxide (duration 21 min, max ET N2O 60.5%) during OAC for the right eye. This patient’s choroidal ischemia was identified by RetCam images at her one-month follow-up appointment.\n\nThere were no systemic thrombotic events in these patients following OAC. Post-OAC cerebral angiograms performed in each patient (standard of care) showed no evidence of vasospasm in the ipsilateral arteries. In each patient, these angiograms confirmed anterograde flow in the internal carotid artery, anterior cerebral artery, and middle cerebral artery, as well as patent ophthalmic arteries. In all four patients, indirect ophthalmoscopy and fundus photography 1 month after OAC showed marked disturbance of the retinal pigment epithelium and OCT confirmed distinct thinning of the choroid. In all four patients, the choroidal damage covered the lateral 180° from the central pole to the periphery. See Fig. 2 for a representative RetCam fundus photographs and OCT images from patients 2 and 3. Post-infarct brain magnetic resonance images were performed in patients with bilateral RB (1, 2, and 4) to monitor for pinealoblastoma, and no past cerebrovascular events were identified.Fig. 2 RetCam retinal photographs and OCT choroidal imaging of Patients 2 and 3 one month after OAC with nitrous oxide. Yellow bars indicate choroidal thickness in area not affected by choroidal infarction. Teal blue arrows point to location of thinned choroid in area of infarction\n\n\n\n\nDiscussion and conclusions\nOphthalmic artery chemotherapy is an effective oncologic treatment; however, side effects do exist, ranging from temporary lid swelling, strabismus, and loss of eye lashes [3] to less frequent substantial adverse events such as vitreous hemorrhages [4], sectoral choroidal occlusive vasculopathy [5], and choroidal ischemia, as seen in our patients. Post-OAC vascular obstruction and subsequent ischemia has also been attributed to substances such as cotton and synthetic fibers when Melphalan isn’t properly filtered [6], particles from unfiltered melphalan solutions in experimental animals [7], and thromboses [5, 6]. We suspect our patients to have experienced thromboembolic choroidal infarctions based on the timeline and clinical exam and two other key considerations. We have previously reported thrombotic events due to sickle cell trait, prothrombin mutation, and plasminogen activator inhibitor-1 polymorphism [8, 9]. Even though sickle trait, Factor V Leiden, Protein C and S deficiencies, and prothrombin mutations are some of the most common thrombophilic conditions (see Table 1), our patients all exhibited genetic mutations of MTHFR (heterozygous or homozygous) which has an estimated prevalence in the United States of 11% for homozygotes and 40% for heterozygotes [13]. This enzyme mutation causes a moderate increase in circulating homocysteine (though to a lesser extent than its homozygous counterpart), which has shown to cause endothelial dysfunction [2] and a dose-dependent causality association with thromboembolisms [1]. We unfortunately cannot comment on the population with the treatment who did not experience choroidal infarctions because our center does not routinely, prospectively test for MTHFR (and other prothrombotic) mutations. The patients in our report also all received inhaled nitrous oxide during the procedure, a gas that inhibits methionine synthetase activity by 50% during a 2-h procedure and independently causes a dose-dependent increase of homocysteine [2], thereby increasing the risk of thrombosis [14]. A potential synergistic effect of at least one mutated MTHFR allele and nitrous oxide on blood levels of homocysteine in conjunction with the drugs’ intrinsic vascular toxicity may have increased the clotting propensity sufficiently to result in arterial thrombosis and subsequent segmental choroidal infarctions. Homocysteine levels were not obtained at the time of OAC in our patients because of the retrospective nature of this study, however the aforementioned studies enable us to infer homocysteine elevation.Table 1 Prevalence and relative risk of inherited thrombophilia in the general population [9–12]\n\nCoagulation disorder\tPrevalence in the general population (%)\tRelative risk of venous thromboembolism\t\nAnti-phospholipid syndrome\t5–10\t5–10\t\nHyperhomocysteinemia (MTHFR homozygote)\t11\t2.5\t\nFactor V Leiden (heterozygote)\t5\t6–8\t\nProthrombin G20210A mutation (heterozygote)\t2.3\t2.8\t\nProtein S deficiency\t1.3\t2.4\t\nSickle cell trait\t1\t1.5\t\nProtein C deficiency\t0.2\t6.5\t\nAntithrombin deficiency\t0.02–0.04\t17.5\t\n\n\n\nThough many occlusive etiologies can logically explain the choroidal damage in our four patients, the uncharacteristic distribution of the infarct begs the question—was the choroidal damage the result of an infarction at all? Infarctions typically cause smaller, lobular areas of ischemia at affected choriocapillaries, while the infarctions seen in our patients were larger, segmental territories. There were also no systemic ischemic events in these patients (though we previously reported a patient with systemic vascular manifestations [9]), thus a purely microthrombotic event does not convincingly explain these choroidal infarctions. Chemotherapeutic agents (varying combinations of melphalan, topotecan, and carboplatin) have been linked to pH-related toxicity (melphalan and carboplatin are acidic) to the ocular blood vessels, particularly retinal endothelial cell inflammation and leukostasis, following drug administration [7]. Melphalan has shown a direct choroidal toxicity as the result of preferential drug uptake of the retinal pigmented epithelium and poor efflux to the retina [15]. This, however, does not explain why the toxicity only affected one portion of the eye, rather than the entire territory fed by the ophthalmic artery. The patients may also have had pre-existing retinal detachments enabling chemotherapy accumulation and choroidal toxicity (though no serous retinal detachments were visualized on examination) [16], dietary deficiencies (i.e. vitamin B12, a necessary cofactor for the MTHFR pathway), or metabolic derangements.\n\nThese alternative explanations highlight important considerations, yet they don’t offer a unifying reason why these patients were affected and not others. We suspect that these four patients suffered visually significant choroidal complications following OAC due to a combination of their genetic predisposition to form blood clots and the nitrous oxide administered during these procedures for induction anesthesia focally in the setting of local melphalan. We hope that our observation on the association between MTHFR abnormalities and exposure to nitrous oxide exposure during OAC for RB will lead centers to prospectively study the incidence of MTHFR abnormalities, homocysteine levels before and during procedures and overall relationship to choroidal infarcts. It would be reasonable to consider withholding nitrous oxide in these children during OAC until additional information can rigorously determine its importance.\n\nAbbreviations\nMTHFRmethylhydrofolate reductase\n\nN2Onitrous oxide\n\nOACophthalmic artery chemotherapy\n\nOCToptical coherence tomography\n\nRBretinoblastoma\n\nET N2Oend tidal nitrous oxide\n\nAuthors’ contributions\nAll editors were instrumental in developing the ideas discussed in the article presented above. KB and GM collected and analyzed patient data, and KB was a major contributor in writing the manuscript. JF, YG, and DA also were major contributing writers and editors of the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nFederica Catalanotti, Ph.D.\n\nFunding\nThis research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 and the Fund for Ophthalmic Knowledge, Inc.\n\nCompeting interests\nThe authors report no competing interests. The authors alone are responsible for the content and writing of this article.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n\nConsent for publication\nNot applicable.\n\nEthics approval and consent to participate\nThe Institutional Review Board at Memorial Sloan Kettering Cancer Center approved of the proposal for this retrospective observational study.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Cronin SS Furle KL Kelly PJ Dose-related association of MTHFR C677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis Stroke 2005 36 7 1581 1587 10.1161/01.STR.0000169946.31639.af 15947278 \n2. Myles PS Chan MV Leslie K Effect of nitrous oxide on plasma homocysteine and folate in patients undergoing major surgery Br J Anaesth 2008 100 6 780 786 10.1093/bja/aen085 18400808 \n3. Abramson DH Dunkel IJ Brodie SE Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery) Ophthalmology 2010 117 8 1623 1629 10.1016/j.ophtha.2009.12.030 20381868 \n4. Shields CL Bianciotto CG Jabbour P Intra-arterial chemotherapy for retinoblastoma: report no. 2, treatment complications Arch Ophthalmol 2011 129 11 1407 1415 10.1001/archophthalmol.2011.151 21670326 \n5. Munier FL Beck-Popovic M Balmer A Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma Retina 2011 31 566 573 10.1097/IAE.0b013e318203c101 21273941 \n6. Eagle RC Shields CL Bianciotto CG Histopathologic observations after intra-arterial chemotherapy for retinoblastoma Arch Ophthalmol 2011 129 11 1416 1421 10.1001/archophthalmol.2011.223 21746972 \n7. Steinle JJ Zhang Q Thompson KE Intra-ophthalmic artery chemotherapy triggers vascular toxicity through endothelial cell inflammation and leukostasis Inv Ophthalmol Vis Sci 2012 53 4 2439 2445 10.1167/iovs.12-9466 \n8. Abramson DH Marr BP Brodie SE Intraocular hemorrhage after intra-arterial chemotherapy for retinoblastoma in sickle cell trait Open Ophthalmol J 2012 6 1 3 10.2174/1874364101206010001 22291865 \n9. Francis JH Gobin YP Nagiel A Thrombophilia in patients with retinoblastoma receiving ophthalmic artery chemosurgery Arch Ophthalmol 2012 130 12 1605 1608 10.1001/archophthalmol.2012.2284 23229706 \n10. Fegan CD Central retinal vein occlusion and thrombophilia Eye 2002 16 98 106 10.1038/sj.eye.6700040 11913903 \n11. Helt JA Thrombophilia: common questions on laboratory assessment and management Hematology Education Program 2007 2007 1 127 135 \n12. Folsom AR Tang W Roetker NS Prospective study of sickle cell trait and venous thromboembolism incidence J Thromb Haemost 2015 13 1 2 9 10.1111/jth.12787 25393788 \n13. Yang Q Botto LD Gallagher M Prevalence and effects of gene–gene and gene–nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank Am J Clin Nutr 2008 88 1 232 246 10.1093/ajcn/88.1.232 18614746 \n14. Badner NH Beattie SW Freeman D Spence DJ Nitrous oxide-induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy Anesth Analg 2000 91 5 1073 1079 11049886 \n15. Schaiquevich P Buitrago E Taich P Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients Arch Ophthalmol 2012 53 7 4205 4212 \n16. Abramson DH Gobin YP Dunkel I Highlighting complications over successes in occurrence of sectoral choroidal occlusive vasculopathy Retina 2011 31 8 1746 10.1097/IAE.0b013e31822650ab 21826040\n\n",
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"title": "Choroidal infarction following ophthalmic artery chemotherapy.",
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"abstract": "This paper explores how poor health outcomes in the HIV/AIDS and opioid epidemics in the United States are undergirded by iatrogenesis. Data are drawn from two projects in Southern California: one among men who have sex with men (MSM) engaging with pre-exposure prophylaxis to HIV (PrEP) and the other in a public hospital system encountering patients with chronic pain and opioid use disorder (OUD). Ethnographic evidence demonstrates how efforts to minimize risk via PrEP and opioid prescription regulation paradoxically generate new forms of risk. Biomedical risk management paradigms engaged across the paper's two ethnographic field sites hinge on the production and governance of deserving patienthood, which is defined by providers and experienced by patients through moral judgments about risk underlying both increased surveillance and abandonment. This paper argues that the logic of deservingness disconnects clinical evaluations of risk from patients' lived, intersectional experiences of race, class, gender, and sexuality. This paper's analysis thus re-locates patients in the context of broader historical and sociopolitical trajectories to highlight how notions of clinical risk designed to protect patients can in fact imperil them. Misalignment between official, clinical constructions of risk and the embodied experience of risk borne by patients produces iatrogenesis.",
"affiliations": "Department of Anthropology and David Geffen School of Medicine at UCLA, Los Angeles, California, USA.;Department of Anthropology and David Geffen School of Medicine at UCLA, Los Angeles, California, USA.",
"authors": "Textor|Lauren|L|https://orcid.org/0000-0003-1242-2967;Schlesinger|William|W|https://orcid.org/0000-0002-2096-972X",
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"issue": "28(2)",
"journal": "Anthropology & medicine",
"keywords": "HIV/AIDS; Risk; iatrogenesis; opioids",
"medline_ta": "Anthropol Med",
"mesh_terms": "D060432:Anthropology, Medical; D019380:Anti-HIV Agents; D001291:Attitude of Health Personnel; D005260:Female; D015658:HIV Infections; D018451:Homosexuality, Male; D006801:Humans; D007049:Iatrogenic Disease; D008297:Male; D008875:Middle Aged; D000080052:Opioid Epidemic; D009293:Opioid-Related Disorders; D065129:Pre-Exposure Prophylaxis; D012308:Risk Management; D014481:United States",
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"title": "Treating risk, risking treatment: experiences of iatrogenesis in the HIV/AIDS and opioid epidemics.",
"title_normalized": "treating risk risking treatment experiences of iatrogenesis in the hiv aids and opioid epidemics"
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"abstract": "The efficacy of temozolomide (TMZ) chemotherapy for treating newly diagnosed glioblastoma (GBM), a primary brain tumor with short survival, was demonstrated in a clinical trial in 2005, and since then, the standard-of-care for newly diagnosed GBM has been maximal safe surgery followed by 60 Gray of radiation with concomitant and adjuvant TMZ (standard radiotherapy and TMZ). In 2009, clinical trials also reported on the efficacy of bevacizumab for treating recurrent GBM. We performed a retrospective cohort study to evaluate the impact of treatment regimens on overall survival for patients with GBM at a rural tertiary healthcare practice.\nWe retrospectively reviewed the medical records of 307 consecutive, newly diagnosed GBM patients at one institution between 1995 and 2012 and assessed treatment patterns. We also compared overall survival according to the treatment received.\nOnly 0.6% (1/163) of patients diagnosed before 2005 received standard radiotherapy and TMZ versus 36.1% (52/144) of patients diagnosed since 2005 (P < 0.0001). For patients who received standard radiotherapy and TMZ, the median overall survival was 17.0 months versus 7.0 months for patients who received 60 Gray of radiation but no chemotherapy (P = 0.0000078). The median overall survival was 15.4 months in the 19 patients treated with bevacizumab monotherapy at first GBM recurrence versus 6.8 months in the 32 patients with no treatment at first GBM recurrence (P = 0.00015), but patients who received bevacizumab were younger and more likely to have had a surgical resection and 60 Gray of radiation at diagnosis.\nTMZ and bevacizumab therapies were rapidly adopted in a rural tertiary healthcare setting, and patients who received these treatments had increased overall survival. However, advantageous prognostic factors in patients who received bevacizumab at recurrence may have influenced the extent of the increase in overall survival attributed to this treatment.",
"affiliations": "Center for Human Genetics, Marshfield Clinic Research Institute, 1000 North Oak Avenue, Marshfield, WI 54449, USA.;Department of Pathology (Neuropathology), Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449, USA.;Department of Neurology (Neuro-oncology), Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449, USA.",
"authors": "Carter|Tonia C|TC|0000-0002-2107-7838;Medina-Flores|Rafael|R|;Lawler|Benjamin E|BE|",
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"fulltext": "\n==== Front\nBiomed Res IntBiomed Res IntBMRIBioMed Research International2314-61332314-6141Hindawi 10.1155/2018/6204676Research ArticleGlioblastoma Treatment with Temozolomide and Bevacizumab and Overall Survival in a Rural Tertiary Healthcare Practice http://orcid.org/0000-0002-2107-7838Carter Tonia C. carter.tonia@mcrf.mfldclin.edu\n1\nMedina-Flores Rafael \n2\nLawler Benjamin E. \n3\n\n1Center for Human Genetics, Marshfield Clinic Research Institute, 1000 North Oak Avenue, Marshfield, WI 54449, USA\n2Department of Pathology (Neuropathology), Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449, USA\n3Department of Neurology (Neuro-oncology), Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449, USAAcademic Editor: PD Dr. Thomas Reithmeier\n\n2018 31 12 2018 2018 62046769 8 2018 3 11 2018 2 12 2018 Copyright © 2018 Tonia C. Carter et al.2018This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\n The efficacy of temozolomide (TMZ) chemotherapy for treating newly diagnosed glioblastoma (GBM), a primary brain tumor with short survival, was demonstrated in a clinical trial in 2005, and since then, the standard-of-care for newly diagnosed GBM has been maximal safe surgery followed by 60 Gray of radiation with concomitant and adjuvant TMZ (standard radiotherapy and TMZ). In 2009, clinical trials also reported on the efficacy of bevacizumab for treating recurrent GBM. We performed a retrospective cohort study to evaluate the impact of treatment regimens on overall survival for patients with GBM at a rural tertiary healthcare practice.\n\n Methods\n We retrospectively reviewed the medical records of 307 consecutive, newly diagnosed GBM patients at one institution between 1995 and 2012 and assessed treatment patterns. We also compared overall survival according to the treatment received.\n\n Results\n Only 0.6% (1/163) of patients diagnosed before 2005 received standard radiotherapy and TMZ versus 36.1% (52/144) of patients diagnosed since 2005 (P < 0.0001). For patients who received standard radiotherapy and TMZ, the median overall survival was 17.0 months versus 7.0 months for patients who received 60 Gray of radiation but no chemotherapy (P = 0.0000078). The median overall survival was 15.4 months in the 19 patients treated with bevacizumab monotherapy at first GBM recurrence versus 6.8 months in the 32 patients with no treatment at first GBM recurrence (P = 0.00015), but patients who received bevacizumab were younger and more likely to have had a surgical resection and 60 Gray of radiation at diagnosis.\n\n Conclusions\n TMZ and bevacizumab therapies were rapidly adopted in a rural tertiary healthcare setting, and patients who received these treatments had increased overall survival. However, advantageous prognostic factors in patients who received bevacizumab at recurrence may have influenced the extent of the increase in overall survival attributed to this treatment.\n\nphilanthropic gifts in support of medical research at Marshfield ClinicNational Institutes of Health–National Center for Advancing Translational SciencesUL1TR000427\n==== Body\n1. Introduction\nGlioblastoma (GBM) is an aggressive, infiltrative, primary brain malignancy with a poor prognosis [1]. Median survival without treatment is 2-3 months [2, 3]. Surgical resection to reduce tumor volume and postoperative radiotherapy administered to a total dose of 60 Gray (Gy) in 30 fractions are associated with improved survival [4, 5], and surgical resection with subsequent radiotherapy was used to treat new GBM cases diagnosed before 2005 [6]. In 2005, a prospective, randomized trial showed that adding concurrent and adjuvant temozolomide (TMZ), an alkylating agent that causes DNA damage leading to tumor cell death, to standard postoperative radiotherapy (60 Gy/30 fractions) increased median overall survival from 12.1 to 14.6 months [7]. Therefore, since 2005, maximal safe surgery (biopsy or resection) that preserves performance status, 60 Gy of radiation, and concomitant and adjuvant TMZ chemotherapy is considered the standard treatment for newly diagnosed GBM [7]. However, despite initial treatment, GBM often recurs [8]. Bevacizumab, an angiogenesis inhibitor that can retard tumor growth [9], received provisional approval from the United States Food and Drug Administration (FDA) in 2009 for the treatment of recurrent GBM on the basis of results from two clinical trials that showed progression-free survival increased after bevacizumab treatment of recurrent GBM [10, 11], and received full approval in 2017 [12].\n\nWe reviewed the treatment and survival of adult patients consecutively diagnosed with GBM at one rural tertiary healthcare practice between 1995 and 2012, a time period that includes several years before and after TMZ was introduced for newly diagnosed GBM and bevacizumab was approved for the treatment of recurrent GBM. To determine whether these treatments were translated into clinical practice in a rural healthcare setting, we compared treatment type before and after TMZ was introduced and examined the details of GBM treatment in patients who received bevacizumab. To assess whether the treatments showed evidence of a survival benefit, we compared overall survival according to use of the standard-of-care regimen at diagnosis or use of bevacizumab at first GBM recurrence and also evaluated the treatments for independent associations with overall survival. Because many GBM patients are elderly [13], we also compared treatment type and survival according to patient age, as clinical trials of treatments for GBM have often excluded older patients [5, 7].\n\n2. Materials and Methods\n2.1. Subjects\nPatients were identified retrospectively from medical records at Marshfield Clinic, a multispecialty clinic with affiliated hospitals in Wisconsin, USA, that serves a predominantly rural population. Patients were included in the study if they were newly diagnosed with GBM between 1995 and 2012 and at least 18 years of age at the time of diagnosis. Pathology reports and available histopathological material were reviewed by a neuropathologist to confirm the diagnosis of GBM (World Health Organization grade IV astrocytoma) for each patient. Patients without histological confirmation of GBM or who were diagnosed with GBM at autopsy only were excluded. The research was carried out according to the principles outlined in the Declaration of Helsinki (1964) and all subsequent revisions, and the Institutional Review Board of the Marshfield Clinic Research Institute approved the study.\n\n2.2. Healthcare Setting\nThe primary service area of Marshfield Clinic comprises 28 counties in central and northern Wisconsin and Gogebic county in Michigan. In 20 of the 29 counties, ≥ 60% of the population lives in a rural area (city or town with < 2,500 people), according to the 2010 United States Census [14, 15]. For the year 2012, the median (interquartile range) distance between patient residential address in the medical record and the Marshfield Clinic facility where healthcare was received was 19.3 (0.0-43.5) kilometers. The distance to a Marshfield Clinic facility was calculated using an algorithm that matched patient and facility addresses to zip code regions, assigned each address to the center point of its matching zip code region, and calculated the distance between zip code center points. Five linear accelerators, each located at one of five different Marshfield Clinic facilities within the Marshfield Clinic primary service area, were available for radiotherapy services. The team of physicians providing healthcare to GBM patients included specialists in neuro-oncology, neuro-pathology, neuro-surgery, radiation-oncology, neuro-radiology, and neuro-psychology.\n\n2.3. Demographic and Clinical Data\nMedical records were reviewed to obtain data on patient age at GBM diagnosis, sex, race, year of GBM diagnosis, presenting symptoms, comorbidities, extent of surgery, tumor location and size, use of radiotherapy and chemotherapy, tumor recurrence, and date of death. Comorbidities were represented in this study by the Charlson comorbidity score, a weighted sum of comorbid conditions based on the risk of mortality for each condition [16]. A score of zero indicates no comorbidities, and the higher the score, the greater the burden of comorbidities. The extent of surgery was based on surgery reports, and tumor size and location were obtained from neuroimaging reports. Tumor size was defined as the largest diameter of contrast-enhancing tumor. Overall survival was the only survival outcome analyzed and was measured from the date of surgery for GBM until either the date of death or December 31, 2015.\n\n2.4. Statistical Analysis\nData were summarized as mean ± standard deviation for parametric variables and median (interquartile range) for nonparametric variables. Groups were compared using the chi-squared test for categorical data and the Wilcoxon rank sum test for continuous data.\n\nNo patients were lost to follow-up and data were censored for patients alive on December 31, 2015. For bivariate analyses, survival curves were generated using the Kaplan-Meier method and were compared using the log-rank test. Cox proportional hazards regression analysis was used to determine whether TMZ and bevacizumab therapies were independently associated with survival in a multiple regression model. All variables associated with survival in bivariate analyses (P < 0.10) were included as covariates in the regression model. Statistical significance was considered as a two-sided P value < 0.05.\n\n3. Results\n3.1. Patient and Clinical Characteristics\nBetween 1995 and 2012, 307 adult patients were newly diagnosed with GBM. The mean age at diagnosis was 64.9 ± 13.9 years; 59% of patients were male, 96% were Caucasian, and approximately 50% had comorbid conditions (Table 1). Fifty-three percent of patients were diagnosed before 2005, the year when TMZ chemotherapy for newly diagnosed GBM was introduced. One or more presenting symptoms were reported for every patient, and headaches were the most commonly reported symptom. The tumor was surgically resected in 58.6% of patients and 36.8% had a biopsy only. The reason for not receiving a surgical resection was noted in the medical records of 22.1% (25/113) of patients who received a biopsy. Of the 25 patients, 12 had a tumor that was deemed not able to be resected because the tumor was located in or near eloquent brain areas or was bilateral, another 10 had severe neurological deficits and it was considered unlikely that a surgical resection would reverse the deteriorating clinical course of these patients, and the remaining three patients declined any type of treatment and chose to receive supportive care instead. Radiotherapy was documented in the medical records of 218 patients and 67.4% (n = 147) of these patients received 60 Gy of radiation. The extent of surgery and the radiation dose were unknown for some patients who received these treatments at other institutions. Of the 176 patients who had chemotherapy, 130 (73.9%) were treated with TMZ. Tumors were most often located in the frontal, temporal, and parietal areas of the brain and often occupied more than one lobe. GBM was less common in the thalamus, cerebellum, and brainstem. Tumor size was available for 254 patients, and mean tumor size was 4.4 ± 1.6 cm.\n\n3.2. Treatment before and after Widespread Use of Temozolomide\nWe defined standard treatment as maximal safe surgery followed by standard radiotherapy (60 Gy), completion of concomitant TMZ, and completion of at least one cycle of adjuvant TMZ. The percentage of patients who received any radiotherapy, standard radiotherapy, any chemotherapy, TMZ chemotherapy, or standard treatment was higher when the diagnosis occurred during 2005-2012 than during 1995-2004 (Table 2). Of the 112 patients who received TMZ after a GBM diagnosis in 2005-2012, 103 (92.0%) started concomitant TMZ and 69 (61.6%) started adjuvant TMZ. Sixty (53.6%) of the 112 patients completed concomitant TMZ and at least one cycle of adjuvant TMZ, 27 (24.1%) patients completed concomitant TMZ but did not receive any adjuvant TMZ, nine (8.0%) patients completed at least one cycle of adjuvant TMZ without having received any concomitant TMZ, and 16 (14.3%) patients started but did not complete concomitant TMZ and also did not receive any adjuvant TMZ. The reasons for not completing concomitant or adjuvant TMZ included disease progression (n = 27), toxic effects (n = 13), patient refusal to continue treatment (n = 5), and the poor medical condition of the patient (n = 2). The reasons were unknown for another five patients. Thirty-two (22.2%) of the 144 patients diagnosed during 2005-2012 were not treated with TMZ. The reasons for not receiving TMZ included the decision of the patient to decline further treatment and to continue with supportive care only (n = 19 patients), the development of severe illness after surgery that led to a worsening of the medical condition of the patient (n = 2 patients), and the presence of complications due to serious comorbidites (n = 1 patient). The reason for the remaining 10 of the 32 patients was unknown because a reason was not documented in their medical records.\n\n3.3. Treatment by Age at Diagnosis\nA comparison between patients ≥ 65 years at diagnosis and those < 65 years at diagnosis showed that older patients experienced more comorbid conditions, were less likely to have surgical resection, 60 Gy of radiation, TMZ chemotherapy, or standard treatment, and were more likely to have no radiotherapy and no chemotherapy than younger patients (Table 3).\n\n3.4. Bevacizumab Treatment\nSixty patients received bevacizumab treatment and for 10 (16.7%) of these patients, bevacizumab was administered before GBM recurrence. One of the 10 patients was included in a clinical trial that used bevacizumab as first-line treatment. For the other nine patients, subtle increases in tumor size were observed following the start of radiotherapy and chemotherapy, and patients were given bevacizumab because it was uncertain whether these changes were due to tumor progression or the effects of treatment. The other 50 (83.3%) of the 60 patients were treated with bevacizumab after GBM recurrence, determined from brain imaging reports that indicated an increase in tumor size or the appearance of new lesions. Forty-three (86.0%) of the 50 patients received bevacizumab at the first recurrence and seven (14.0%) at the second recurrence. Patients who were treated with bevacizumab also received radiotherapy and TMZ during the course of treatment (Table 4). Bevacizumab was received at the first or second GBM recurrence by 24.1% (33/137) of patients diagnosed at age < 65 years compared with 10.0% (17/170) of patients diagnosed at age ≥ 65 years (P = 0.00089).\n\n3.5. Patient Overall Survival\nThree hundred and one (98.0%) of the 307 patients were deceased at last follow-up and the median survival in our patient population was 7.6 (3.2-14.9) months. The percentage of patients that survived one, two, and five years was 32.6%, 11.4%, and 2.3%, respectively. Median survival in the 53 patients who received the standard treatment was 17.0 (13.3-27.1) months compared with 7.0 (4.4-11.5) months in the 29 patients who received 60 Gy of radiation but no chemotherapy (P = 0.0000078). The median survival in patients ≥ 65 years was 5.2 (2.0-9.5) months compared with 12.0 (5.9-18.6) months in patients < 65 years (P < 0.0001). When analyzed by type of treatment received, the median overall survival did not differ by age group for patients who received the standard treatment and for those who received no treatment (biopsy only) (Table 5). However, the median overall survival was significantly extended in younger patients who received TMZ but did not complete the standard regimen and those who received treatment that did not include TMZ.\n\n3.6. Overall Survival with Bevacizumab Treatment\nBecause the 43 patients treated with bevacizumab at first GBM recurrence had all received some radiotherapy and TMZ chemotherapy at diagnosis, we compared survival in these patients with survival in the 54 patients who received some radiotherapy and TMZ chemotherapy at diagnosis but no bevacizumab at first GBM recurrence. The groups included in the analysis were the 24 patients who received bevacizumab with other chemotherapy and/or radiotherapy at first GBM recurrence, the 19 patients who received bevacizumab alone at first GBM recurrence, 22 patients who received other (non-bevacizumab) treatment at first GBM recurrence, and 32 patients who received no treatment at first GBM recurrence. The median survival was 17.8 (13.5-29.2) months in patients treated with bevacizumab and other agents, 15.4 (9.2-19.7) months in patients treated with bevacizumab alone, 13.6 (6.1-20.0) months in patients who received other (non-bevacizumab) treatment only, and 5.6 (3.4-9.8) months in patients who received no treatment at first GBM recurrence (Figure 1). Patients who received no treatment had a median survival that was significantly shorter than that of patients treated with bevacizumab and other agents (P = 0.0000033) and patients treated with bevacizumab alone (P = 0.00015) (Figure 1). The median survival in patients who received other (non-bevacizumab) treatment was not significantly different from that of patients who received bevacizumab and other agents (P = 0.064) or patients who received bevacizumab alone (P = 0.48). Also, the median survival in patients treated with bevacizumab and other agents did not differ significantly from that of patients treated with bevacizumab alone (P = 0.17).\n\nWe considered the possibility that factors other than bevacizumab treatment, such as age, extent of surgery, and dose of radiation at diagnosis, may have contributed to the difference in median overall survival between patients who received bevacizumab and those who received no treatment at first GBM recurrence. The median age at diagnosis was 61.9 (54.7-67.4) years in the 43 patients who received bevacizumab treatment (with or without other agents) at first recurrence versus 70.6 (63.8-79.9) years in the 32 patients with no treatment at first recurrence (P = 0.0011). The percentage of patients who had a surgical resection at diagnosis was 67.4% (29/43) for patients treated with bevacizumab at first recurrence versus 40.6% (13/32) for patients with no treatment at first recurrence (P = 0.021). Additionally, the percentage of patients who were given 60 Gy of radiation at diagnosis was 83.7% (36/43) for patients with bevacizumab treatment at first recurrence compared with 50.0% (16/32) for patients with no treatment at first recurrence (P = 0.0017). Because of the small sample size, analyses were not performed for the group of seven patients treated with bevacizumab after the second GBM recurrence.\n\n3.7. Factors Associated with Survival\nIn bivariate analyses, decreased survival was associated with age ≥ 65 years at diagnosis, no surgical resection of the tumor, < 60 Gy of radiation or no radiotherapy, non-TMZ chemotherapy or no chemotherapy, a Charlson comorbidity score > 0, and tumor location in the occipital region or corpus callosum (Table 6). Patient sex, type of presenting symptoms, tumor size > 5 cm, and tumor location in regions other than the occipital region or corpus callosum were not associated with survival (P > 0.10). In Cox proportional hazards regression analysis, TMZ chemotherapy with or without bevacizumab was independently associated with increased survival (Table 6).\n\n4. Discussion\nAt our institution, the standard treatment became more widely used soon after demonstration of the ability of TMZ chemotherapy to increase survival in a clinical trial, and survival was longer in patients who received the standard treatment, consistent with reports from other population-based studies [2, 17, 18]. Patients who were ≥ 65 years at diagnosis were less likely to receive the standard treatment, and for both older and younger patients, survival with the standard treatment was longer than survival with other treatment or no treatment, indicating that improved survival after standard treatment was not restricted to younger patients. The lower probability of receiving surgical resection and adjuvant treatment with increasing patient age [2, 18, 19] as well as improved survival for older patients who received the standard treatment [20, 21] have been documented previously. We also observed that TMZ chemotherapy (with or without use of bevacizumab) was an independent predictor of survival in our study population and that tumor location in the occipital region or corpus callosum was associated with shorter survival in bivariate analyses. Surgical resection is often not performed for tumors in the occipital region or corpus callosum because aggressive surgery can lead to loss of function, and in the regression model adjusted for extent of surgery and other covariates, tumor location in these brain regions was no longer associated with survival.\n\nOf the 307 patients in our study, 36.8% received a biopsy, and of the 144 patients diagnosed during the period 2005-2012, 77.8% received radiotherapy, 77.8% received some TMZ, and 41.7% received concomitant and adjuvant TMZ. Similar findings have been reported in previous studies of patterns of care for GBM but estimates varied among studies. In these studies, 4.6-44.4% of patients received a biopsy [18, 22–25], and since 2005, 72.2-80.0% of patients received radiotherapy [18, 25, 26], 59.9-70.7% of patients received some TMZ chemotherapy [17, 18, 26, 27], and 51.2-57.0% of patients received concomitant and adjuvant TMZ [18, 27]. Also, of the 144 patients diagnosed during 2005-2012 at our institution, 18.1% received neither radiotherapy nor chemotherapy, which is comparable to the range of 20.0-22.3% reported in previous studies for patients diagnosed since 2005 and who received no radiotherapy and no chemotherapy [18, 25].\n\nOur findings that a substantial fraction of the study population received a biopsy as maximal safe surgery and as much as 22.2% of patients diagnosed in 2005-2012 were not given TMZ motivate consideration of the factors that influence decisions about GBM treatment at our institution. The available medical record data indicated that the presence of a tumor not amenable to resection, the poor medical condition of the patient, and patient preference were among the factors involved. In a study of GBM patients diagnosed after 2005 in Spain, reasons why patients received no radiotherapy and no chemotherapy after surgery included low performance status, surgical complications, tumor-related symptoms, probable tumor progression, and patient decision [18]. Information on why patients in our study did not get treatment was limited because the reasons were often not stated in the medical records. However, documenting and evaluating these reasons potentially could facilitate identification of the main factors that influence physicians and patients when making treatment decisions about GBM, enhance understanding of how patients make treatment decisions during a crisis such as a GBM diagnosis, and reveal opportunities for improving the oncological care of GBM patients at our institution.\n\nBevacizumab at first GBM recurrence was associated with a statistically significant increase in overall survival when compared with no treatment in this study. In a systematic review of 17 other studies, a gain in overall survival with use of bevacizumab compared with use of other treatment for recurrent GBM has been observed [28]. Median overall survival was 39.5 ± 6.2 weeks for bevacizumab combination therapy and 36.2 ± 3.8 weeks for bevacizumab monotherapy compared with 22.4± 4.3 weeks for other treatment for recurrent GBM (based on five studies of other treatment). However, many of these studies did not have adequate control groups of patients unexposed to bevacizumab and, in nine of the studies, only patients with good performance status were included [28]. In our study population, several factors that were independent predictors of longer overall survival in GBM (younger age, surgical resection, and standard postoperative radiotherapy at diagnosis) were more common in patients who received bevacizumab than in patients who received no treatment at first GBM recurrence. This indicates a need for caution when interpreting our study's findings because our comparison between bevacizumab treatment and no treatment probably did not provide an unbiased estimate of the effect of bevacizumab treatment at GBM recurrence on overall survival. In two randomized, controlled trials of bevacizumab treatment at GBM recurrence, overall survival did not differ significantly between patients on bevacizumab monotherapy and those on lomustine monotherapy, and whereas progression-free survival increased for patients who received the combination therapy of bevacizumab added to lomustine compared with those who received lomustine monotherapy, the combination therapy did not result in a gain in overall survival [29, 30]. Therefore, the efficacy of bevacizumab for the treatment of recurrent GBM is in question.\n\nThe limited options currently available for the treatment of recurrent GBM also include tumor-treating fields, electric fields that are delivered by a noninvasive, portable device and that can physically disrupt cell division leading to antimitotic effects on tumor cells [31]. The FDA approved this therapy for recurrent glioblastoma in 2011 based on the results of a randomized, controlled trial which showed that median overall survival was comparable between tumor-treating fields and chemotherapy regimens and that tumor-treating fields provided the added benefit of reduced toxicity and improved quality of life [32]. Following this, the FDA also approved tumor-treating fields therapy for newly diagnosed GBM based on observations in a randomized, controlled trial that overall survival and progression-free survival were longer when patients received tumor-treating fields with maintenance chemotherapy compared with maintenance chemotherapy only at GBM diagnosis [33]. Although tumor-treating fields therapy was demonstrated to be efficacious in this trial, median overall survival in newly diagnosed patients who received the therapy was no longer than two years [33]; therefore, the development of new treatments that further improve patient outcomes remains a priority for GBM research.\n\nAn advantage of this study was the availability of clinical data for an unselected patient population seen in routine clinical practice in a rural tertiary healthcare center. These patients had less opportunity to participate in research treatment protocols established in many academic centers to treat newly diagnosed or recurrent GBM. Yet, data on this patient population allowed us to assess changes in GBM treatment that occurred once reports demonstrating the efficacy of new treatments became available and to evaluate the effects of the new treatments on survival in patients who were not required to meet any specific criteria such as those used to select patients for enrollment in clinical trials. Disadvantages included the lack of data on several factors known to be associated with prognosis including performance status [34], marital status [4], and molecular markers such as promoter methylation of the O-6 methylguanine-DNA methyltransferase gene [35] and mutations in the isocitrate dehydrogenase 1 gene [36]. Molecular testing was performed only at the discretion of clinicians to aid histological classification of the tumor; however, our institution plans to incorporate a next-generation sequencing gene panel tailored for gliomas [37] into the diagnostic process for GBM in the future. Another disadvantage was the limited data available on tumor progression, residual tumor volume after surgical resection, the decision-making process for selecting treatment, and quality of life. Additionally, because this study was retrospective, direct causal relationships between treatment type and survival should not be inferred.\n\n5. Conclusions\nThis study captured one rural healthcare institution's transition to treating GBM with TMZ and bevacizumab once these therapies were introduced. The standard regimen of maximal safe surgery, standard radiotherapy, and concomitant and adjuvant TMZ chemotherapy was more often used to treat patients diagnosed since 2005 than patients diagnosed in previous years, and patients who received this regimen survived longer than patients who received standard radiotherapy without TMZ chemotherapy. Overall survival improved with bevacizumab treatment compared with no treatment at first GBM recurrence but because patients who received bevacizumab at first recurrence had more favorable prognostic factors than patients who received no treatment at first recurrence, the magnitude of the observed increase in survival with bevacizumab treatment may be biased by these prognostic factors. Few studies of GBM in rural populations have been done and ours supports continued use of standard radiotherapy with concomitant and adjuvant TMZ chemotherapy for treatment of GBM in a rural tertiary healthcare setting.\n\nAcknowledgments\nWe are grateful to the staff of the Center for Clinical Epidemiology and Population Health and the Histology Laboratory at Marshfield Clinic for assistance with data collection. We also thank Ronald Hamilton for providing valuable comments on the manuscript. This work was supported by philanthropic gifts in support of medical research at Marshfield Clinic and by the National Institutes of Health–National Center for Advancing Translational Sciences [grant number UL1TR000427].\n\nData Availability\nThe data used to support the findings of this study are available from the corresponding author upon request.\n\nConflicts of Interest\nBenjamin E. Lawler owns stock in Novocure. The other authors declare that they have no conflicts of interest regarding the publication of this paper.\n\nFigure 1 Overall survival according to bevacizumab treatment at first glioblastoma recurrence. Sample sizes were n = 24 for patients who received bevacizumab and other agents (BVZ and other), n = 19 for patients who received bevacizumab alone (BVZ alone), n = 22 for patients who received only non-bevacizumab treatment (Other), and n = 32 for patients who received no treatment (None). The distance spanned by the bottom and top of each box represents the interquartile range, the enclosed line represents the 50th percentile, and the whiskers stretch to the data point that is not > 1.5 times the interquartile range from the box. Data points that fell outside the range of the whiskers were represented by small, open circles. ∗P = 0.0000033 and ∗∗P = 0.00015 for paired comparisons between treatment groups using Wilcoxon rank sum test. Abbreviation: BVZ, bevacizumab.\n\nTable 1 Characteristics of patients diagnosed with glioblastoma.\n\nCharacteristic\t\nn (%)\t\nAge at diagnosis (years)\t \t\n 18-39\t15 (4.9)\t\n 40-49\t29 (9.4)\t\n 50-59\t58 (18.9)\t\n 60-69\t85 (27.7)\t\n 70-79\t75 (24.4)\t\n ≥ 80\t45 (14.7)\t\nYear of diagnosis\t \t\n 1995-1999\t89 (29.0)\t\n 2000-2004\t74 (24.1)\t\n 2005-2009\t89 (29.0)\t\n 2010-2012\t55 (17.9)\t\nMale\t181 (59.0)\t\nRace\t \t\n White\t295 (96.0)\t\n African-American\t1 (0.3)\t\n Asian\t2 (0.7)\t\n American Indian or Alaska native\t2 (0.7)\t\n Unknown\t7 (2.3)\t\nCharlson comorbidity score\t \t\n 0\t155 (50.5)\t\n 1\t29 (9.5)\t\n 2\t60 (19.5)\t\n ≥ 3\t63 (20.5)\t\nPresenting symptoms\t \t\n Headaches\t160 (52.1)\t\n Seizures\t75 (24.4)\t\n Nausea/vomiting\t48 (15.6)\t\n Sensory deficit1\t56 (18.2)\t\n Motor deficit2\t137 (44.6)\t\n Confusion/memory loss\t175 (57.0)\t\nExtent of surgery\t \t\n Resection\t180 (58.6)\t\n Biopsy\t113 (36.8)\t\n Unknown\t14 (4.6)\t\nRadiation dose\t \t\n 60 Gy\t147 (47.9)\t\n < 60 Gy\t47 (15.3)\t\n Unknown dose\t24 (7.8)\t\n No radiotherapy\t89 (29.0)\t\nChemotherapy\t \t\n Temozolomide only\t44 (14.3)\t\n Temozolomide and other agents\t86 (28.0)\t\n Non-temozolomide agents only\t46 (15.0)\t\n No chemotherapy\t131 (42.7)\t\nTumor location - supratentorial\t \t\n Frontal\t124 (40.4)\t\n Parietal\t105 (34.2) \t\n Temporal\t136 (44.3)\t\n Occipital\t43 (14.0)\t\n Corpus callosum\t42 (13.7)\t\n Thalamus\t13 (4.2)\t\nTumor location - infratentorial\t \t\n Cerebellum\t11 (3.6)\t\n Brainstem\t6 (2.0)\t\nTumor location - unknown\t4 (1.3)\t\n\n1A sensory deficit was defined as decreased sensation to any stimulus. 2A motor deficit was defined as decreased strength and/or difficulty with movement or coordination.\n\nTable 2 Treatment with surgical resection, radiotherapy, and chemotherapy by time period of glioblastoma diagnosis.\n\nTreatment\tTime period of diagnosis\t\nP-value1\t\n1995-2004\t2005-2012\t\n\nn = 163\t\nn = 144\t\n\nn (%)\t\nn (%)\t\nSurgical resection\t100 (61.3)\t80 (55.6)\t0.30\t\nAny radiotherapy\t106 (65.0)\t112 (77.8)\t0.014\t\n60 Gray of radiation\t66 (40.5)\t81 (56.3)\t0.0058\t\nAny chemotherapy\t63 (38.7)\t113 (78.5)\t< 0.0001\t\nTemozolomide chemotherapy\t18 (11.0)\t112 (77.8)\t< 0.0001\t\nOther (non-temozolomide) chemotherapy\t45 (27.6)\t1 (0.7)\t< 0.0001\t\nConcomitant and adjuvant temozolomide chemotherapy\t2 (1.2)\t60 (41.7)\t< 0.0001\t\nStandard treatment2\t1 (0.6)\t52 (36.1)\t< 0.0001\t\nRadiotherapy without chemotherapy\t50 (30.7)\t5 (3.5)\t< 0.0001\t\nNo radiotherapy and no chemotherapy\t50 (30.7)\t26 (18.1)\t0.011\t\n\n1Chi-squared test used to compare the percentage of patients between the two time periods.\n\n\n2Standard treatment was maximal safe surgery, postoperative administration of 60 Gray of radiation, completion of concomitant temozolomide chemotherapy, and completion of at least one cycle of adjuvant temozolomide.\n\nTable 3 Glioblastoma patient comorbidities and treatments according to age at diagnosis.\n\nCharacteristic\tAge at diagnosis\t\nP-value1\t\n< 65 years\t≥ 65 years\t\n\nn = 137\t\nn = 170\t\n\nn (%)\t\nn (%)\t\nCharlson comorbidity score\t \t \t< 0.0001\t\n 0\t90 (65.7)\t65 (38.2)\t \t\n 1\t8 (5.8)\t21 (12.4)\t \t\n 2\t23 (16.8)\t37 (21.8)\t \t\n ≥ 3\t16 (11.7)\t47 (27.6)\t \t\nExtent of surgery\t \t \t0.00065\t\n Resection\t89 (65.0)\t91 (53.5)\t \t\n Biopsy\t37 (27.0)\t76 (44.7)\t \t\n Unknown\t11 (8.0)\t3 (1.8)\t \t\nRadiation dose\t \t \t0.00026\t\n 60 Gy\t84 (61.3)\t63 (37.1)\t \t\n < 60 Gy\t18 (13.1)\t29 (17.0)\t \t\n Unknown dose\t9 (6.6)\t15 (8.8)\t \t\n No radiotherapy\t26 (19.0)\t63 (37.1)\t \t\nChemotherapy\t \t \t< 0.0001\t\n Temozolomide with or without other agents\t70 (51.1)\t60 (35.3)\t \t\n Non-temozolomide agents only\t30 (21.9)\t16 (9.4)\t \t\n No chemotherapy\t37 (27.0)\t94 (55.3)\t \t\nStandard treatment\t38 (27.7)\t15 (8.8)\t< 0.0001\t\nNo radiation and no chemotherapy\t20 (14.6)\t56 (32.9)\t0.00021\t\n\n1Chi-squared test used to compare characteristics between the two age groups.\n\nTable 4 Treatments for glioblastoma administered to 60 patients who received bevacizumab therapy.\n\nBevacizumab treatment sub-groups (number of subjects) \tPeriod when treatment for glioblastoma was received\tTreatment received for glioblastoma\t\nSurgical resection\tAny radiotherapy\tTemozolomide\tBevacizumab\tOther chemotherapy\t\n\nn (%)\t\nn (%)\t\nn (%)\t\nn (%)\t\nn (%)\t\nBevacizumab received before tumor recurrence (n = 10)\tAt diagnosis\t9 (90.0)\t10 (100.0)\t10 (100.0)\t10 (100.0)\t2 (20.0)\t\nAt first recurrence\t2 (20.0)\t0 (0.0)\t0 (0.0)\t2 (20.0)\t3 (30.0)\t\n\n\n\t\nBevacizumab received at first tumor recurrence (n = 43)\tAt diagnosis\t29 (67.4)\t43 (100.0)\t43 (100.0)\t0 (0.0)\t0 (0.0)\t\nAt first recurrence\t0 (0.0)\t2 (4.7)\t9 (20.9)\t43 (100.0)\t19 (44.2)\t\n\n\n\t\nBevacizumab received at second tumor recurrence (n = 7)\tAt diagnosis\t7 (100.0)\t6 (85.7)\t5 (71.4)\t0 (0.0)\t2 (28.6)\t\nAt first recurrence\t7 (100.0)\t3 (42.9)\t6 (85.7)\t0 (0.0)\t1 (14.3)\t\nAt second recurrence\t0 (0.0)\t1 (14.3)\t0 (0.0)\t7 (100.0)\t5 (71.4)\t\nTable 5 Overall survival according to treatment for glioblastoma and age at diagnosis.\n\nTreatment received\t< 65 years of age at diagnosis\t≥ 65 years of age at diagnosis\t\nP-value1\t\n\nn\n\tOverall survival (months)\t\nn\n\tOverall survival (months)\t\nStandard radiotherapy with concomitant and adjuvant temozolomide\t38\t18.9 (13.7-29.4)\t15\t16.4 (10.0-19.1)\t0.14\t\nOther treatment including temozolomide\t32\t12.5 (8.1-19.6)\t45\t6.5 (3.9-13.0)\t0.0036\t\nOther non-temozolomide treatment\t55\t10.2 (5.4-13.8)\t76\t5.5 (2.1-8.6)\t0.0013\t\nNo treatment\t12\t1.9 (1.0-4.1)\t34\t1.5 (0.6-3.5)\t0.40\t\n\n1Wilcoxon rank sum test used for comparing overall survival between the two age groups.\n\nTable 6 Factors associated with survival in patients with glioblastoma.\n\nFactor\tLog rank test P-value1\tHazard ratio\t95% Confidence interval\t\nP-value\t\nAge at diagnosis (years)2\t< 0.0001\t1.02\t1.01, 1.03\t0.00015\t\nExtent of surgery (Ref: Biopsy)\t< 0.0001\t \t \t \t\n Resection\t \t0.52\t0.40, 0.67\t< 0.0001\t\n Unknown\t \t0.63\t0.35, 1.13\t0.12\t\nRadiation dose (Ref: No radiotherapy)\t< 0.0001\t \t \t \t\n 60 Gy\t \t0.67\t0.48, 0.93\t0.015\t\n < 60 Gy\t \t0.98\t0.66, 1.46\t0.93\t\n Unknown\t \t0.90\t0.54, 1.48\t0.67\t\nChemotherapy (Ref: No chemotherapy)\t< 0.0001\t \t \t \t\n Temozolomide and bevacizumab\t \t0.32\t0.22, 0.49\t< 0.0001\t\n Temozolomide without bevacizumab\t \t0.58\t0.41, 0.82\t0.0018\t\n Non-temozolomide agents only\t \t0.68\t0.46, 1.01\t0.054\t\nCharlson comorbidity score2\t0.049\t1.06\t0.99, 1.13\t0.12\t\nTumor located in occipital region – Yes/No (Ref: No)\t0.0044\t1.33\t0.95, 1.86\t0.10\t\nTumor located in corpus callosum – Yes/No (Ref: No)\t0.00066\t1.27\t0.90, 1.79\t0.17\t\n\n1Age at diagnosis and Charlson comorbidity score were categorized to perform the log rank test. For age at diagnosis, two categories were compared: < 65 years and ≥ 65 years. For Charlson comorbidity score, three categories were compared: 0, 1-2, and ≥ 3.\n\n\n2Age at diagnosis and Charlson comorbidity score were continuous variables in the Cox proportional hazards regression model.\n==== Refs\n1 Thakkar J. P. Dolecek T. A. Horbinski C. Epidemiologic and molecular prognostic review of glioblastoma Cancer Epidemiology, Biomarkers & Prevention 2014 23 10 1985 1996 2-s2.0-84907565288 10.1158/1055-9965.EPI-14-0275 \n2 Yabroff K. R. Harlan L. Zeruto C. Abrams J. Mann B. Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006 Neuro-Oncology 2012 14 3 351 359 10.1093/neuonc/nor218 22241797 \n3 Brodbelt A. Greenberg D. Winters T. Williams M. Vernon S. Collins V. P. Glioblastoma in England: 2007–2011 European Journal of Cancer 2015 51 4 533 542 10.1016/j.ejca.2014.12.014 2-s2.0-84924959583 25661102 \n4 Pan I. Ferguson S. D. Lam S. Patient and treatment factors associated with survival among adult glioblastoma patients: A USA population-based study from 2000–2010 Journal of Clinical Neuroscience 2015 22 10 1575 1581 10.1016/j.jocn.2015.03.032 26122381 \n5 Bleehen N. M. Stenning S. P. A medical research council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma British Journal of Cancer 1991 64 4 769 774 2-s2.0-0025738929 10.1038/bjc.1991.396 1654987 \n6 Johnson D. R. O'Neill B. P. Glioblastoma survival in the United States before and during the temozolomide era Journal of Neuro-Oncology 2012 107 2 359 364 10.1007/s11060-011-0749-4 2-s2.0-84863562673 22045118 \n7 Stupp R. Mason W. P. van den Bent M. J. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma The New England Journal of Medicine 2005 352 10 987 996 10.1056/NEJMoa043330 2-s2.0-20044366163 15758009 \n8 Filippini G. Falcone C. Boiardi A. Prognostic factors for survival in 676 consecutive patients with newly diagnosed primary glioblastoma Neuro-Oncology 2008 10 1 79 87 2-s2.0-39149113073 10.1215/15228517-2007-038 17993634 \n9 Rubenstein J. L. Kim J. Ozawa T. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption Neoplasia 2000 2 4 306 314 2-s2.0-0033822622 10.1038/sj.neo.7900102 11005565 \n10 Friedman H. S. Prados M. D. Wen P. Y. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma Journal of Clinical Oncology 2009 27 28 4733 4740 2-s2.0-70350461699 10.1200/JCO.2008.19.8721 19720927 \n11 Kreisl T. N. Kim L. Moore K. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma Journal of Clinical Oncology 2009 27 5 740 745 10.1200/jco.2008.16.3055 2-s2.0-59949083263 19114704 \n12 Genentech FDA grants Genentech’s Avastin full approval for most aggressive form of brain cancer 2018, https://www.gene.com/media/press-releases/14695/2017-12-05/fda-grants-genentechs-avastin-full-appro \n13 Ostrom Q. T. Gittleman H. Liao P. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014 Neuro-Oncology 2017 19 suppl_5 v1 v88 10.1093/neuonc/nox158 29117289 \n14 United States Census Bureau Wisconsin: 2010. Population and housing unit counts. 2010 Census of population and housing 2018, https://www.census.gov/prod/cen2010/cph-2-51.pdf \n15 United States Census Bureau Michigan: 2010. Population and housing unit counts. 2010 Census of population and housing 2010, https://www.census.gov/prod/cen2010/cph-2-24.pdf \n16 Charlson M. E. Pompei P. Ales K. L. MacKenzie C. R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation Journal of Chronic Diseases 1987 40 5 373 383 10.1016/0021-9681(87)90171-8 2-s2.0-0023092594 3558716 \n17 Rønning P. A. Helseth E. Meling T. R. Johannesen T. B. A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme Neuro-Oncology 2012 14 9 1178 1184 10.1093/neuonc/nos153 22869622 \n18 Graus F. Bruna J. Pardo J. Patterns of care and outcome for patients with glioblastoma diagnosed during 2008-2010 in Spain Neuro-Oncology 2013 15 6 797 805 10.1093/neuonc/not013 23460319 \n19 Morgan E. Norman A. Laing K. Seal M. Treatment and outcomes for glioblastoma in elderly compared with non-elderly patients: a population-based study Current Oncology 2017 24 2 e92 e98 10.3747/co.24.3424 28490931 \n20 Brandes A. A. Vastola F. Basso U. A prospective study on glioblastoma in the elderly Cancer 2003 97 3 657 662 10.1002/cncr.11097 12548608 \n21 Ewelt C. Goeppert M. Rapp M. Steiger H. Stummer W. Sabel M. Glioblastoma multiforme of the elderly: the prognostic effect of resection on survival Journal of Neuro-Oncology 2011 103 3 611 618 10.1007/s11060-010-0429-9 20953662 \n22 Chang S. M. Parney I. F. Huang W. Patterns of Care for Adults With Newly Diagnosed Malignant Glioma Journal of the American Medical Association 2005 293 5 557 564 10.1001/jama.293.5.557 15687310 \n23 Bauchet L. Mathieu-Daude H. Fabbro-Peray P. Oncological patterns of care and outcome for 952 patients with newly diagnosed glioblastoma in 2004 Neuro-Oncology 2010 12 7 725 735 10.1093/neuonc/noq030 20364023 \n24 Darefsky A. S. King J. T. Jr. Dubrow R. Adult glioblastoma multiforme survival in the temozolomide era: a population-based analysis of surveillance, epidemiology, and end results registries Cancer 2012 118 8 2163 2172 10.1002/cncr.26494 2-s2.0-84859629008 21882183 \n25 Ho V. K. Y. Reijneveld J. C. Enting R. H. Changing incidence and improved survival of gliomas European Journal of Cancer 2014 50 13 2309 2318 10.1016/j.ejca.2014.05.019 24972545 \n26 Dubrow R. Darefsky A. S. Jacobs D. I. Time trends in glioblastoma multiforme survival: the role of temozolomide Neuro-Oncology 2013 15 12 1750 1761 10.1093/neuonc/not122 24046259 \n27 Scoccianti S. Magrini S. M. Ricardi U. Patterns of care and survival in a retrospective analysis of 1059 patients with glioblastoma multiforme treated between 2002 and 2007: a multicenter study by the central nervous system study group of Airo (Italian association of radiation oncology) Neurosurgery 2010 67 2 446 458 10.1227/01.NEU.0000371990.86656.E8 2-s2.0-77955002912 20644432 \n28 Diaz R. J. Ali S. Qadir M. G. De La Fuente M. I. Ivan M. E. Komotar R. J. The role of bevacizumab in the treatment of glioblastoma Journal of Neuro-Oncology 2017 133 3 455 467 10.1007/s11060-017-2477-x 28527008 \n29 Taal W. Oosterkamp H. M. Walenkamp A. M. E. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial The Lancet Oncology 2014 15 9 943 953 10.1016/s1470-2045(14)70314-6 2-s2.0-84904913239 25035291 \n30 Wick W. Gorlia T. Bendszus M. Lomustine and Bevacizumab in Progressive Glioblastoma The New England Journal of Medicine 2017 377 20 1954 1963 10.1056/NEJMoa1707358 29141164 \n31 Hottinger A. F. Pacheco P. Stupp R. Tumor treating fields: a novel treatment modality and its use in brain tumors Neuro-Oncology 2016 18 10 1338 1349 10.1093/neuonc/now182 27664860 \n32 Stupp R. Wong E. T. Kanner A. A. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality European Journal of Cancer 2012 48 14 2192 2202 2-s2.0-84865528882 10.1016/j.ejca.2012.04.011 22608262 \n33 Stupp R. Taillibert S. Kanner A. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma Journal of the American Medical Association 2017 318 23 2306 2316 10.1001/jama.2017.18718 29260225 \n34 Gately L. Collins A. Murphy M. Dowling A. Age alone is not a predictor for survival in glioblastoma Journal of Neuro-Oncology 2016 129 3 479 485 10.1007/s11060-016-2194-x 27406585 \n35 Hegi M. E. Diserens A.-C. Gorlia T. MGMT gene silencing and benefit from temozolomide in glioblastoma The New England Journal of Medicine 2005 352 10 997 1003 10.1056/NEJMoa043331 2-s2.0-20044372154 15758010 \n36 Hartmann C. Hentschel B. Wick W. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas Acta Neuropathologica 2010 120 6 707 718 10.1007/s00401-010-0781-z 2-s2.0-78651082266 21088844 \n37 Zacher A. Kaulich K. Stepanow S. Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel Brain Pathology 2017 27 2 146 159 10.1111/bpa.12367 26919320\n\n",
"fulltext_license": "CC BY",
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"issue": "2018()",
"journal": "BioMed research international",
"keywords": null,
"medline_ta": "Biomed Res Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001932:Brain Neoplasms; D059248:Chemoradiotherapy; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D005909:Glioblastoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D012189:Retrospective Studies; D000077204:Temozolomide; D063128:Tertiary Healthcare; D055815:Young Adult",
"nlm_unique_id": "101600173",
"other_id": null,
"pages": "6204676",
"pmc": null,
"pmid": "30687753",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "11005565;12548608;15687310;15758009;15758010;1654987;17993634;19114704;19720927;20364023;20644432;20953662;21088844;21882183;22045118;22241797;22608262;22869622;23460319;24046259;24972545;25035291;25053711;25661102;26122381;26919320;27406585;27664860;28490931;28527008;29117289;29141164;29260225;3558716",
"title": "Glioblastoma Treatment with Temozolomide and Bevacizumab and Overall Survival in a Rural Tertiary Healthcare Practice.",
"title_normalized": "glioblastoma treatment with temozolomide and bevacizumab and overall survival in a rural tertiary healthcare practice"
} | [
{
"companynumb": "US-009507513-1902USA000452",
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"activesubstancename": "TEMOZOLOMIDE"
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... |
{
"abstract": "Immunoglobulin light-chain amyloidosis (AL) is a disease with limited treatment options due to the frailty of patients caused by organ damage. Since the clonal plasma cells often contain the cytogenetic aberration t(11;14), the Bcl-2 inhibitor venetoclax is suggested to have a role in the treatment of AL. Here, we report of a heart-transplanted patient, refractory to multiple therapies, reaching a rapid complete response with single-agent venetoclax.",
"affiliations": "Department of Medicine, Karolinska Institutet, Stockholm, Sweden, charlotte.gran@ki.se.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.;Department of Medicine, Kalmar Hospital, Kalmar, Sweden.;Department of Medicine, Karolinska Institutet, Stockholm, Sweden.",
"authors": "Gran|Charlotte|C|;Borg Bruchfeld|Johanna|J|;Ellin|Fredrik|F|;Nahi|Hareth|H|",
"chemical_list": "D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000069286:Bortezomib; D003907:Dexamethasone; C579720:venetoclax",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000504355",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "143(5)",
"journal": "Acta haematologica",
"keywords": "Heart-transplantation; Rapid complete response; Single-agent Bcl-2 inhibitor; Triple refractory immunoglobulin light-chain amyloidosis; Venetoclax",
"medline_ta": "Acta Haematol",
"mesh_terms": "D000970:Antineoplastic Agents; D000069286:Bortezomib; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003907:Dexamethasone; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014178:Translocation, Genetic",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "500-503",
"pmc": null,
"pmid": "31896106",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Rapid Complete Response to Single-Agent Bcl-2 Inhibitor Venetoclax in a Heart-Transplanted Patient with Triple Refractory Immunoglobulin Light-Chain Amyloidosis.",
"title_normalized": "rapid complete response to single agent bcl 2 inhibitor venetoclax in a heart transplanted patient with triple refractory immunoglobulin light chain amyloidosis"
} | [
{
"companynumb": "SE-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-271034",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARATUMUMAB"
},
"dru... |
{
"abstract": "In Belgium, linezolid is indicated for pneumonia and skin and soft tissue infections, but is more broadly used, due to its oral bioavailability and activity against multiresistant organisms. This could increase the risk of adverse drug reactions (ADR), notably hematological disorders (anemia, thrombocytopenia), neuropathy, or lactic acidosis. We analyzed linezolid clinical use in relationship with occurrence of ADR in Belgian hospitals and highlighted risk factors associated with the development of thrombocytopenia. A retrospective analysis of electronic medical records and laboratory tests of adult patients treated with linezolid in four Belgian hospitals in 2016 allowed the collection of ADR for 248 linezolid treatments. Only 19.7% of indications were in-label. ADR included 43 thrombocytopenia, 17 anemia, 4 neuropathies, and 4 increases in lactatemia. In a multi-variate analysis, risk factors of thrombocytopenia were a treatment duration > 10 days, a glomerular filtration rate < 60 mL/min, and a Charlson index ≥ 4. Off-label use of linezolid is frequent in Belgium, and ADR more frequent than reported in the summary of product characteristics, but not statistically associated with any indication. This high prevalence of ADR could be related to a high proportion of patients presenting risk factors in our population, highlighting the importance of detecting them prospectively.",
"affiliations": "Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, B1200 Brussels, Belgium.;Groupe de Gestion de L'antibiothérapie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, B1200 Brussels, Belgium.;Infectiologie, Centre Hospitalier Universitaire de Liège, Université de Liège, B4000 Liège, Belgium.;Infectious Diseases Department, Cliniques Universitaires Erasme, Université libre de Bruxelles, B1070 Brussels, Belgium.;Grand Hôpital de Charleroi, Infectiologie, B6000 Charleroi, Belgium.;Clinical Pharmacy, Louvain Drug Research Institute, Université Catholique de Louvain, B1200 Brussels, Belgium.;Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, B1200 Brussels, Belgium.;Clinical Pharmacy, Louvain Drug Research Institute, Université Catholique de Louvain, B1200 Brussels, Belgium.;Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, B1200 Brussels, Belgium.",
"authors": "Thirot|Hélène|H|;Briquet|Caroline|C|0000-0002-0142-8741;Frippiat|Frédéric|F|;Jacobs|Frédérique|F|;Holemans|Xavier|X|0000-0001-7812-2196;Henrard|Séverine|S|0000-0002-0389-8093;Tulkens|Paul M|PM|0000-0002-7121-3623;Spinewine|Anne|A|;Van Bambeke|Françoise|F|0000-0002-0052-7991",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/antibiotics10050530",
"fulltext": "\n==== Front\nAntibiotics (Basel)\nAntibiotics (Basel)\nantibiotics\nAntibiotics\n2079-6382\nMDPI\n\n10.3390/antibiotics10050530\nantibiotics-10-00530\nArticle\nClinical Use and Adverse Drug Reactions of Linezolid: A Retrospective Study in Four Belgian Hospital Centers\nThirot Hélène 12\nhttps://orcid.org/0000-0002-0142-8741\nBriquet Caroline 3\nFrippiat Frédéric 4\nJacobs Frédérique 5\nHolemans Xavier 6\nhttps://orcid.org/0000-0002-0389-8093\nHenrard Séverine 27\nhttps://orcid.org/0000-0002-7121-3623\nTulkens Paul M. 1\nSpinewine Anne 28\nhttps://orcid.org/0000-0002-0052-7991\nVan Bambeke Françoise 1*\nFigueras Albert Academic Editor\n1 Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, B1200 Brussels, Belgium; helene.thirot@uclouvain.be (H.T.); paul.tulkens@uclouvain.be (P.M.T.)\n2 Clinical Pharmacy, Louvain Drug Research Institute, Université Catholique de Louvain, B1200 Brussels, Belgium; severine.henrard@uclouvain.be (S.H.); anne.spinewine@uclouvain.be (A.S.)\n3 Groupe de Gestion de L’antibiothérapie, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, B1200 Brussels, Belgium; caroline.briquet@uclouvain.be\n4 Infectiologie, Centre Hospitalier Universitaire de Liège, Université de Liège, B4000 Liège, Belgium; f.frippiat@chuliege.be\n5 Infectious Diseases Department, Cliniques Universitaires Erasme, Université libre de Bruxelles, B1070 Brussels, Belgium; Frederique.Jacobs@erasme.ulb.ac.be\n6 Grand Hôpital de Charleroi, Infectiologie, B6000 Charleroi, Belgium; Xavier.HOLEMANS@ghdc.be\n7 Institute of Health and Society (IRSS), Université Catholique de Louvain, B1200 Brussels, Belgium\n8 CHU UCL Namur, Pharmacy Department, Université Catholique de Louvain, B5530 Yvoir, Belgium\n* Correspondence: francoise.vanbambeke@uclouvain.be; Tel.: +32-2-764-73-78\n04 5 2021\n5 2021\n10 5 53019 4 2021\n29 4 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/).\nIn Belgium, linezolid is indicated for pneumonia and skin and soft tissue infections, but is more broadly used, due to its oral bioavailability and activity against multiresistant organisms. This could increase the risk of adverse drug reactions (ADR), notably hematological disorders (anemia, thrombocytopenia), neuropathy, or lactic acidosis. We analyzed linezolid clinical use in relationship with occurrence of ADR in Belgian hospitals and highlighted risk factors associated with the development of thrombocytopenia. A retrospective analysis of electronic medical records and laboratory tests of adult patients treated with linezolid in four Belgian hospitals in 2016 allowed the collection of ADR for 248 linezolid treatments. Only 19.7% of indications were in-label. ADR included 43 thrombocytopenia, 17 anemia, 4 neuropathies, and 4 increases in lactatemia. In a multi-variate analysis, risk factors of thrombocytopenia were a treatment duration > 10 days, a glomerular filtration rate < 60 mL/min, and a Charlson index ≥ 4. Off-label use of linezolid is frequent in Belgium, and ADR more frequent than reported in the summary of product characteristics, but not statistically associated with any indication. This high prevalence of ADR could be related to a high proportion of patients presenting risk factors in our population, highlighting the importance of detecting them prospectively.\n\nlinezolid\nadverse drug reaction\nthrombocytopenia\nanemia\nserotonin syndrome\nneuropathy\nlactic acidosis\noff label use\n==== Body\n1. Introduction\n\nThe antibiotic linezolid was approved in the beginning of the year 2000. As first marketed representative of the oxazolidinone class, it opened new opportunities for the treatment of infections by Gram-positive bacteria, its mechanism of action being different from that of the other antibiotics acting on bacterial protein synthesis. Indeed, linezolid targets the peptidyl transferase center of the bacterial ribosome, causing preferential arrest of translation at specific sites and redistribution of the ribosomes on mRNA [1]. The indications reported in the Summary of Product Characteristics (SmPC) in European countries include exclusively community-acquired and nosocomial pneumonia as well as complicated and uncomplicated skin and skin structure infections [2]. The US label [3] adds to these indications the infections attributable to vancomycin-resistant Enterococcus faecium (VRE). However, linezolid presents a series of advantages that could incite the clinicians to use it in a larger number of circumstances. Indeed, linezolid is active against multiresistant Gram-positive organisms like methicillin-resistant Staphylococcus epidermidis or S. aureus (MRSE, MRSA) and VRE. Moreover, it shows a maximal oral bioavailability and large tissue distribution [4]. It is therefore a useful option when a switch from intravenous therapy (with linezolid or another drug like vancomycin) to oral treatment is possible to reduce the duration and cost of the hospitalization or to avoid renal toxicity related to vancomycin. It has also shown to be of interest in the treatment of difficult-to-treat infections by multiresistant pathogens, like endocarditis [5] or osteomyelitis [6]. Despite these advantages, linezolid usage is limited by rare but severe adverse drug reactions (ADR), namely hematological toxicity (thrombocytopenia, anemia), risk of developing peripheral and optic neuropathy [7,8] or, rarely, lactic acidosis [9,10]. Linezolid is also an inhibitor of monoamine oxidases, putting the patients at risk of developing a serotonin syndrome if it is associated with other drugs presenting the same risk [11]. In the registration clinical trials referred to in the SmPC or in the US label, the frequency of these ADR is either low or not well described [12,13]. ADR are rare but the presence of risk factors seems to increase the risk of developing them. The most frequently reported risk factors, especially for thrombocytopenia, are a long treatment duration [14], a bad renal function [15,16], and a low body weight [17,18]. In spite of these drawbacks, off-label use of linezolid is quite common [19,20,21].\n\nYet, it has been suggested that the off-label use of drugs could be associated with a higher risk of ADR [22]. Off-label use consists in using a drug in conditions that are not described in the authorized product information in terms of dose, route of administration, treatment duration, indication, or target patients’ population [23]. Pharmacovigilance good practices recommend to collect and report data about possible ADR related to off-label use [24], because these conditions of usage are new and may result in toxicity issues that were not highlighted during the registration clinical trials. Current reports that examined linezolid safety in relation with its local conditions of use (including off-label indications) are scarce and concern Japanese patients [14,15,16] or, in Europe, hematological toxicity in a single hospital in Spain (see for example [25,26]). A meta-analysis also compiled 12 studies from 11 countries and focused on safety of linezolid in patients with TB [27]. We are thus critically lacking of data considering more globally the safety profile of linezolid in its actual conditions of use in a European country.\n\nThe primary objective of this study was to assess the clinical use of linezolid in relationship with its toxicity in the Belgian hospital daily clinical practice. To reach this goal, we characterized in-label vs. off-label indications and the occurrence of ADR compared to safety reported in SmPC/US label. A secondary objective was to identify risk factors associated with the development of thrombocytopenia, the most frequently reported ADR in our study population.\n\n2. Results\n\n2.1. Study Subjects\n\nIn total, 230 patients met the inclusion criteria over the study period, representing 248 treatments (16 patients received two or three courses of linezolid therapy in the same year, usually for prosthetic joint infections). The general characteristics of the whole patient population are summarized in Table 1. Among the population, 37.1% were male. The median age is 65.\n\nInpatients showed a significantly lower renal function, shorter treatment duration, and lower basal platelet counts, but no difference in their Charlson index [28] as compared to outpatients (Table S1 (Supplementary Materials)).\n\n2.2. Linezolid Treatments: Characteristics\n\nThe indications of linezolid and their relative proportions are described in Table 2.\n\nLinezolid was used in-label according to the indications of the SmPC in European countries [2] (SSTI and pneumonia) in 19.7% of the cases only. A non-negligible proportion of the treatments exceeded 28 days (N = 35, 14.1%), including for some in-label SSTI (N = 4), and more frequently for bone and joint infections (N = 20) and endocarditis (N = 3).\n\nIndications were also variable among the participating hospitals (Figure S1 (Supplementary Materials)). Posology was in all cases 600 mg twice daily. Linezolid was administered intravenously in 101 patients and orally in 155 patients (with an IV to oral switch in 8 patients).\n\nThe most frequently isolated pathogens were Enterococcus faecium (25.7%), methicillin-resistant Staphylococcus epidermidis (23.7%), methicillin-resistant Staphylococcus aureus (17.5%), and vancomycin-resistant Enterococcus principally faecium (9.3%). Of the various cases, 67% of pneumonia cases were caused by methicillin-resistant S. aureus, 52% of bone and joint infections by methicillin-resistant S. epidermidis, 67% of gastrointestinal infections by E. faecium (out of which 5 are vancomycin-resistant Enterococcus), and 62% of urinary tract infections by E. faecium (Figure S2 (Supplementary Materials)).\n\nLinezolid was prescribed as first and second line anti-infective therapy in 25% and 75% of cases, respectively (Figure 1). The main reasons for choosing linezolid (whether as first or second line) can be classified in three categories: oral route convenience, safety issues with other drugs, or efficacy. The oral route was chosen to discharge patients and shorten the duration of the hospitalization (27%) or because the intravenous line had to be removed (3.2%).\n\nSafety reasons included: (1) renal insufficiency caused by vancomycin (10.1%), (2) renal insufficiency unrelated to vancomycin or avoiding the use of vancomycin by fear of toxicity (9.2%) and (3) allergy principally including DRESS syndrome (6%). Lastly, linezolid was selected in case of inefficacy of the first-choice drug, based on microbiological criteria (isolation of a vancomycin-resistant microorganism (9.7%)) or clinical criteria (absence of improvement despite antibiotic treatment (10.8%)). When prescribed as first line, reasons were principally the safety and the effectiveness of the treatment. When prescribed as second line, it was after vancomycin in most of the cases (139 patients; 75% of the second line), to allow switch to oral route or because of safety issues with vancomycin (renal insufficiency, or allergy). Among the other 25% of second line prescriptions, the first line drug was a β-lactam (18.5%; broad spectrum in most of the cases) or an antibiotic with a broader spectrum than linezolid (6.5%; tigecycline, clindamycin, moxifloxacin, trimethoprim/sulfamethoxazole). A complete analysis of the reasons for prescribing linezolid as first line and second line is illustrated in Figure 1.\n\n2.3. Adverse Drug Reactions\n\nAt least one ADR was reported in the medical file of 39 (15.7%) patients (without considering ADR detected based on laboratory tests as anemia and thrombocytopenia), with a number of ADR per patient of 1 in 21 patients, 2 in 10 patients, 3 in 5 patients, and 4 in 3 patients, respectively. The treatment was discontinued in 16 patients (6.45%) because of toxicity (7 for thrombocytopenia, 4 for hypersensitivity, 2 for serious intestinal disorders, 1 for a suspicion of serotonin syndrome, 1 for increase in plasma lactate level, 1 for acute renal failure). The calculated Naranjo score for each of these ADR (see Methods; Ref. [29]) shows that they were possibly (i.e., score of 1–4) to probably (i.e., score of 5–8) associated with linezolid (Table 3).\n\nThe proportion of ADR was not statistically different between patients treated for in- or off-label indications, with 8 patients having developed an ADR (16%) among those treated for in-label infections (49 patients), vs. 31 patients (15.6%) among those treated for off-label indications (199 patients).\n\nThrombocytopenia was the most frequent ADR, with 20 cases notified in the medical records but a total of 43 cases detected based on values from blood tests. Thrombocytopenia appeared after a median of 10 days. It was as frequently observed in inpatients and outpatients (Table S1 (Supplementary Materials)), but the time of onset was shorter in inpatients (10 days) compared to outpatients (15 days) [p-value = 0.009]. Charlson comorbidity index was associated to an earlier development of thrombocytopenia if ≥5, with patients with a value ≥ 5 developing thrombocytopenia earlier (10 days) than those with a value ≤ 5 (15 days) [p-value = 0.032]. The severity of the thrombocytopenia was variable among patients, with 2 patients in grade 4 (<25,000 platelets/mm3), 10 patients in grade 3 (25,000–50,000 platelets/mm3) and 8 patients in grade 2 (50,000–75,000 platelets/mm3). The remaining 23 patients with thrombocytopenia had levels comprised between 75,000 and 150,000 platelets/mm3.\n\nLikewise, 9 cases of anemia were notified but 17 were identified from biological data, in similar proportions in inpatients and outpatients (Table S1 (Supplementary Materials)). Among these cases, 9 patients developed both thrombocytopenia and anemia. Anemia appeared after a median of 16 days of treatment with linezolid, with no statistical difference between inpatients and outpatients.\n\nAmong gastrointestinal disorders category, diarrhea (N = 2), nausea (N = 2), vomiting (N = 3), and loss of appetite (N = 6) were notified.\n\nFour patients developed peripheral neuropathy. Two of them received linezolid for a longer than recommended duration, i.e., 90 days and 84 days, respectively. The third patient received the drug during 22 days and the last one during 15 days but this patient was previously treated with linezolid during 52 days 2 months earlier. Two of these patients received an antiepileptic drug to relieve the peripheral neuropathy.\n\nFour patients developed an increase in lactatemia notified in their EMR (Reported values: 3.3, 4.1, 5.2, and 33.8 mmol/L, respectively [normal range: 0.5 and 2.2 mmol/L]). Among these patients, one took metformin at the same time. After the cessation of the treatment, values returned to normality.\n\nAmong concomitant treatments, at least one drug increasing the risk of developing a serotonin syndrome was noted in the medical files of 97 patients (39%), namely tramadol (53) or antidepressant drugs (Serotonin Selective Reuptake Inhibitors (SSRI) (23), trazodone (15), Serotonin-Norepinephrine reuptake inhibitors (11), mirtazapine (11), and tricyclic antidepressants (TCA) (5)). Based on the SmPC, linezolid is contraindicated in patients taking those kinds of drugs concomitantly, especially in the absence of close monitoring of serotonin syndrome signs. Despite the high level of comedication with molecules considered as contraindicated, only one clinical evidence of serotonin syndrome was declared in a patient taking trazodone and duloxetine at the same time as linezolid. Symptoms were delirium and agitation that disappeared a few days after interrupting linezolid treatment.\n\n2.4. Factors Associated with Thrombocytopenia\n\nAmong the 248 treatments, 228 medical files contained complete data from blood samples. These 228 data sets were used for the analysis of parameters associated with the development of thrombocytopenia (Table S2 (Supplementary Materials)). Table 4 shows results from the univariate and the multivariate analysis.\n\nIn the multivariate analysis, factors significantly associated with thrombocytopenia were: Charlson comorbidity index ≥ 4 (OR = 2.534 [1.128–5.694]), glomerular filtration rate < 60 mL/min (OR = 3.694 [1.649–8.275]), and treatment duration > 10 days (OR = 7.944 [3.197–19.738]). The comorbidities identified in patients with thrombocytopenia are detailed in Table S4 (Supplementary Materials).\n\n3. Discussion\n\nOur study shows that the off-label use of linezolid is frequent in Belgian clinical practice and that the prevalence of ADR is much higher than what is described in the SmPC in Europe or in the US label (Table S3 (Supplementary Materials)). Thrombocytopenia was the most frequent, with a prevalence of 18.9% (compared to ≥1/1000 to <1/100 in SmPC or 3% in the US label). Three factors were identified as being associated to thrombocytopenia, namely a high Charlson index, renal failure, and a long treatment duration.\n\nConcerning first the infections treated, we found that linezolid use covers a broader panel of indications than those specified in the SmPC in Europe (off-label use: 80.3%). In our cohort, off-label use concerns principally the indications and the treatment duration. Interestingly, marked differences in these indications are observed among the participating hospitals, probably unveiling discrepancies in local recommendations. This situation is not unique to Belgium. As an example, a French study assessing the appropriateness of linezolid prescriptions in three hospitals found that, among 81 treatments, 65% were considered off-label regarding the indications [30]. A second study performed in a single French hospital recorded an off-label use of 45% between 2009 and 2013 [21]. A similar proportion (40%) was described in a monocentric Spanish study [31]. Linezolid is not the only antibiotic with reports of frequent off-label use. In a systematic review from 2012, the percentage of off-label use of antibiotics varied from 19 to 43% in adult critical-care patients [32]. In a prospective study, 31.2% of antibiotic prescriptions in a French tertiary hospital were off-label regarding the indications, which was attributed to a lack of update of market authorizations with new guidelines and a lack of investment of industries to extend their market authorizations for drugs that are often generic [33]. These arguments can also apply to linezolid.\n\nOff-label does not necessarily mean that prescribing is inappropriate. First, the majority of bacteria isolated in our cohort of patients were susceptible to linezolid (except one Enterococcus that was discovered resistant to linezolid after three days of treatment and for which the therapy was switched to tedizolid). Second, some of the indications evidenced in our study are part of those accepted by the FDA (VRE infections) or recommended as second line therapy by the Infectious Disease Society of America (persistent bacteremia, central nervous system infections, and osteomyelitis caused by MRSA) [34]. Based on these American criteria, off-label use in our population would concern 60% of the prescriptions, a smaller but still important value. At the end, among off-label indications, 21.6% of the prescriptions may be considered as inappropriate as no clear reason for choosing linezolid (need for oral route, safety or efficacy reasons) was described or because of linezolid resistance (in a single isolate). For the rest (78.4%), acceptable reasons are specified, like oral administration and switch from IV route, activity against strains resistant to first-line drugs, or switch from vancomycin in case of renal insufficiency.\n\nA question arising related to this large off-label use is the potentially associated risk of developing ADR [22]. In a previous study, among 1488 adult inpatients who received a systemic antibiotic, 20% developed at least one ADR, among which 20% were associated to an antibiotic used off-label [35]. In our analysis, the prevalence of ADR was not statistically influenced by the indication, nor by the fact that the indication was in- or off-label. Although the number of prescriptions we analyzed is limited, our conclusion remains coherent with that of a study considering a large cohort of more than 46,000 patients receiving all types of drugs, for whom higher rates of ADR were observed for off-label prescriptions that specifically lacked strong scientific evidence [22]. This was not the case here for linezolid, since the majority of prescriptions remained appropriate.\n\nThe most striking difference in prevalence of ADR was noticed for thrombocytopenia, which concerned 18.9% in our population vs. 0.1 to 1% in the SmPC. Other studies also show high percentages of thrombocytopenia, with values ranging from 17 to 57% [14,15,16,17,18,25,36,37,38]. The way thrombocytopenia is defined may partly explain this disparity. We defined it as a reduction in platelet counts ≥ 30% from baseline and a value ≤ 150,000 cells/µL while other studies considered a decrease of 25% in platelet counts [25] or a decrease in platelet counts ≥ 50% from baseline [17]. The reasons why this prevalence is more than 20 times higher than that reported in the SmPC are possibly related to the high proportion of patients presenting associated risk factors in our cohort. We identified a Charlson index ≥ 4, a glomerular filtration rate < 60 mL/min, and a treatment duration > 10 days as significantly increasing the risk of developing thrombocytopenia. We may have identified Charlson index here because of the large proportion of patients presenting comorbidities in our population. Charlson index has been cited as a risk factor in only one study, combined to patient age [36]. Renal failure has already been described as a risk factor in previous studies [14,15,16,17,37]. Our cut-off value for renal failure was 60 mL/min as in Hanai’s [15] and Nukui’s [16] studies, but others described lower values, between 30 and 50 mL/min [14,25,38]. The renal function is also included in the Charlson index, but based on serum creatinine levels, with a cut-off value set at 3 mg/dL. This may represent a higher degree of renal insufficiency than a glomerular filtration rate < 60 mL/min and therefore concern a lower proportion of patients. Lastly, a treatment duration > 14 days is a demonstrated risk factor [14]. A surprising observation in our study is that patients with the longest treatment (> 55 days) did not develop thrombocytopenia. A probable explanation is that all these patients had a glomerular filtration rate > 60 mL/min and a Charlson index < 4. This observation indicates that the risk becomes more important when all risk factors are present. However as previously shown, linezolid is often used as an alternative in patients who developed renal failure potentially caused by vancomycin. This demonstrates that the implication of renal function in the toxicity of linezolid is still poorly known.\n\nOther risk factors have been described in the literature, which were not highlighted in our study, like a low body weight [17,18], a low basal platelet count [18,25], or an older age [17]. The discrepancy may reside in the differences in the selected population. First, we chose to include all treated patients while other studies exclude patients treated with anticancer drugs [18,39] or hospitalized in intensive care unit (ICU) [25] or treated for less than seven days [15]. Noteworthy in this respect, the proportion of patients developing thrombocytopenia or anemia in our cohort was not higher among hospitalized patients or those receiving anticancer chemotherapy than among others. Second, most of the studies looking at factors associated with the development of thrombocytopenia were performed in Asia, where the morphometric parameters of the patients are highly different from Europe. As an example, the percentage of patients with a BMI < 20 in our study (9.6%) is lower than in studies reporting low body weight as a risk factor (33%) [17].\n\nPredictive scores specifically developed to assess linezolid toxicity have been proposed, which take into account some of these risk factors. The first one includes variables as a basal platelet count ≤ 90,000/mm3, renal failure (creatinine clearance below 50 mL/min), moderate or severe liver disease, and cerebrovascular disease as a way to predict thrombocytopenia risk [25]. The second one includes age-adjusted comorbidity index and the duration of therapy to assess the risk of developing ADR [36], which actually corresponds to the factors we identified here. Another type of described risk factor is related to the global exposure of the patients to the drug. Different studies conclude that keeping linezolid Cmin between 2 and 7 mg/L is efficacious and safe [40,41]. As inter-individual variations in serum levels are frequent among patients, these data would plead for implementing therapeutic monitoring [42], which is not used in routine so far.\n\nRegarding the other ADR, anemia was as frequent (6.8%) as described in the SmPC or in the US label (1–10%). A similar prevalence of 10% was observed in a previous study [15], which identified as the only risk factor a long treatment duration. The frequency of peripheral neuropathy and lactic acidosis is indeterminate in the SmPC or in the US label. Our study found four patients with peripheral neuropathy and four patients with an increase in their lactic acid level, which is quite high for a limited patients’ population. This may be due to the presence of patients with multiple comorbidities and/or with profile differing from those included in registration studies in our population. Some ADR reported in the US label [3] (hypoglycemia, elevated blood pressure, seizures, or Clostridium difficile diarrhea) were not reported in the EMR of our patients. In this context, underreporting of ADR is problematic, as it may prevent updating drug labels. It is worth mentioning here that only 31 ADR potentially related to the use of linezolid have been reported in Belgium between 2002 and 2016 to the national pharmacovigilance center (Data comes from the VigiBase (WHO global database of individual case safety reports). This information comes from a variety of sources. The likelihood that the suspected adverse reaction is drug-related is not the same in all cases. The information does not represent the opinion of the World Health Organization). Possible reasons are the additional workload for the healthcare providers, but also the difficulty to attribute an ADR to a specific drug, especially in multimorbid or polymedicated patients. Probability scales do exist, like the Naranjo score we used here, but all criteria were not applicable because of missing data, so that we could not exceed a score > 7 defining a probable ADR.\n\nA total of 39% of the patients received at least one drug increasing the risk of developing a serotonin syndrome. However only one patient potentially presented this reaction. Publications concerning the serotonin syndrome and linezolid are generally limited to case-reports and the incidence remains unclear [11]. The major class concerned by this interaction is the class of antidepressants (as SSRI or TCA). These treatments are sometimes taken for a long time and cannot be stopped before the beginning of linezolid. As this syndrome generally develops in the hours after taking drugs that increase serotonin levels, a follow-up of the typical symptoms could be performed in patients at risk that begin linezolid.\n\nOur study has several limitations. First, due the retrospective character of our analysis, we were facing missing information, like unreported ADR or lack of detailed information on patient’s characteristics (weight, medical history) or on the reported ADR (blood monitoring). Second, despite the multicentric design, we cannot guarantee that the data collected represent the real global use in Belgium as the four centers selected are all in the French-speaking part of the country. In addition, VRE infections are often epidemic and their number may thus be variable from one year to the other.\n\n4. Conclusions\n\nThis work allowed us to describe for the first time linezolid use and toxicity in representative Belgian hospitals, which may fuel discussion within hospitals or among them in order to better define the conditions of use of this drug and setup initiatives to predict and avoid the risk of developing ADR, not only in Belgium, but also in other countries with similar usage. It shows that ADR are much more frequent than reported in the SmPC or US label, demonstrating the impact of daily life practice for the safety of drugs, which has been assessed only in well-defined populations and conditions of use in registration trials. The discrepancy is particularly high for thrombocytopenia, underlining the need for an increased vigilance in the follow-up of multimorbid patients, those with a moderate to severe renal failure, and those with a long treatment duration.\n\nIn a broader context, our study may also stimulate critical thinking on the way clinical trials for antibiotics are set up to obtain their registration vs. the need to which they should respond in the clinics in terms of indications. Additionally, it points to the role healthcare professionals may play in reporting adverse events in order to correctly assess the benefit-risk balance of drugs for individual patients, considering their specific risk factors.\n\n5. Materials and Methods\n\nThis retrospective observational study was performed in 4 Belgian hospital centers practicing tertiary care: 3 university hospitals (respectively 945 beds, 858 beds, 925 beds) and 1 non-university hospital (1154 beds) selected as using linezolid in at least 40 patients/year. All adult (≥18 years) patients treated with linezolid for at least 1 day between January 2016 and December 2016 were identified through dispensing data from the hospital pharmacy. In Belgium, linezolid is always prescribed in the hospital setting and delivered by the hospital pharmacy. Some patients receive the entire treatment in the hospital, while others start their treatment at the hospital for a few days and then continue it at home. There were no exclusion criteria; all patients, whatever the treatment duration, were included for the data descriptive analysis. For the analysis of thrombocytopenia, only patients with platelets data were included.\n\nThe following data, available for all in- and outpatients, were extracted from the electronic medical record (EMR) by the main researcher (HT) (from the beginning to the end of the treatment): demographic data, comorbidities to calculate the Charlson comorbidity index [28] (calculated through the creatinine level of the first day of the treatment), body weight, renal function (creatinine level and glomerular filtration rate estimated with MDRD (Modification of Diet in Renal Disease)), hemogram (frequency of platelet counts determinations for inpatients: every 3–4 days approximately; for outpatients: every 7–10 days approximately), microbiological data, previous antibiotic treatment, type of infection and reason for linezolid prescription, dosage, treatment duration, route of administration, and hospitalization status of the patient (inpatients received the entire treatment in the hospital and outpatients were defined here as patients starting their treatment at the hospital for 2 or 3 days and continuing it at home). Comedications that could increase the risk of developing a serotonin syndrome [43] or thrombocytopenia [44] were also considered.\n\nADR related to linezolid and reported in the EMR were collected (description, time of onset, management, recovery) and the potential relationship between linezolid administration and each ADR was assessed using the Naranjo probability scale [29]. For inpatients, data were extracted from hospitalization reports and the daily visits reports depending on the hospitalization service. For outpatients, consultation reports and previous reports of the hospitalization were consulted.\n\nRegarding hematological disorders, thrombocytopenia was defined as a reduction in platelet counts higher than 30% from baseline and a value less than 150,000 cells/µL, and anemia, as a higher than 30% decrease in hemoglobin level from baseline and a value lower than 12 g/dL. The time of onset of thrombocytopenia was defined as the day when the platelets count decreases higher than 30% from baseline and reaches a value less than 150,000 cells/µL. Hyperlactatemia was defined when values were higher than the normal range 0.5 and 2.2 mmol/L.\n\nData extracted from the EMR allowed us to analyze the parameters associated to the development of thrombocytopenia. These parameters were partly chosen based on previous publications expounding linezolid thrombocytopenia [14,15,16,17,25,36] and on available data collected in the medical record (see all parameters tested in Table S5 (Supplementary Materials)).\n\nStatistical analyses were performed using IBM® SPSS® statistics version 26.0 (IBM®, Armonk, NY, USA). Distribution and normality of quantitative variables were assessed based on Kolmogorov-Smirnov test. As all variables tested were not normally distributed, data were expressed as median and inter-quartile range. Data were compared between groups using the non-parametric Mann-Whitney U test. Categorical variables were compared between groups using Pearson’s Chi-squared test or Fisher exact test according to the condition of validity of each test. The analysis of parameters associated with the development of thrombocytopenia was performed on the subset of patients for whom hemogram data were available. A univariate analysis and a multivariable logistic regression analysis were used to identify determinants associated with the development of thrombocytopenia. All variables with a p value < 0.2 in the univariate analysis were included in the multivariable analysis. A backward procedure was then performed to select the final multivariate model. The goodness-of-fit of the final model was evaluated thanks to the Hosmer-Lemeshow test. Results of the model were expressed using adjusted odds ratios (OR) 95% confidence interval. Finally, the median time of onset of thrombocytopenia was assessed through a Kaplan-Meier analysis. Non-parametric Mann-Whitney U test was performed to compare the time of onset in different groups of patients.\n\nAcknowledgments\n\nF.V.B. is Research Director of the Belgian Fonds de la Recherche Scientifique (FRS-FNRS).\n\nSupplementary Materials\n\nThe following are available online at https://www.mdpi.com/article/10.3390/antibiotics10050530/s1. Figure S1: Distribution of the number of infections treated with linezolid among the four included hospital centers. Figure S2: Distribution of the isolated microorganisms per type of infection. Table S1: Characteristics of inpatients and outpatients. Table S2: Characteristics of patients with or without thrombocytopenia. Table S3: Frequency of ADR in this study as compared to the incidence reported in the SmPC or the US label. Table S4: Comorbidities included in Charlson comorbidity index and identified in patients with thrombocytopenia. Table S5: Parameters tested as possibly associated with the development of thrombocytopenia.\n\nClick here for additional data file.\n\nAuthor Contributions\n\nConceptualization: H.T., P.M.T., A.S., F.V.B.; methodology: H.T., S.H., P.M.T., A.S., F.V.B.; formal analysis, H.T., S.H.; investigation, H.T., C.B., F.F., F.J., X.H.; writing—original draft preparation, H.T., A.S., F.V.B.; writing—review and editing, C.B., F.F., F.J., X.H., S.H., P.M.T. 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 protocol was approved by the ethical committee of each center (Cliniques Universitaires Saint-Luc (reference 2017-035), Centre hospitalier universitaire de Liège (reference 2017/71), Grand hôpital de Charleroi (reference G2-2017-E003) and Cliniques universitaires Erasme (reference P2017/173)).\n\nData Availability Statement\n\nData are available from the authors upon request.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Flowchart: Reasons for prescribing linezolid. The color of the box defines the type of reason: convenience of oral route (blue), safety (red); efficacy (green).\n\nantibiotics-10-00530-t001_Table 1 Table 1 Patients’ baseline characteristics.\n\nPatient Characteristics\tN (%) or Median (Range)\t\nPatients\t230\t\nTreatment\t248\t\nMale\t93 (37.1)\t\nAge (years)\t65 (21–95)\t\nWeight (kg)\t76 (34–178)\t\nBody mass index (kg/m2)\t25 (15–48)\t\nGlomerular filtration rate 1 (mL/min)\t57 (10–196)\t\nGFR ≥ 60 mL/min\t102\t\n30 mL/min ≤ GFR < 60 mL/min\t107\t\nGFR < 30 mL/min\t10\t\nCharlson index\t3 (0–11)\t\nInpatients/Outpatients\t163 (66)/85 (34)\t\nICU 2 patients 3\t92 (56.4)\t\n1 Estimated with MDRD, 2 Intensive Care Unit, 3 Proportion among inpatients.\n\nantibiotics-10-00530-t002_Table 2 Table 2 Infections treated, microorganisms, and treatment duration.\n\nInfection Treated 1\tNumber (%)\tMedian Treatment\nDuration (Range)\tMicroorganisms\tNumber = 257\n(%)\t\nSSTI 2\t31 (12.5)\t19.5 (1–72)\tE. faecium\t66 (25.7)\t\nPneumonia\t18 (7.2)\t7 (1–16)\tMRSE 2\t61 (23.7)\t\nPrimary bacteremia 3\t33 (13.3)\t8 (2–52)\tMRSA 2\t45 (17.5)\t\nSecondary bacteremia 3\t43 (17.4)\t7 (1–29)\tVRE 2\t24 (9.3)\t\nBone & joint infections\t33 (13.3)\t3 (7–90)\tMSSA 2\t12 (4.7)\t\nGastrointestinal infections\t21 (8.5)\t8 (2–44)\tE. faecalis\t11 (4.3)\t\nMedical device infections\t15 (6)\t10 (1–30)\tMSSE 2\t2 (0.8)\t\nUrinary tract infections\t13 (5.2)\t8 (1–21)\tOthers 4\t36 (14)\t\nMediastinitis\t9 (3.6)\t11 (5–28)\t\t\t\nEndocarditis\t5 (2)\t30 (7–45)\t\t\t\nCNS 2 infections\t5 (2)\t10 (4–14)\t\t\t\nMRSA 2 decolonization\t5 (2)\t7.5 (4–20)\t\t\t\nOthers\t17 (7)\t\t\t\t\n1 Infections classification inspired by the Global PPS project https://www.global-pps.com/project/, (accessed on 3 May 2021). 2 Acronyms: SSTI, skin and soft tissue infection; CNS, central nervous system; MRSA, methicillin resistant staphylococcus aureus; MRSE, methicillin resistant staphylococcus epidermidis; VRE, vancomycin resistant Enterococcus; MSSA, methicillin sensitive Staphylococcus aureus; MSSE, methicillin sensitive Staphylococcus epidermidis. 3 Primary bacteremia: No other source identified; Secondary bacteremia: Associated to another source of infection. 4 Diverse linezolid-susceptible species, including other Staphylococci, Streptococci, Corynebacteria, non-tuberculosis Mycobacteria).\n\nantibiotics-10-00530-t003_Table 3 Table 3 Adverse drug reactions reported in medical records and/or identified from laboratory data and their corresponding Naranjo score.\n\nType of Adverse Drug Reactions\tN (%)\tNaranjo Score\nMedian (Range)\tN of ADR with a Naranjo Score ≥ 5 (%)\t\nThrombocytopenia\t43 (18.9)\t4 (1–7)\t15 (34.9)\t\nAnemia\t17 (6.8)\t4 (0–7)\t6 (46.2)\t\nGastrointestinal disorders\t13 (5.2)\t4 (2–7)\t4 (30.8)\t\nPeripheral neuropathy\t4 (1.6)\t4 (3–5)\t2 (50)\t\nLactic acid serum level > 2.2 mmol/L\t4 (1.6)\t4 (0–5)\t1 (25)\t\nParesthesia\t4 (1.6)\t3 (3–6)\t1 (25)\t\nSkin disorders\t3 (1.2)\t1.5 (0–3)\t0\t\nFatigue\t3 (1.2)\t5 (0–6)\t2 (40)\t\nNeutropenia\t2 (0.8)\t4\t2 (100)\t\nLeucopenia 1\t2 (0.8)\t2.5 (1–4)\t0\t\nRenal failure 2\t1 (0.8)\t4\t0\t\nTaste alteration\t1 (0.4)\t6\t1 (100)\t\nSuspicion of serotonin syndrome\t1 (0.4)\t4\t0\t\nSIADH 3\t1 (0.4)\t3\t0\t\n1 Leucocytes < 4 × 103/mm3 (1.1 × 103/mm3–1.9 × 103/mm3). 2 Creatinine level > 1.4 mg/dL (3.8 mg/dL). 3 SIADH, Syndrome of Inappropriate Antidiuretic Hormone.\n\nantibiotics-10-00530-t004_Table 4 Table 4 Univariate and multivariate analysis of the parameters associated with the development of thrombocytopenia.\n\nParameters\tUnivariate Analysis OR [95% CI]\tp-Value\tMultivariate Analysis Adjusted OR [95% CI]\tp-Value\t\nInpatients\t0.598 [0.3–1.192]\t0.144\t\t\t\nCharlson index ≥ 4\t2.218 [1.088–4.522]\t0.005\t2.534 [1.128–5.694]\t0.024\t\nDiabetes\t2.065 [1.043–4.087]\t0.037\t\t\t\nRenal function (<60 mL/min)\t2.088 [1.015–4.294]\t0.045\t3.694 [1.649–8.275]\t0.01\t\nTreatment duration > 10 days\t5.687 [2.501–12.933]\t0.000\t7.944 [3.197–19.738]\t<0.001\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Marks J. Kannan K. Roncase E.J. Klepacki D. Kefi A. Orelle C. Vazquez-Laslop N. Mankin A.S. Context-specific inhibition of translation by ribosomal antibiotics targeting the peptidyl transferase center Proc. Natl. Acad. Sci. USA 2016 113 12150 12155 10.1073/pnas.1613055113 27791002\n2. Zyvox 600 mg Film-Coated Tablets—Summary of Product Characteristics (SmPC) Available online: https://www.medicines.org.uk/emc/medicine/9857#gref (accessed on 9 April 2021)\n3. FDA FDA Label Zyvox Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021130s037,021131s030,021132s035lbl.pdf (accessed on 12 April 2021)\n4. Stalker D.J. Jungbluth G.L. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial Clin. Pharmacokinet. 2003 42 1129 1140 10.2165/00003088-200342130-00004 14531724\n5. Falagas M.E. Manta K.G. Ntziora F. Vardakas K.Z. Linezolid for the treatment of patients with endocarditis: A systematic review of the published evidence J. Antimicrob. Chemother. 2006 58 273 280 10.1093/jac/dkl219 16735427\n6. Rayner C.R. Baddour L.M. Birmingham M.C. Norden C. Meagher A.K. Schentag J.J. Linezolid in the treatment of osteomyelitis: Results of compassionate use experience Infection 2004 32 8 14 10.1007/s15010-004-3029-9\n7. Brandariz-Nunez D. Hernandez-Corredoira V. Guarc-Prades E. Garcia-Navarro B. Optic neuropathy associated with linezolid: Systematic review of cases Farm. Hosp. 2019 43 61 65 10.7399/fh.11133 30848179\n8. Manji H. Drug-induced neuropathies Handb. Clin. Neurol. 2013 115 729 742 10.1016/B978-0-444-52902-2.00042-4 23931812\n9. Im J.H. Baek J.H. Kwon H.Y. Lee J.S. Incidence and risk factors of linezolid-induced lactic acidosis Int. J. Infect. Dis. 2015 31 47 52 10.1016/j.ijid.2014.12.009 25499040\n10. Mao Y. Dai D. Jin H. Wang Y. The risk factors of linezolid-induced lactic acidosis: A case report and review Med. (Baltim.) 2018 97 e12114 10.1097/MD.0000000000012114 30200095\n11. Woytowish M.R. Maynor L.M. Clinical relevance of linezolid-associated serotonin toxicity Ann. Pharmacother. 2013 47 388 397 10.1345/aph.1R386 23424229\n12. Rubinstein E. Isturiz R. Standiford H.C. Smith L.G. Oliphant T.H. Cammarata S. Hafkin B. Le V. Remington J. Worldwide assessment of linezolid’s clinical safety and tolerability: Comparator-controlled phase III studies Antimicrob. Agents Chemother. 2003 47 1824 1831 10.1128/AAC.47.6.1824-1831.2003 12760854\n13. French G. Safety and tolerability of linezolid J. Antimicrob. Chemother. 2003 51 Suppl. S2 ii45 ii53 10.1093/jac/dkg253 12730142\n14. Hirano R. Sakamoto Y. Tachibana N. Ohnishi M. Retrospective analysis of the risk factors for linezolid-induced thrombocytopenia in adult Japanese patients Int. J. Clin. Pharm. 2014 36 795 799 10.1007/s11096-014-9961-6 24913359\n15. Hanai Y. Matsuo K. Ogawa M. Higashi A. Kimura I. Hirayama S. Kosugi T. Nishizawa K. Yoshio T. A retrospective study of the risk factors for linezolid-induced thrombocytopenia and anemia J. Infect. Chemother. 2016 22 536 542 10.1016/j.jiac.2016.05.003 27321773\n16. Nukui Y. Hatakeyama S. Okamoto K. Yamamoto T. Hisaka A. Suzuki H. Yata N. Yotsuyanagi H. Moriya K. High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia J. Antimicrob. Chemother. 2013 68 2128 2133 10.1093/jac/dkt133 23625638\n17. Natsumoto B. Yokota K. Omata F. Furukawa K. Risk factors for linezolid-associated thrombocytopenia in adult patients Infection 2014 42 1007 1012 10.1007/s15010-014-0674-5 25119433\n18. Niwa T. Watanabe T. Suzuki A. Ohmori T. Tsuchiya M. Suzuki T. Ohta H. Murakami N. Itoh Y. Reduction of linezolid-associated thrombocytopenia by the dose adjustment based on the risk factors such as basal platelet count and body weight Diagn. Microbiol. Infect. Dis. 2014 79 93 97 10.1016/j.diagmicrobio.2014.01.012 24565849\n19. Vardakas K.Z. Ntziora F. Falagas M.E. Linezolid: Effectiveness and safety for approved and off-label indications Expert Opin. Pharmacother. 2007 8 2381 2400 10.1517/14656566.8.14.2381 17927491\n20. Dryden M.S. Alternative clinical indications for novel antibiotics licensed for skin and soft tissue infection? Curr. Opin. Infect. Dis. 2015 28 117 124 10.1097/QCO.0000000000000142 25692274\n21. Guillard P. de La B.A. Cattoir V. Fischer M.O. Verdon R. Saint-Lorant G. Antimicrobial stewardship and linezolid Int. J. Clin. Pharm. 2014 36 1059 1068 10.1007/s11096-014-9995-9 25135806\n22. Eguale T. Buckeridge D.L. Verma A. Winslade N.E. Benedetti A. Hanley J.A. Tamblyn R. Association of Off-label Drug Use and Adverse Drug Events in an Adult Population JAMA Intern. Med. 2016 176 55 63 10.1001/jamainternmed.2015.6058 26523731\n23. European Medicines Agency Reflection Paper on Collecting and Reporting Information on Off-Label Use in Pharmacovigilance Available online: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/reflection-paper-collecting-reporting-information-label-use-pharmacovigilance_en.pdf (accessed on 14 April 2021)\n24. Dal Pan G.J. Monitoring the Safety of Medicines Used Off-Label Available online: https://www.pharmaco-vigilance.eu/content/monitoring-safety-medicines-used-label (accessed on 14 April 2021)\n25. Gonzalez-Del C.J. Candel F.J. Manzano-Lorenzo R. Arias L. Garcia-Lamberechts E.J. Martin-Sanchez F.J. Predictive score of haematological toxicity in patients treated with linezolid Eur. J. Clin. Microbiol. Infect. Dis. 2017 36 1511 1517 10.1007/s10096-017-2960-5 28343274\n26. Perez-Cebrian M. Suarez-Varela M.M. Font-Noguera I. Monte-Boquet E. Poveda-Andres J.L. Martin-Moreno J.M. Rubio-Lopez N. Ruiz-Rojo E. Llopis-Gonzalez A. Study on the Linezolid Prescription According to the Approval of Indication in a University Hospital Iran J. Pharm. Res. 2015 14 857 864 26330874\n27. Sotgiu G. Centis R. D’Ambrosio L. Alffenaar J.W. Anger H.A. Caminero J.A. Castiglia P. De L.S. Ferrara G. Koh W.J. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: Systematic review and meta-analysis Eur. Respir. J. 2012 40 1430 1442 10.1183/09031936.00022912 22496332\n28. Charlson M.E. Pompei P. Ales K.L. MacKenzie C.R. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation J. Chronic. Dis. 1987 40 373 383 10.1016/0021-9681(87)90171-8 3558716\n29. Naranjo C.A. Busto U. Sellers E.M. Sandor P. Ruiz I. Roberts E.A. Janecek E. Domecq C. Greenblatt D.J. A method for estimating the probability of adverse drug reactions Clin. Pharmacol. Ther. 1981 30 239 245 10.1038/clpt.1981.154 7249508\n30. Dentan C. Forestier E. Roustit M. Boisset S. Chanoine S. Epaulard O. Pavese P. Assessment of linezolid prescriptions in three French hospitals Eur. J. Clin. Microbiol. Infect. Dis. 2017 36 1133 1141 10.1007/s10096-017-2900-4 28127641\n31. Rivas R. Barrera M. Gonzalez L. Dominguez V. Sanchez R. Romero M.M. Effectiveness and use of linezolid in hospitalisation wards Farm. Hosp. 2011 35 322 325 10.1016/j.farma.2011.04.001 22035598\n32. Tansarli G.S. Rafailidis P.I. Kapaskelis A. Falagas M.E. Frequency of the off-label use of antibiotics in clinical practice: A systematic review Expert Rev. Anti. Infect. Ther. 2012 10 1383 1392 10.1586/eri.12.137 23253317\n33. Davido B. Bouchand F. Calin R. Makhloufi S. Lagrange A. Senard O. Perronne C. Villart M. Salomon J. Dinh A. High rates of off-label use in antibiotic prescriptions in a context of dramatic resistance increase: A prospective study in a tertiary hospital Int. J. Antimicrob. Agents 2016 47 490 494 10.1016/j.ijantimicag.2016.04.010 27208900\n34. Liu C. Bayer A. Cosgrove S.E. Daum R.S. Fridkin S.K. Gorwitz R.J. Kaplan S.L. Karchmer A.W. Levine D.P. Murray B.E. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children Clin. Infect. Dis. 2011 52 e18 e55 10.1093/cid/ciq146 21208910\n35. Tamma P.D. Avdic E. Li D.X. Dzintars K. Cosgrove S.E. Association of Adverse Events with Antibiotic Use in Hospitalized Patients JAMA Intern. Med. 2017 177 1308 1315 10.1001/jamainternmed.2017.1938 28604925\n36. Buzele R. Lemaignen A. Pourrat X. Rosset P. Gras G. Druon J. Bernard M.C. Sautenet B. Bastides F. Bernard L. Linezolid-related adverse events predictive score (LAPS): Usefulness in clinical practice Int. J. Antimicrob. Agents 2015 46 727 728 10.1016/j.ijantimicag.2015.09.002 26526894\n37. Giunio-Zorkin N. Brown G. Real-Life Frequency of New-Onset Thrombocytopenia during Linezolid Treatment Can. J. Hosp. Pharm. 2019 72 133 138 10.4212/cjhp.v72i2.2883 31036974\n38. Rabon A.D. Fisher J.P. MacVane S.H. Incidence and Risk Factors for Development of Thrombocytopenia in Patients Treated With Linezolid for 7 Days or Greater Ann. Pharmacother. 2018 52 1162 1164 10.1177/1060028018783498 29911390\n39. Ichie T. Suzuki D. Yasui K. Takahashi H. Matsuda M. Hayashi H. Sugiura Y. Sugiyama T. The association between risk factors and time of onset for thrombocytopenia in Japanese patients receiving linezolid therapy: A retrospective analysis J. Clin. Pharm. Ther. 2015 40 279 284 10.1111/jcpt.12260 25732525\n40. Pea F. Viale P. Cojutti P. Del P.B. Zamparini E. Furlanut M. Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients J. Antimicrob. Chemother. 2012 67 2034 2042 10.1093/jac/dks153 22553142\n41. Dong H.Y. Xie J. Chen L.H. Wang T.T. Zhao Y.R. Dong Y.L. Therapeutic drug monitoring and receiver operating characteristic curve prediction may reduce the development of linezolid-associated thrombocytopenia in critically ill patients Eur. J. Clin. Microbiol. Infect. Dis. 2014 33 1029 1035 10.1007/s10096-013-2041-3 24515096\n42. Pea F. Cojutti P.G. Baraldo M. A 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital-wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients? Basic Clin. Pharmacol. Toxicol. 2017 121 303 308 10.1111/bcpt.12797 28419737\n43. Buckley N.A. Dawson A.H. Isbister G.K. Serotonin syndrome BMJ 2014 348 g1626 10.1136/bmj.g1626 24554467\n44. Rondina M.T. Walker A. Pendleton R.C. Drug-induced thrombocytopenia for the hospitalist physician with a focus on heparin-induced thrombocytopenia Hosp. Pract. 2010 38 19 28\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2079-6382",
"issue": "10(5)",
"journal": "Antibiotics (Basel, Switzerland)",
"keywords": "adverse drug reaction; anemia; lactic acidosis; linezolid; neuropathy; off label use; serotonin syndrome; thrombocytopenia",
"medline_ta": "Antibiotics (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101637404",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34064418",
"pubdate": "2021-05-04",
"publication_types": "D016428:Journal Article",
"references": "25119433;25732525;24913359;26523731;22496332;30848179;31036974;23253317;15007736;27791002;16735427;12730142;24565849;7249508;28127641;25135806;27208900;22035598;23625638;28419737;23424229;14531724;24554467;3558716;26330874;25499040;25692274;28343274;28604925;17927491;30200095;26526894;24515096;20469610;22553142;29911390;27321773;21208910;23931812;12760854",
"title": "Clinical Use and Adverse Drug Reactions of Linezolid: A Retrospective Study in Four Belgian Hospital Centers.",
"title_normalized": "clinical use and adverse drug reactions of linezolid a retrospective study in four belgian hospital centers"
} | [
{
"companynumb": "BE-NOVARTISPH-NVSC2021BE255705",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nSerotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD).\n\n\nOBJECTIVE\nTo determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD.\n\n\nMETHODS\nA 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure.\n\n\nMETHODS\nRisperidone (up to 4 mg once daily) or placebo.\n\n\nMETHODS\nThe Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V).\n\n\nRESULTS\nChange in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% CI, -19.7 to -12.9) and in the placebo group, -12.5 (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, -0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, -0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, -0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, -0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, -1.13, 95% CI, -2.58 to 0.32; P = .13; SF-36V mental component mean difference, -0.26; 95% CI, -2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively.\n\n\nCONCLUSIONS\nAmong patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms.\n\n\nBACKGROUND\nclinicaltrials.gov Identifier: NCT00099983.",
"affiliations": "Clinical Neuroscience Division, Department of Veterans Affairs National Center for PTSD, VA Connecticut Healthcare System, West Haven, USA. john.krystal@yale.edu",
"authors": "Krystal|John H|JH|;Rosenheck|Robert A|RA|;Cramer|Joyce A|JA|;Vessicchio|Jennifer C|JC|;Jones|Karen M|KM|;Vertrees|Julia E|JE|;Horney|Rebecca A|RA|;Huang|Grant D|GD|;Stock|Christopher|C|;|||",
"chemical_list": "D012702:Serotonin Antagonists; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.2011.1080",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-7484",
"issue": "306(5)",
"journal": "JAMA",
"keywords": null,
"medline_ta": "JAMA",
"mesh_terms": "D000328:Adult; D055826:Afghan Campaign 2001-; D002908:Chronic Disease; D003863:Depression; D004311:Double-Blind Method; D004351:Drug Resistance; D005260:Female; D006801:Humans; D054542:Iraq War, 2003-2011; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D018967:Risperidone; D012702:Serotonin Antagonists; D012720:Severity of Illness Index; D013313:Stress Disorders, Post-Traumatic; D016896:Treatment Outcome; D014728:Veterans; D047829:Vietnam Conflict",
"nlm_unique_id": "7501160",
"other_id": null,
"pages": "493-502",
"pmc": null,
"pmid": "21813427",
"pubdate": "2011-08-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial.",
"title_normalized": "adjunctive risperidone treatment for antidepressant resistant symptoms of chronic military service related ptsd a randomized trial"
} | [
{
"companynumb": "US-JNJFOC-20140512611",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe D-index and the L-index, calculated as the area over the neutrophil and lymphocyte curves, respectively, reflect both the intensity and duration of cytopenia. We, retrospectively, investigated the impact of these indexes on pulmonary infection (PI) in induction chemotherapy for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL).\n\n\nMETHODS\nWe included 92 patients (ALL 83, LBL 9) from two institutions. We calculated the D-index and cumulative D-index until the development of PI (c-D-index), which enables real-time risk assessment for infection. We also calculated the L-index (35), defined as the area over the lymphocyte curve during lymphopenia (<700/µl) until day 35 and the cumulative-L-index until the development of PI (c-L-index).\n\n\nRESULTS\nEight patients developed PI on day 20 (median). Two patients were strongly suspected to have bacterial pneumonia, and the others were suspected to have pulmonary fungal infection. The D-index and the L-index (35) in patients with PI were higher than those in patients without PI (7230 ± 4734 vs. 4519 ± 3416, P = 0.041 and 15 458 ± 5243 vs. 8920 ± 5901, P = 0.018), while the c-D-index and the c-L-index were not significantly different. Although the c-L-index did not have predictive value for PI, c-D-index, when treated as a dichotomous variable with a cutoff value of 5589 as determined by a receiver operating characteristic curve analysis, showed a significant difference between two groups (P = 0.045). This association became clearer when we focused on suspected pulmonary fungal infection.\n\n\nCONCLUSIONS\nIn induction chemotherapy for ALL/LBL, c-D-index with a cutoff value of 5589 might have predictive value for the development of PI.",
"affiliations": null,
"authors": "Ishihara|Yuko|Y|;Kimura|Shun-ichi|S|;Akahoshi|Yu|Y|;Harada|Naonori|N|;Nakano|Hirofumi|H|;Kameda|Kazuaki|K|;Ugai|Tomotaka|T|;Wada|Hidenori|H|;Yamasaki|Ryoko|R|;Kawamura|Koji|K|;Sakamoto|Kana|K|;Ashizawa|Masahiro|M|;Sato|Miki|M|;Terasako-Saito|Kiriko|K|;Kikuchi|Misato|M|;Nakasone|Hideki|H|;Yamazaki|Rie|R|;Kanda|Junya|J|;Kako|Shinichi|S|;Tanihara|Aki|A|;Nishida|Junji|J|;Usuki|Kensuke|K|;Kanda|Yoshinobu|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1179/1607845415Y.0000000051",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1024-5332",
"issue": "21(1)",
"journal": "Hematology (Amsterdam, Netherlands)",
"keywords": "Acute lymphoblastic leukemia; D-index; L-index; Lymphoblastic lymphoma; Pulmonary infection",
"medline_ta": "Hematology",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D007958:Leukocyte Count; D008168:Lung; D008172:Lung Diseases, Fungal; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D011014:Pneumonia; D018410:Pneumonia, Bacterial; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D012372:ROC Curve; D012189:Retrospective Studies",
"nlm_unique_id": "9708388",
"other_id": null,
"pages": "19-25",
"pmc": null,
"pmid": "26352559",
"pubdate": "2016-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of D-index and L-index on pulmonary infection in induction chemotherapy for acute lymphoblastic leukemia and lymphoblastic lymphoma.",
"title_normalized": "impact of d index and l index on pulmonary infection in induction chemotherapy for acute lymphoblastic leukemia and lymphoblastic lymphoma"
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"companynumb": "JP-AMGEN-JPNSP2017038449",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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"abstract": "Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.",
"affiliations": "Division of Hematology, Faculty of Medicine, Kagawa University, Kagawa, Japan.;Division of Hematology, Faculty of Medicine, Kagawa University, Kagawa, Japan.;Division of Hematology, Faculty of Medicine, Kagawa University, Kagawa, Japan.;Division of Hematology, Faculty of Medicine, Kagawa University, Kagawa, Japan.;Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.;Department of Hematology, Kagawa Prefectural Central Hospital, Kagawa, Japan.;Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.;Division of Hematology, Faculty of Medicine, Kagawa University, Kagawa, Japan.",
"authors": "Imataki|Osamu|O|;Ishida|Tomoya|T|;Kubo|Hiroyuki|H|;Uemura|Makiko|M|;Nanya|Yasuhito|Y|;Kawakami|Kimihiro|K|;Ogawa|Seishi|S|;Kadowaki|Norimitsu|N|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000506452",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000506452\ncro-0013-0449\nCase Report\nA Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation\nImataki Osamu a* Ishida Tomoya ab Kubo Hiroyuki a Uemura Makiko a Nanya Yasuhito c Kawakami Kimihiro d Ogawa Seishi c Kadowaki Norimitsu a aDivision of Hematology, Faculty of Medicine, Kagawa University, Kagawa, Japan\nbKagawa University Hospital Post Graduate Clinical Education Center, Kagawa, Japan\ncDepartment of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan\ndDepartment of Hematology, Kagawa Prefectural Central Hospital, Kagawa, Japan\n*Osamu Imataki, MD, Division of Hematology, Department of Internal Medicine, Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793 (Japan), oima@med.kagawa-u.ac.jp\nJan-Apr 2020 \n22 4 2020 \n22 4 2020 \n13 1 449 455\n7 2 2020 10 2 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.\n\nKeywords\nChronic myeloid leukemiaTyrosine kinase inhibitorDrug resistanceLeukemia oncogenesisClonal evolution\n==== Body\nIntroduction\nChronic myeloid leukemia (CML) is a myeloid clonal disease driven by the bcr-abl fusion gene, which creates a constitutively active tyrosine kinase. This led to the development of BCR-ABL1 tyrosine kinase inhibitors (TKIs), which provided long-term remission and improved life expectancy of TKI-treated CML patients [1]. The mechanism of TKI resistance in CML, caused by mutation of the BCR-ABL1 kinase domain has been extensively investigated [2]. Importantly, the BCR-ABL1 kinase-independent resistance mechanism due to newly acquired mutations or other genetic aberrations has been reported in a minority of TKI-resistant CML cases [3]. One such mutation was found in ASXL1, a histone-binding protein located on chromosome 20q11.2, that disrupts chromatin by enhancing or repressing gene transcription [4]. Then ABL1 kinase-dependent resistance may promote a change of a patient's TKI treatment strategy. As a while, however, it is obscure how much impact the BCR-ABL1 kinase-independent resistance brings on CML therapy plan.\n\nOriginally identified from sequence analysis of myelodysplastic syndrome (MDS) patients [5], mutations in ASXL1 were a nonspecific genetic abnormality, associated with poor prognosis not only in MDS [6] but also in bcr-abl-negative myeloproliferative neoplasms [6]. Mutations in ASXL1 have been found in the accelerated phase or blast phase [7] and in CML-chronic phase (CP) [8]. Surprisingly, several ASXL1 mutations have also been reported in healthy people [9, 10, 11], indicating the pleiotropic nature of ASXL1. We present a case of CML-CP resistant to various TKIs and discuss the association between mutations in ASXL1 and TKI resistance in CML.\n\nCase Presentation\nA 31-year-old male was diagnosed as CML-CP after an annual occupational health check-up revealed leukocytosis (WBC 187,200/µL), which was subjected to a further examination. The physical examination at his diagnosis revealed giant splenomegaly (palpable 15 cm below costal margin). Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. The patient's Sokal score was 1.5 indicating high risk, Hasford score was 1,332.4 indicating intermediate risk, EUTOS score was 134 indicating high risk, and ELTS score was 2.0877 indicating intermediate risk. A month after the diagnosis, the patient underwent TKI therapy comprising nilotinib up to 600 mg/day, followed by 600 mg bosutinib, 45 mg ponatinib, and 100 mg dasatinib maximum daily dose. Laboratory data prior to TKI treatment are shown in Table 1. None of the TKIs exerted a clinical response, except for ponatinib, which yielded a hematological response (Fig. 1). No known mutations in the ABL1 kinase domain were detected after TKI therapy, prompting sequencing analysis. We performed targeted panel sequencing, by using prior-stem cell transplantation sample, which includes 377 genes implicated in myeloid malignancies. This analysis revealed a frameshift mutation in ASXL1 on chromosome 20q11. The patient underwent a stem cell transplantation with bone marrow donated by an unrelated HLA 7/8-matched (HLA-Cw1 locus mismatched, GVH direction) male from the Japan Marrow Donor Program. Tacrolimus and short-term methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. On the 18th day after transplantation, the patient received neutrophil engraftment followed by reticulocyte engraftment 14 days later and platelet engraftment 22 days later. The patient achieved complete remission, with the bone marrow showing undetectable levels of BCR-ABL1 mRNA by RT-PCR (International Scale). Despite treatment, the patient died on the 121st day from GVHD and thrombotic microangiopathy, which developed after the patient presented with GVHD.\n\nDiscussion\nPhysiologically, ASXL1 encodes a chromatin-binding protein involved in epigenetic regulation [12] by recruiting the polycomb repressive complex 2 (PRC2), a histone methyltransferase, which regulates gene activity by trimethylation of lysine 27 on histone 3 (H3K27me) [13, 14]. Mutations in ASXL1 were originally reported and conferred poor prognosis in MDS [15] and chronic myelomonocytic leukemia (CMMoL) [5]. Frameshift mutations or nonsense mutations in exon 12 of ASXL1 abrogate protein expression [12] and consequently disrupt its function as a tumor suppressor, often in a variety of hematological malignancies [8]. Mutations in ASXL1 contribute to oncogenesis in hematopoietic cells, especially leukemogenesis, and promote myeloid transformation through loss of PRC2-mediated gene repression in MDS and CMMoL [12, 16].\n\nASXL1 mutations are common and associated with disease progression in acute myeloid leukemia (AML) [17] and similarly in CML, where ASXL1 mutations might be associated with poor prognosis and acute transformation [5]. Variation in prognosis and survival associated with ASXL1 mutations is seen across studies [18]. ASXL1 mutations are commonly associated with clonal hematopoiesis in healthy individuals [9, 10, 11], indicating that ASXL1 mutation may be a pre-leukemic event in hematopoiesis. Accumulating evidence points to a role for ASXL1 mutations in leukemogenesis during early hematopoietic events in many hematological malignancies, as described in AML [18] and CML [19, 20]. In the latter case, mutations in ASXL1 occur early in CML stem cells, prior to bcr-abl translocation stage [19], as these cells clonally evolve [20]. This is considered an intrinsic event, rather than a bcr-abl fusion, which occurs after myeloid lineage differentiation [20].\n\nIn the two-hit model of AML development, class I mutation confers a proliferative or survival advantage, and class II mutations result in impaired myeloid differentiation as a secondary event [21]. Class II mutations in ASXL1 lead to its loss of function, impairing granulomonocytic differentiation in early human hematopoietic progenitors and contributing to leukemogenesis. Indeed, silencing of ASXL1 impairs the granulomonocytic lineage potential of human CD34+ progenitor cells by altering its gene expression profile, but not proliferation and apoptosis [11, 14]. Alternatively, ASXL1 mutations might enhance other leukemogenesis pathways via other mechanisms, including epigenetic regulation.\n\nASXL1 plays a key role in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies [22]. Also, ASXL1 mutations may affect epigenetic regulation by inhibiting ubiquitination of lysine 119 at histone H2A (H2AK119). This may contribute to leukemogenesis though this remains to be proven [23]. Thus, even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression.\n\nASXL1 mutations occur early in CML stem cells, prior to bcr-abl translocation stage, and therefore, there might not be a high risk of treatment failure following TKI therapy [20]. The patient received hematopoietic stem cell transplantation and went into remission. This optimal response could have been prolonged without TKI maintenance therapy. Taken together, ASXL1 mutation might follow the HSCT trait as observed in this CML-CP case, which does not progress for years.\n\nConclusions\nWhole exome sequence facilitated a clinical decision in this patient who went into remission. Though the clinical impact of ASXL1 for CML is still under investigation, mutated ASXL1 possibly explain the TKI resistance mechanism. This case illustrated the necessity of HSCT in ASXL1 mutation-associated TKI-resistant CML-CP. In future, a discussion of CML with mutated ASXL1 will facilitate treatment options.\n\nStatement of Ethics\nThe Institutional Review Board approved the case report and submission of medical literature. We obtained written informed consent from the patient for participation in this study. We obtained consent to publish from the participants.\n\nDisclosure Statement\nThe authors declare no competing interests. The authors declare no potential conflicts of interest.\n\nFunding Sources\nInternal funding support is disclosed. This work was supported by internal funding, JSPS KAKENHI Grant Numbers JP16K19315, JP15K09570, and JP19K17927.\n\nAuthor Contributions\nO.I. and T.I. wrote the manuscript and made substantial contributions to concept and design; M.U., Y.N., K.K., and H.K. suggested important intellectual content and took part in the critical discussion; S.O. and N.K. managed the study and reviewed the manuscript; all authors read and approved the final version of the manuscript.\n\nAvailability of Data and Material\nThere are no other data analyzed in this study.\n\nFig. 1 The patient's clinical course. Nilotinib administration had an adverse effect on white blood cell and platelets, but did not diminish the bcr-abl fusion gene. The switch to bosutinib and dasatinib therapy did not change the response. The patient responded only to ponatinib treatment, which achieved a hematological response with 18% of bcr-abl1 FISH. However, no durable response was available. Hematopoietic stem cell transplantation yielded a molecular response without detection of major BCR-ABL1 mRNA by RT-PCR. The patient died of transplantation-related mortality, GVHD and TMA on the 121st day after transplantation. FISH, fluorescence in situ hybridization; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; PLT, platelet; TMA, thrombotic microangiopathy; WBC, white blood cells.\n\nTable 1 Laboratory data before tyrosine kinase inhibitor treatment\n\nWBC\t125,200\t/µL\t\n Stab.\t11.5\t%\t\n Seg.\t31.0\t%\t\n Lym.\t3.5\t%\t\n Mono.\t0.0\t%\t\n Eos.\t6.0\t%\t\n Baso.\t6.5\t%\t\n Blast\t6.5\t%\t\n Promyelo.\t1.0\t%\t\n Myelo.\t26.5\t%\t\n Metamyelo.\t7.5\t%\t\nRBC\t327×104\t/µL\t\nHb\t9.3\tg/dL\t\nHct\t30.4\t%\t\nMCV\t93.0\tfL\t\nMCHC\t30.6\t%\t\nPLT\t51.0×104\t/µL\t\nCRP\t1.20\tmg/dL\t\nTP\t6.0\tg/dL\t\nAlb\t4.1\tg/dL\t\nBUN\t15.2\tmg/dL\t\nCr\t0.68\tmg/dL\t\nUA\t6.2\tmg/dL\t\nT-Bil\t0.6\tmg/dL\t\nGOT\t14\tU/L\t\nGPT\t17\tU/L\t\nALP\t235\tU/L\t\nγ-GTP\t28\tU/L\t\nCPK\t12\tU/L\t\nCHE\t181\tU/L\t\nLDH\t601\tU/L\t\nNa\t140\tmmol/L\t\nK\t4.5\tmmol/L\t\nCl\t105\tmmol/L\t\nPT\t70\t%\t\nPT-INR\t1.17\t\t\nAPTT\t46.5\ts\t\nFIB\t311\tmg/dL\t\nATIII\t72\t%\t\nFDP\t3\tµg/mL\t\nD-dimer\t1.0\tµg/mL\n==== Refs\nReferences\n1 Cortes J Rea D Lipton JH Treatment-free remission with first- and second-generation tyrosine kinase inhibitors Am J Hematol 2019 3 94 (3) 346 57 30394563 \n2 Ren R Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia Nat Rev Cancer 2005 3 5 (3) 172 83 15719031 \n3 Patel AB O'Hare T Deininger MW Mechanisms of resistance to ABL kinase inhibition in chronic myeloid leukemia and the development of next generation ABL Kinase inhibitors Hematol Oncol Clin North Am 2017 8 31 (4) 589 612 28673390 \n4 Abdel-Wahab O Figueroa ME Interpreting new molecular genetics in myelodysplastic syndromes Hematol Am Soc Hematol Educ Program 2012 2012 56 64 \n5 Gelsi-Boyer V Trouplin V Adélaïde J Bonansea J Cervera N Carbuccia N Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia Br J Haematol 2009 6 145 (6) 788 800 19388938 \n6 Tefferi A Pardanani A Myeloproliferative neoplasms: a contemporary review JAMA Oncol 2015 4 1 (1) 97 105 26182311 \n7 Grossmann V Kohlmann A Zenger M Schindela S Eder C Weissmann S A deep-sequencing study of chronic myeloid leukemia patients in blast crisis (BC-CML) detects mutations in 76.9% of cases Leukemia 2011 3 25 (3) 557 60 21274004 \n8 Togasaki E Takeda J Yoshida K Shiozawa Y Takeuchi M Oshima M Frequent somatic mutations in epigenetic regulators in newly diagnosed chronic myeloid leukemia Blood Cancer J 2017 Apr 28 7 (4) e559 28452984 \n9 Genovese G Kähler AK Handsaker RE Lindberg J Rose SA Bakhoum SF Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence N Engl J Med 2014 Dec 25 371 (26) 2477 87 25426838 \n10 Jaiswal S Fontanillas P Flannick J Manning A Grauman PV Mar BG Age-related clonal hematopoiesis associated with adverse outcomes N Engl J Med 2014 Dec 25 371 (26) 2488 98 25426837 \n11 Xie M Lu C Wang J McLellan MD Johnson KJ Wendl MC Age-related mutations associated with clonal hematopoietic expansion and malignancies Nat Med 2014 12 20 (12) 1472 8 25326804 \n12 Pellagatti A Boultwood J The molecular pathogenesis of the myelodysplastic syndromes Eur J Haematol 2015 7 95 (1) 3 15 25645650 \n13 Abdel-Wahab O Adli M LaFave LM Gao J Hricik T Shih AH ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression Cancer Cell 2012 Aug 14 22 (2) 180 93 22897849 \n14 Davies C Yip BH Fernandez-Mercado M Woll PS Agirre X Prosper F Silencing of ASXL1 impairs the granulomonocytic lineage potential of human CD34⁺ progenitor cells Br J Haematol 2013 3 160 (6) 842 50 23294243 \n15 Bejar R Stevenson K Abdel-Wahab O Galili N Nilsson B Garcia-Manero G Clinical effect of point mutations in myelodysplastic syndromes N Engl J Med 2011 Jun 30 364 (26) 2496 506 21714648 \n16 Gelsi-Boyer V Brecqueville M Devillier R Murati A Mozziconacci MJ Birnbaum D Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases J Hematol Oncol 2012 Mar 21 5 12 22436456 \n17 Boultwood J Perry J Pellagatti A Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia Leukemia 2010 24 1062 5 20182461 \n18 Eriksson A Lennartsson A Lehmann S Epigenetic aberrations in acute myeloid leukemia: early key events during leukemogenesis Exp Hematol 2015 8 43 (8) 609 24 26118500 \n19 Boultwood J Perry J Zaman R Fernandez-Santamaria C Littlewood T Kusec R High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression Leukemia 2010 6 24 (6) 1139 45 20410925 \n20 Kim T Tyndel MS Kim HJ Ahn JS Choi SH Park HJ Spectrum of somatic mutation dynamics in chronic myeloid leukemia following tyrosine kinase inhibitor therapy Blood 2017 Jan 5 129 (1) 38 47 27733357 \n21 Gilliland DG Molecular genetics of human leukemias: new insights into therapy Semin Hematol 2002 10 39 (4 Suppl 3) 6 11 12447846 \n22 Inoue D Fujino T Sheridan P Zhang YZ Nagase R Horikawa S A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies Leukemia 2018 6 32 (6) 1327 37 29556021 \n23 Inoue D Fujino T Kitamura T ASXL1 as a critical regulator of epigenetic marks and therapeutic potential of mutated cells Oncotarget 2018 Oct 16 9 (81) 35203 4 30443287\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(1)",
"journal": "Case reports in oncology",
"keywords": "Chronic myeloid leukemia; Clonal evolution; Drug resistance; Leukemia oncogenesis; Tyrosine kinase inhibitor",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "449-455",
"pmc": null,
"pmid": "32399015",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26118500;25426838;30394563;23233561;28673390;21274004;21714648;25326804;22436456;27733357;12447846;29556021;15719031;25645650;23294243;28452984;20182461;22897849;30443287;20410925;19388938;26182311;25426837",
"title": "A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation.",
"title_normalized": "a case of tyrosine kinase inhibitor resistant chronic myeloid leukemia chronic phase with asxl1 mutation"
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"abstract": "Transplantation-associated thrombotic microangiopathy (TA-TMA) is relatively rare and requires immediate intervention to avoid irreversible organ damage or death; however, consensus regarding the treatment approach is lacking. Atypical haemolytic uraemic syndrome (aHUS) is a rare disease caused by dysregulation of the alternative complement pathway resulting in TMA. aHUS is histologically similar to TA-TMA; approximately 60% of TA-TMA patients have complement dysregulation. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal membrane-attack complex formation and TMA progression. Eculizumab has been successfully used to treat aHUS post-transplant. We present two cases of kidney TA-TMA due to unknown causes, suspected antibody-mediated rejection, or calcineurin inhibitor (CNI)-related toxicity that developed on day 1 or 2 post-kidney transplantation. Low platelet count and haemoglobin level with red cell fragments were detected. Despite steroid pulse, plasma exchange (PE), and intravenous immunoglobulin therapy, TA-TMA did not improve; therefore, eculizumab was administered despite no genetic testing. Laboratory data, including renal function, improved immediately. TA-TMA treatment primarily involves PE initiation or CNI discontinuation; eculizumab can be used to safely treat TA-TMA and then be ceased in the short term. Therefore, eculizumab administration might be beneficial for kidney TA-TMA as early as the diagnosis of refractory to PE.",
"affiliations": "Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.;Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.;Internal Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan.;Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.;Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.;Surgical Pathology, Tokyo Women's Medical University, Tokyo, Japan.;Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.;Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.;Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.",
"authors": "Ikeda|Takashi|T|;Okumi|Masayoshi|M|;Unagami|Kohei|K|;Kanzawa|Taichi|T|;Sawada|Anri|A|;Kawanishi|Kunio|K|;Omoto|Kazuya|K|;Ishida|Hideki|H|;Tanabe|Kazunari|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; C481642:eculizumab",
"country": "Australia",
"delete": false,
"doi": "10.1111/nep.12768",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1320-5358",
"issue": "21 Suppl 1()",
"journal": "Nephrology (Carlton, Vic.)",
"keywords": "atypical haemolytic uraemic syndrome; eculizumab; kidney transplantation; plasma exchange; thrombotic microangiopathies",
"medline_ta": "Nephrology (Carlton)",
"mesh_terms": "D000328:Adult; D000368:Aged; D064591:Allografts; D061067:Antibodies, Monoclonal, Humanized; D001706:Biopsy; D003167:Complement Activation; D051056:Complement Inactivating Agents; D005260:Female; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D012074:Remission Induction; D057049:Thrombotic Microangiopathies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9615568",
"other_id": null,
"pages": "35-40",
"pmc": null,
"pmid": "26970541",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two cases of kidney transplantation-associated thrombotic microangiopathy successfully treated with eculizumab.",
"title_normalized": "two cases of kidney transplantation associated thrombotic microangiopathy successfully treated with eculizumab"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1024657",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BASILIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Oculocutaneous albinism (OCA) is a group of autosomal recessive disorders characterized by impairment in the melanin synthesis. We report two siblings with OCA who presented with symptoms of autism spectrum disorder and attention deficit hyperactivity disorder (ADHD). Ocular side effects occured after methylphenidate (MPH) treatment in the patient with ADHD and OCA. The diagnosis of OCA has been associated with difficulties in academic and social fields due to decreased visual activity and differentiation of phenotypic characteristics. Delayed diagnosis of comorbid neuropsychiatric disorders and MPH therapy may increase these difficulties. Patients with OCA require careful evaluation and treatment for neuropsychiatric disorders.",
"affiliations": "Department of Child and Adolescent Psychiatry, Balıkesir University , Balıkesir, Turkey.",
"authors": "Ünsel Bolat|Gül|G|0000-0002-4574-421X",
"chemical_list": "D000697:Central Nervous System Stimulants; D008774:Methylphenidate",
"country": "England",
"delete": false,
"doi": "10.1080/13554794.2020.1853174",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-4794",
"issue": "26(6)",
"journal": "Neurocase",
"keywords": "ADHD; ASD; albinism; methylphenidate; visual side effect",
"medline_ta": "Neurocase",
"mesh_terms": "D000293:Adolescent; D016115:Albinism, Oculocutaneous; D001289:Attention Deficit Disorder with Hyperactivity; D000067877:Autism Spectrum Disorder; D000697:Central Nervous System Stimulants; D002648:Child; D006801:Humans; D008297:Male; D008774:Methylphenidate; D035781:Siblings",
"nlm_unique_id": "9511374",
"other_id": null,
"pages": "360-363",
"pmc": null,
"pmid": "33241980",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report: diagnosis and treatment of attention deficit hyperactivity disorder and autism spectrum disorder in patients diagnosed with oculocutaneous albinism.",
"title_normalized": "case report diagnosis and treatment of attention deficit hyperactivity disorder and autism spectrum disorder in patients diagnosed with oculocutaneous albinism"
} | [
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2020-08785",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
... |
{
"abstract": "Post-hepatectomy liver failure (PHLF) is a leading cause of morbidity and mortality following major liver resection. The development of PHLF is dependent on the volume of the remaining liver tissue and hepatocyte function. Without effective pre-operative assessment, patients with undiagnosed liver disease could be at increased risk of PHLF. We report a case of a 60-year-old male patient with PHLF secondary to undiagnosed alpha-1-antitrypsin deficiency (AATD) following major liver resection. He initially presented with acute large bowel obstruction secondary to a colorectal adenocarcinoma, which had metastasized to the liver. There was no significant past medical history apart from mild chronic obstructive pulmonary disease. After colonic surgery and liver directed neo-adjuvant chemotherapy, he underwent a laparoscopic partially extended right hepatectomy and radio-frequency ablation. Post-operatively he developed PHLF. The cause of PHLF remained unknown, prompting re-analysis of the histology, which showed evidence of AATD. He subsequently developed progressive liver dysfunction, portal hypertension, and eventually an extensive parastomal bleed, which led to his death; this was ultimately due to a combination of AATD and chemotherapy. This case highlights that formal testing for AATD in all patients with a known history of chronic obstructive pulmonary disease, heavy smoking, or strong family history could help prevent the development of PHLF in patients undergoing major liver resection.",
"affiliations": "Benjamin Norton, Peninsula College of Medicine and Dentistry, Tamar Science Park, Plymouth PL6 8BU, United Kingdom.;Benjamin Norton, Peninsula College of Medicine and Dentistry, Tamar Science Park, Plymouth PL6 8BU, United Kingdom.;Benjamin Norton, Peninsula College of Medicine and Dentistry, Tamar Science Park, Plymouth PL6 8BU, United Kingdom.;Benjamin Norton, Peninsula College of Medicine and Dentistry, Tamar Science Park, Plymouth PL6 8BU, United Kingdom.;Benjamin Norton, Peninsula College of Medicine and Dentistry, Tamar Science Park, Plymouth PL6 8BU, United Kingdom.;Benjamin Norton, Peninsula College of Medicine and Dentistry, Tamar Science Park, Plymouth PL6 8BU, United Kingdom.",
"authors": "Norton|Benjamin|B|;Denson|Jemimah|J|;Briggs|Christopher|C|;Bowles|Matthew|M|;Stell|David|D|;Aroori|Somaiah|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v22.i11.3289",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "22(11)",
"journal": "World journal of gastroenterology",
"keywords": "Alpha-1-antitrypsin deficiency; Functional liver remnant; Hepatectomy; Liver resection; Post-hepatectomy liver failure",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000230:Adenocarcinoma; D001706:Biopsy; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms; D057210:Delayed Diagnosis; D017809:Fatal Outcome; D006498:Hepatectomy; D006801:Humans; D017114:Liver Failure, Acute; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D019896:alpha 1-Antitrypsin Deficiency",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "3289-95",
"pmc": null,
"pmid": "27004008",
"pubdate": "2016-03-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25392842;19730239;25392835;17551779;14762841;21236455;20303723;8090762;20947471;309708;14522813;16327492;18796107;19106687;23135735;9037225;7986822;23428310;17481498;12426287;15758596;16447274;8938188;25498135;17464974;24778768",
"title": "Delayed diagnosis of alpha-1-antitrypsin deficiency following post-hepatectomy liver failure: A case report.",
"title_normalized": "delayed diagnosis of alpha 1 antitrypsin deficiency following post hepatectomy liver failure a case report"
} | [
{
"companynumb": "GB-SA-2016SA076605",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "We investigated the occurrence and management of therapy-related hematological disorders (tr-HDs) in women with epithelial ovarian cancer (EOC) exposed to poly-ADP-ribose polymerase inhibitors (PARPi), after previous chemotherapy. We analyzed 130 consecutive EOC patients treated with PARPi at the European Institute of Oncology, Milan. In line with the literature, overall survival of the entire population was 37% at 5.5 years (89% were advanced stages). Cell blood counts were collected prior to start PARPi, at each new cycle and at monthly intervals. Patients displaying persistent and/or marked hematological abnormalities underwent bone marrow evaluation, with cytogenetic and molecular analysis. Nine patients (6,9%) developed tr-HDs, after a median 22.8 months of PARPi exposure. Two patients died early and could not be treated. Two patients have no indication for active treatment and are presently under close hematological monitoring. Five patients underwent chemotherapy followed, in three cases, by allogeneic hematopoietic transplantation: three patients are in complete remission of their hematological and gynecological malignancies at 13, 19, and 25 months; the remaining two patients died due to progression of their hematological disease. We show the potential risk of hematological disorders in EOC patients treated with chemotherapy and prolonged PARPi therapy. In our series, tr-HDs incidence was higher compared to recent reports in large series. Our observations suggest careful monitoring in order to conclusively define, on large series and prolonged follow-up, the actual risk of tr-HDs in patients under PARPi. Notably, prompt diagnosis of hematological abnormalities and appropriate management allow achievement of remission from severe hematological complications, at least in most patients.",
"affiliations": "Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Gynecologic Oncology Unit, Fondazione IRCCS National Cancer Institute, Milan, Italy.;Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Laboratory of Clinical Genomics, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Department of Gynecology, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Department of Gynecology, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.;Laboratory of Hematology-Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Laboratory of Hematology-Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Laboratory of Hematology-Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Laboratory of Hematology-Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy.;Gynecologic Cancer Program, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy.;Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milan, Italy.",
"authors": "Todisco|Elisabetta|E|;Gigli|Federica|F|;Mantiero|Mara|M|;Sammassimo|Simona|S|;Pastano|Rocco|R|;Ronchini|Chiara|C|0000-0003-3908-4021;Parma|Gabriella|G|;Lapresa|Maria Teresa|MT|;Iori|Anna Paola|AP|;Bertolini|Francesco|F|;Corsini|Chiara|C|;Gregato|Giuliana|G|;Poletti|Claudia|C|;Colombo|Nicoletta|N|;Tarella|Corrado|C|",
"chemical_list": "D000067856:Poly(ADP-ribose) Polymerase Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.33269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "148(1)",
"journal": "International journal of cancer",
"keywords": "PARP-inhibitors; clinical management; epithelial ovarian cancer; hematological monitoring; therapy-related hematological disorders",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001772:Blood Cell Count; D001853:Bone Marrow; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D006402:Hematologic Diseases; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D010051:Ovarian Neoplasms; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012189:Retrospective Studies; D014184:Transplantation, Homologous",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "170-177",
"pmc": null,
"pmid": "32856727",
"pubdate": "2021-01-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical presentation, diagnosis and management of therapy-related hematological disorders in women with epithelial ovarian cancer treated with chemotherapy and poly-ADP-ribose polymerase inhibitors: A single-center experience.",
"title_normalized": "clinical presentation diagnosis and management of therapy related hematological disorders in women with epithelial ovarian cancer treated with chemotherapy and poly adp ribose polymerase inhibitors a single center experience"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-284226",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DECITABINE"
},
"drug... |
{
"abstract": "D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in D-2-hydroxyglutarate dehydrogenase (D2HGDH) or a single gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2). Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) is a type of D-2-HGA that has been previously reported in ten patients (OMIM 614875), three of whom had somatic mosaicism for R132 variants in isocitrate dehydrogenase 1 (IDH1). We describe a 3-year-old boy with MC-HGA who subsequently developed acute myeloid leukemia (AML) and was found to have an IDH1 R132C mutation in a leukemic bone marrow sample. Further testing revealed presence of somatic mosaicism for IDH1 R132C variant, suggesting an association of IDH1 in inducing myeloid leukemogenesis.",
"affiliations": "Jimmy Everest Section of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Department of Radiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Senior Clinical Consultant at Mayo Clinic, Jacksonville, FL. Prior affiliation: Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma, USA.;Division of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Children's Mercy Hospital, Kansas City, MO. Prior affiliation: Jimmy Everest Section of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Jimmy Everest Section of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.;Jimmy Everest Section of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.",
"authors": "Srinivasan|Anand|A|http://orcid.org/0000-0002-4983-5039;Zhou|Yaolin|Y|;Scordino|Teresa|T|;Prabhu|Sandeep|S|;Wierenga|Andrea|A|;Simon|Garfield|G|;Wierenga|Klaas J|KJ|;Thompson|Joel|J|;Shah|Rikin|R|;Sinha|Arpan A|AA|http://orcid.org/0000-0001-9882-4291",
"chemical_list": "D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human",
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2020.1737284",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "37(5)",
"journal": "Pediatric hematology and oncology",
"keywords": "AML; IDH1 mutation; MC-HGA",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D020739:Brain Diseases, Metabolic, Inborn; D002675:Child, Preschool; D018210:Chondromatosis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007521:Isocitrate Dehydrogenase; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009154:Mutation; D016896:Treatment Outcome",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "431-437",
"pmc": null,
"pmid": "32166993",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "IDH1 mutated acute myeloid leukemia in a child with metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria.",
"title_normalized": "idh1 mutated acute myeloid leukemia in a child with metaphyseal chondromatosis with d 2 hydroxyglutaric aciduria"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-03760",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAUNORUBICIN"
},
... |
{
"abstract": "Up to 30% of patients undergoing cardiac surgery develop AKI, with 1% requiring RRT. AKI is an independent risk factor for morbidity and mortality. Postoperatively, even minimal changes in serum creatinine are associated with a substantial increase in mortality. No intervention has been definitely proven effective in reducing kidney injury. The successful prevention and management of AKI involves identifying patients at risk for AKI, recognizing subtle abnormalities in a timely manner, performing basic clinical assessments, and responding appropriately to data obtained. With that in mind, in this Attending Rounds, a woman with AKI in the setting of cardiac surgery is presented to highlight the use of history, physical exam, hemodynamic monitoring, laboratory data trends, and urine indices in establishing the correct diagnosis and appropriate management.",
"affiliations": "Division of Nephrology, University of Alabama, Birmingham, Alabama atolwani@uab.edu.",
"authors": "Tolwani|Ashita J|AJ|",
"chemical_list": "D015415:Biomarkers",
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.10461013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1555-9041",
"issue": "9(8)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": "acute renal failure; cardiovascular; clinical nephrology",
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D015415:Biomarkers; D002305:Cardiac Tamponade; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease; D005260:Female; D006406:Hematoma; D006439:Hemodynamics; D006801:Humans; D011237:Predictive Value of Tests; D012086:Reoperation; D012307:Risk Factors; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "1470-8",
"pmc": null,
"pmid": "24651071",
"pubdate": "2014-08-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20630639;18852580;17715412;12683567;23628654;21256305;22340031;8986487;15563569;18230632;18243724;15809463;17291932;18582254;19153273;23302716;16504529;20332738;15678051;22449296;15045170;19624581;18492867;12666060;16096452;23443311;20605299;22626819;21232094;21400231;18311733;23800191;9083231;21394005;21677302;19660420;21716258;19846848;24008395;22301562;18216610;23915489;19820480;21352532;19648183;19778954;23265598;20459609;21851876;10203370;23131078;22186469;11378603;22459931;22595302;18533029;14981602;21856761;21310818;23833316;23610561;23265599;12917306;17291938;18562058;20671222;19215833;18354101;22096038;11089739;19282300;23254894;23273532;10616845;22240498;20375302;17699187;23685640;18667735;22117606;20631451;22867021;23736723;19101287;19436332;21911805;17660024",
"title": "A patient with AKI after cardiac surgery.",
"title_normalized": "a patient with aki after cardiac surgery"
} | [
{
"companynumb": "US-BAYER-2015-052827",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "Maternal neurological injuries may be intrinsic to the labour and delivery process or may result directly or indirectly from obstetric or anaesthetic intervention. This intrinsic obstetric palsy is a rare complication of labour but can have devastating impact on a previously healthy mother. A 23-year-old gravida1, para0 who had epidural for labour analgesia, was augmented for slow progress and had a normal vaginal delivery. She was diagnosed post delivery with intrinsic obstetric palsy involving several peripheral nerves and lumbosacral nerve roots with a guarded prognosis. In this article we have discussed the risk factors and mechanisms of intrinsic obstetric palsy and proposed further investigation into the potential protective role of ambulatory analgesia i.e. CSE (Combined Spinal Epidural) or LDI (Low Dose Infusion).",
"affiliations": "CMO, Department of Obstetrics & Gynaecology, Joondalup Health Campus , Joondalup WA Australia .;Director, Department of Obstetrics & Gynaecology, Joondalup Health Campus , Joondalup WA Australia .",
"authors": "Hakeem|Rashida|R|;Neppe|Cliff|C|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/18797.7693",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "10(4)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Ambulatory analgesia; Combined spinal epidural; Epidural; Low dose infusion; Postpartum",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "QD06-7",
"pmc": null,
"pmid": "27190901",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports",
"references": "20053587;12576251;22881282;11777506;11454372;19302638;25625259;23076897;23459069;15059151;7577273",
"title": "Intrinsic Obstetric Palsy: Case Report and Literature Review.",
"title_normalized": "intrinsic obstetric palsy case report and literature review"
} | [
{
"companynumb": "AU-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-31142BI",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministrationrou... |
{
"abstract": "Drug-induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti-inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%.\n\n\n\nThis is a multicentre case-control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis.\n\n\n\nWe included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21-2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28-3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73-90.88) and to higher doses (OR 10.69, 95% CI 4.02-28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13-3.26) and at higher doses (OR 3.73, 95% CI 1.11-12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33-10.00).\n\n\n\nAmong all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity.",
"affiliations": "Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.;Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy.;Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), Tuscan Regional Centre of Pharmacovigilance, University of Florence, 50139, Florence, Italy.;Department of Experimental Medicine, Second University of Neaples, via de Crecchio 7, 80138, Neaples, Italy.;Hospital Statistic Unit, University Hospital of Verona, p.le Aristide Stefani, 1, 37126, Verona, Italy.;Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.;Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy.;Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), Tuscan Regional Centre of Pharmacovigilance, University of Florence, 50139, Florence, Italy.;Department of Experimental Medicine, Second University of Neaples, via de Crecchio 7, 80138, Neaples, Italy.;Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.;Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy.;Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), Tuscan Regional Centre of Pharmacovigilance, University of Florence, 50139, Florence, Italy.;Department of Experimental Medicine, Second University of Neaples, via de Crecchio 7, 80138, Neaples, Italy.;Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy.",
"authors": "Donati|Monia|M|;Conforti|Anita|A|;Lenti|Maria Carmela|MC|;Capuano|Annalisa|A|;Bortolami|Oscar|O|;Motola|Domenico|D|;Moretti|Ugo|U|;Vannacci|Alfredo|A|;Rafaniello|Concetta|C|;Vaccheri|Alberto|A|;Arzenton|Elena|E|;Bonaiuti|Roberto|R|;Sportiello|Liberata|L|;Leone|Roberto|R|;|||",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D013449:Sulfonamides; D007660:Ketoprofen; C012655:nimesulide; D007052:Ibuprofen",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.12938",
"fulltext": "\n==== Front\nBr J Clin PharmacolBr J Clin Pharmacol10.1111/(ISSN)1365-2125BCPBritish Journal of Clinical Pharmacology0306-52511365-2125John Wiley and Sons Inc. Hoboken 2699179410.1111/bcp.12938BCP12938MP-00611-15.R2PharmacoepidemiologyPharmacoepidemiologyRisk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug‐induced liver injury case–control study in Italy Acute liver injury associated to NSAIDsM. Donati et al.Donati Monia \n1\nConforti Anita \n2\nLenti Maria Carmela \n3\nCapuano Annalisa \n4\nBortolami Oscar \n5\nMotola Domenico \n1\nMoretti Ugo \n2\nVannacci Alfredo \n3\nRafaniello Concetta \n4\nVaccheri Alberto \n1\nArzenton Elena \n2\nBonaiuti Roberto \n3\nSportiello Liberata \n4\nLeone Roberto \n2\non behalf of DILI-IT Study Group 1 Unit of Pharmacology, Department of Medical and Surgical SciencesUniversity of Bolognavia Irnerio 4840126BolognaItaly2 Pharmacology Unit, Department of Diagnostics and Public HealthUniversity of Veronap.le L.A. Scuro, 1037134VeronaItaly3 Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), Tuscan Regional Centre of PharmacovigilanceUniversity of Florence50139FlorenceItaly4 Department of Experimental MedicineSecond University of Neaplesvia de Crecchio 780138NeaplesItaly5 Hospital Statistic UnitUniversity Hospital of Veronap.le Aristide Stefani, 137126VeronaItaly* \nCorrespondence\n\nProfessor Roberto Leone, Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro, 10, 37134, Verona, Italy. Tel.: +39 04 5812 4706; Fax: +39 04 5812 4876; E‐mail: roberto.leone@univr.it\n27 4 2016 7 2016 82 1 10.1111/bcp.v82.1238 248 02 10 2015 20 1 2016 13 3 2016 © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological SocietyThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Aim\nDrug‐induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti‐inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%.\n\nMethods\nThis is a multicentre case–control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis.\n\nResults\nWe included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21–2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28–3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73–90.88) and to higher doses (OR 10.69, 95% CI 4.02–28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13–3.26) and at higher doses (OR 3.73, 95% CI 1.11–12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33–10.00).\n\nConclusion\nAmong all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity.\n\ncase–control studyDILIliver injurynimesulideNSAIDs source-schema-version-number2.0component-idbcp12938cover-dateJuly 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:23.06.2016\n\n\nDonati , M. \n, \nConforti , A. \n, \nLenti , M. C. \n, \nCapuano , A. \n, \nBortolami , O. \n, \nMotola , D. \n, \nMoretti , U. \n, \nVannacci , A. \n, \nRafaniello , C. \n, \nVaccheri , A. \n, \nArzenton , E. \n, \nBonaiuti , R. \n, \nSportiello , L. \n, \nLeone , R. \n, and on behalf of DILI-IT Study Group (2016 ) Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug‐induced liver injury case–control study in Italy . Br J Clin Pharmacol , 82 : 238 –248 . doi: 10.1111/bcp.12938.26991794\n==== Body\nWhat is Already Known about this Subject\n\nDrug‐induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for failure of approval, restriction of indications or withdrawal of drugs.\n\nSome NSAIDs were withdrawn from the market because of serious hepatotoxicity.\n\nNimesulide is an NSAID suspended from the market in several countries because of high frequency of hepatotoxicity.\n\n\n\n\nWhat this Study Adds\n\nThese findings add new elements to the available data on incidence of drug‐induced hepatotoxicity.\n\nThere is an association between the use of some NSAIDs and risk of acute serious liver injury in Italian patients.\n\nAmong commonly used anti‐inflammatory drugs, nimesulide is associated with a slight increase of risk, which raises with time exposure and dosage. For ibuprofen and high dosage of ketoprofen, an increased risk was also found.\n\n\n\n\nIntroduction\nDrug‐induced liver injury (DILI) is a condition that can symptomatically mimic most kinds of acute and chronic liver pathologies and is the most common cause of acute liver failure both in the USA 1, 2 and in Europe 3, 4. DILI is considered among the most serious adverse drug reactions (ADRs) and represents the main cause of discontinuing the development of new drugs at early stages and the most frequent reason for refusal to approve, restriction of indications or withdrawal of drugs by regulatory agencies 5, 6, 7.\n\nSince the diagnosis of this condition is not simple and pre‐marketing studies are unable to detect all possible hepatic ADRs, little is known about the incidence of DILI in the general population and the available data come from spontaneous reports and few epidemiologic studies 8. Björnsson and colleagues defined the incidence of DILI by prospectively examining a population‐based cohort in Iceland: 96 cases of DILI were identified between 2010 and 2011, with an annual incidence of 19.1 cases per 100 000 inhabitants (95% CI, 1.54–23.3) 9. Another French population‐based study reported an incidence of 13.9 cases per 100 000 inhabitants per year, with a 6% mortality rate 10. Two studies from Sweden and the UK, in contrast, found a lower incidence, that is 2.3 and 2.4 per 100 000 inhabitants per year respectively 11, 12. Liver injury can be associated with several drug classes, most commonly antibiotics, antifungal, antituberculosis, antiepileptic and NSAIDs 13.\n\nNSAIDs represent one of the most widely used drug classes in the world and the most commonly used analgesics 14. The major adverse effects of NSAIDs are gastrointestinal, cardiovascular and renal injuries, which are well documented 15, 16; hepatotoxicity is a rare ADR, usually not dose related, but serious and even fatal 15, 17, 18, 19, 20, 21.\n\nSeveral NSAIDs were withdrawn from the market because of hepatic ADRs (bromfenac, ibufenac, benoxaprofen, droxicam, pirprofen, fenclofenac and, more recently, lumiracoxib); others, such as nimesulide, were never marketed in some countries or withdrawn in others. In 2002 Finland and Spain suspended the marketing of this drug because of the high frequency of hepatotoxicity 22, 23. Consequently, the European Medicines Agency (EMA) started an evaluation procedure on nimesulide safety and in 2004 it concluded that the benefit–risk profile of this drug was favourable. However, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended restriction of nimesulide indications to the treatment of acute pain, symptomatic treatment of painful osteoarthritis and primary dysmenorrhea, and withdrawal from the market of the 200 mg pharmaceutical formulation, restricting the maximal drug dosage at 100 mg twice a day; nimesulide was also contraindicated in children under 12 years of age 24. In May 2007 the Irish medicines regulatory authority decided to suspend the marketing authorization for systemic nimesulide‐containing medicines owing to new information regarding cases of fulminant hepatic failure requiring liver transplantation, which led the EMA to a further review process 25. Also in this case the risk–benefit balance of nimesulide remained positive, although the EMA restricted the duration of therapy to 15 days, and recommended the drug only as a second‐line treatment. Two years later, in 2009, nimesulide was withdrawn from the market in Argentina as well 26. In 2012 the EMA completed a review of the safety and effectiveness of systemic medicines containing nimesulide and concluded that, compared with other NSAIDs, nimesulide was associated with an increased risk of liver toxicity and its risk–benefit ratio remained positive for its use in acute pain and dysmenorrhea but not for osteoarthritis 27. An important contribution to the debate on the hepatotoxicity of nimesulide was provided by the Italian study published by Traversa and colleagues, which concluded that although the risk of liver injury in patients taking nimesulide and other NSAIDs is small, such risk is higher for nimesulide 28. Another study, conducted in Italy in 2010, showed that NSAIDs were more commonly associated with DILI and 70% of the observed cases were attributable to nimesulide 29. The aim of the Drug‐Induced Liver Injury in Italy (DILI‐IT) study was to estimate the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs with a prevalence of use greater than or equal to 5% of the total number of drugs taken by the study population. The hepatotoxic risk associated with paracetamol was assessed as well.\n\nFurthermore, the study assessed the risk of acute and serious liver injury induced by amoxicillin and amoxicillin with clavulanic acid, macrolides, antidepressants and statins.\n\nHere, we present the results of the main analysis on the risk of liver injury associated to nimesulide and NSAIDs.\n\nMethods\nStudy population\nWe conducted a multicentre case–control study where cases and controls were all recruited among hospital patients in Italy, from October 2010 to January 2014.\n\nNine hospitals located in four regions representative of the North (Veneto and Emilia Romagna), Central (Tuscany) and South (Campania) of Italy participated in the study; the population covered by the hospitals involved is approximately 4938 700 inhabitants (8.3% of the Italian population). Patients eligible were those visited by hospital physicians participating in the study.\n\nCases were defined as all patients aged 18 or over admitted with a primary diagnosis of acute liver injury. According to the definition of DILI 13 and in accordance with the hepatologists involved in the study, we used the following criteria for case definition: (1) increase of 2 N (N is the upper limit of normal range and each activity is expressed as a multiple of N) for alanine aminotransferase (ALT), aspartate aminotransferase (AST) serum activity in patients who presented symptoms or not; (2) increase of 1.5 N of alkaline phosphatase (AP) associated with an increase of ALT or AST and/or total bilirubin in patients with or without symptoms.\n\nTen hospital controls were selected consecutively for each case, matched according to gender and age (+/− 5 years), and to hospital and time from admission (within 2 months).\n\nControls were patients with a minimum age of 18 years, admitted for acute clinical disorders not related to chronic conditions, not involving the liver (with normal liver enzyme values) and without specific indications or contraindications for NSAID use. The selected admission diagnoses were: non‐alcohol‐related trauma or fracture, acute appendicitis, bowel obstruction, intestinal perforation, acute pancreatitis, pneumonia in patients without risk factors, pneumothorax without previous chronic obstructive bronchitis or chronic obstructive pulmonary disease, renal colic, euthyroid nodule, bite, accidental injuries or burns, foreign bodies, abdominal gestation/fallopian tube rupture or miscarriage, testicular torsion and umbilical hernia.\n\nBoth cases and controls were excluded if the patients had a diagnosis of viral hepatitis, biliary abnormality, history of alcohol abuse, autoimmune disease, genetic and metabolic disorders which may determine liver injury, a low alpha‐1‐antitrypsin level and an abnormal phenotype (that may suggest disease associated with a deficiency of this protein), Wilson's disease, HIV/AIDS, hepatic neoplasia or liver metastasis, systemic lupus erythematosus, mushroom poisoning and drug addiction or detoxification treatment in the last 3 months; finally, patients who were not resident in the study areas were also excluded (primary exclusion criteria). Patients who were discharged or died before interview and those refusing the interview or unable to answer were also excluded (secondary exclusion criteria). A panel of experts (External Advisory Board) was established to monitor the appropriateness of inclusion and exclusion criteria for cases and controls; they represented also an important support in the debate about the problems that emerged during patient recruitment.\n\nExposure to drugs\nExposure to drugs was defined as any use in the 90 days prior to the index day (ID) 30. For each case, the ID was considered as the onset day of the liver damage symptoms or the date corresponding to the first available abnormal value of liver enzyme tests. For controls, the ID was taken as the onset day of any symptom relating to the disease for which the patient was selected as a control.\n\nFor NSAIDs with a prevalence of use >5% and for paracetamol, different periods of use/non‐use were compared and cumulative time of exposure was defined as less than or equal to 15 days, between 15 and 30 days and greater than 30 days. Moreover, the average daily dose of each NSAID and paracetamol was calculated for each patient and two dose categories were considered on the basis of the corresponding DDD (defined daily dose) 31. The number of exposed patients according to time and dose categories was calculated.\n\nInformation retrieval\nDrug exposure was investigated by trained monitors by face‐to‐face interview using a standardized questionnaire (Case Report Form, CRF). Before the interview, the aim of the study was explained to patients and written informed consent was obtained. The CRF covered information regarding demographic data, medical history, coexisting illnesses, lifestyle and dietary habits, alcohol, tobacco and coffee intake and use of herbal products. Data concerning the diagnosis of liver injury and the evolution of the disease were collected from medical records. Clinical records were also used to evaluate the diagnoses of the controls.\n\nTo ensure that drug history was as complete as possible and to reduce recall bias, after an open question about previous use of drugs, patients were questioned about a list of common symptoms often prompting use of medicines of interest. Patients were also shown a photographic collection reproducing the packaging of main medicinal products concerned (most used NSAIDs, amoxicillin and amoxicillin with clavulanic acid, macrolides, antidepressants and statins).\n\nStatistical analysis\nData are presented as mean values (SD) and frequencies (%). Odds ratios (OR) and their 95% confidence intervals (95% CI) have been calculated by means of a conditional logistic regression for matched case–control groups, using the Stata Statistical Software version 11.0 (StataCorp, College Station, TX, 2009). OR has been computed initially with a bivariate and then multivariate analysis, to assure that the risk estimates for liver injury and use of drugs were appropriately adjusted for possible confounders and effect modifiers. Covariates included were: smoking, alcohol, body mass index (BMI), liver comorbidities (hepatitis, gallstones, liver cirrhosis, hepatic nodules and other hepatic diseases), heart comorbidities (stroke, angina pectoris, heart failure, arrhythmia and cardiac surgery), and coprescribed drugs (other NSAIDs, paracetamol, amoxicillin, amoxicillin/clavulanic acid, macrolides, antidepressants and statins). There was a negligible amount of missing data (all found on control group) for: BMI (less than 1%; 11 subjects out of 1770), alcohol consumption (less than 1%; 3 subjects out of 1770), and smoking (less than 1%; 2 subjects out of 1770). Therefore no methods to account for missing data have been used and complete case analyses have been performed. The effect of gender and age on risk of liver injury among NSAID users have been evaluated using an unconditional logistic regression.\n\nThe sample size for the first primary objective (relative risk of nimesulide‐induced liver injury) was estimated assuming a minimal detectable risk (OR) of 2.0 with alpha 0.05 and at a power of 80%, and a prevalence of nimesulide use of 8%. Given these assumptions, 163 cases and 1630 controls (matched case–control ratio 1:10) were required. This sample size was considered adequate even with a slightly different prevalence in the control population (range: 5–10%): this would detect an odds ratio ranging from 2.28 (alpha 0.05; power: 80%) for a 5% prevalence to an odds ratio of 1.91 (alpha 0.05; power: 80%) for a 10% prevalence. The latter proportion has been found (184 nimesulide users among 1770 matched controls) in the present study. The Pass 11 statistical software, version 11.0.7, was used for these calculations.\n\nEthical considerations\nThe study was approved by the Independent Ethics Committee (IEC) of Verona Hospital (principal investigator and coordinating centre) and consecutively notified to the IECs of participating centres.\n\nResults\nPopulation\nOverall, 2232 patients with diagnosis of acute serious liver injury were recorded; of those, 2028 were not included in the study, according to the primary exclusion criteria. The 204 incident cases resulted in an annual incidence of DILI of 4.1 cases per 100 000 inhabitants. Subsequently, 25 other cases were excluded on the basis of secondary criteria. Therefore, the analysis was performed on 179 cases. In the same period, 3059 patients were selected and interviewed as possible controls. From this sample, 1770 patients were matched to the 179 cases, according to gender, age, centre and time from admission (Figure 1). Controls included in the analysis were enrolled for the following diagnosis: trauma or fracture (46%), acute appendicitis (15%), gastrointestinal disorders (14%), respiratory disorders (13%) and other acute events (12%).\n\nFigure 1 Flow diagram of patients included in the study\n\nTable 1 shows the baseline characteristics of recruited patients. Women were slightly more represented than men (58% vs 42%). Controls were found to be slightly more overweight compared to cases and they consumed alcohol (as current drinkers) and tobacco (as former smokers) more frequently than cases. Again, in a slightly greater number of cases compared to controls liver and heart co‐morbidities were observed. Cases used more drugs than controls (with an average number of drugs of 5.0 and 2.6 respectively). Nevertheless, except for drug consumption, there were no significant differences between cases and controls. The profile of cases and controls utilizing NSAIDs did not differ from that of the whole study population.\n\nTable 1 Baseline characteristics of patients in study population and in NSAID users\n\n\t\nStudy population\n\t\nNSAID users\n\t\n\nCharacteristic\n\t\nCases n = 179\n\t\nControls n = 1770\n\t\nP value\n\t\nCases NSAIDs n = 97\n\t\nControls NSAIDs n = 737\n\t\nP value NSAIDs\n\t\n\nSex, n (%)\n\t\t\t\n—\n\t\t\t\n—\n\t\n\nMale\n\t75 (42)\t750 (42)\t43 (44)\t306 (42)\t\n\nFemale\n\t104 (58)\t1020 (58)\t54 (56)\t431 (58)\t\n\nAge (years), mean (SD)\n\t52.8 (19.4)\t53.3 (19.3)\t0.74\t49.4 (18.7)\t51.6 (19.4)\t0.29\t\n\nSchooling level (years), mean (SD)\n\t10.5 (4.8) (n = 174)\t10.5 (5.2) (n = 1721)\t0.86\t10.6 (4.5) (n = 96)\t10.7 (4.7) (n = 714)\t0.84\t\n\nBMI, mean (SD)\n\t24.8 (4.6)\t25.3 (4.4) (n = 1759)\t0.15\t25.0 (5.1)\t25.3 (4.7)\t0.56\t\n\nAlcohol, n (%)\n\t\t\t0.58\t\t\t0.62\t\n\nCurrent drinker\n\t102 (57)\t1072 (61)\t59 (61)\t481 (65)\t\n\nFormer drinker\n\t8 (4)\t67 (4)\t3 (3)\t26 (4)\t\n\nNon‐drinker\n\t69 (39)\t628 (35)\t35 (36)\t227 (31)\t\n\nSmoke, n (%)\n\t\t\t0.59\t\t\t0.38\t\n\nCurrent smoker\n\t45 (25)\t445 (25)\t32 (33)\t202 (27)\t\n\nFormer smoker\n\t26 (15)\t311 (18)\t14 (14)\t141 (19)\t\n\nNon‐smoker\n\t108 (60)\t1012 (57)\t\t51 (53)\t392 (53)\t\n\nCo‐morbidities, n (%)\n\t\t\t\t\t\t\t\n\nLiver diseases\n\t19 (10)\t146 (8)\t0.26\t15 (15)\t99 (13)\t0.64\t\n\nHeart diseases\n\t30 (17)\t237 (13)\t0.21\t17 (17)\t140 (19)\t0.78\t\n\nDrugs, mean (SD)\n\t5.0 (3.2)\t2.6 (2.4)\t<0.001\t5.1 (3.0)\t3.4 (2.3)\t<0.001\t\nRisk of acute liver injury related to NSAIDs and nimesulide\nTable 2 shows the OR estimates of acute serious liver injury associated with all NSAIDs: during the three months before the index day, 97 out of 179 cases (corresponding to 54%) and 737 out of 1770 controls (42%) were exposed to NSAIDs. The annual incidence of DILI induced by NSAIDs (N‐DILI) was two cases per 100 000 inhabitants and the OR, adjusted for all covariates considered in the analysis, was 1.69 (95% CI, 1.21–2.37).\n\nTable 2 Odds Ratios (OR) and 95% confidence intervals (95% CI) of acute serious liver injury associated with NSAIDs (sex and age related analysis)\n\n\nDrug\n\t\nNo. (%) of cases\n\t\nNo. (%) of controls\n\t\nOR (95% CI)\n\t\nOR\nAdg\n(95% CI)\n†\n\t\n\nNSAIDs\n*\n\t97 (54)\t737 (42)\t1.71 (1.23–2.36)\t1.69 (1.21–2.37)\t\n\nSex\n\t\t\t\t\t\n\nMale\n\t43 (44)\t306 (42)\t1\t1\t\n\nFemale\n\t54 (56)\t431 (58)\t0.89 (0.57–1.40)\t0.71 (0.42–1.19)\t\n\nAge\n\t\t\t\t\t\n\n<45\n\t46 (47)\t293 (40)\t1\t1\t\n\n45–65\n\t29 (30)\t225 (30)\t0.82 (0.48–1.38)\t1.21 (0.66–2.20)\t\n\n>65\n\t22 (23)\t219 (30)\t0.64 (0.36–1.12)\t0.75 (0.36–1.56)\t\n* \nNSAIDs with at least one case included nimesulide, acetylsalicylic acid (ASA), ibuprofen, ketoprofen, diclofenac, celecoxib, etoricoxib, naproxen, flurbiprofen, piroxicam, indomethacin, and dexibuprofen.\n\n† \nSee methods sections for details of adjustment.\n\nTaking into account sex and age, we did not find any statistically significant differences in the risk of DILI. Table 3 reports the acute serious liver injury OR for single NSAIDs with a prevalence of use greater than or equal to 5% and for paracetamol. Apart from ASA, which is also used in cardiovascular disorders, nimesulide was the most used NSAID in the study period (prevalence of use of 11.1%). Paracetamol too was largely utilized in our patients, with a prevalence of use of 16.7%.\n\nTable 3 Odds ratios (OR) and 95% confidence intervals (95% CI) of acute serious liver injury associated with all NSAIDs and paracetamol\n\n\nDrug (prevalence of use)\n\t\nNo. (%) of cases\n\t\nNo. (%) of controls\n\t\nOR (95% CI)\n\t\nOR\nAdg\n(95% CI)\n*\n\t\n\nASA (13.5)\n\t31 (17)\t253 (14)\t1.30 (0.85–2.00)\t1.54 (0.95–2.48)\t\n\nNimesulide (11.1)\n\t30 (17)\t184 (10)\t1.88 (1.20–2.95)\t2.10 (1.28–3.47)\t\n\nKetoprofen (10.7)\n\t19 (11)\t177 (10)\t0.98 (0.57–1.68)\t1.10 (0.60–2.00)\t\n\nIbuprofen (8.1)\n\t25 (14)\t170 (10)\t1.59 (0.98–2.57)\t1.92 (1.13–3.26)\t\n\nDiclofenac (5.1)\n\t12 (7)\t85 (5)\t1.48 (0.77–2.84)\t1.50 (0.74–3.06)\t\n\nParacetamol (16.7)\n\t69 (39)\t309 (17)\t3.27 (2.32–4.59)\t2.97 (2.09–4.21)\t\n* \nSee methods sections for details of adjustment.\n\nAs shown in Table 3, 30 cases (17%) and 184 controls (10%) were exposed to nimesulide resulting in an adjusted risk of acute and serious liver injury of 2.10 (95% CI, 1.28–3.47). Besides nimesulide, only ibuprofen was associated to a statistically significant increased risk of liver damage, with an adjusted OR equal to 1.92 (95% CI, 1.13–3.26). The well‐known paracetamol‐associated hepatotoxicity is confirmed by three‐fold increase of risk (adjusted OR 2.97, 95% CI 2.09–4.21).\n\nDuring the study four fatal cases of hepatitis were observed. For three patients the physicians established a possible relation between hepatitis and drug treatment (metolazone, rifaximin and amiodarone); the fourth patient was suffering from many concomitant diseases and he was treated with several drugs, some of which are known to be associated with disorders of the hepatobiliary system (e.g. valproic acid, phenobarbital, lansoprazole, carbamazepine). Both this patient and that associated with metolazone also received low‐dose ASA. No deaths were observed among the controls.\n\nRisk of acute liver injury related to time of exposure and dose\nExcept for ASA (mainly used as an antiplatelet drug), NSAIDs and paracetamol seem to be used for a short period of time not exceeding 15 days, suggesting, therefore, an occasional consumption.\n\nThe analysis showed an increased risk of liver injury related to the length of exposure to nimesulide (OR > 30 days: 12.55; 95% CI, 1.73–90.88) and paracetamol (OR > 30 days: 18.36; 95% CI, 4.60–73.34). Considering exposures shorter than 15 days, nimesulide, ibuprofen and paracetamol are associated with a statistically significant adjusted odd ratio (OR 1.89; 95% CI, 1.12–3.20; OR 1.89; 95% CI, 1.09–3.26; OR 2.66; 95% CI, 1.83–3.88 respectively). Due to the low number of cases, time‐related analysis was not completely possible for ketoprofen (Table 4).\n\nTable 4 Odds ratios (OR) and 95% confidence intervals (95% CI) of acute serious liver injury associated with different time of exposure of NSAIDs and paracetamol\n\n\nDRUG Time of exposure\n\t\nNo. (%) of cases\n\t\nNo. (%) of controls\n\t\nOR (95% CI)\n\t\nOR\nAdg\n(95% CI)\n*\n\t\n\nNIMESULIDE\n\t\t\t\t\t\n\n<15 days\n\t25 (13.97)\t176 (9.94)\t1.66 (1.03–2.68)\t1.89 (1.12–3.20)\t\n\n15–30 days\n\t2 (1.12)\t5 (0.28)\t4.82 (0.92–25.34)\t4.89 (0.80–30.00)\t\n\n>30 days\n\t3 (1.68)\t3 (0.17)\t16.05 (2.60–98.94)\t12.55 (1.73–90.88)\t\n\nASA\n\t\t\t\t\t\n\n<15 days\n\t7 (3.93)\t76 (4.30)\t0.93 (0.42–2.08)\t1.06 (0.45–2.50)\t\n\n15–30 days\n\t1 (0.56)\t1 (0.06)\t10.60 (0.66–169.75)\t6.31 (0.37–106.38)\t\n\n>30 days\n\t22 (12.36)\t173 (9.79)\t1.40 (0.83–2.35)\t1.66 (0.93–2.96)\t\n\nKETOPROFEN\n\t\t\t\t\t\n\n<15 days\n\t18 (10.06)\t173 (9.77)\t0.94 (0.54–1.64)\t1.05 (0.57–1.93)\t\n\n15–30 days\n\t1 (0.56)\t2 (0.11)\t4.97 (0.45–54.87)\t6.55 (0.56–76.66)\t\n\n>30 days\n\t0 (0)\t2 (0.11)\tNA\tNA\t\n\nIBUPROFEN\n\t\t\t\t\t\n\n<15 days\n\t23 (12.85)\t162 (9.16)\t1.52 (0.92–2.50)\t1.89 (1.09–3.26)\t\n\n15–30 days\n\t1 (0.56)\t4 (0.23)\t2.57 (0.29–23.05)\t2.53 (0.26–24.69)\t\n\n>30 days\n\t1 (0.56)\t3 (0.17)\t3.46 (0.36–33.29)\t2.58 (0.25–26.95)\t\n\nDICLOFENAC\n\t\t\t\t\t\n\n<15 days\n\t10 (5.59)\t74 (4.19)\t1.42 (0.70–2.87)\t1.35 (0.63–2.92)\t\n\n15–30 days\n\t1 (0.56)\t3 (0.17)\t3.47 (0.36–33.40)\t4.23 (0.40–45.07)\t\n\n>30 days\n\t1 (0.56)\t4 (0.23)\t2.58 (0.29–23.13)\t4.66 (0.49–44.15)\t\n\nPARACETAMOL\n\t\t\t\t\t\n\n<15 days\n\t61 (34.08)\t286 (16.16)\t3.08 (2.14–4.43)\t2.66 (1.83–3.88)\t\n\n15–30 days\n\t3 (1.68)\t7 (0.40)\t6.01 (1.51–23.89)\t5.25 (1.21–22.82)\t\n\n>30 days\n\t5 (2.79)\t6 (0.34)\t14.78 (3.90–56.00)\t18.36 (4.60–73.34)\t\n* \nSee methods sections for details of adjustment\n\nNo single NSAID was associated with a significant risk of hepatotoxicity when taken at doses equal to or less than recommended, while for paracetamol this condition is present (Table 5). Exposure to higher doses of nimesulide was associated with a six‐fold increase in risk of acute liver injury (adjusted OR 10.69; 95% CI, 4.02–28.44 vs adjusted OR 1.55; 95% CI, 0.89–2.70 for recommended dose). Risk of hepatotoxicity was increased also for patients receiving higher doses of ketoprofen (adjusted OR 4.65; 95% CI, 1.33–10.00) and ibuprofen (adjusted OR 3.73; 95% CI, 1.11–12.46). The number of cases and controls considered in the time of exposure and dosage analysis may not correspond to the total, due to missing data on duration of therapy and doses.\n\nTable 5 Odds ratios (OR) and 95% confidence intervals (95% CI) of acute serious liver injury associated with different doses of NSAIDs and paracetamol\n\n\nDRUG Dose\n\t\nNo. (%) of cases\n\t\nNo. (%) of controls\n\t\nOR (95% CI)\n\t\nOR\nAdg\n(95% CI)\n†\n\t\n\nNIMESULIDE\n\t\t\t\t\t\n\n<200 mg\n\t21 (11.73)\t172 (9.72)\t1.41 (0.85–2.35)\t1.55 (0.89–2.70)\t\n\n≥200 mg\n\t9 (5.03)\t12 (0.68)\t8.03 (3.36–9.22)\t10.69 (4.02–28.44)\t\n\nASA\n\t\t\t\t\t\n\n<300 mg\n\t21 (11.73)\t168 (9.49)\t1.35 (0.80–2.27)\t1.46 (0.82–2.58)\t\n\n≥300 mg\n\t10 (5.59)\t85 (4.80)\t1.22 (0.62–2.43)\t1.70 (0.81–3.54)\t\n\nKETOPROFEN\n\t\t\t\t\t\n\n<150 mg\n\t10 (5.62)\t142 (8.02)\t0.67 (0.34–1.34)\t0.73 (0.35–1.54)\t\n\n≥150 mg\n\t8 (4.49)\t19 (1.07)\t3.29 (1.35–8.04)\t4.65 (1.33–10.00)\t\n\nIBUPROFEN\n\t\t\t\t\t\n\n<1200 mg\n\t20 (11.24)\t155 (8.76)\t1.45 (0.86–2.43)\t1.71 (0.97–3.02)\t\n\n≥1200 mg\n\t4 (2.23)\t15 (0.85)\t2.62 (0.82–8.32)\t3.73 (1.11–12.46)\t\n\nDICLOFENAC\n\t\t\t\t\t\n\n<100 mg\n\t5 (2.79)\t30 (1.69)\t1.69 (0.64–4.48)\t2.13 (0.77–5.91)\t\n\n≥100 mg\n\t3 (1.68)\t25 (1.41)\t1.19 (0.35–4.09)\t1.21 (0.30–4.85)\t\n\nPARACETAMOL\n\t\t\t\t\t\n\n<3000 mg\n\t42 (23.46)\t265 (14.97)\t2.22 (1.48–3.15)\t2.04 (1.35–3.09)\t\n\n≥3000 mg\n\tI26 (14.52)\tI44 (2.49)\tI7.80 (4.53–13.43)\tI6.31 (3.56–11.20)\t\n† \nSee methods sections for details of adjustment\n\nDiscussion\nThe annual incidence of DILI observed in this study was 4.1 cases per 100 000 inhabitants and about half of these patients received NSAIDs (giving an annual incidence of N‐DILI of two cases per 100 000 inhabitants). These data are partially in agreement with the evidence available until now: the incidence of DILI reported from Swedish and English studies confirms our results 11, 12; however, these retrospective studies found a six to eight times lower incidence than the population‐based studies from Björnsson and colleagues and Sgro and colleagues 9, 10. Probably, these results reflect some differences between the study methodology that should be taken into account: first, the studies which revealed the lower incidence of DILI used databases as primary sources of information, while the studies by Sgro and Björnsson were based on active participation of physicians and specialists which, in turn, recruited patients in a hospital and/or outpatient setting. Moreover, the first of these two studies considered only DILI in an outpatient setting while the second observed the incidence of DILI in both in‐ and outpatients. Also the period of patient recruitment varied among studies, ranging from 2 to 10 years 9, 10, 11. Our findings about the incidence of N‐DILI corresponds to what is reported in the literature: in most studies these data are rather uniform, ranging from one to nine cases per 100 000 persons exposed to NSAIDs 32.\n\nConsidering the association between acute and serious liver injury and NSAID utilization, our results showed that there is a small risk of acute and serious liver injury in NSAID users and that nimesulide and ibuprofen are associated with a higher risk of hepatotoxicity than other NSAIDs.\n\nIn general, the available evidence reports that DILI is more likely to occur in females and in elderly people and this is also supported in some NSAID‐associated hepatotoxicity analysis. Traversa and colleagues 28 reported that risk of liver injury was increased among elderly people (age over or equal to 75 years) and a case–control study in primary care in a southwestern area of France showed a significant association between hepatic ADRs and NSAID use only in women 18. At variance with what such studies reported, in our population no significant differences were associated with patients’ gender and age with regard to risk of liver injury.\n\nAlthough hepatotoxicity is an adverse effect of NSAID class considered worldwide as rare, serious liver damage is the main adverse event which caused some NSAIDs to be withdrawn from the market and the epidemiological data about the individual NSAID risk of liver injury is still divergent 15, 28, 33.\n\nPopulation‐based studies on liver toxicity induced by NSAIDs indicated a higher risk for diclofenac; however, in these studies the rate of serious hepatic adverse events, hospitalization or death was low 12, 32, 34, 35. In contrast, in a survey on suspected drug‐induced liver fatalities reported to the WHO database (in 88% of the cases the reporting country was the United States), diclofenac was the only NSAID implicated among the top 20 causes and a systematic review reported the prevalence of hospitalization as 22.4 per 100 000 patient‐year of diclofenac exposure 36, 37. These data deviate from our results, which have not revealed any risk of acute and serious liver damage associated with the use of diclofenac. Regulatory actions, restrictions and, in some countries, withdrawal from the market have been applied to nimesulide, another NSAID possibly implicated in hepatotoxicity. The first cases of serious or fatal liver injury in Finland and subsequently in Spain and Ireland led to the withdrawal of the drug in these countries; however, the last EMA evaluation concluded that the risk–benefit profile remains favourable and recommended restrictions in its use [27]. These decisions were supported by epidemiological studies confirming that nimesulide was associated with only a small increase in risk 28, 38. Our study corroborates this conclusion, providing further information on time of exposure and dosage. In most cases nimesulide was administered at recommended time of exposure and daily dosages (time lower than 15 days and dosage lower than 200 mg) and in these conditions the risk seems to be very low; however, an exponential increase of hepatotoxicity risk is observed with increasing duration of treatment and with higher dosages.\n\nThe increased risk of liver injury associated with nimesulide is of particular concern in Italy since the use of this drug is still widespread, despite the restriction in indications (only acute pain and dysmenorrhea) and treatment duration. In fact, according to national drug utilization data, nimesulide was the fourth most prescribed NSAID in 2013, with a consumption of 3.1 DDD/1000 inhabitants/day 39.\n\nFurthermore, our research found a significant risk of serious and acute liver damage associated with ibuprofen and the dose‐related analysis showed that this risk increased with the dose administered. This finding was quite unexpected, as the current literature reports a very low liver toxicity incidence for ibuprofen 28, 32, 33. Some case reports of liver damage associated with ibuprofen were described in the scientific literature 40, 41 and some information emerged from recent observational studies and reviews which investigated DILI and the risk of hepatotoxicity in patients exposed to NSAIDs 38, 42. A case series from Riley and colleagues also suggested that ibuprofen may increase the risk of liver injury in patients with hepatitis C 43, though we were not able to confirm this observation as, people suffering from hepatitis C were excluded from our study. Nevertheless, our result for ibuprofen should be taken into consideration as ibuprofen is the most commonly used NSAID worldwide and among these drugs it is associated with the lower risk of gastrointestinal, cardiovascular and renal serious events.\n\nIn the present study, ketoprofen was associated with a significant increased risk of acute and serious liver injury only at dosages higher than recommended. We did not find any additional specific information on ketoprofen hepatotoxicity and our data strengthen the importance of using all NSAIDs within the therapeutic dosages.\n\nHepatotoxicity of high doses of paracetamol is a well‐documented risk, but the question whether therapeutic use causes acute liver failure is still open, as several individual factors, such as concomitant alcohol use or abuse, concurrent medications, genetic factors and nutritional status, can influence the susceptibility of patients to paracetamol hepatotoxicity [44]. A moderate risk of acute liver injury associated with paracetamol at usual analgesic doses has been reported in some documented cases and in observational studies 45, 46.\n\nA limitation of our study was related to the number of recruited cases, which was lower than expected; in fact, the actual incidence of liver injury events involving hospitalization was lower than reported in the literature, probably due to relevant recent changes in hospital practice (e.g. increased outpatient management of liver injury). The precision of risk estimates of serious liver injury for the time and dosage analysis is affected by the low number of recruited cases and this is reflected in the calculated CI values. Moreover, our analysis did not provide information about the characterization of the liver damage.\n\nThe main strength of our case–control analysis is the precision and accuracy in the selection of patients: we excluded other possible causes of hepatic disease to prevent a potential bias of misdiagnosis and we considered all the variables that could influence the risk of developing liver damage. Definition of inclusion and exclusion criteria was made in collaboration with a panel of expert hepatologists. Our findings are also representative of the Italian situation: the study was conducted in four regions distributed in the Northern, Central and Southern Italy and the population covered by this area represents about 10% of the national population. Furthermore, patients were recruited over a long period of time, subsequent to the measures taken by the European and Italian Regulatory Agency, which allowed us to evaluate the effects of these regulatory measures in the clinical practice. Finally, quality control and assurance measures were implemented to ensure that procedures were shared by all centres and data were reasonably valid and coherent as regarding both cases controls. Quality assurance measures were applied to the interview technique, to recruitment and management of the patients, and finally to the quality of data entry in the database. The interview was standardized and the questionnaire tested in a pilot phase to ensure the readability of its content. The monitors were trained before and during the study and appropriate explanations were integrated into the training plan and monitor manuals. Quality control and assurance measures were set for all centres by the Coordinating Centre.\n\nOur findings confirm that hepatotoxicity represents a rare but serious adverse drug reaction and that NSAIDs are associated with an increased risk.\n\nAmong NSAIDs, nimesulide is associated with the higher risk, whereas ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity. The results on nimesulide are especially relevant to Italy, where, despite regulatory restrictions by the EMA, the drug is still largely utilized causing a risk of hepatotoxicity that increases with dosage and time of exposure.\n\nFinally, the issue of liver injury induced by NSAIDs at dosage exceeding the DDD should not be underestimated, as extensive evidence is available showing that these drugs are often used inappropriately [47]. In fact, several NSAIDs are currently worldwide available on the market as over‐the‐counter (OTC) drugs, not requiring any medical prescription and with a management of treatment duration and dosage performed only by the patient, without any medical supervision. The consequence of this attitude is the total lack of medical assessment of the possible risks and contraindications, duration and dose of NSAID treatment, which can lead to a greater number of side effects, sometimes serious and unexpected.\n\nCompeting Interests\nAll authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: all institutions received financial support from Italian Medicines Agency (AIFA) for the research study; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.\n\nThis study was funded by the Italian Medicines Agency (AIFA), through a call for independent research (ID Study. FARM8B2TY7).\n\nContributors\nRL, ACa, DM and AVan conceived the study. RL and UM designed the study. MD, OB, RL, ACo, MCL and RB analysed the data. MD and ACo wrote the manuscript. MD, ACo, MCL, ACa, OB, DM, UM, AVan, CR, AVac, EA, RB, LS and RL contributed to the discussion and reviewed the manuscript.\n\nThe lead author affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.\n\nNo additional data available.\n\nWe are grateful for the help and support of the DILI‐IT Study Group, who include the following.\n\nClinical investigators: Franco Capra, Angelo Tonon, University Hospital of Verona; Marco Zoli, University Hospital S. Orsola‐Malpighi of Bologna and the Head of each Internal Medicine, Geriatric and other participating Units; Enrica Cecchi, Stefano Grifoni, Careggi Hospital of Florence; Fulvio Calise, Cardarelli Hospital of Neaples; Pietro Amoroso, Cotugno Hospital of Neaples; Evangelista Sagnelli, San Sebastiano Hospital of Caserta; Annamaria Frola, Umberto I Hospital Unit of Salerno.\n\nStudy monitors: Elena Arzenton, Giovanna Stoppa, Verona; Maria Carmela Lenti, Gemma Benelli, Florence; Carolina Tiani, Bologna; Carla Migliaccio, Andrea Vitale, Nancy Acampa, Neaples.\n\nSteering Committee: Nicola Montanaro, University of Bologna; Francesco Lapi and Alessandro Mugelli, University of Florence; Francesco Rossi, University of Naples.\n\nData manager: Giulia Bisoffi, University Hospital of Verona.\n\nWe thank the components of External Advisory Board: Maria Grazia Franzosi, Nicola Magrini, Luigi Pagliaro, Giuseppe Traversa and Mauro Venegoni.\n==== Refs\nReferences\n1 \n\nOstapowicz \nG \n, \nFontana \nRJ \n, \nSchiødt \nFV \n, \nLarson \nA \n, \nDavern \nTJ \n, \nHan \nSH \n, et al.\nResults of a prospective study of acute liver failure at 17 tertiary care centers in the United States . 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Fundam Clin Pharmacol \n2004 ; 18 : 201 –6 .15066135 \n19 \n\nPillans \nPI \n, \nGhiculescu \nRA \n, \nLampe \nG \n, \nWilson \nR \n, \nWong \nR \n, \nMacdonald \nGA \n. Severe acute liver injury associated with lumiracoxib . J Gastroenterol Hepatol \n2012 ; 27 : 1102 –5 .22142375 \n20 \n\nPage \nM \n, \nChristin \nF \n, \nHayi‐Slayman \nD \n, \nBaillon \nJJ \n, \nBer \nCE \n, \nDelafosse \nB \n, et al.\nAcute liver failure due to a treatment by nimesulide: another case and review . Ann Fr Anesth Reanim \n2008 ; 27 : 742 –6 .18760563 \n21 \n\nMerlani \nG \n, \nFox \nM \n, \nOehen \nHP \n, \nCathomas \nG \n, \nRenner \nEL \n, \nFattinger \nK \n, et al.\nFatal hepatoxicity secondary to nimesulide . Eur J Clin Pharmacol \n2001 ; 57 : 321 –6 .11549211 \n22 \nFIMEA, Finnish Medicines Agency \n. The sale of Nimed, an anti‐inflammatory analgesic, is temporarily suspended due to its adverse liver effects , 15 March 2002 . Available at http://www.fimea.fi/whatsnew/1/0/thesaleofnimedananti‐inflammatoryanalgesic,istemporarilysuspendedduetoitsadverselivereffects (last accessed 16 April 2015).\n23 \nAEMPS, Agencia Española de Medicamentos y Productos Sanitarios \n. Comunicación sobre riesgos de Medicamentos . Ref: 2002/03. Nota Informativa Nimesulida (Guaxan®, Antifloxil®): suspensión cautelar de comercialización, 6 May 2002 . Available at http://www.aemps.gob.es/informa/notasInformativaUsoHumano/seguridad/2002/NI_2002‐03_nimesulida.htm (last accessed 16 April 2015).\n24 \nEMEA, European Agency for the Evaluation of Medicinal Products \n. Committee for Proprietary Medicinal Products (CPMP) opinion following an article 31 referral . Nimesulide containing medicinal products, 7 May 2004 . Available at http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_31/WC500013818.pdf (last accessed 16 April 2015).\n25 \nHPRA, Health Products Regulatory Authority \n. Nimesulide suspension , 15 May 2007 . Available at https://www.hpra.ie/homepage/medicines/safety‐notices/item?t=/nimesulide‐suspension&id=7d69f825‐9782‐6eee‐9b55‐ff00008c97d0 (last accessed 16 April 2015).\n26 \nANMAT, Administración Nacional de Medicamentos, Alimentos y Tecnología Médica \n. ANMAT suspende la comercializacion de la droga nimesulide . Boletin para profesionales \n2009 ; XVII (3 ): 17 –24 .\n27 \nEMEA, European Agency for the Evaluation of Medicinal Products \n. Assessment report for Nimesulide containing medicinal products for systemic use , 20 January 2012 . Available at http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Nimesulide_31/WC500125574.pdf (last accessed 16 April 2015).\n28 \n\nTraversa \nG \n, \nBianchi \nC \n, \nDa Cas \nR \n, \nAbraha \nI \n, \nMenniti‐Ippolito \nF \n, \nVenegoni \nM \n. Cohort study of hepatotoxicity associated with nimesulide and other nonsteroidal anti‐inflammatory drugs . BMJ \n2003 ; 327 : 18 –22 .12842950 \n29 \n\nLicata \nA \n, \nCalvaruso \nV \n, \nCappello \nM \n, \nCraxì \nA \n, \nAlmasio \nPL \n. Clinical course and outcomes of drug‐induced liver injury: nimesulide as the first implicated medication . Dig Liver Dis \n2010 ; 42 : 143 –8 .19625223 \n30 \n\nBénichou \nC \n. Criteria of drug‐induced liver disorders. Report of an international consensus meeting . J Hepatol \n1990 ; 1 : 272 –6 .2254635 \n31 \nWHO Collaborating Centre for Drug Statistics Methodology \n. Guidelines for ATC classification and DDD assignment, 2015 . Oslo, 2014 . Available at http://www.whocc.no/atc_ddd_index/ (last accessed 21 July 2015).\n32 \n\nBessone \nF \n. Non‐steroidal anti‐inflammatory drugs: What is the actual risk of liver damage? \nWorld J Gastroenterol \n2010 ; 16 : 5651 –61 .21128314 \n33 \n\nUnzueta \nA \n, \nVargas \nHE \n. Nonsteroidal anti‐inflammatory drug‐induced hepatoxicity . Clin Liver Dis \n2013 ; 17 : 643 –56 .24099022 \n34 \n\nLaine \nL \n, \nGoldkind \nL \n, \nCurtis \nSP \n, \nConnors \nLG \n, \nYanqiong \nZ \n, \nCannon \nCP \n. How common is diclofenac‐associated liver injury? Analysis of 17,289 arthritis patients in a long‐term prospective clinical trial . Am J Gastroenterol \n2009 ; 104 : 356 –62 .19174782 \n35 \n\nRostom \nA \n, \nGoldkind \nL \n, \nLaine \nL \n. Nonsteroidal anti‐inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients . Clin Gastroenterol Hepatol \n2005 ; 3 : 489 –98 .15880319 \n36 \n\nBjörnsson \nE \n, \nOlsson \nR \n. Suspected drug‐induced liver fatalities reported to the WHO database . Dig Liver Dis \n2006 ; 38 : 33 –8 .16054882 \n37 \n\nRubenstein \nJH \n, \nLaine \nL \n. Systematic review: the hepatotoxicity of non‐steroidal anti‐inflammatory drugs . Aliment Pharmacol Ther \n2004 ; 20 : 373 –80 .15298630 \n38 \n\nLee \nCH \n, \nWang \nJD \n, \nChen \nPC \n. Increased risk of hospitalization for acute hepatitis in patients with previous exposure to NSAIDs . Pharmacoepidemiol Drug Saf \n2010 ; 19 : 708 –14 .20582911 \n39 \nThe Medicines Utilisation Monitoring Centre \n. National Report on Medicines use in Italy, 2013 (English edition). Available at http://www.agenziafarmaco.gov.it/sites/default/files/OsMed_Report13_Eng.pdf (last accessed 15 July 2015).\n40 \n\nBorel \nI \n, \nHedelius \nF \n, \nBaumgartner \nC \n, \nVial \nT \n, \nScoazec \nJY \n, \nDumortier \nJ \n. Severe acute hepatitis associated with ibuprofen treatment . Gastroenterol Clin Biol \n2001 ; 25 : 430 –2 .11449133 \n41 \n\nLeoz \nMK \n, \nConcejo \nFB \n, \nFernández \nJM \n, \nUrmeneta \nJM \n, \nPeñuela \nAM \n. Ibuprofen‐induced cholestatic hepatitis . Gastroenterol Hepatol \n2011 ; 34 : 660 –1 .21621876 \n42 \n\nDouros \nA \n, \nBronder \nE \n, \nAndersohn \nF \n, \nKlimpel \nA \n, \nThomae \nM \n, \nSarganas \nG \n, et al.\nDrug‐induced liver injury: results from the hospital‐based Berlin Case–Control Surveillance Study . Br J Clin Pharmacol \n2015 ; 79 : 988 –99 .25444550 \n43 \n\nRiley \nTR \n, \nSmith \nJP \n. Ibuprofen‐induced hepatotoxicity in patients with chronic hepatitis C: a case series . Am J Gastroenterol \n1998 ; 93 : 1563 –5 .9732947 \n44 \n\nBunchorntavakul \nC \n, \nReddy \nKR \n. Acetaminophen‐related hepatotoxicity . Clin Liver Dis \n2013 ; 17 : 587 –607 .24099020 \n45 \n\nSabaté \nM \n, \nIbáñez \nL \n, \nPérez \nE \n, \nVidal \nX \n, \nButi \nM \n, \nXiol \nX \n, et al.\nParacetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series . BMC Gastroenterol \n2011 ; 11 : 80 .21762481 \n46 \n\nSabaté \nM \n, \nIbáñez \nL \n, \nPérez \nE \n, \nVidal \nX \n, \nButi \nM \n, \nXiol \nX \n, et al.\nRisk of acute liver injury associated with the use of drugs: a multicentre population survey . Aliment Pharmacol Ther \n2007 ; 25 : 1401 –9 .17539979 \n47 \n\nKoffeman \nAR \n, \nValkhoff \nVE \n, \nCelik \nS \n, \nW't Jong \nG \n, \nSturkenboom \nMC \n, \nBindels \nPJ \n, et al.\nHigh‐risk use of over‐the‐counter non‐steroidal anti‐inflammatory drugs: a population‐based cross‐sectional study . Br J Gen Pract \n2014 ; 64 : e191 –8 .24686883\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0306-5251",
"issue": "82(1)",
"journal": "British journal of clinical pharmacology",
"keywords": "DILI; NSAIDs; case-control study; liver injury; nimesulide",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007558:Italy; D007660:Ketoprofen; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012306:Risk; D013449:Sulfonamides",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "238-48",
"pmc": null,
"pmid": "26991794",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "24760689;24686883;12143055;15298630;26991794;17408305;11549211;16054882;19625223;18760563;16481640;17539979;21128314;11449133;17697161;25444550;21621876;19174782;15066135;23419359;2254635;15206996;20949552;21762481;15880319;9732947;17119945;12842950;24099020;12484709;24388027;25163793;16496329;22142375;24099022;23757736;25618544;25862494;17014577;20582911",
"title": "Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy.",
"title_normalized": "risk of acute and serious liver injury associated to nimesulide and other nsaids data from drug induced liver injury case control study in italy"
} | [
{
"companynumb": "IT-JNJFOC-20160626409",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
"d... |
{
"abstract": "Immune checkpoint inhibitors (ICIs) are an evolving class of drugs for the treatment of various cancers; for example, their use is recommended as a second-line chemotherapy for non-small cell lung cancer. With the expanding use of ICIs, we are discovering their unique side effects, called immune-related adverse events (irAEs), which can impair gastrointestinal, hepatic, dermatological, endocrine and other systems. Nivolumab is an ICI that blocks the human programmed death receptor-1 (PD-1) on T cells to prevent the interaction between the receptor, PD-1, and human programmed death ligand-1 expressed on tumour cells. Here, we report a case of a 65-year-old woman with recurrent lung adenocarcinoma who was treated with nivolumab and developed immune-related adrenalitis, which was managed with hydrocortisone and fludrocortisone. This case highlights the importance of understanding the irAEs of ICIs to allow prompt recognition and management of life-threatening complications of the treatment.",
"affiliations": "Internal Medicine, Abington Jefferson Health, Abington, Pennsylvania, USA.;Internal Medicine, Abington Jefferson Health, Abington, Pennsylvania, USA.;Internal Medicine, Abington Jefferson Health, Abington, Pennsylvania, USA waqasullah.dr@gmail.com.;Internal Medicine, Damascus University, Damascus, Syrian Arab Republic.",
"authors": "Iqbal|Iqra|I|;Khan|Muhammad Atique Alam|MAA|;Ullah|Waqas|W|http://orcid.org/0000-0002-4850-0309;Nabwani|Dina|D|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231829",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(11)",
"journal": "BMJ case reports",
"keywords": "adrenal disorders; chemotherapy; lung cancer (oncology); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000309:Adrenal Insufficiency; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D000077594:Nivolumab",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31791986",
"pubdate": "2019-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "3311477;24695602;30197906;26412456;30790009;26715621;26028407;26884577;27935813",
"title": "Nivolumab-induced adrenalitis.",
"title_normalized": "nivolumab induced adrenalitis"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2019-122943",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "Closed rupture of the thumb flexor tendon pulleys is rare and, to our knowledge, the MRI findings associated with this injury have not been described in the radiology literature. The injury can result in nonspecific clinical and physical exam findings and advanced imaging may be crucial to diagnosis. A familiarity with the normal anatomy of the flexor mechanism of the thumb and the imaging appearance of pathology is therefore necessary. We report a case of a 31-year-old female nurse with ruptures of several of the thumb flexor pulleys and the corresponding findings on MRI.",
"affiliations": "Department of Radiology, Northwell Health, 300 Community Drive, Manhasset, NY 11030, United States of America. Electronic address: Mbrown26@northwell.edu.;Department of Radiology, Northwell Health, 300 Community Drive, Manhasset, NY 11030, United States of America. Electronic address: jodonnell@northwell.edu.;Department of Radiology, Northwell Health, 300 Community Drive, Manhasset, NY 11030, United States of America. Electronic address: dwalz@northwell.edu.",
"authors": "Brown|Michael S|MS|;O'Donnell|John|J|;Walz|Daniel|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinimag.2019.06.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-7071",
"issue": "58()",
"journal": "Clinical imaging",
"keywords": null,
"medline_ta": "Clin Imaging",
"mesh_terms": "D000328:Adult; D005260:Female; D005383:Finger Injuries; D006801:Humans; D008279:Magnetic Resonance Imaging; D012421:Rupture; D013708:Tendon Injuries; D013933:Thumb",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "66-69",
"pmc": null,
"pmid": "31252213",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Closed rupture of the flexor tendon pulleys of the thumb.",
"title_normalized": "closed rupture of the flexor tendon pulleys of the thumb"
} | [
{
"companynumb": "US-009507513-1907USA005249",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAgranulocytosis is a rare but serious complication of antithyroid drug (ATD) therapy. Characteristics of agranulocytosis have been reported in only a small number of patients.\n\n\nMETHODS\nWe studied 754 cases of ATD-induced agranulocytosis reported over 30 years. The age distribution and sex ratio were compared with those in 12 503 untreated Graves' patients at Kuma Hospital. The annual number of new Graves' patients in Japan was estimated from the Japan Medical Data Center Data Mart-Pharmacovigilance health insurance receipt database.\n\n\nRESULTS\nAgranulocytosis developed within 90 days after starting ATD therapy in most patients (84.5%). The methimazole dose given at onset was 25.2 ± 12.8 mg/d (mean ± SD). The mean age was 43.4 ± 15.2 years, and the male to female ratio was 1:6.3. When compared with patients at Kuma Hospital, patients with agranulocytosis were older (P < .001) and more females (P < .0001). Of 211 patients with more than 1 granulocyte measurement before onset, 131 (62%) showed normal counts (>1000/μL) within 2 weeks before onset, demonstrating real sudden onset of agranulocytosis. In contrast, some of the 20 patients with more than 4 measurements showed gradual decreases in granulocyte counts. Analysis of physician reports for 30 fatal cases revealed that some deaths might have been prevented. The number of new Graves' patients treated with ATD was estimated at about 35 000 per year, and the incidence rate of agranulocytosis was 0.1% to 0.15% in Japan.\n\n\nCONCLUSIONS\nThis is the largest study of agranulocytosis. Agranulocytosis tends to occur abruptly within 3 months after initiation of ATD therapy, although it develops gradually in some patients. Providing every patient with sufficient information on agranulocytosis is critical.",
"affiliations": "Kuma Hospital, Shimoyamate-dori, Chuo-ku, Kobe 650-0011, Japan. hirotosh@kuma-h.or.jp.",
"authors": "Nakamura|Hirotoshi|H|;Miyauchi|Akira|A|;Miyawaki|Natsuko|N|;Imagawa|Junichi|J|",
"chemical_list": "D013956:Antithyroid Agents; D008713:Methimazole; D011441:Propylthiouracil",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2013-2569",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "98(12)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000380:Agranulocytosis; D000741:Anemia, Aplastic; D013956:Antithyroid Agents; D004359:Drug Therapy, Combination; D005260:Female; D006111:Graves Disease; D006786:Hospitals, Urban; D006801:Humans; D015994:Incidence; D007564:Japan; D019891:Leukopoiesis; D008297:Male; D008713:Methimazole; D008875:Middle Aged; D010198:Pancytopenia; D060735:Pharmacovigilance; D011441:Propylthiouracil; D017678:Sex Distribution",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "4776-83",
"pmc": null,
"pmid": "24057289",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan.",
"title_normalized": "analysis of 754 cases of antithyroid drug induced agranulocytosis over 30 years in japan"
} | [
{
"companynumb": "JP-MYLANLABS-2015M1010409",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFew case reports describe the development of a hematoma under oral anticoagulation as the cause of an atraumatic carpal tunnel syndrome.\n\n\nMETHODS\nA 76 years old woman presented an acute atraumatic carpal tunnel syndrome of her left hand under oral anticoagulation with rivaroxaban due to atrial fibrillation. 12 years ago, palmar plate osteosynthesis of a distal radius fracture had been performed on the affected wrist. Open decompression of the carpal canal was performed due to persistent severe pain under intense pain therapy and progressive neurological symptoms. The cause of the pain was a hematoma due to a rupture of the flexor pollicis longus and the second flexor digitorum profundus tendon with concomitant synovitis at the plate's distal rim. After decompression, pain relieved and neurological deficits improved rapidly.\n\n\nCONCLUSIONS\nRuptures of the flexor tendons occur in palmar plate osteosynthesis in up to 1.5% in the long term postoperative course. Very distal plate positions, like in this case, increase that risk. Under anticoagulation, the rupture induced a hematoma increasing local pressure resulting in an acute carpal tunnel syndrome. Acute nerve compression syndromes should be treated surgically without delay.\n\n\nCONCLUSIONS\nTherapy with anticoagulants may increase hematoma after tendon rupture, thus supporting the development of an atraumatic acute carpal tunnel syndrome and complicating the surgical therapy. Hardware removal after fracture healing should be advised in patients with Soong grade 2 plate positions especially those taking anticoagulants.",
"affiliations": "Department of Trauma, Hand and Reconstructive Surgery, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany. wolfram.weschenfelder@med.uni-jena.de.;Department of Trauma, Hand and Reconstructive Surgery, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany.;Department of Trauma, Hand and Reconstructive Surgery, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany.;Department of Trauma, Hand and Reconstructive Surgery, University Hospital Jena, Am Klinikum 1, 07747, Jena, Germany.",
"authors": "Weschenfelder|Wolfram|W|http://orcid.org/0000-0002-4828-1812;Friedel|Reinhard|R|;Hofmann|Gunther O|GO|;Lenz|Mark|M|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00402-019-03116-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0936-8051",
"issue": "139(3)",
"journal": "Archives of orthopaedic and trauma surgery",
"keywords": "Carpal tunnel syndrome; Oral anticoagulants; Palmar plate osteosynthesis; Tendon rupture",
"medline_ta": "Arch Orthop Trauma Surg",
"mesh_terms": "D000368:Aged; D002349:Carpal Tunnel Syndrome; D019299:Decompression, Surgical; D065427:Factor Xa Inhibitors; D005260:Female; D005593:Fracture Fixation, Internal; D006406:Hematoma; D006801:Humans; D053401:Palmar Plate; D011885:Radius Fractures; D000069552:Rivaroxaban; D012421:Rupture; D013708:Tendon Injuries",
"nlm_unique_id": "9011043",
"other_id": null,
"pages": "435-438",
"pmc": null,
"pmid": "30631915",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute atraumatic carpal tunnel syndrome due to flexor tendon rupture following palmar plate osteosynthesis in a patient taking rivaroxaban.",
"title_normalized": "acute atraumatic carpal tunnel syndrome due to flexor tendon rupture following palmar plate osteosynthesis in a patient taking rivaroxaban"
} | [
{
"companynumb": "DE-JNJFOC-20190136289",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "3",
... |
{
"abstract": "An 82-year-old woman on long-term prednisolone for chronic obstructive airways disease presented with a 2-month history of nodules on her left forearm. This occurred 10 years after nodules on her right forearm caused by a culture-proven Mycobacterium marinum infection. Histopathological examination, polymerase chain reaction and culture of biopsy specimens were positive for M. chelonae. To our knowledge this is the first case of metachronous nontuberculous mycobacterial skin infection reported, and it highlights the diagnostic and therapeutic challenges of such infections.",
"affiliations": "Department of Medicine (Dermatology), St. Vincent's Hospital Melbourne, Australia; Skin and Cancer Foundation Inc.",
"authors": "Li|Jane|J|;Chong|Alvin H|AH|;O'Keefe|Rod|R|;Johnson|Paul D R|PD|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12094",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "55(4)",
"journal": "The Australasian journal of dermatology",
"keywords": "fish-borne skin disease; nontuberculous mycobacterial skin infection",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000369:Aged, 80 and over; D000818:Animals; D005260:Female; D005399:Fishes; D005542:Forearm; D006686:Hobbies; D006801:Humans; D016867:Immunocompromised Host; D009165:Mycobacterium Infections, Nontuberculous; D016926:Mycobacterium chelonae; D019910:Mycobacterium marinum; D012008:Recurrence; D017192:Skin Diseases, Bacterial",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "e77-9",
"pmc": null,
"pmid": "23991645",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The fish tank strikes again: metachronous nontuberculous mycobacterial skin infection in an immunosuppressed host.",
"title_normalized": "the fish tank strikes again metachronous nontuberculous mycobacterial skin infection in an immunosuppressed host"
} | [
{
"companynumb": "AU-MYLANLABS-2016M1048330",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXYCYCLINE"
},
"drugadditional": "1",
... |
{
"abstract": "There have been many complications associated with transurethral resection of the prostate (TURP), known as TURP syndrome. Of the various irrigation fluids used for TURP, glycine irrigant has been historically popular given its relatively low cost. It is also a nonconductive solution and only slightly hypoosmolar, reducing the risk of burn injury or significant hemolysis. However, there have been many case reports of central nervous system toxicity such as transient blindness and encephalopathy related to glycine toxicity. Here, we report blue vision (cyanopsia), which has never been reported as a symptom of TURP syndrome.",
"affiliations": "From the Department of Anesthesiology.;General, Vascular, Transplant Division, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina.",
"authors": "Fox|William C|WC|;Moon|Richard E|RE|",
"chemical_list": "D005998:Glycine",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000809",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "11(10)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D000368:Aged; D005998:Glycine; D006801:Humans; D007010:Hyponatremia; D008297:Male; D011183:Postoperative Complications; D011470:Prostatic Hyperplasia; D013577:Syndrome; D007507:Therapeutic Irrigation; D020728:Transurethral Resection of Prostate; D014786:Vision Disorders",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "279-281",
"pmc": null,
"pmid": "29851690",
"pubdate": "2018-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Blue Vision (Cyanopsia) Associated With TURP Syndrome: A Case Report.",
"title_normalized": "blue vision cyanopsia associated with turp syndrome a case report"
} | [
{
"companynumb": "US-B. BRAUN MEDICAL INC.-2067270",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SODIUM CHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Germline GATA2 mutations have been associated with a vast array of clinical manifestations, as well as hematological deficiencies and a propensity to AML or MDS. We present two cases of pediatric AML/MDS with underlying GATA2 mutations who underwent a successful umbilical cord hematopoietic stem cell transplantation using two different conditioning regimens. These cases illustrate the importance of recognizing the clinical features associated with GATA2 mutations and performing the appropriate molecular testing. Diagnosis of heritable gene mutations associated with familial AML/MDS has significant clinical implication for the patients and affected families.",
"affiliations": "Division of Hematology/Oncology/BMT, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.;Division of Hematology/Oncology/BMT, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.;Department of Medical Genetics, Provincial Medical Genetics Program, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.;Department of Medical Genetics, Provincial Medical Genetics Program, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.;Division of Hematology/Oncology/BMT, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada. jrozmus@cw.bc.ca.",
"authors": "Mallhi|Kanwaldeep|K|;Dix|David B|DB|;Niederhoffer|Karen Y|KY|;Armstrong|Linlea|L|;Rozmus|Jacob|J|",
"chemical_list": "D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12764",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "20(7)",
"journal": "Pediatric transplantation",
"keywords": "GATA2; acute myeloid leukemia; hematopoietic stem cell transplantation; myelodysplastic syndrome; pediatrics; umbilical cord",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D002648:Child; D036101:Cord Blood Stem Cell Transplantation; D050989:GATA2 Transcription Factor; D057895:Haploinsufficiency; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes; D019172:Transplantation Conditioning; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "1004-1007",
"pmc": null,
"pmid": "27416790",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Successful umbilical cord blood hematopoietic stem cell transplantation in pediatric patients with MDS/AML associated with underlying GATA2 mutations: two case reports and review of literature.",
"title_normalized": "successful umbilical cord blood hematopoietic stem cell transplantation in pediatric patients with mds aml associated with underlying gata2 mutations two case reports and review of literature"
} | [
{
"companynumb": "CA-SA-2016SA221240",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "Atopic dermatitis (AD) is a common, chronic, recurrent inflammatory skin disease. Poorly controlled AD can lead to reduced quality of life (QoL) and psychosocial impairment. Dupilumab is the first approved monoclonal antibody targeting type 2 inflammation, for adolescent and adult patients with moderate-to-severe AD. We performed a retrospective analysis of the efficacy and safety of dupilumab in a cohort of Asian children and adolescents with moderate-to-severe AD. Clinical response was documented with investigator global assessment (IGA) and eczema area and severity index (EASI) scores. Improvement in QoL was assessed using child dermatology life quality index (CDLQI) or Teenager's quality of life (T-QoL), and caregivers' QoL was assessed using dermatitis family impact (DFI) questionnaire. Twelve patients were recruited, aged between 6 to 18 years of age (mean 13.3 years), with mean duration of AD of 9.8 years. At baseline, the mean IGA score was four and the mean EASI was 48.2. The mean T-QoL and DFI scores at baseline were 18.7 and 19.6, respectively. After 12 to 16 weeks of treatment, the mean IGA score decreased to 2.2. The mean EASI decreased to 19.3 with mean reduction of 28.9. The mean T-QoL decreased to 7.5 with mean reduction of 11.2, and the mean DFI decreased to 8.6 with mean reduction of 11. Adverse events included mild conjunctivitis in two patients and paradoxical head and neck erythema in one patient. Our study supports dupilumab as an effective and safe treatment option for Asian children and adolescents with moderate-to-severe AD.",
"affiliations": "Paediatric Medicine, KK Women's and Children's Hospital, Singapore, Singapore.;Paediatric Medicine, KK Women's and Children's Hospital, Singapore, Singapore.;Dermatology Service, KK Women's and Children's Hospital, Singapore, Singapore.",
"authors": "Chia|Shi Yun|SY|0000-0002-5005-3499;Wee|Lynette Wei Yi|LWY|;Koh|Mark Jean Aan|MJA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582203:dupilumab",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.14933",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "34(3)",
"journal": "Dermatologic therapy",
"keywords": "IL-13; IL-4; adolescent atopic dermatitis; dupilumab; eczema; pediatric atopic dermatitis",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D002648:Child; D003876:Dermatitis, Atopic; D004311:Double-Blind Method; D004485:Eczema; D006801:Humans; D011788:Quality of Life; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e14933",
"pmc": null,
"pmid": "33751751",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Dupilumab for children and adolescents with atopic dermatitis: An Asian perspective.",
"title_normalized": "dupilumab for children and adolescents with atopic dermatitis an asian perspective"
} | [
{
"companynumb": "SG-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-313443",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"dr... |
{
"abstract": "OBJECTIVE\nTo compare the incidence of medical closure of patent ductus arteriosus (PDA) and adverse events (acute renal dysfunction, necrotizing enterocolitis, spontaneous intestinal perforation, and gastrointestinal bleeding) between preterm infants who received indomethacin and ibuprofen for the treatment of PDA.\n\n\nMETHODS\nA retrospective comparative effectiveness evaluation study was conducted on preterm infants (≤32 weeks) who received indomethacin or ibuprofen for treatment of symptomatic PDA.\n\n\nRESULTS\nOf the 124 eligible infants, 54 received indomethacin and 70 received ibuprofen. The overall incidence of medical PDA closure with indomethacin was 37/54 (68.5%) as compared with 42/70 (60%) in the ibuprofen group (p = 0.32). The proportion of infants with surgical PDA ligation was similar between the two groups (18.5% in both the groups). There was no difference in the incidences of acute renal dysfunction, necrotizing enterocolitis stage ≥ 2, spontaneous intestinal perforation, and gastrointestinal bleeding between indomethacin and ibuprofen groups.\n\n\nCONCLUSIONS\nIbuprofen is as effective as indomethacin in the treatment of symptomatic PDA in preterm infants. This study also shows that both agents have similar adverse effects and the choice of one agent over the other should be based on local availability and dosing preference.",
"affiliations": "Section of Neonatology, Department of Pediatrics, University of Calgary, Calgary, Canada.",
"authors": "Sivanandan|Sindhu|S|;Bali|Varun|V|;Soraisham|Amuchou Singh|AS|;Harabor|Andrei|A|;Kamaluddeen|Majeeda|M|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen; D007213:Indomethacin",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0032-1332800",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1631",
"issue": "30(9)",
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004374:Ductus Arteriosus, Patent; D020345:Enterocolitis, Necrotizing; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D007052:Ibuprofen; D007213:Indomethacin; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D007416:Intestinal Perforation; D008297:Male; D051437:Renal Insufficiency; D012189:Retrospective Studies",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "745-50",
"pmc": null,
"pmid": "23322388",
"pubdate": "2013-10",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Effectiveness and safety of indomethacin versus ibuprofen for the treatment of patent ductus arteriosus in preterm infants.",
"title_normalized": "effectiveness and safety of indomethacin versus ibuprofen for the treatment of patent ductus arteriosus in preterm infants"
} | [
{
"companynumb": "CA-JNJFOC-20150219050",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INDOMETHACIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo report a case of severe tamoxifen-induced maculopathy with associated cystoid macular edema treated with intravitreal triamcinolone acetonide.\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nThe patient presented with bilateral cystoid macular edema that persisted despite treatment, which included intravitreal bevacizumab injections. He received 7 triamcinolone injections in each eye over 20 months, resulting in the most recent best-corrected Snellen visual acuities of 20/40 in the right eye and 20/30 in the left eye. Complete resolution of the cystoid macular edema was achieved in each eye, but recurrent edema necessitated continued intermittent injections. Macular crystals persisted despite treatment but decreased since presentation.\n\n\nCONCLUSIONS\nIntravitreal triamcinolone should be considered for treatment of tamoxifen-associated macular edema, especially if the condition responds poorly to anti-vascular endothelial growth factor treatments.",
"affiliations": "*Rutgers-Robert Wood Johnson Medical School, Piscataway, New Jersey; and †NJ Retina, New Brunswick, New Jersey.",
"authors": "Jeng|Karen W|KW|;Wheatley|H Matthew|HM|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D014222:Triamcinolone Acetonide",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000093",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "9(1)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D018931:Antineoplastic Agents, Hormonal; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema; D008297:Male; D008875:Middle Aged; D013629:Tamoxifen; D016896:Treatment Outcome; D014222:Triamcinolone Acetonide",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "64-6",
"pmc": null,
"pmid": "25383850",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravitreal triamcinolone acetonide treatment of tamoxifen maculopathy with associated cystoid macular edema.",
"title_normalized": "intravitreal triamcinolone acetonide treatment of tamoxifen maculopathy with associated cystoid macular edema"
} | [
{
"companynumb": "US-ACTAVIS-2015-18352",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TAMOXIFEN CITRATE"
},
"drugadditional": null,
... |
{
"abstract": "We report here the rare case of a 61-year-old man with multiple organ dysfunction caused by an aspirin overdose (4 g orally). The patient presented with a fever that reached 39.2 °C, a peptic ulcer, and massive upper gastrointestinal bleeding. His blood test results were as follows: white blood cell count, 1.8 × 10(9)/L; absolute lymphocytes, 0.4 × 10(9)/L; absolute neutrophils, 1.2 × 10(9)/L; and electrolyte disturbances. A computed tomography (CT) scan showed evidence of bilateral inferior pulmonary infection and acute pancreatitis. Thick dark bile with visible floccule was drawn via a percutaneous transhepatic cholangiodrainage (PTCD). Klebsiella pneumoniae was detected in microbiological bile tests. Two years later, the patient died of chronic liver failure.",
"affiliations": "Department of Nursing, School of Medicine, Shihezi University, Shihezi, 832002, China.",
"authors": "Cao|Zhuping|Z|;Liu|Shiqi|S|;Niu|Jianhua|J|;Wei|Bing|B|;Xu|Jie|J|",
"chemical_list": "D001241:Aspirin",
"country": "China",
"delete": false,
"doi": "10.1007/s11684-015-0398-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2095-0217",
"issue": "9(3)",
"journal": "Frontiers of medicine",
"keywords": null,
"medline_ta": "Front Med",
"mesh_terms": "D001241:Aspirin; D056486:Chemical and Drug Induced Liver Injury; D062787:Drug Overdose; D006801:Humans; D017093:Liver Failure; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101549428",
"other_id": null,
"pages": "388-91",
"pmc": null,
"pmid": "26085469",
"pubdate": "2015-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19155536;23704822;11752356;712501;7483055;25125957;7436178;15883478;12017163;21357821",
"title": "Severe hepatoxicity caused by aspirin overdose: a case report.",
"title_normalized": "severe hepatoxicity caused by aspirin overdose a case report"
} | [
{
"companynumb": "CN-BAYER-2015-371118",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND Mycobacterium abscessus is one of the most important mycobacteria, but its associated peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD) appears relative rare, and the treatment regimen of the antibiotics are still unclear. CASE REPORT A 38-year-old female with chronic glomerulonephritis on CAPD who was diagnosed with M. abscessus-associated peritonitis. Symptoms exacerbated despite treatment with a 3-antibiotic regimen combining clarithromycin, imipenem/cilastatin (IPM/CS), and minocycline (MINO). However, after changing IPM/CS and MINO to linezolid (LZD), her condition and inflammation improved, and she was able to be maintained on oral tedizolid (TZD). CONCLUSIONS Oxazolidinones such as LZD and TZD might be candidate antibiotics for the treatment of M. abscessus-associated diseases with chronic renal failure due to their immunomodulatory effects and non-renal excretion.",
"affiliations": "Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan.;Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan.;Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan.;Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan.;Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan.;Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan.;Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan.;Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan.",
"authors": "Seki|Masafumi|M|;Kamioka|Yasuhiro|Y|;Takano|Kazuki|K|;Imai|Haruka|H|;Shoji|Mai|M|;Hariu|Maya|M|;Kabutoya|Yukari|Y|;Watanabe|Yuji|Y|",
"chemical_list": "D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D013777:Tetrazoles; C546016:tedizolid; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.924642",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n32598338\n10.12659/AJCR.924642\n924642\nArticles\nMycobacterium abscessus Associated Peritonitis with CAPD Successfully Treated Using a Linezolid and Tedizolid Containing Regimen Suggested Immunomodulatory Effects\nSeki Masafumi ACDEFG1 Kamioka Yasuhiro BC12 Takano Kazuki BCD13 Imai Haruka BC1 Shoji Mai BC13 Hariu Maya BCD13 Oikawa Nozomi BCDE13 Kabutoya Yukari B13 Watanabe Yuji ABCD13 \n1 Division of Infectious Diseases and Infection Control, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan\n\n2 Division of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan\n\n3 Laboratory for Clinical Microbiology, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Miyagi, Japan\nCorresponding Author: Masafumi Seki, e-mail: m-seki@tohoku-mpu.ac.jp, seki@hosp.tohoku-mpu.ac.jpAuthors’ 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\nSource of support: This work was supported by a Grant-in-Aid for Scientific Research (17K09623 to M.S.) from the Japanese Society for the Promotion of Science\n\n\n2020 \n29 6 2020 \n21 e924642-1 e924642-5\n28 3 2020 25 4 2020 19 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 38-year-old\n\nFinal Diagnosis: Peritonitis\n\nSymptoms: Abdominal and/or epigastric pain\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Infectious Diseases\n\nObjective:\nRare disease\n\nBackground:\nMycobacterium abscessus is one of the most important mycobacteria, but its associated peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD) appears relative rare, and the treatment regimen of the antibiotics are still unclear.\n\nCase Report:\nA 38-year-old female with chronic glomerulonephritis on CAPD who was diagnosed with M. abscessus-associated peritonitis. Symptoms exacerbated despite treatment with a 3-antibiotic regimen combining clarithromycin, imipenem/cilastatin (IPM/CS), and minocycline (MINO). However, after changing IPM/CS and MINO to linezolid (LZD), her condition and inflammation improved, and she was able to be maintained on oral tedizolid (TZD).\n\nConclusions:\nOxazolidinones such as LZD and TZD might be candidate antibiotics for the treatment of M. abscessus-associated diseases with chronic renal failure due to their immunomodulatory effects and non-renal excretion.\n\nMeSH Keywords:\nAntibiotics, AntitubercularImmunocompromised HostMycobacterium Infections, NontuberculousRenal Insufficiency, Chronic\n==== Body\nBackground\nNon-tuberculous mycobacteria (NTM)-associated peritonitis during continuous ambulatory peritoneal dialysis (CAPD) is considered relative rare although peritonitis is one of the most serious complications associated with peritoneal dialysis [1].\n\nPeritonitis is a frequent complication of CAPD and most of the episodes of peritonitis are caused by touch contamination of the dialysis tubing or by extension of the catheter exit site or tunnel infection [2]. Coagulase-negative and coagulase-positive staphylococci are the 2 most common organisms, accounting for 50% or more of all CAPD peritonitis, and other Gram-positive and Gram-negative bacteria and fungi account for the rest. Intraperitoneal antibiotic treatments are usually effective in eradicating the infection, and the choice of antibiotics depends on organisms isolated from cultured dialysate.\n\nFurthermore, Tian et al. reported that they had 31 patients die among 2917 CAPD patients during the study period from 2002 to 2014 and that the most common causes of CAPD-related death were cerebrovascular disease (29.0%) and infection (19.4%) [3]. They also found similar common pathogens, such as Gram-positive bacteria followed by Gram-negative bacteria in CAPD peritonitis\n\nHere, we report a case of definite Mycobacterium abscessus associated peritonitis in a woman on CAPD treated by linezolid (LZD) and tedizolid (TZD) in addition to clarithromycin (CAM). This case and related study were approved by the Committee for Clinical Scientific Research of Tohoku Medical and Pharmaceutical University Hospital in October 9, 2015 as No. ID2015-2-023 and the patients whose specimens were used provided written informed consent to have the case details and any accompanying images published.\n\nCase Report\nA 38-year-old female developed renal failure and glomerulonephritis and mainly received immunosuppressive agents such as prednisolone, tacrolimus, and cyclophosphamide. However, extensive chronic renal failure subsequently developed.\n\nDuring the 2 years following onset of chronic kidney disease, she experienced repeated infectious diseases, including cytomegalovirus and aspergillosis. Kidney function was gradually worsened due to long-term administration of nephrotoxic agents, including tacrolimus (controlled concentration range: 5–10 ng/mL), voriconazole, and valganciclovir. CAPD was started after 2 years of follow-up on an outpatient basis.\n\nThe patient experienced bacterial peritonitis several times mainly due to Staphylococcus aureus including methicillin resistant S. aureus (MRSA) and received some antibiotics, such as cefazolin 1 g/day, levofloxacin 0.5 g/day, and vancomycin 1 g/day in the first year of CAPD. Each antibiotic was used 2 to 4 weeks every day or every other day, and her condition had improved. However, her peritoneal tube has not removed because the patient requested peritoneal dialysis and rejected the change to hemodialysis.\n\nShe was admitted to our hospital because of turbidity in the peritoneal drainage fluid with fever and abdominal pain after 18 months on CAPD administration although levofloxacin was received orally in the outpatient clinic for 1 week. Physical examination showed slight tenderness around the umbilicus in abdomen. Her blood pressure was 120/70 mmHg, temperature of 37.2°C, respiratory rate of 18 breaths per minute, and consciousness level of E4V5M6 on the Glasgow coma scale (GCS). Laboratory data were as follows: white blood cell (WBC) count, 6.1×103/µL with 76.5% neutrophils, 11.3% lymphocytes, 9.3% monocytes, 0.6% basophils, and 2.3% eosinophils; platelet count, 224×103/µL; hemoglobin, 7.6 g/dL; serum creatinine, 7.85 mg/dL; blood urea nitrogen, 51 g/L; uric acid, 5.1 mg/dL; and C-reactive protein, 2.16 mg/dL. Peritoneal fluid contained WBCs (2234/µL; 4% mononuclear cells, 96% polymorphonuclear cells). We found slight pus and erythema at the peritoneal dialysis catheter exit site and the ascites and thickening of the peritoneum with edema were shown in the computed tomography of the abdomen (Figure 1).\n\nWe did not find the other pathological changes, including the intra-abdominal abscess and the perforation of intestines, therefore, CAPD-associated peritonitis was diagnosed and peritoneal fluid from the peritoneal tube and blood were collected as culture specimens. Treated with 1 g of intravenous meropenem on alternate days in combination with intraperitoneal administration of cefazolin 1 g/day and ceftazidime 1 g/day were started empirically. Although these antibiotic were continued for a week, WBC in the peritoneal fluid were increased to 2796/µL and the condition of the patient deteriorated with vomiting and abdominal pain, and high fever of 38.3°C was found, although her blood pressure of 116/60 mmHg, respiratory rate of 19 breaths per minute, and consciousness level was E4V5M6 of GCS had not worsen. Peritoneal fluid showed WBC counts in her peritoneal fluid and serum C-reactive protein were increased to 3463/µL and 3.72 mg/dL, respectively.\n\nBacterial cultures, including blood and sputum, which are collected on admission routinely to rule out the bacteremia and pneumonia due to resistant pathogens, yielded negative results on day 3 post-admission, but acid-fast bacilli were identified from smears of peritoneal fluid (Figure 2). M. abscessus was collected after culture of peritoneal fluid and was confirmed by amino acid analysis using Time-of-Flight Mass Spectrometer (TOF-MS), leading to definitive diagnosis of M. abscessus associated CAPD peritonitis.\n\nBecause a severe condition of the patient was suspected, the peritoneal dialysis catheter was removed, and she was started on hemodialysis. In addition, the combination antibiotic therapy comprising oral CAM at 800 mg, intravenous imipenem/cilastatin (IPM/CS) 1 g, and minocycline (MINO) 200 mg was started and continued for more 1 week. However, her condition and laboratory data worsened, and intra-abdominal fluid cell numbers were still high at 3014/µL. We then changed 2 of the 3 antibiotics, removing IPM/CS and MINO, and adding intravenous LZD at 1.2 g/day because the agent was known as immunomodulation, and non-dose adjustment necessary even in patients with renal failure.\n\nHer condition subsequently improved, and WBC in the perito-neal fluid decreased to 1876/µL and C-reactive protein in the serum returned to 1.26 mg/dL. More than 2 weeks later, we found decreased of platelet counts in the blood from 2.2×105/µL to 1.0×105/µL, which is a well- known side effect of LZD, therefore, we changed intravenous LZD to oral TZD, an oxazolidinone similar to LZD but not associated with thrombocytopenia, and found that her condition remained stable and her WBC in the peritoneal fluid and C-reactive protein in the serum decreased to 1072/µL and 0.17 mg/dL, respectively, although the drug sensitivity of M. abscessus had shown susceptibility to CAM, but not LZD (Table 1).\n\nM. abscessus treatment was planned to be continued for half a year. She was discharged on day 40 because improvement of her condition was found. Her fever and WBC count in her peritoneal fluids were decreased to 36.8°C and 84/µL, respectively, although thickening of the peritoneum on computed tomography (CT) images remained; she continued the hemo-dialysis to avoid the recurrence of the peritonitis. One year after discharge, the patient remains well without recurrence of M. abscessus infection.\n\nDiscussion\nM. abscessus is the most important rapidly growing mycobacteria, and 80% of chronic pulmonary diseases were caused by this rapid growth-type of mycobacterium. However, mycobacteria are also responsible for extrapulmonary disease, especially in terms of cutaneous and surgery-related infections [1,4,5].\n\nWe previously reported M. avium complex-associated peritonitis in patients on CAPD, but this condition appears to be relative rare [6]. It has been reported that most cases of NTM peritonitis occur in patients with immunosuppression underlying disease, such as systemic lupus erythematosus, diabetes, human immunodeficiency virus infection, and CAPD among the cases of peritoneal dialysis associated NTM peritonitis [7]. In our case, peritoneal dialysis may have been the most important risk factor of M. abscessus infection, and our patient’s low-immunological condition might be related to her severe infection.\n\nAbdominal M. abscessus infections related with CAPD are extremely rare and few cases have been reported [8–10] (Table 2). Ding et al. analyzed 11 patients with abdominal NTM infections identified during a 7-year period, and found immuno-compromised status (liver cirrhosis, malignancy, acquired immunodeficiency syndrome) was noted in 10 patients (91%); however, none of the patients who developed NTM peritonitis had received CAPD although M. abscessus played a major role (27% of cases) [8].\n\nM. abscessus is considered the most pathogenic, antibiotic-resistant of the mycobacteria [1,5]. Among the various antibiotics, macrolides such as CAM and azithromycin have usually been considered highly effective against M. abscessus. However, recent studies have suggested that more than 75% of isolates demonstrate inducible resistance to macrolides, including CAM [1,5]. IPM/CS data have varied markedly among studies and depend on the countries/regions [5]. Amikacin, an aminoglycoside, has consistently demonstrated good activity against M. abscessus, with susceptibilities usually greater than 90% [1,5]. However, amikacin is known for its renal side effects, and little is known about its in vivo efficacy and whether myco-bacterial minimal inhibitory concentrations (MICs) are reached within peritoneal fluid [7]. Ruth et al. found no clear role for MINO in the treatment of M. abscessus infection, because of the high MIC, rapid acquisition of drug resistance, and lack of synergistic effects with other antibiotics [11]. Fluoroquinolones have been the most widely available antibiotics, but increasing evidence suggests resistance to most representative drugs of this class after repeated use [5]. We therefore did not use levofloxacin although we found intermediate susceptibility of M. abscessus to levofloxacin later (Table 1).\n\nMoxifloxacin, azithromycin, and cefoxitin might be good alterative candidates, however, we had already use levofloxacin, which was similar to moxifloxacin, and found less improvement. In addition, azithromycin is a macrolide, as is CAM which was already used, and cefoxitin is a beta-lactams as is IPM/CS which was already used, too. Therefore, we selected LZD, which was very different from the other agents we had already used that had poor effects clinically, although LZD showed less susceptibility in vivo.\n\nLZD has been used as an emerging treatment option for systemic NTM infections. Susceptibility of M. abscessus to LZD varies from about 40% to 100% across various studies although the M. abscessus isolates showed multiple resistances to the other conventional drugs [4,12]. In our in vitro data, the isolated M. abscessus showed resistance to LZD. However, clinical improvement was seen after administration of LZD, which was started in place of IPM/CS and MINO.\n\nLZD, one of the oxazolidinone antibiotics, is known as an immunomodulatory drug, and inhibitory effects on cytokines and inflammation have been reported [13]. Decreased levels of chemokines KC and MIP-2, and proinflammatory cytokine IFN-γ, TNFα, and IL-1β were found in the lungs of influenza-related community-acquired MRSA pneumonia mice models after treatment with LZD as compared to vancomycin [8].\n\nThese effects might have been sufficient in the present case, in addition to macrolides antibiotics such as CAM and azithromycin which are also known to exert immunomodulatory effects [14,15]. Furthermore, LZD is known to show very good penetration into most tissues in humans, and a full dose can be used even in patients with renal failure, including patients on CAPD as in the present case [16,17].\n\nIn addition, TZD has become available as an oxazolidinone with immunomodulatory effects similar to LZD but offering greater effectiveness at only half the dose of LZD [18,19]. We might be able to treat M. abscessus-associated peritonitis more successfully with CAM and LZD/TZD instead of conventional regimens comprising CAM, IMP/CS, and MINO combinations, because TZD has shown effectiveness against clinical isolates of M. abscessus [20].\n\nConclusions\nWe report a M. abscessus-associated peritonitis in a CAPD patient. We achieved improvement in this patient using treatment with LZD and TZD, even though drug susceptibility testing had shown resistance in vitro, while IPM/CS and MINO had resulted in worsening of her condition. Oxazolidinone antibiotics, especially TZD, might have immunomodulatory effects in addition to better tissue penetration and anti-bacterial activities, and longer half reduction time than LZD. Thus, these agents represent strong candidates for the treatment of M. abscessus-associated diseases in patients with chronic renal failure due to independence from kidney function.\n\nConflict of interest\n\nNone.\n\nFigure 1. Abdominal computed tomography of the patients. Slight ascites and thickening of the peritoneum with edema were found (arrows).\n\nFigure 2. Light microscopy showing Ziehl-Nelsen staining in the peritoneal fluid. Red and thin stained acid-fast bacilli were detected (×1000).\n\nTable 1. Drug susceptibilities of Mycobacterium abscessus isolated from peritoneal fluid.\n\nNo.\tDrugs\tMIC\tS/I/R\t\n1\tSM\t32\tR\t\n2\tEB\t32\tR\t\n3\tKM\t16\tR\t\n4\tRIP\t>32\tR\t\n5\tLVFX\t2\tI\t\n6\tCAM\t0.125\tS\t\n7\tTH\t>16\tR\t\n8\tAMK\t16\tR\t\n9\tIPM/CS\t>32\t\t\n10\tMINO\t>256\t\t\n11\tDAP\t>256\t\t\n12\tLZD\t>256\t\t\nMIC – minimal inhibitory concentrations; S – susceptible; I – intermediate; R – resistance; SM – streptomycin; EB – ethambutol; KM – kanamycin; RIP – rifampicin; LVFX – levofloxacin; CAM – clarithromycin; TH – ethionamide; AMK – amikacin; IPM/CS – imipenem/cilastatin; MINO – minocycline; DAP – daptomycin; LZD – linezolid.\n\nTable 2. Reported peritonitis cases where Mycobacterium abscessus was isolated.\n\nStudy\tPatients (n)\tMale/Female\tAge (yrs)\tUnderlying diseases\tMajor pathogen\tAntibiotics\tSurvived/death\t\nDing et al. [8]\t11\t6/5\t64.5\tMalignancy (73%)\tM. abscessus (27%)\tUnknown\t1 patient survived more than 1 year\t\nKleinpeter and Krane [9]\t2\t1/1\t63/28\tDiabetes/nephritis\tM. fortumtum/M. abscessus\tCAM and/or AMK\tBoth survived\t\nYoshimura et al. [10]\t1\t1/0\t56\tDiabetes\tM. abscessus\tCAM and IPM/CS\tSurvived\t\nyrs – years; M. abscessus – Mycobacterium abscessus; M. fortumtum – Mycobacterium fortumtum; CAM – clarithromycin; AMK – amikacin; IMP/CS – imipenem/cilastatin.\n==== Refs\nReferences:\n1. Chen J Zhao L Mao Y Clinical efficacy and adverse effects of antibiotics used to treat Mycobacterium abscessus pulmonary disease Front Microbiol 2019 10 1977 31507579 \n2. Saktayen MG CAPD peritonitis. Incidence, pathogens, diagnosis, and management Med Clin North Am 1990 74 997 1010 2195268 \n3. Tian Y Xie X Xiang S Risk factors and outcomes of high peritonitis rate in continuous ambulatory peritoneal dialysis patients: A retrospective study Medicine (Baltimore) 2016 2 95 e5569 27930566 \n4. Bostan C Slim E Choremis J Successful management of severe post-LASIK Mycobacterium abscessus keratitis with topical amikacin and linezolid, flap ablation, and topical corticosteroids J Cataract Refract Surg 2019 45 1032 35 31182265 \n5. Shen Y Wang X Jin J In vitro susceptibility of Mycobacterium abscessus and Mycobacterium fortuitum isolates to 30 antibiotics Biomed Res Int 2018 2018 4902921 \n6. Miyashita E Yoshida H Mori D Mycobacterium avium complex-associated peritonitis with CAPD after unrelated bone marrow transplantation Pediatr Int 2014 56 e96 98 25521993 \n7. Song Y Wu J Yan H Chen J Peritoneal dialysis-associated nontuberculous mycobacterium peritonitis: A systematic review of reported cases Nephrol Dial Transplant 2012 27 1639 44 21891775 \n8. Ding LW Lai C Lee LN Hsueh PR Abdominal nontuberculous mycobacterial infection in a university hospital in Taiwan from 1997 to 2003 J Formos Med Assoc 2006 105 370 76 16638646 \n9. Kleinpeter MA Krane N Treatment of mycobacterial exit-site infections in patients on continuous ambulatory peritoneal dialysis Adv Perit Dial 2001 17 172 75 11510269 \n10. Yoshimura R Kawanishi M Fujii S Peritoneal dialysis-associated infection caused by Mycobacterium abscessus : A case report BMC Nephrol 2018 19 1 341 30497395 \n11. Ruth MM Sangen J Pennings LJ Minocycline has no clear role in the treatment of Mycobacterium abscessus disease Antimicrob Agents Chemother 2018 62 pii: e01208 18 30104268 \n12. Kim SY Jhun B Moon SM Genetic mutations in linezolid-resistant Mycobacterium avium complex and Mycobacterium abscessus clinical isolates Diagn Microbiol Infect Dis 2019 94 38 40 30581010 \n13. Bhan U Podstad A Kovach MA Linezolid has unique immunomodulatory effects in post-influenza community acquired MRSA pneumonia PLoS One 2015 10 1 e114574 \n14. Seki M Sakata T Toyokawa M A chronic respiratory Pasteurella multocida infection is well-controlled by long-term macrolide therapy Intern Med 2016 55 307 10 26831030 \n15. Kakeya H Seki M Izumikawa K Efficacy of combination therapy with oseltamivir phosphate and azithromycin for influenza: A multicenter, open-label, randomized study PLoS One 2014 14 e91293 \n16. Bogard KN Peterson N Plumb TJ Antibiotic dosing during sustained low-efficiency dialysis: Special considerations in adult critically ill patients Crit Care Med 2011 2 39 56 70 \n17. El-Naggari M El Nour I Al-Nabhani D Nocardia asteroides peritoneal dialysis-related peritonitis: First case in pediatrics, treated with protracted linezolid J Infect Public Health 2016 9 2 192 97 26768669 \n18. Housman ST Pope J Russomanno J Pulmonary disposition of tedizolid following administration of once-daily oral 200-milligram tedizolid phosphate in healthy adult volunteers Antimicrob Agents Chemother 2012 56 2627 34 22330925 \n19. Lemaire S Van Bambeke F Appelbaum PC Tulkens PM Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines J Antimicrob Chemother 2009 64 1035 43 19759040 \n20. Tang YW Cheng B Yeoh SF Tedizolid activity against clinical Mycobacterium abscessus complex isolatesan in vitro characterization study Front Microbiol 2018 9 e20950\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D002908:Chronic Disease; D005260:Female; D005921:Glomerulonephritis; D006801:Humans; D016867:Immunocompromised Host; D000069349:Linezolid; D009165:Mycobacterium Infections, Nontuberculous; D000073358:Mycobacterium abscessus; D023303:Oxazolidinones; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010538:Peritonitis; D013777:Tetrazoles",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e924642",
"pmc": null,
"pmid": "32598338",
"pubdate": "2020-06-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24632748;26768669;31507579;31182265;21891775;25635685;19759040;30581010;30104268;2195268;26831030;30245674;16638646;30497395;25521993;21221000;30687747;27930566;11510269;22330925",
"title": "Mycobacterium abscessus Associated Peritonitis with CAPD Successfully Treated Using a Linezolid and Tedizolid Containing Regimen Suggested Immunomodulatory Effects.",
"title_normalized": "mycobacterium abscessus associated peritonitis with capd successfully treated using a linezolid and tedizolid containing regimen suggested immunomodulatory effects"
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"companynumb": "JP-TEVA-2020-JP-1812588",
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"patient": {
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"activesubstancename": "LINEZOLID"
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{
"abstract": "The practice of neurocritical care encompasses multiple acute neurologic and neurosurgical diseases and requires detailed knowledge of neurology and critical care. This article presents 5 cases that illustrate just some of the conditions encountered in the daily practice of neurocritical care and exemplify some of the common diagnostic, therapeutic, and prognostic challenges facing the neurointensivist. Life-threatening medical complications after severe acute ischemic stroke, seizures and extreme agitation from autoimmune encephalitis, refractory seizures after subdural hemorrhage, neurologic and systemic complications related to aneurysmal subarachnoid hemorrhage, and status epilepticus after cardiac arrest are discussed in this article.",
"affiliations": "Department of Critical Care, Mayo Clinic, Rochester, MN, USA; Department of Internal Medicine, Tuzla University Medical Center, Tuzla, Bosnia and Herzegovina; Department of Pulmonary Medicine, Tuzla University Medical Center, Tuzla, Bosnia and Herzegovina.;Department of Neurology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. Electronic address: rabinstein.alejandro@mayo.edu.",
"authors": "Sakusic|Amra|A|;Rabinstein|Alejandro A|AA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0733-8619",
"issue": "34(3)",
"journal": "Neurologic clinics",
"keywords": "Acute stroke; Cardiac arrest; Seizures; Subarachnoid hemorrhage; Subdural hemorrhage",
"medline_ta": "Neurol Clin",
"mesh_terms": "D000368:Aged; D003422:Critical Care; D004660:Encephalitis; D005260:Female; D050031:Hashimoto Disease; D006801:Humans; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases; D011379:Prognosis; D012640:Seizures; D020521:Stroke; D013345:Subarachnoid Hemorrhage; D055815:Young Adult",
"nlm_unique_id": "8219232",
"other_id": null,
"pages": "683-97",
"pmc": null,
"pmid": "27445248",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Case Studies in Neurocritical Care.",
"title_normalized": "case studies in neurocritical care"
} | [
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"companynumb": "US-UCBSA-2016047521",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
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... |
{
"abstract": "Reported is the case of a patient with vertebrobasilar artery ischemia who received tissue plasminogen activator with resulting hemorrhage into the tongue and nearly exsanguinating hemorrhage from a branch of the lingual artery. Suggestions for immediate management of the hemorrhage as well as prevention are presented. As the use of thrombolytic agents increases and the list of their indications expands, unusual life-threatening hemorrhagic problems other than gastrointestinal or intracranial bleeding will be seen, and management decisions may be life saving.",
"affiliations": "Emergency Medicine Residency Program, Grady Memorial Hospital, Emory University School of Medicine, Atlanta, Georgia.",
"authors": "Wrenn|K|K|",
"chemical_list": "D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1016/s0196-0644(05)81526-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0196-0644",
"issue": "19(10)",
"journal": "Annals of emergency medicine",
"keywords": null,
"medline_ta": "Ann Emerg Med",
"mesh_terms": "D001933:Brain Stem; D006801:Humans; D007511:Ischemia; D008297:Male; D008875:Middle Aged; D006472:Oral Hemorrhage; D010959:Tissue Plasminogen Activator",
"nlm_unique_id": "8002646",
"other_id": null,
"pages": "1184-6",
"pmc": null,
"pmid": "2121076",
"pubdate": "1990-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Tissue plasminogen activator-associated lingual artery hemorrhage.",
"title_normalized": "tissue plasminogen activator associated lingual artery hemorrhage"
} | [
{
"companynumb": "US-ROCHE-1174448",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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"activesubstancename": "HEPARIN SODIUM"
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... |
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"abstract": "OBJECTIVE\nReactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti-tumor necrosis factor (anti-TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase III Program (3 with rheumatoid arthritis, 1 with psoriatic arthritis, and 1 with ankylosing spondylitis) through 1 year among 2,210 patients receiving golimumab.\n\n\nMETHODS\nData from global studies were used for an in-depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti-TB therapy.\n\n\nRESULTS\nNo active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients not treated with isoniazid by week 52 (in 2 patients by week 24); all of the patients had negative TB screening tests (per the local guidelines) and resided in countries with high background rates of TB. No deaths were due to TB. Across all of the groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (<3 times the upper limit of normal).\n\n\nCONCLUSIONS\nComprehensive TB screening kept the number of active TB cases relatively low despite conducting the studies in TB-endemic regions. Treatment for latent TB infection appeared effective, since no patients treated for latent TB had TB reactivation. Concurrent treatment with golimumab and anti-TB medication was generally well tolerated. Clinicians should remain vigilant for development of active TB after initiation of TNF inhibitors, since prompt diagnosis and treatment can improve outcomes.",
"affiliations": "Janssen Research & Development, LLC, Spring House, and University of Pennsylvania School of Medicine, Philadelphia, USA. EHsia@its.jnj.com",
"authors": "Hsia|Elizabeth C|EC|;Cush|John J|JJ|;Matteson|Eric L|EL|;Beutler|Anna|A|;Doyle|Mittie K|MK|;Hsu|Benjamin|B|;Xu|Stephen|S|;Rahman|Mahboob U|MU|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000995:Antitubercular Agents; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D007538:Isoniazid",
"country": "United States",
"delete": false,
"doi": "10.1002/acr.21788",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2151-464X",
"issue": "65(2)",
"journal": "Arthritis care & research",
"keywords": null,
"medline_ta": "Arthritis Care Res (Hoboken)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D000995:Antitubercular Agents; D001168:Arthritis; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D007538:Isoniazid; D055985:Latent Tuberculosis; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "101518086",
"other_id": null,
"pages": "309-13",
"pmc": null,
"pmid": "22782640",
"pubdate": "2013-02",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Comprehensive tuberculosis screening program in patients with inflammatory arthritides treated with golimumab, a human anti-tumor necrosis factor antibody, in Phase III clinical trials.",
"title_normalized": "comprehensive tuberculosis screening program in patients with inflammatory arthritides treated with golimumab a human anti tumor necrosis factor antibody in phase iii clinical trials"
} | [
{
"companynumb": "KR-JNJFOC-20070603104",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
},
"drugadditional": "1",
"d... |
{
"abstract": "OBJECTIVE\nNamibia has been suffering from an outbreak of hepatitis E genotype 2 since 2017. As nearly half of hepatitis E-related deaths were among pregnant and postpartum women, we analysed maternal and fetal outcomes of pregnancies complicated by acute hepatitis E and assessed whether HIV-status impacted on outcome.\n\n\nMETHODS\nA retrospective cross-sectional study was performed at Windhoek Hospital Complex. Pregnant and postpartum women, admitted between 13 October 2017 and 31 May 2019 with reactive IgM for Hepatitis E, were included. Outcomes were acute liver failure (ALF), maternal death, miscarriage, intra-uterine fetal death and neonatal death. Odds ratios (OR) and 95% confidence interval (CI) were calculated.\n\n\nRESULTS\nSeventy women were included. ALF occurred in 28 (40.0%) of whom 13 died amounting to a case fatality rate of 18.6%. Sixteen women (22.9%) were HIV infected, compared to 16.8% among the general pregnant population (OR 1.47, 95% CI 0.84-2.57, P = .17). ALF occurred in 4/5 (80%) HIV infected women not adherent to antiretroviral therapy compared to 1/8 (12.5%) women adherent to antiretroviral therapy (OR 28.0, 95% CI 1.4-580.6). There were 10 miscarriages (14.3%), five intra-uterine fetal deaths (7.1%) and four neonatal deaths (5.7%).\n\n\nCONCLUSIONS\nOne in five pregnant women with Hepatitis E genotype 2 died, which is comparable to genotype 1 outbreaks. Despite small numbers, HIV infected women receiving antiretroviral therapy appear to be less likely to develop ALF in contrast with HIV infected women not on treatment. As there is currently no curative treatment, this phenomenon needs to be assessed in larger cohorts.",
"affiliations": "Department of Obstetrics and Gynaecology, Katutura State Hospital, Windhoek, Namibia.;Department of Obstetrics and Gynaecology, Katutura State Hospital, Windhoek, Namibia.;Department of Obstetrics and Gynaecology, Katutura State Hospital, Windhoek, Namibia.;Department of Obstetrics and Gynaecology, Katutura State Hospital, Windhoek, Namibia.;Department of Health Sciences, Global Health Unit, University Medical Center Groningen, Groningen, The Netherlands.;Department of Obstetrics and Gynaecology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Obstetrics and Gynaecology, Katutura State Hospital, Windhoek, Namibia.",
"authors": "Heemelaar|Steffie|S|https://orcid.org/0000-0002-1172-4237;Hangula|Anna L|AL|;Chipeio|Melody L|ML|https://orcid.org/0000-0001-5776-9599;Josef|Mirjam|M|https://orcid.org/0000-0003-3526-0788;Stekelenburg|Jelle|J|https://orcid.org/0000-0002-2732-6620;van den Akker|Thomas H|TH|;Pischke|Sven|S|https://orcid.org/0000-0003-3370-3274;Mackenzie|Shonag B P|SBP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/liv.15076",
"fulltext": "\n==== Front\nLiver Int\nLiver Int\n10.1111/(ISSN)1478-3231\nLIV\nLiver International\n1478-3223\n1478-3231\nJohn Wiley and Sons Inc. Hoboken\n\n34623734\n10.1111/liv.15076\nLIV15076\nOriginal Article\nViral Hepatitis\nMaternal and fetal outcomes of pregnancies complicated by acute hepatitis E and the impact of HIV status: A cross‐sectional study in Namibia\nHEEMELAAR et al\nHeemelaar Steffie https://orcid.org/0000-0002-1172-4237\n1 7 s.heemelaar@lumc.nl\n\nHangula Anna L. 1\nChipeio Melody L. https://orcid.org/0000-0001-5776-9599\n1\nJosef Mirjam https://orcid.org/0000-0003-3526-0788\n1\nStekelenburg Jelle https://orcid.org/0000-0002-2732-6620\n2 3\nvan den Akker Thomas H. 4 5\nPischke Sven https://orcid.org/0000-0003-3370-3274\n6\nMackenzie Shonag B. P. 1 8\n1 Department of Obstetrics and Gynaecology Katutura State Hospital Windhoek Namibia\n2 Department of Health Sciences Global Health Unit University Medical Center Groningen Groningen The Netherlands\n3 Department of Obstetrics and Gynaecology Medical Center Leeuwarden Leeuwarden The Netherlands\n4 Department of Obstetrics and Gynaecology Leiden University Medical Center Leiden The Netherlands\n5 Faculty of Science VU University Athena Institute Amsterdam The Netherlands\n6 Department of Medicine University Medical Center Hamburg‐Eppendorf Hamburg Germany\n7 Present address: Department of Obstetrics and Gynaecology Leiden University Medical Center Leiden The Netherlands\n8 Present address: Department of Obstetrics and Gynaecology Borders General Hospital Melrose United Kingdom\n* Correspondence\nSteffie Heemelaar, Department of Obstetrics and Gynaecology, Leiden University Medical Center, Leiden, The Netherlands.\nEmail: s.heemelaar@lumc.nl\n\n28 10 2021\n1 2022\n42 1 10.1111/liv.v42.1 5058\n26 8 2021\n19 4 2021\n27 9 2021\n© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nBackground & Aims\n\nNamibia has been suffering from an outbreak of hepatitis E genotype 2 since 2017. As nearly half of hepatitis E‐related deaths were among pregnant and postpartum women, we analysed maternal and fetal outcomes of pregnancies complicated by acute hepatitis E and assessed whether HIV‐status impacted on outcome.\n\nMethods\n\nA retrospective cross‐sectional study was performed at Windhoek Hospital Complex. Pregnant and postpartum women, admitted between 13 October 2017 and 31 May 2019 with reactive IgM for Hepatitis E, were included. Outcomes were acute liver failure (ALF), maternal death, miscarriage, intra‐uterine fetal death and neonatal death. Odds ratios (OR) and 95% confidence interval (CI) were calculated.\n\nResults\n\nSeventy women were included. ALF occurred in 28 (40.0%) of whom 13 died amounting to a case fatality rate of 18.6%. Sixteen women (22.9%) were HIV infected, compared to 16.8% among the general pregnant population (OR 1.47, 95% CI 0.84‐2.57, P = .17). ALF occurred in 4/5 (80%) HIV infected women not adherent to antiretroviral therapy compared to 1/8 (12.5%) women adherent to antiretroviral therapy (OR 28.0, 95% CI 1.4‐580.6). There were 10 miscarriages (14.3%), five intra‐uterine fetal deaths (7.1%) and four neonatal deaths (5.7%).\n\nConclusions\n\nOne in five pregnant women with Hepatitis E genotype 2 died, which is comparable to genotype 1 outbreaks. Despite small numbers, HIV infected women receiving antiretroviral therapy appear to be less likely to develop ALF in contrast with HIV infected women not on treatment. As there is currently no curative treatment, this phenomenon needs to be assessed in larger cohorts.\n\nhepatitis E virus\nHIV\nmaternal mortality\nNamibia\nsource-schema-version-number2.0\ncover-dateJanuary 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:20.07.2022\nHeemelaar S , Hangula AL , Chipeio ML , et al. Maternal and fetal outcomes of pregnancies complicated by acute hepatitis E and the impact of HIV status: A cross‐sectional study in Namibia. Liver Int. 2022;42 :50–58. doi:10.1111/liv.15076 34623734\n\nHandling Editor: Alessio Aghemo\n\nFunding information\n\nThere was no funding for this study.\n==== Body\npmcAbbreviations\n\nALF Acute liver failure\n\nART Antiretroviral therapy\n\nCFR Case fatality rate\n\nCI Confidence interval\n\nHEV Hepatitis E virus\n\nICU Intensive care unit\n\nIgM Immunoglobulin M\n\nINR International normalized ratio\n\nOR Odds ratio\n\nLay summary\n\nWe assessed the outcomes of pregnancy in women infected with hepatitis E in Namibia. One in five women who had acute hepatitis E during their pregnancy died, one in seven had a miscarriage and one out of eight babies died before or after birth. Women who were also infected with HIV, appear to be less frequently critically ill, especially when they were on treatment for HIV.\n\nKey points\n\n● We analysed maternal and fetal outcomes of pregnancies complicated by acute hepatitis E during an outbreak in Namibia caused by genotype 2.\n\n● One in five pregnant women with acute hepatitis E died.\n\n● One in four pregnancies of women with acute hepatitis E resulted in a miscarriage, intra‐uterine fetal death or neonatal death.\n\n● Women in the third trimester were at higher risk for acute liver failure.\n\n● Despite small numbers, HIV infected women receiving antiretroviral therapy appear to be at lower risk to develop acute liver failure, in contrast to HIV infected women not on treatment.\n\n1 INTRODUCTION\n\nHepatitis E virus (HEV) is a leading cause of acute viral hepatitis in low‐ and middle‐income countries, with an estimated 20.1 million HEV infections and 70 000 deaths annually. 1 Epidemiology and clinical presentation differ in the four main genotypes that may infect humans. Genotypes 1 and 2 are transmitted via contaminated drinking water, and outbreaks are mainly seen in Asia and Africa in regions with poor sanitation, whereas genotypes 3 and 4 are transmitted through infected swine meat and more common in high‐income countries and Asia. 2 , 3 , 4 Usually, HEV infection is self‐limiting with a low mortality rate. However, during pregnancy, a severe clinical course is frequently seen with fulminant hepatic failure, high case fatality rates and high rates of fetal complications such as miscarriage, stillbirth or premature birth. These considerable adverse outcomes are particularly described in areas where genotype 1 is endemic, and confirmed in reports from genotype 2 endemic areas, which is far less prevalent. However, it has not been identified in genotype 3 and 4 endemic areas. 5 , 6 The pathogenesis of the severe clinical course in pregnant women is not fully understood. It has been suggested that it may be related to the suppressed cellular immunity and immune response in general in pregnancy. 6 Currently there is no approved effective treatment available for acute HEV infections. 7 , 8\n\nNamibia has been suffering from an outbreak of HEV genotype 2 since December 2017, with more than 6000 infections reported from all 14 regions by August 2019. 9 Nearly half of the deaths because of HEV were among pregnant and postpartum women and HEV became the leading cause of maternal deaths in 2018‐2019. 9 , 10 Namibia had a high HIV prevalence estimated at 12.6% among adults aged 15‐64 years in 2017. 11 The impact of HIV/HEV co‐infection on outcome is not yet clear. Some studies reported a higher seroprevalence of HEV among people with HIV in the general population, while others could not confirm this finding. 12 , 13 Infection with HEV genotype 3 can develop into a chronic infection among immunosuppressed patients, including HIV‐infected persons with a low CD4 count, but this has not been described for the other genotypes. 4 , 12 Considering pregnant women there is hardly any data on HIV/HEV co‐infection since most previous genotype 1 and 2 outbreaks occurred in regions with a low HIV prevalence.\n\nAs data on outcome of hepatitis E in pregnant women in the setting of an HEV genotype 2 outbreak are still scare, in particular with a focus on HIV infected women, our aim was to analyse maternal and fetal outcomes of pregnancies complicated by acute HEV in Namibia and assess whether HIV status had clinical implications in our cohort.\n\n2 METHODS\n\n2.1 Study design and setting\n\nThis retrospective cross‐sectional study was performed in Windhoek Hospital Complex, which has around 12 000 births annually. The first HEV case of the outbreak in Namibia was reported on 13 October 2017 in Khomas region, in which the capital Windhoek is located. The outbreak continued in the city and by August 2019, there were 6151 reported cases nationally and the outbreak had spread to 10 of the 14 regions with sporadic cases in the other regions as well. 9 The national case fatality rate (CFR) was 0.9% with 56 fatalities. 9 The majority of HEV cases were reported to be among people from informal settlements. These settlements are densely populated with limited access to sanitation, safe drinking water and hygiene. Most people live in the capital for work but travel to different parts of the country to visit family members several times a year. This continuous movement to different regions has likely facilitated the spread of HEV throughout the country. In 2018, two blood samples were tested for genotyping and showed HEV genotype 2. There are reports from two previous outbreaks in Namibia. Both were in the informal settlements of Rundu, a town in northern Namibia, of which the first outbreak was in 1983 because of HEV genotype 1 and the second outbreak in 1995 because of genotype 2. 14 , 15 Whereas most outbreaks last on average a year, the outbreak in Namibia which started in 2017 has been ongoing for more than 3 years. 2\n\nAccording to the national HIV guidelines, all adults with HIV are started on antiretroviral therapy (ART) in Namibia, regardless of CD4 count or clinical stage. 16 In comparison to their neighbouring countries, Namibia performs well in implementation of the ART services: in 2017, 97.1% of HIV‐infected females were on ART and of these, 92.2% were virally suppressed. 11\n\n2.2 Study population and data collection\n\nAll pregnant women and women whose birth was terminated less than 42 days earlier, who were admitted to Windhoek Hospital Complex between 13 October 2017 and 31 May 2019 with acute HEV, confirmed by a reactive HEV immunoglobulin M (IgM), were eligible for inclusion in this study. Women were excluded if no positive IgM test result was available, the woman was not admitted to a health facility, her pregnancy or recent pregnancy could not be confirmed, or her clinical file could not be traced. The Ministry of Health and Social Services, together with the World Health Organization, developed clinical management guidelines, recommending all pregnant and postpartum women with jaundice to be admitted and tested for reactive HEV IgM, regardless if other clinical symptoms were present. Therefore, many women with mild disease were admitted and included in our cohort.\n\nCases were identified using a list of all suspected HEV cases in Khomas region from the Ministry of Health and Social Sciences of Namibia, which was established from the start of the outbreak, as hepatitis E is a notifiable disease. Because of budget restrictions, it was not possible to apply this list to other affected regions. Nevertheless, our cohort included the majority of pregnant women with HEV in Namibia, as the capital and it's referring regions were most severely affected by the outbreak. In the referring regions intensive care unit (ICU) facilities were not available and nearly all pregnant women with a confirmed HEV infection were therefore transferred to our study site for further monitoring and care. In the hospital complex the capital ICU facilities were available to provide supportive care for patients with ALF.\n\nFor identification of possible missed cases, data from the National Maternal Death Review Committee of the Ministry of Health and Social Services was used. This committee analysed all maternal deaths occurring in the country between 1st of April 2018 and 31st of March 2019 and all cases of severe morbidity between 1st of March 2018 and 31st of May 2018 in the capital and between 1st of October 2018 till 31st of March 2019 nationally. 10 , 17 , 18 Considering the severe clinical course among pregnant women, these cohorts contained many women with complicated pregnancies because of HEV.\n\nFor identified cases, data were collected anonymously from medical records using a structured data collection tool, including socio‐demographic characteristics, maternal outcomes, fetal outcomes, obstetric complications, signs of liver failure and HIV status. This was done by AH and MC and verified by SH and MJ, both medical doctors with several years of experience providing obstetric care in Namibia.\n\nLaboratory test results on admission and the most abnormal value during admission were collected from the database of the National Institute of Pathology, including alanine aspartate aminotransferases, alanine aminotransferases, bilirubin, haemoglobin, platelets, creatinine and international normalized ratio (INR). Serology test for hepatitis A, B and C were performed by Alinity Abbott. Hepatitis E serology was performed using Aria rapid tests. Glucose values were obtained through capillary blood tests. If the woman was HIV infected, data on ART treatment adherence, latest CD4 count and viral load value were retrieved from medical records, the database of the National Institute of Pathology and additional information was collected through the ART clinic the patient was attending. Data regarding fetal outcome was obtained from the woman's medical record. If a neonate had been admitted to neonatal ICU, survival status was obtained from neonatal ICU admission records. No neonate was tested for vertical transmission of HEV, as PCR testing was not available. HIV prevalence among the general pregnant population was collected through the Prevention Mother to Child Transmission Program of the Ministry of Health and Social Services.\n\n2.3 Outcomes and data analysis\n\nMain maternal outcomes were number of women with acute liver failure (ALF) and death. ALF was defined according to the definition of European Association for the Study of the Liver; acute abnormality of liver blood tests(elevated serum transaminases) in an individual without underlying chronic liver disease followed by hepatic encephalopathy of any grade and a INR > 1.5. 19 Severity of hepatic encephalopathy was graded using the West Haven Criteria, ranging from grade 1 with mild altered mental stage up to grade 4 which is complete coma. Acute hepatitis B was identified with a reactive test for IgM anti‐HBc. Chronic hepatitis B was diagnosed when a woman had a reactive test for both HBsAG and anti‐HBc. Hypoglycaemia was defined as any capillary blood glucose <4.0 mmol/L. Postpartum haemorrhage was defined as >1000 mL blood loss after birth. Premature birth was defined as birth between 26 weeks and 0 days of gestation and 36 weeks and 6 days. Intra‐uterine fetal death was defined as a death before birth in a fetus with a gestational age of 26 weeks and 0 days or more. For miscarriage, the threshold of less than 26 weeks and 0 days was used. Neonatal death was death during the first 28 days of life. All results were reported as numbers (n) and frequencies (%). An ART defaulter was defined as any woman who interrupted her treatment and missed at least one clinic visit. 16 Maternal case fatality rate was defined as the number of maternal deaths divided by the number of pregnancies complicated by acute hepatitis E and presented as a percentage. Fetal case fatality rate was defined as the number of intra‐uterine fetal deaths and neonatal deaths, divided by the number of pregnancies complicated by acute hepatitis E and presented as a percentage.\n\nContinuous variables are presented as means with standard deviations and differences in normally distributed variables were assessed using a student t‐test. Missing data were assumed to be ‘no’ for categorical data, whereas complete case analysis was used to handle missing data for continuous variables and data regarding ART adherence. Categorical variables are presented as percentages. Differences were assessed using chi‐square test or Fisher's Exact test when indicated and odds ratios (OR) with 95% confidence intervals (CI) are presented. Statistical significance was assumed at a two‐sided value of P < .05. Data analysis was performed with SPSS version 26. We followed the STROBE reporting guidelines.\n\n3 RESULTS\n\nSeventy women were included into this study. The Ministry data identified 196 women who had been pregnant or recently pregnant and suspected to have contracted hepatitis E. Of these, 57 women had not been admitted to a health facility or tested for HEV. Four women had a negative IgM result and for 59 women it was indicated they were tested for HEV, but no IgM result could be found on the system. We were unable to trace medical records of 20/76 women, so 56 women were included in our study from the Ministry's data. An additional 14 women were identified through the national severe morbidity and mortality registries. Table 1 shows the baseline characteristics of the 70 women in our cohort.\n\nTABLE 1 Baseline characteristics\n\n\tN = 70 (%)\t\nAge (y)\t\t\n<20\t3 (4.3)\t\n20‐34\t60 (85.7)\t\n≥35\t7 (10.0)\t\nParity\t\t\nPara 0\t9 (12.9)\t\nPara 1‐3\t51 (72.9)\t\n≥4\t8 (11.4)\t\nUnknown\t2 (2.9)\t\nGestational age on admission (weeks + days)\t\t\n<13 + 0\t6 (8.6)\t\n13 + 0‐25 + 6\t14 (20.0)\t\n26 + 0‐36 + 6\t34 (48.6)\t\n≥37 + 0\t5 (7.1)\t\nUnknown\t11 (15.7)\t\nHIV status\t\t\nPositive\t16 (22.9)\t\nNegative\t52 (74.3)\t\nUnknown\t2 (2.9)\t\nHepatitis\t\t\nHepatitis A\t0 (0)\t\nHepatitis B, acute\t0 (0)\t\nHepatitis B, chronic\t4 (5.7)\t\nHepatitis C\t0 (0)\t\nPregnancy outcome\t\t\nVaginal birth\t37 (52.9)\t\nCaesaren section\t5 (7.1)\t\nMiscarriage\t10 (14.3)\t\nStill pregnant at discharge\t18 (25.7)\t\nMaternal outcome\t\t\nDied\t13 (18.6)\t\nSurvived\t53 (75.7)\t\nNote\n\nValues are n (%).\n\nJohn Wiley & Sons, Ltd\n\n3.1 Maternal outcome\n\nALF occurred in 28/70 (40.0%) women, of whom 13 died leading to a maternal case fatality rate of 18.6%. Twelve women died because of fulminant liver failure after being in ICU for several days with hepatic encephalopathy grade 4 and one woman died because of hypovolemic shock secondary to postpartum haemorrhage and disseminated coagulopathy. Table 2 compares the characteristics of women who developed ALF and women without ALF. Women with ALF, compared to women without ALF, were more frequently in the third trimester, OR 3.45 (95% CI 1.10‐10.83, P = .04), had one or more episodes of hypoglycaemia, OR 4.41 (95% CI 1.54‐12.66, P = .01), and had a higher INR (6.2 ± 3.1, compared to 1.7 ± 0.7, P < .01). Women with ALF were more likely to give birth or lose their pregnancy because of a miscarriage compared to women without ALF during their admission for acute HEV, OR 4.63 (95% CI 1.20‐17.93, P = .03). Of the women with ALF, 20/28 (71.4%) developed hepatic encephalopathy grade 4 and 24/28 (85.7%) needed mechanical ventilation. An INR >1.5 was found in 42/70 (60.0%) of our study population. We identified a trend of higher elevated serum transaminases for women with ALF. For six patients with ALF birth was complicated by postpartum haemorrhage. Two women developed pregnancy‐induced hypertension and four had pre‐existent hypertension. There were no other hypertension‐related complications such as pre‐eclampsia/eclampsia.\n\nTABLE 2 Characteristics of women with acute liver failure compared to no acute liver failure\n\nTotal\tALF\tNo ALF\tAll women\tOR (95% CI)\tP value\t\nn = 28\tn = 42\tn = 70\t\nAge\t26.5 ± 4.8\t28.7 ± 5.7\t27.8 ± 5.4\t\t.11\t\nThird trimester a\t23 (82.1)\t24 (57.1)\t47 (67.1)\tOR 3.45 (1.1‐10.8)\t.04\t\nPregnancy outcome at discharge\t\t\t\t\t\t\nGiven birth/miscarried\t25 (89.3)\t27 (64.3)\t52 (74.3)\tOR 4.63 (1.2‐17.9)\t.03\t\nStill pregnant\t3 (10.7)\t15 (35.7)\t18 (25.7)\t\t\t\nHIV‐status\t5 (17.9)\t11 (26.2)\t16 (22.9)\tOR 0.61 (0.2‐2.0)\t.56\t\nOn ART\t1 (20.0)\t7 (63.6)\t8 (50.0)\tOR 0.14 (0.0‐1.8)\t.28\t\nART defaulted/interrupted\t4 (80.0)\t1 (9.1)\t5 (31.3)\tOR 28.0 (1.4‐580.6)\t.03\t\nUnknown if on treatment\t0 (0)\t3 (27.3)\t3 (18.8)\t\t\t\nEncephalopathy\t28 (100)\t0 (0)\t28 (40.0)\t\t\t\nNone\t0 (0)\t0 (0)\t42 (60.0)\t\t\t\nGrade 1\t1 (3.6)\t0 (0)\t1 (1.4)\t\t\t\nGrade 2\t0 (0)\t0 (0)\t0 (0)\t\t\t\nGrade 3\t6 (21.4)\t0 (0)\t6 (8.6)\t\t\t\nGrade 4\t20 (71.4)\t0 (0)\t20 (28.6)\t\t\t\nGrade not specified\t1 (3.6)\t0 (0)\t1 (1.4)\t\t\t\nHypoglycemia\t21 (75.0)\t17 (40.5)\t38 (54.3)\tOR 4.41 (1.5‐12.7)\t.01\t\nMechanical ventilation\t24 (85.7)\t0 (0)\t24 (34.3)\t\t\t\nINR\t6.2 ± 3.1\t1.7 ± 0.7\t3.4 ± 2.9\t\t<.01\t\nAST IU/L admission\t2874 ± 2232\t1925 ± 1610\t2302 ± 1924\t\t.06\t\nAST IU/L highest\t3118 ± 2579\t2487 ± 1725\t2734 ± 2106\t\t.27\t\nALT IU/L admission\t1827 ± 847\t1512 ± 1150\t1634 ± 1047\t\t.23\t\nALT IU/L highest\t1929 ± 983\t1770 ± 1111\t1832 ± 1058\t\t.55\t\nTotal bilirubin mg/dL admission\t225 ± 95\t183 ± 101\t199 ± 100\t\t.10\t\nTotal bilirubin mg/dL highest\t278 ± 109\t223 ± 132\t244 ± 126\t\t.08\t\nNote\n\nValues are mean ± standard deviation, n (%) and odds ratio (95% confidence interval).\n\nAbbreviations: ALF, acute liver failure; ALT, alanine aminotransferases; ARV, anti retroviral treatment; AST, alanine aspartate aminotransferases; CI, confidence interval; INR, international normalized ratio; OR, odds ratio.\n\na ≥26 weeks completed weeks of gestation.\n\nJohn Wiley & Sons, Ltd\n\n3.2 HIV\n\nIn our study population 16/70 (22.9%) women were HIV infected, compared to a prevalence of 16.8% among the general pregnant population in Namibia in 2018, which was not significantly higher (OR 1.47, 95% CI 0.84‐2.57, P = .17). 10 Among the women with ALF, HIV prevalence was lower compared to women without ALF (17.9% vs 26.2%), but there was no statistical significance (OR 0.61, CI 0.19‐2.01, P = .56). Notably 4/5 HIV infected women who interrupted their ART (80%) developed ALF compared to 1/8 (12.5%) HIV infected women adherent to their ART (OR 28.0, 95% CI 1.4‐580.6, P = .03). Table 3 presents the ART regimen, adherence, most recent available CD4 count and viral load of all HIV‐infected women in our study. One woman with ALF forgot her ART when she was admitted for observation with HEV infection during pregnancy in a stable condition. She developed encephalopathy 5 days after admission and was transferred to ICU where she developed hepatic encephalopathy grade 3. Her ART was restarted 7 days after admission and she fully recovered. For three women we were unable to trace information regarding their ART regimen or adherence, of whom one woman had a recent viral load blood test indicating she was virally suppressed and therefore on treatment.\n\nTABLE 3 Details of HIV positive women with acute hepatitis E during pregnancy\n\n\tOutcome\tGestational age\tARV adherence\tARV regimen\tCD4 cells/mm3\tViral load (copies/mL)\tComments\t\n1\tALF—died\t3rd trimester\tOn treatment\tTDF/3TC/ AZT/ATVr\t\t<20 copies\t2nd line regimen a\t\n2\tALF—died\t3rd trimester\tDefaulted\tN/A\t279\t\t\t\n3\tALF—survived\t3rd trimester\tDefaulted\t\t739\t\t\t\n4\tALF—survived\t3rd trimester\tDefaulted\tTDF/3TC/EFV\t560\t\tRestarted in ICU 2 weeks after onset ALF\t\n5\tALF—survived\t2nd trimester\tSee comments\tTDF/FTC/EFV\t639\t\tNo ARVs from day 1 admission, ALF on day 5, restarted ARVs in ICU on day 7\t\n6\tNo ALF\t3rd trimester\tOn treatment\tTDF/FTC/EFV\t\t<20 copies\t\t\n7\tNo ALF\t3rd trimester\tOn treatment\tUnknown\t\t<20 copies\t\t\n8\tNo ALF\t3rd trimester\tOn treatment\tTDF/AZT/3tC/LPV‐r\t\t<20 copies\t2nd line regimen a\t\n9\tNo ALF\t3rd trimester\tDefaulted\tTDF/FTC/EFV\t329\t\tRestarted on admission before signs ALF\t\n10\tNo ALF\t2nd trimester\tUnknown\t\t\t\t\t\n11\tNo ALF\t2nd trimester\tOn treatment\tTDF/3TC/EFV\t\t\t\t\n12\tNo ALF\t1st trimester\tUnknown\t\t\t\tStarted in 2016, lost to follow up\t\n13\tNo ALF\t3rd trimester\tOn treatment\tTDF/FTC/EFV\t559\t<20 copies\t\t\n14\tNo ALF\t3rd trimester\tOn treatment\tTDF/3TC/AZT/ATVr\t\t<20 copies\t\t\n15\tNo ALF\t3rd trimester\tUnknown\t\t\t<20 copies\t\t\n16\tNo ALF\t3rd trimester\tOn treatment\tTDF/FTC/EFV\t600\t<20 copies\t\t\nNote\n\nAll available data is presented.\n\nAbbreviations: 3TC, lamivudine; ALF, acute liver failure; ARV, antiretroviral; ATVr, atazanavir/ritonavir; AZT, zidovudine; EFV, efavirenz; ICU, intensive care unit; LPV‐r, lopinavir/ritonavir; N/A not applicable; TDF, tenofovir.\n\na No recent amendments in drug regimen.\n\nJohn Wiley & Sons, Ltd\n\nTwelve (75.0%) HIV positive women were in the third trimester, compared to 35/54 (64.8%) HIV negative women, which was not a significant difference (P = .45). For women in the third trimester, there was a trend of a lower HIV prevalence in women with ALF compared to women without ALF (17.4% vs 33.3%, OR 0.42, 95% CI 0.11‐1.66, P = .21).\n\n3.3 Fetal outcome\n\nEven though only 5/70 (7.1%) of the women had a term pregnancy at the time they were admitted with acute HEV, 42/70 (60.0%) gave birth during admission for HEV and 10/70 (14.3%) had a miscarriage. One woman died while still pregnant and only 17/70 (24.3%) were discharged still pregnant after they had recovered from their HEV infection. There were five intra‐uterine fetal deaths and four neonatal deaths leading to a fetal‐neonatal case fatality rate of 12.9%. Six neonates were admitted to neonatal ICU and we were unable to verify whether they were discharged alive. One woman gave birth at 35 weeks of gestation but was admitted postpartum with signs of ALF and no information regarding fetal outcome was available. Figure 1 presents the fetal outcome of our cohort, according to gestational age at the time of HEV infection. Preterm birth took place among 30/70 (42.9%) women and 20 neonates needed admission to neonatal ICU for this reason.\n\nFIGURE 1 Fetal outcome according to gestational age. Largest pie chart presents fetal outcome of the complete cohort. Smaller pie charts present fetal outcome based on gestational age at end of pregnancy. One woman died while still pregnant, fetal outcome in this woman was counted as intra‐uterine fetal death. GA, gestational age; IUFD, intra‐uterine fetal death; NICU, neonatal intensive care unit\n\n4 DISCUSSION\n\nIn our cohort of pregnant women with acute hepatitis E in the setting of an HEV genotype 2 outbreak we identified a high maternal case fatality rate, as well as a high fetal case fatality rate. Women who were HIV positive seemed to be more frequently infected with HEV, although not statistically significant. Also HIV infected women appeared to have a better outcome, especially when on ART.\n\nTo our knowledge, this is the first cohort reporting acute HEV in pregnancy caused by genotype 2. Our high maternal case fatality rate corresponds with the available literature for genotype 1, as well as the more severe outcome among women in the third trimester and a high mortality rate among women who develop ALF. 5 , 20 A systematic review and meta‐analysis performed by Jin et al, identified a CFR of 21%, reporting on 3968 pregnancies from both community‐based and facility based studies, whereas Berglov et al, identified a CFR of 26%, reporting on 1338 pregnancies from facility‐based studies only. 5 , 20 It's important to realize, even though most review articles present CFR for genotype 1 and 2 combined, data regarding pregnancy outcomes of genotype 2 are actually scarce as genotype 1 is far more prevalent, especially in Asia. 2 , 5 , 6 , 20 , 21 , 22 Besides Namibia, genotype 2 has only been identified in Mexico, Chad, Nigeria, Burkina Faso and Central African Republic. 22 , 23 , 24 Berglov et al 20 solely included studies from areas with genotype 1. Jin et al included only one report from an African country where genotype 2 was prevalent, namely Central African Republic, reporting on seven pregnant women with acute HEV, of which one died. 25 We were able to identity one additional study from Chad, reporting on four pregnant women with acute HEV, of whom two died. 26\n\nOur fetal outcome also corresponds with the fetal outcome identified in cohorts reporting on genotype 1. The review of Berglov included miscarriage in the intra‐uterine stillbirth rate and identified a stillbirth rate of 33% and a neonatal CFR of 8%. 20 Jin et al 5 identified a fetal case fatality rate of 34%, but it is unclear whether miscarriages were included in their definition. Berglov et al 20 reported a similar high premature birth rate to ours of 52%. There was no premature birth rate available in the report of Jin et al 5 We did not test for vertical transmission in our cohort. Berglov et al reported a vertical transmission rate ranging from 28% to 79%, based on the findings of five studies. 20\n\nThis is one of the first cohorts reporting on the outcome of pregnant women with HIV and acute HEV. The literature is scarce regarding the clinical impact of HIV/HEV co‐infection in pregnant women, as in most of the areas with outbreaks of genotype 1 and 2 there was a low HIV prevalence. Firstly, we identified a slightly higher HIV prevalence in our cohort, compared to the general pregnant population, although not statistically significant. This finding may suggest that HIV positive women are more easily infected by HEV. For all genotypes, the literature is conflicting on whether or not there is a higher seroprevalence of HEV among people with HIV. 12 , 13 We found three reports from other African countries. Only in the report from Gabon, a slightly higher seroprevalence was reported among 183 asymptomatic HIV positive pregnant women, as 7% were IgG positive for HEV, compared with 5% of their control group. 27 In a Ethiopian cohort with 386 asymptomatic pregnant women, 31.6% were IgG positive and two women were IgM positive. Only 18 women were HIV positive and HEV prevalence did not differ between both groups. 28 In the Central African Republic, they found a seroprevalence of 68% among 200 HIV positive adults, which was comparable to the general population. 28 Secondly, in our cohort of HIV infected women, in particular those receiving ART, appeared to be at lower risk of a severe clinical course including developing ALF. Although this finding needs to be interpretated with caution because of the small numbers, it is an interesting observation as, with most infections among HIV infected individuals, a more severe outcome could be anticipated. Possible mechanisms contributing to our observations are a reduced immune response, resulting in a mitigated level of hepatitis or a direct effect of the antiretroviral therapy against HEV. Among the eight women on ART there were four different drug regimens and therefore we could not further assess the potential protective role of individual ART drugs. Also the duration of pregnancy could not explain this finding as the number of women in the third trimester appeared to be similar for both HIV positive and negative women. Furthermore, a similar trend of a lower HIV prevalence among women with ALF compared to no ALF was identified, when analysing data of women in the third trimester only. To our knowledge, there are no studies available reporting the outcome of pregnant women with acute HEV comparing HIV infected and non‐infected women. However, a recent large meta‐analysis revealed that ongoing chronic HEV was seen significantly less frequently among HIV infected adults in comparison to transplant recipients, which also suggests that HIV infected adults tend to clear the HEV virus more easily compared to those who are not infected. 29\n\nWe identified a trend of higher elevated serum transaminases for women with ALF compared to women without ALF, which was not significant and there was a very wide range for these parameters. This is most likely explained by a large variation in condition on admission of the women. While some women presented asymptomatic, others presented after the onset of signs of acute liver failure and a few women only presented in the terminal phase when serum transaminases are decreasing again.\n\nThe hepatitis E outbreak had a significant impact on the limited resources of the public healthcare system of Namibia. There were only 14 ICU beds available in the hospital complex in the capital, serving the entire population. A woman with hepatic encephalopathy because of HEV often needed ventilatory support for two to three weeks. Since the start of the outbreak on average one to two ICU beds have been occupied by a young woman with HEV. This increased demand on an already overburdened ICU resulted in more referrals to ICUs of private institutions, resulting in high costs for the Ministry of Health. Similar problems were seen at the neonatal ICU, because of the high frequency of extreme premature birth of HEV infected women. Lastly, the frequent loss of a young woman and unavailability of an effective treatment had an enormous impact on the mental well‐being of our staff. The number of maternal deaths has nearly doubled since the start of the outbreak. One of the consultants stated: ‘it feels like the HIV era, when we could only hope for the best’.\n\nIn our facility we experienced challenges with providing good care to the HEV patients, because of unfamiliarity with the disease, fear of transmission and lack of resources. Especially at the start of the epidemic, several women were misdiagnosed with alcohol intoxication when they presented with hepatic encephalopathy. Others were brought in by the police, accused of performing an illegal abortion when they had a spontaneous premature birth at home. Furthermore, out of fear for transmission, observations were not always done as requested and subsequently deterioration was noted at a late stage. As a result of limited availability of glucose strips, diagnosis of hypoglycaemia was in some cases delayed until clinical symptoms were present. We feel glucose monitoring is essential for all pregnant women with acute HEV, as hypoglycaemia was often the first sign of the progression towards acute liver failure. To improve care, healthcare workers working in regions affected by the HEV outbreak, were trained in the management of pregnant women with jaundice. This was through video conferencing and sharing management guidelines, which resulted in the provision of better care.\n\nOur study has several limitations. Firstly, there might have been selection bias as hospitalized women were included only. We identified additional patients through our severe morbidity and mortality registry and it is highly likely that the true case fatality rate might be lower. Secondly, our cohort was small and because of the retrospective design some important data, such as HIV status of two women or ART regimen of four women, were missing. Thirdly, we did not determine the HEV genotype or subtype in our cohort, while genotype 2 has been proven to be the causative agent of the outbreak. Lastly, we did not test for vertical transmission from mother to baby, which may have assisted with the interpretation of our poor fetal outcome. A prospective cohort with larger numbers may have resulted in more answers but was not feasible because of limited resources and the sudden onset of the outbreak.\n\n5 CONCLUSION\n\nHepatitis E is a disease with many faces: while sporadic chronic HEV infections in immunosuppressed individuals and extrahepatic manifestations are of main interest in high‐income countries, low‐ and middle‐income countries suffer from endemic outbreaks involving large populations causing a high mortality in pregnant women. HEV genotype 2 infections and outcome of pregnancy have not been studied in detail previously. This retrospective study shows a mortality rate of almost 20% caused by an ongoing HEV genotype 2 outbreak in Namibia, which is similar to outbreaks with genotype 1. For the first time it was possible to study a potential role of underlying HIV infection and ART in pregnant women threatened by HEV infection. Despite the total numbers being low, it is surprising that HIV infected women in particular those on ART, seem to be less likely to developed acute liver failure in contrast with non‐HIV infected pregnant women. These data for the first time indicate that underlying HIV infection or the ART itself might attenuate the severity of HEV genotype 2 infections in pregnant women. More research is urgently needed to confirm or refute this phenomenon in larger cohorts. Understanding the underlying mechanism may potentially lead to treatment options to alter the often fatal outcome of this disease among pregnant women.\n\nETHICS\n\nThis study was reviewed and approved by the research unit of the Namibian Ministry of Health and Social Services. All data were collected from medical records, de‐identified and study inclusion did not have any effect on clinical management. Therefore, the need for individual informed consent was waived. Ref 17/3/3 SBM.\n\nCONFLICT OF INTEREST\n\nThe authors report no conflict of interest.\n\nDATA AVAILABILITY STATEMENT\n\nAll available data are presented in the manuscript and tables.\n==== Refs\nREFERENCES\n\n1 Rein DB , Stevens GA , Theaker J , Wittenborn JS , Wiersma ST . The global burden of hepatitis E virus genotypes 1 and 2 in 2005. Hepatology. 2012;55 :988‐997.22121109\n2 Hakim MS , Wang W , Bramer WM , et al. The global burden of hepatitis E outbreaks: a systematic review. Liver Int. 2017;37 :19‐31.\n3 World Health Organization . The Global Prevalence of Hepatitis E Virus Infection and Susceptibility: A Systematic Review. World Health Organization. https://apps.who.int/iris/handle/10665/70513. Accessed January 13, 2020.\n4 Kamar N , Bendall R , Legrand‐Abravanel F , et al. Hepatitis E. Lancet. 2012;379 :2477‐2488.22549046\n5 Jin H , Zhao Y , Zhang X , Wang B , Liu P . Case‐fatality risk of pregnant women with acute viral hepatitis type E: a systematic review and meta‐analysis. Epidemiol Infect. 2016;144 :2098‐2106.26939626\n6 Perez‐Gracia MT , Suay‐Garcia B , Mateos‐Lindemann ML . Hepatitis E and pregnancy: current state. Rev Med Virol. 2017;27 :e1929.28318080\n7 World Health Organization . Hepatitis E vaccine: WHO position paper, May 2015. Wkly Epidemiol Rec. 2015;90 :185‐200.25935931\n8 Nishiyama T , Kobayashi T , Jirintai S , et al. Screening of novel drugs for inhibiting hepatitis E virus replication. J Virol Methods. 2019;270 :1‐11.31004661\n9 Ministry of Health and Social Services . Outbreak of Hepatitis E Virus (HEV) in Namibia, Situation Report (SITREP No. 64). Ministry of Health and Social Services. https://www.afro.who.int/sites/default/files/2019‐08/National%20SITREP%2064%20on%20Hepatitis%20E%20%20%20outbreak%20Final.pdf. Accessed January 19, 2020.\n10 National Maternal Death, Near Miss, Stillbirth and Neonatal Death Review Committee . Report on the Confidential Enquiry into Maternal Deaths 1 April 2018 to 31 March 2019 and Near Miss 1 October 2018 to 31 March 2019. Ministry of Health and Social Services. In press.\n11 Ministry of Health and Social Services . Namibia Population‐Based HIV Impact Assessment NAMPHIA 2017. Ministry of Health and Social Services; 2018. https://phia.icap.columbia.edu/countries/namibia/. Accessed January 27, 2020.\n12 Debes JD , Pisano MB , Lotto M , Re V . Hepatitis E virus infection in the HIV‐positive patient. J Clin Virol. 2016;80 :102‐106.27243210\n13 Krain LJ , Nelson KE , Labrique AB . Host immune status and response to hepatitis E virus infection. Clin Microbiol Rev. 2014;27 :139‐165.24396140\n14 Isaacson M , Frean J , He J , Seriwatana J , Innis BL . An outbreak of hepatitis E in Northern Namibia, 1983. Am J Trop Med Hyg. 2000;62 :619‐625.11289674\n15 Maila HT , Bowyer SM , Swanepoel R . Identification of a new strain of hepatitis E virus from an outbreak in Namibia in 1995. J Gen Virol. 2004;85 :89‐95.14718623\n16 Ministry of Health and Social Services . National Guidelines for Antiretroviral Therapy, 5th Edition. Ministry of Health and Social Services; 2016. https://www.namhivsociety.org/resources‐docs. Accessed January 27, 2020.\n17 Heemelaar S , Josef M , Diener Z , et al. Maternal near‐miss surveillance, Namibia. Bull World Health Organ. 2020;98 :548‐557.32773900\n18 Heemelaar S , Kabongo L , Ithindi T , et al. Measuring maternal near‐miss in a middle‐income country: assessing the use of WHO and sub‐Saharan Africa maternal near‐miss criteria in Namibia. Glob Health Action. 2019;12 :1646036.31405363\n19 European Association for the Study of the Liver . EASL clinical practical guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66 :1047‐1081.28417882\n20 Berglov A , Hallager S , Weis N . Hepatitis E during pregnancy: maternal and foetal case‐fatality rates and adverse outcomes—a systematic review. J Viral Hepat. 2019;26 :1240‐1248.31095813\n21 Hartl J , Wehmeyer MH , Pischke S . Acute hepatitis E: two sides of the same coin. Viruses. 2016;8 :299.\n22 Aggarwal R , Goel A . Natural history, clinical manifestations, and pathogenesis of hepatitis E virus genotype 1 and 2 infections. Cold Spring Harb Perspect Med. 2019;9 :a032136.29735580\n23 Dimeglio C , Kania D , Mantono JM , et al. Hepatitis E virus infections among patients with acute febrile jaundice in Burkina Faso. Viruses. 2019;11 :554.\n24 Kim JH , Nelson KE , Panzner U , Kasture Y , Labrique AB , Wierzba TF . A systematic review of the epidemiology of hepatitis E virus in Africa. BMC Infect Dis. 2014;14 :308.24902967\n25 Goumba CM , Yandoko‐Nakoune ER , Komas NP . A fatal case of acute hepatitis E among pregnant women, Central African Republic. BMC Res Notes. 2010;3 :103.20398305\n26 Coursaget P , Buisson Y , N'Gawara MN , Van Cuyck‐Gandre H , Roue R . Role of hepatitis E virus in sporadic cases of acute and fulminant hepatitis in an endemic area (Chad). Am J Trop Med Hyg. 1998;58 :330‐334.9546413\n27 Caron M , Bouscaillou J , Kazanji M . Acute risk for hepatitis E virus infection among HIV‐1‐positive pregnant women in central Africa. Virol J. 2012;9 :254.23114258\n28 Demi Sibiro OA , Manirakiza A , Komas NP . Seroprevalence of hepatitis E virus infection among people living with HIV in the Central African Republic. Open Forum Infect Dis. 2018;5 :ofy307.30568981\n29 Buescher G , Ozga AK , Lorenz E , et al. Hepatitis E seroprevalence and viremia rate in immunocompromised patients: a systematic review and meta‐analysis. Liver Int. 2021;41 :449‐455 33034121\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1478-3223",
"issue": null,
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "HIV; Namibia; hepatitis E virus; maternal mortality",
"medline_ta": "Liver Int",
"mesh_terms": null,
"nlm_unique_id": "101160857",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34623734",
"pubdate": "2021-10-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Maternal and fetal outcomes of pregnancies complicated by acute hepatitis E and the impact of HIV status: A cross-sectional study in Namibia.",
"title_normalized": "maternal and fetal outcomes of pregnancies complicated by acute hepatitis e and the impact of hiv status a cross sectional study in namibia"
} | [
{
"companynumb": "NA-CIPLA (EU) LIMITED-2022NA00464",
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"activesubstance": {
"activesubstancename": "LAMIVUDINE\\TENOFOVIR"
},
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{
"abstract": "Stevens-Johnson syndrome (SJS) is a cutaneous mucosal disorder characterized by extended necrosis and detachment of the epidermis affecting <10% of the body surface, caused by drugs or infections. The authors report a case of a girl with Depakine resistant epilepsy, who develops a SJS in the third week of introducing lamotrigine. The girl also presents an acute diarrheal disease with double viral etiology - rotavirus and norovirus. The clinical image comprises polymorphic erythematous maculopapular exanthema with vesicular and bullous elements, with ulcerations and desquamations at the level of the eyelids, mouth, anogenital area and tegument denuding at the level of the abdomen and limbs. The SCORTEN score (SCORe of Toxic Epidermal Necrosis) for establishing the seriousness is 1. The evolution of the disease is slowly favorable under conservative treatment, which does not involve the use of corticotherapy or intravenous immunoglobulins. Although there is a low incidence of this syndrome in pediatrics, it may occur as complication of using some drugs - mostly anti-epileptics or antibiotics, corroborated or not with an infectious process.",
"affiliations": "Department of Pediatrics, \"Vasile Goldis\" Western University of Arad, Romania; dumitrasimona@yahoo.com; carmencrisan73@yahoo.com.",
"authors": "Dumitra|Simona|S|;Pilat|LuminiŢa|L|;Iftode|Alina|A|;Bălan|Ozana Nicoleta|ON|;StănculeŢ|Carmen Ramona|CR|;Covaci|Elena Claudia|EC|;Onel|Alexandru Fica Mircea|AFM|;Crişan|Carmen Nicoleta|CN|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1220-0522",
"issue": "58(2)",
"journal": "Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie",
"keywords": null,
"medline_ta": "Rom J Morphol Embryol",
"mesh_terms": "D002675:Child, Preschool; D005260:Female; D006801:Humans; D029322:Norovirus; D012400:Rotavirus Infections; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9112454",
"other_id": null,
"pages": "681-683",
"pmc": null,
"pmid": "28730261",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Post-medication Stevens-Johnson syndrome in a girl hospitalized for a norovirus and rotavirus infection.",
"title_normalized": "post medication stevens johnson syndrome in a girl hospitalized for a norovirus and rotavirus infection"
} | [
{
"companynumb": "RO-GLAXOSMITHKLINE-RO2017GSK182676",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
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"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
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{
"abstract": "To present the clinical features of a rare case of atypical acute retinal necrosis in a Coronavirus Disease 2019 (COVID-19) positive immunosuppressed patient.\nRetrospective observational case report.\nA 75-year-old lady presented with a left eye pan uveitis picture with vitritis and extensive peripheral and mid-peripheral necrotising retinitis. In the right eye, she had a very mild superior peripheral retinitis with minimal anterior or vitreous inflammation. Two months prior to her diagnosis she completed a course of rituximab and chlorambucil chemotherapy for a relapse of diffuse large cell B-cell lymphoma (DLBCL). The patient's nasopharyngeal swabs tested positive for COVID-19 in a reverse transcription polymerase chain reaction (RT-PCR) assay. The vitreous sample PCR tested positive for Varicella Zoster Virus and was negative for SARS-CoV-2.\nTo the best of our knowledge this is the first description of a case that has undergone vitreous PCR testing for COVID-19. It is interesting to note the high level of vitreous inflammation which would not be expected in an immunosuppressed state. We present a number of possible links between the SARS-CoV-2 virus and the unusual ocular presentation of bilateral VZV viral retinitis in this patient.While extra ocular VZV outbreaks have been reported with rituximab treated patients, this report should also raise the awareness of VZV related viral retinitis in DLBCL patients on rituximab chemotherapy which is a very rare occurrence.This case may provide some evidence to healthcare policy makers who are making decisions regarding the re-introduction of routine Ophthalmic surgery.",
"affiliations": "Imperial College Healthcare NHS Trust, Western Eye Hospital, London, UK.;Imperial College Healthcare NHS Trust, Western Eye Hospital, London, UK.;Imperial College Healthcare NHS Trust, Western Eye Hospital, London, UK.;Imperial College Healthcare NHS Trust, Western Eye Hospital, London, UK.",
"authors": "Gupta|Ankur|A|;Dixit|Bhavini|B|;Stamoulas|Konstantinos|K|;Akshikar|Rashmi|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1120672120974941",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": null,
"journal": "European journal of ophthalmology",
"keywords": "Uveitis; immunology; infectious endophthalmitis; posterior uveitis; retina; retinal herpetic infections; vitreous/endophthalmitis",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "1120672120974941",
"pmc": null,
"pmid": "33225728",
"pubdate": "2020-11-22",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Atypical bilateral acute retinal necrosis in a coronavirus disease 2019 positive immunosuppressed patient.",
"title_normalized": "atypical bilateral acute retinal necrosis in a coronavirus disease 2019 positive immunosuppressed patient"
} | [
{
"companynumb": "GB-CELLTRION INC.-2021GB004680",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CHLORAMBUCIL"
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{
"abstract": "Choking in adults can prove fatal, despite resuscitation attempts. The manner of death can be natural, homicide or accident. When a death is due to choking, one must consider what conditions contributed to or predisposed the person to choking (eg. alcohol, drugs and physical and mental impairments). Homicidal deaths by choking are relatively uncommon, being more frequently accidental. The diagnosis of death by choking is made at autopsy when the airway is found occluded. If the individual had an occluded airway and the object or food was removed during resuscitation, the only way to make the diagnosis would be on the history. Here, we present a case of asphyxia (accidental or suicidal) by choking on a handkerchief in a patient with a long history of schizophrenia. The woman had attempted a previous suicide driven by evil spirits coming from inside her body, especially from the head and throat; in order to \"shut-up\" the spirit, she was trying to suffocate it with her hands or by a belt from her pants.",
"affiliations": "Section of Legal Medicin, Policlinico Hospital, University of Bari \"Aldo Moro\", Bari.;Section of Legal Medicin, Policlinico Hospital, University of Bari \"Aldo Moro\", Bari.;Section of Legal Medicin, Policlinico Hospital, University of Bari \"Aldo Moro\", Bari.;Section of Legal Medicin, Policlinico Hospital, University of Bari \"Aldo Moro\", Bari.;Section of Legal Medicin, Policlinico Hospital, University of Bari \"Aldo Moro\", Bari.;Department of Education, Psychology and Communication, University of Bari \"Aldo Moro\", Bari, Italy.;Section of Legal Medicin, Policlinico Hospital, University of Bari \"Aldo Moro\", Bari.",
"authors": "De Donno|A|A|;Marrone|M|M|;Santoro|V|V|;Ostuni|A|A|;Cassano|A|A|;Grattagliano|I|I|;Introna|F|F|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.7417/T.2017.2023",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9074",
"issue": "168(5)",
"journal": "La Clinica terapeutica",
"keywords": "Asphyxia; Choking; Psychotic disorder; Suicide",
"medline_ta": "Clin Ter",
"mesh_terms": "D000059:Accidents; D000328:Adult; D000402:Airway Obstruction; D001237:Asphyxia; D005260:Female; D006801:Humans; D012559:Schizophrenia; D012565:Schizophrenic Psychology; D000067496:Spirit Possession; D013405:Suicide",
"nlm_unique_id": "0372604",
"other_id": null,
"pages": "e293-e296",
"pmc": null,
"pmid": "29044350",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A singular case of asphyxia by choking on a handkerchief: accidental event or suicide to \"shut-up\" spirits.",
"title_normalized": "a singular case of asphyxia by choking on a handkerchief accidental event or suicide to shut up spirits"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1075342",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "Stevens-Johnson syndrome is one of the few dermatological emergencies in clinical practice. The syndrome is often secondary to the usage of drugs, of which allopurinol, penicillins, sulfa drugs, ibuprofen, sodium valproate, phenytoin, lamotrigine and carbamazepine are commonly implicated. Agranulocytosis is the existence of a clinically significant reduction in neutrophil count. This condition is a serious threat to the patient, as he/she is at a greater risk of contracting bacterial or fungal infections, which may prove to be fatal. The co-existence of Stevens-Johnson syndrome and agranulocytosis in the same patient further increases the risk of morbidity and mortality. To the best of our knowledge, there are no reports available in the existing literature, of cases that were reported with both these life-threatening conditions in a single patient, at the same point of time. This is a case narrative of a patient who presented with both Stevens-Johnson syndrome and agranulocytosis, following the administration of carbamazepine The patient's differential leucocyte count revealed a neutrophil proportion of 2.33%. A causality assessment done using Naranjo's algorithm showed that carbamazepine \"definitely\" caused Agranulocytosis and \"probably\" caused Stevens-Johnson syndrome.",
"affiliations": "Postgraduate, Department of Pharmacology, Kasturba Medical College, Manipal University , Manipal, Karnataka, India .;Associate Professor, Department of Pharmacology, Kasturba Medical College, Manipal University , Manipal, Karnataka, India .;Postgraduate, Department of Pharmacology, Kasturba Medical College, Manipal University , Manipal, Karnataka, India .;Assistant Professor, Department of Medicine, Kasturba Medical College, Manipal University , Manipal, Karnataka, India .;Associate Professor, Department of Pharmacology, Kasturba Medical College, Manipal University , Manipal, Karnataka, India .",
"authors": "Avinash|A|A|;Amberkar|V Mohanbabu|VM|;Kunder|Sushil Kiran|SK|;Madhyastha|Sharath|S|;Meenakumari|K|K|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2016/23748.9065",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "10(12)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Anticonvulsant; Antiepileptic; Hypersensitivity; Rash; Skin",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "FD01-FD03",
"pmc": null,
"pmid": "28208879",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": "19217690;24600147;17235390;18043241;26170788;26674072;18098216;23036769;26538961;21219413;9798757;23543919;26622347;25657416;25593813;18855540;26387869",
"title": "Carbamazepine-induced Life-threatening Stevens-Johnson Syndrome and Agranulocytosis: The Maiden Case.",
"title_normalized": "carbamazepine induced life threatening stevens johnson syndrome and agranulocytosis the maiden case"
} | [
{
"companynumb": "PHHY2016IN176221",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "22q11.2DS is a significant health problem because of its fairly high incidence. It is relevant to be vigilant regarding the diagnosis of cancer amongst 22q11.2 patients as there might be an increased risk, especially amongst patients with the 22q11.2 distal deletion syndrome.",
"affiliations": "University of Antwerp Antwerp Belgium.;Department of Pediatric Hematology Oncology UZ Brussel Brussels Belgium.;Centre for Medical Genetics, Reproduction and Genetics Reproduction Genetics and Regenerative Medicine UZ Brussel Brussels Belgium.;Centre for Medical Genetics, Reproduction and Genetics Reproduction Genetics and Regenerative Medicine UZ Brussel Brussels Belgium.;Department of Pediatric Hematology Oncology UZ Brussel Brussels Belgium; Department of Pediatrics Queen Paola Children's Hospital Antwerp Belgium.",
"authors": "Stevens|Toer|T|;van der Werff Ten Bosch|Jutte|J|;De Rademaeker|Marjan|M|;Van Den Bogaert|Ann|A|;van den Akker|Machiel|M|0000-0003-2828-6226",
"chemical_list": null,
"country": "England",
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"doi": "10.1002/ccr3.880",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.880CCR3880Case ReportCase ReportsRisk of malignancy in 22q11.2 deletion syndrome T. Stevens et al.Stevens Toer \n1\nvan der Werff ten Bosch Jutte \n2\nDe Rademaeker Marjan \n3\nVan Den Bogaert Ann \n3\nvan den Akker Machiel http://orcid.org/0000-0003-2828-6226machielvdakker@gmail.com \n2\n\n4\n1 University of AntwerpAntwerpBelgium2 Department of Pediatric Hematology OncologyUZ BrusselBrusselsBelgium3 Centre for Medical Genetics, Reproduction and GeneticsReproduction Genetics and Regenerative MedicineUZ BrusselBrusselsBelgium4 Department of PediatricsQueen Paola Children's HospitalAntwerpBelgium* Correspondence\n\nMachiel van den Akker, Queen Paola Children's Hospital, Lindendreef 1, Antwerp 2020, Belgium. Tel: 0032‐3‐2802134; Fax 0032‐3‐2802133; E‐mail: machielvdakker@gmail.com\n02 3 2017 4 2017 5 4 10.1002/ccr3.2017.5.issue-4486 490 10 7 2016 25 1 2017 02 2 2017 © 2017 The Authors. Clinical Case Reports 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.Key Clinical Message\n22q11.2DS is a significant health problem because of its fairly high incidence. It is relevant to be vigilant regarding the diagnosis of cancer amongst 22q11.2 patients as there might be an increased risk, especially amongst patients with the 22q11.2 distal deletion syndrome.\n\nChromosome 22q11.2 Deletion SyndromeDigeorge syndromemalignancypineoblastomaVelocardiofacial syndrome source-schema-version-number2.0component-idccr3880cover-dateApril 2017details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.0.9 mode:remove_FC converted:04.04.2017\n==== Body\nIntroduction\nThe chromosome 22q11.2 deletion syndrome (22q11.2DS) occurs in approximately 1 of 3900 to 1 of 9700 children 1, 2. It is a multisystem disorder which is comprised of a broad variety of phenotypical syndromes that share a common genetic deletion. Amongst these syndromes are the DiGeorge syndrome, the Velocardiofacial syndrome, and the Cayler cardiofacial syndrome.\n\nMajor features can be summarized using the mnemonic CATCH‐22: cardiac abnormality (commonly interrupted aortic arch, truncus arteriosus, and tetralogy of fallot), abnormal facies, thymic hypoplasia (resulting in immune deficiency), cleft palate (velopharyngeal insufficiency), and hypocalcemia/hypoparathroidism 3. Additional findings may include learning difficulties, feeding disorders, early growth restriction, neurological conditions, structural abnormalities, hearing impairment, hypocalcemia, gut motility disorders, psychiatric, and hematological and autoimmune disorders 4, 5, 6, 7.\n\nThe 22q11.2 deletion results from variable‐sized heterozygous deletions of regions of 22q11, ranging from small deletions to deletions spanning approximately 3 megabases (Mb). The 22q11.2 deletion syndrome results most commonly from a 3 Mb deletion of the chromosome 22q11.2 region (about 90% of cases) and less common is a 1.5 Mb deletion (about 7%). In most cases, the deletions occur de novo but it may, however, also be inherited from either parent 6, 25. The prevalence of these de novo 22q11.2 deletions indicates an extremely high mutation rate within this region. Four distinct highly homologous blocks of low copy number repeats (LCRs), named LCR A‐D from proximal to distal, flank the deletion region which can lead to mispairing of the LCRs during meiosis resulting in unequal recombination events and hypothesized to cause the common recurrent rearrangement among patients with chromosome 22q11.2 deletion. With current treatment options, increasing numbers of patients with 22q11.2DS are reaching adulthood. To date, the true risk of malignancy in this patient group has not been defined.\n\nCase Report\nIn May 2012, a 10‐year‐old male patient was diagnosed with a pineoblastoma (Fig. 1) with spinal metastases. He underwent a partial surgical resection and treated with adjuvant craniospinal radiation and chemotherapeutical therapy in accordance with the SJMB03 protocol. He received a total cumulative dose of 39.6 Gy (22 fractions) and an additional boost at his residual tumor which resulted in 59.4 Gy, final dose. Followed by three of the four cycles of high‐dose cyclophosphamide (4000 mg/m2/cycle), cisplatin (75 mg/m2/cycle), and vincristine (two 1.5 mg/m2 doses/cycle) and stem‐cell rescue. The fourth cycle was not given due to bone marrow failure.\n\nFigure 1 MRI of the brain: polynodular lesion in the epiphyseal region, partly calcified. Signs of hydrocephalus.\n\nMedical geneticists were consulted to evaluate his mild mental disability and facial dysmorphism. They ascertained that there had been a delay in speech development (no speech at 2.5 years of age), a moderate intellectual disability, a nasal speech, bad articulation and several foremost facial dysmorphism (small eye folds, mild upslanting of the palpebral fissures, small dysplastic auricles, attached ear lobes, short philtrum, and an upturned upper lip). Array CGH analysis was performed with a 44K Agilent array. A 2.5 Mb deletion was found at chromosome band 22q11.21 which is responsible for the physical and cognitive abnormalities. He was diagnosed with Velocardiofacial syndrome (DGS/VCFS). Genetic testing of the parents did not show this deletion. Like the majority of cases, the deletion occurred de novo. To date, 4 years after initial diagnosis, our patient is in good clinical health without disease recurrence.\n\nDiscussion\nPatients with 22q11.2DS have several features which increase the risk of malignancy. The thymic hypoplasia results in a range of T‐cell deficits, predisposing patients to more frequent or extensive infections with possible involvement of carcinogenic viruses such as Epstein–Barr virus or human papillomavirus, and possible also interfering with the orchestration and execution of the tumor surveillance. The most frequent cancer in primary immune deficiency patients is non‐Hodgkin lymphoma, but Hodgkin lymphoma and acute leukemia occur can also occur 8. The genetic defect itself can possibly play a role in the oncogenesis, by causing increased genomic instability, leading to double‐stranded breaks of the DNA causing genetic aberrations in genes involved in cell cycle and survival 9. Good examples are the RASopathies, diseases involving the RAS–MAPK signaling pathway, in which the overall malignancies risk is about ten‐fold higher than the general population 10.\n\nGiven its high frequency and the fact that with current treatment options, 90–95% of 22q11.2DS patients survive beyond young childhood 4, it is important to further define this risk. McDonald‐McGinn et al. 11 performed a multicenter cohort study which included 687 patients with the 22q11.2DS of which the majority was less than 10 years of age. Six cases of malignancy were identified which gave a relative risk of 0.9% as compared to an overall risk of malignancy in children under the age of 14 of 0.0034% (3.4/100,000/year). Even though one of the largest cohorts, these results are still confounded by population size given its overall low incidence. The authors postulated that the correlation between malignancy and 22q11.2DS is dependent on the severe T‐cell function impairment (associated with an increased risk of lymphoma), the state of chronic inflammation which could occur following the frequent infections predisposing to malignancy 12 and finally, the heterozygous deletion which generally includes the catechol‐O‐methyltransferase (COMT) gene. After deletion of this gene, its function as a detoxifier of certain environmental carcinogens is lost which relates to a mild increase in malignancy 13, 14, 15.\n\nUp until now, 22q11.2DS is not considered to be associated with increased risk of malignancy. To evaluate the risk of malignancy in 22q11.2 deletion syndrome, a PubMed search was conducted in the English‐language literature using the keywords “22q11.2 Deletion Syndrome” or “DiGeorge Syndrome” or “Velocardiofacial Syndrome” and “cancer” or “malignancy.” No age limitation was used to include possible reports of patients with 22q11.2DS developing malignancy after childhood. The papers were reviewed, and the findings are summarized in Table 1.\n\nTable 1 Overview of reported cases of malignancy amongst patients with 22q11.2DS\n\nReference\tMalignancy\tDemographic descriptives\t\nKim et al. (2015) 30\n\tLymphoproliferative mediastinal mass\tF; 7 years\t\nPongpruttipan et al. (2012) 25\n\tPulmonal marginal zone lymphoma\tF; 15 years\t\nFinch et al. (2011) 22\n\tWilms tumor\tM; 4 years\t\nItoh et al. (2011) 24\n\tEBV‐associated T‐cell lymphoma\tM; 25 years\t\nMurray et al. (2011) 21\n\tTemporal lobe pleomorphic xanthoastrocytoma\tM; 16 years\t\nMcDonald‐Mcginn et al. (2006) 11\n\tNeuroblastoma\tM; congenital\t\nALL\tF; 8 years\t\nHepatoblastoma\tM; 3 months\t\nHepatoblastoma\tM; 15 months\t\nWilms tumor\tM; 4 years\t\nThyroid carcinoma\tF; 7 years\t\nOzbek et al. (2004) 20\n\tPeripheral blood dysplasia\t\t\nScattone et al. (2003) 19\n\tHepatoblastoma\tM; 11 days\t\nRenal cell carcinoma\tF; 6 years\t\nHong et al. (2001) 31\n\tEBV+ DLBCL manifested with generalized lymphadenopathy\tM; 7 months\t\nRamos et al. (1999) 23\n\tB‐cell non‐Hodgkin's lymphoma involving mediastinal lymphnodes, brain, liver and kidneys\tF; 10 months\t\nSato et al. (1998) 32\n\tEBV+ DLBCL involving mediastinal lympnodes, mesenterium, lung, trachea, larynx, small intestine and liver\tM; 7 months\t\nPatrone et al. (1990) 18\n\tNeuroblastoma\tUK\t\nAsamoto et al. (1977) 17\n\tGlioma\tUK\t\nTewfik et al. (1977) 16\n\tMultiple squamous cell carcinoma\tUK\t\nF, female; M, male; UK, unknown; ALL, acute lymphoblastic leukemia; EBV, Epstein–Barr virus; DLBCL, diffuse large B‐cell lymphoma.\n\nJohn Wiley & Sons, LtdOn the basis of the architecture of the 22q11.2 region, it was anticipated that other rearrangements, utilizing LCRs as recombination substrates and leading to different deletions might occur in the genomic region. Review of the literature revealed mostly de novo deletions of the LCR22‐4 to LCR22‐5 or LCR22‐4 to LCR22‐6 segment (distally to the critical region associated with DGS/VCFS) based on the existence of a breakpoint cluster region like (BCRL) module in each LCR, suggesting a potential substrate for NAHR‐mediated rearrangement in the distal 22q11.2. 26, 27. It is situated adjacent, but without the typically deleted regions in the conventional 22q11.2DS, leading to DGS/VCFS. Shay et al. 28 concluded that phenotypically there are similarities but also many characteristics distinct from 22q11.2DS. Several reports and reviews on the association between 22q11.2 distal deletion, amongst others containing the SMARCB1 gene, and rhabdoid tumors are published. The malignancies related with 22q11.2 distal deletion, considering this being a different entity from 22q11.2DS, are intentionally not included in the table. Many microdeletion syndromes with identical deletions can share many common features, but can also show a high degree of variability among patients 29. It is therefore advisable that individuals with the characteristic “distal features,” but also with a less suggestive clinical 22q11.2DS phenotype, should also be tested for the 22q11.2 distal deletion. As nowadays array CGH is used to detect chromosomal anomalies and also to confirm a clinical suspicion of 22q11.2DS, the extension of the deletion can be delineated.\n\nConclusion\nMore children with 22q11.2DS are reaching a higher age, and it is relevant to be vigilant regarding the diagnosis of cancer amongst 22q11.2 patients as there might be an increased risk. On top of that, there is a clear increase in the risk of malignancy amongst patients with the 22q11.2 distal deletion syndrome. Even though this is considered to be a separate entity, both clinical conditions have a broad variety of phenotypical presentations with many common features. It is therefore advisable to have a low threshold for testing for the 22q11.2 distal deletion.\n\nAuthorship\nTS, JvdWtB, MDR, and AVDB: were responsible for the writing of the manuscript. MvdA: was responsible for patient screening and supervised the writing of the manuscript.\n\nConflict of Interest\nThe authors have no conflict of interests to disclose.\n==== Refs\nReferences\n1 \n\nTezenas Du Montcel , S. \n, \nH. \nMendizabai \n, \nS. \nAyme \n, \nA. \nLevy \n, and \nN. \nPhilip \n. 1996 \nPrevalence of 22q11 microdeletion . J. Med. Genet. \n33 :719 .\n2 \n\nGoodship , J. \n, \nI. \nCross \n, \nJ. \nLiLing \n, and \nC. \nWren \n. 1998 \nA population study of chromosome 22q11 deletions in infancy . Arch. Dis. Child. \n79 :348 –351 .9875047 \n3 \n\nKobrynski , L. J. \n, and \nK. E. \nSullivan \n. 2007 \nVelocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes . Lancet \n370 :1443 –1452 .17950858 \n4 \n\nMcDonald‐McGinn , D. M. \n, \nR. \nKirschner \n, \nE. \nGoldmuntz \n, \nK. \nSullivan \n, \nP. \nEicher \n, \nM. \nGerdes \n, et al. 1999 \nThe Philadelphia story: the 22q11.2 deletion: report on 250 patients . Genet. 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"issue": "5(4)",
"journal": "Clinical case reports",
"keywords": "Chromosome 22q11.2 Deletion Syndrome; Digeorge syndrome; Velocardiofacial syndrome; malignancy; pineoblastoma",
"medline_ta": "Clin Case Rep",
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"nlm_unique_id": "101620385",
"other_id": null,
"pages": "486-490",
"pmc": null,
"pmid": "28396774",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports",
"references": "9833476;16532473;11506482;21200182;21456030;14729580;17950858;14692228;11559542;9350810;25742478;16734939;2161524;9875047;15831592;18179902;836226;15389824;22920507;20798238;10519724;193003;25861334;8863171;10191425;10191424;21683977;17676630;14614393;11141327;20730472;22918931",
"title": "Risk of malignancy in 22q11.2 deletion syndrome.",
"title_normalized": "risk of malignancy in 22q11 2 deletion syndrome"
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